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1.  Standing Surface Acoustic Wave Based Cell Coculture 
Analytical Chemistry  2014;86(19):9853-9859.
Precise reconstruction of heterotypic cell–cell interactions in vitro requires the coculture of different cell types in a highly controlled manner. In this article, we report a standing surface acoustic wave (SSAW)-based cell coculture platform. In our approach, different types of cells are patterned sequentially in the SSAW field to form an organized cell coculture. To validate our platform, we demonstrate a coculture of epithelial cancer cells and endothelial cells. Real-time monitoring of cell migration dynamics reveals increased cancer cell mobility when cancer cells are cocultured with endothelial cells. Our SSAW-based cell coculture platform has the advantages of contactless cell manipulation, high biocompatibility, high controllability, simplicity, and minimal interference of the cellular microenvironment. The SSAW technique demonstrated here can be a valuable analytical tool for various biological studies involving heterotypic cell–cell interactions.
PMCID: PMC4188268  PMID: 25232648
2.  Icariside II ameliorates diabetic nephropathy in streptozotocin-induced diabetic rats 
To investigate the therapeutic effects and potential mechanisms of icariside II (ICA II) on reversing diabetic nephropathy in streptozotocin (STZ)-induced type I diabetic rats.
Newborn male Sprague Dawley rats were labeled with thymidine analog 5-ethynyl-2-deoxyuridine (EdU) for tracking endogenous label retaining progenitor cells (LRCs). At age of 8 weeks, 48 rats were randomly divided into three groups: normal control group (n=16), diabetes mellitus group (DM; n=16), and diabetes mellitus plus ICA II therapy group (DM+ICA II, n=16). Eight weeks induced for diabetes with STZ, rats in DM group and DM+ICA II group were treated with vehicle or ICA II (5 mg/kg/day) for another 8 weeks, respectively. Then, blood creatinine, 24-hour urine protein, blood urea nitrogen, and glycosylated hemoglobin were measured, as well as the expression of von Willebrand factor, malondialdehyde, transforming growth factor-β/drosophila mothers against decapentaplegic protein/connective tissue growth factor (TGF-β/Smad/CTGF) signaling, marker of proliferation Ki-67, and EdU+ LRCs in renal tissues.
Increased levels of creatinine, 24-hour urine protein, and blood urea nitrogen and remarkably decreased proportion of normal glomeruli and increased proportions of I, IIa, IIb, and III glomeruli were observed in diabetic rats, while ICA II could reverse these changes. Interestingly, ICA II could significantly downregulate the levels of malondialdehyde and TGF-β/Smad/CTGF signaling and increase the expression of von Willebrand factor, Ki-67, and EdU+ LRCs in the kidney.
ICA II treatment could ameliorate diabetic nephropathy in STZ-induced diabetic rats by increasing endothelial cell contents, downregulating TGF-β/Smad/CTGF signaling pathway and oxidative stress level, and promoting cell proliferation both in kidney cortex and medulla. These beneficial effects appear to be mediated by its antioxidant capacity and recruitment of endogenous EdU+ progenitor cells into the kidney tissue.
PMCID: PMC4567177  PMID: 26379427
diabetic nephropathy; icariside II; EdU; diabetes mellitus; label retaining progenitor cells
3.  Genomic Correlate of Exceptional Erlotinib Response in Head and Neck Squamous Cell Carcinoma 
JAMA oncology  2015;1(2):238-244.
Randomized clinical trials demonstrate no benefit for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in unselected patients with head and neck squamous cell carcinoma (HNSCC). However, a patient with stage IVA HNSCC received 13 days of neoadjuvant erlotinib and experienced a near-complete histologic response.
To determine a mechanism of exceptional response to erlotinib therapy in HNSCC.
Single patient with locally advanced HNSCC who received erlotinib monotherapy in a window-of-opportunity clinical trial (patients scheduled to undergo primary cancer surgery are treated briefly with an investigational agent). Whole-exome sequencing of pretreatment tumor and germline patient samples was performed at a quaternary care academic medical center, and a candidate somatic variant was experimentally investigated for mediating erlotinib response.
A brief course of erlotinib monotherapy followed by surgical resection.
Identification of pretreatment tumor somatic alterations that may contribute to the exceptional response to erlotinib. Hypotheses were formulated regarding enhanced erlotinib response in preclinical models harboring the patient tumor somatic variant MAPK1 E322K following the identification of tumor somatic variants.
No EGFR alterations were observed in the pretreatment tumor DNA. Paradoxically, the tumor harbored an activating MAPK1 E322K mutation (allelic fraction 0.13), which predicts ERK activation and erlotinib resistance in EGFR-mutant lung cancer. The HNSCC cells with MAPK1 E322K exhibited enhanced EGFR phosphorylation and erlotinib sensitivity compared with wild-type MAPK1 cells.
Selective erlotinib use in HNSCC may be informed by precision oncology approaches.
PMCID: PMC4557203  PMID: 26181029
4.  High-quality sandwiched black phosphorus heterostructure and its quantum oscillations 
Nature Communications  2015;6:7315.
Two-dimensional materials such as graphene and transition metal dichalcogenides have attracted great attention because of their rich physics and potential applications in next-generation nanoelectronic devices. The family of two-dimensional materials was recently joined by atomically thin black phosphorus which possesses high theoretical mobility and tunable bandgap structure. However, degradation of properties under atmospheric conditions and high-density charge traps in black phosphorus have largely limited its actual mobility thus hindering its future applications. Here, we report the fabrication of stable sandwiched heterostructures by encapsulating atomically thin black phosphorus between hexagonal boron nitride layers to realize ultra-clean interfaces that allow a high field-effect mobility of ∼1,350 cm2V−1 s−1 at room temperature and on–off ratios exceeding 105. At low temperatures, the mobility even reaches ∼2,700 cm2V−1 s−1 and quantum oscillations in black phosphorus two-dimensional hole gas are observed at low magnetic fields. Importantly, the sandwiched heterostructures ensure that the quality of black phosphorus remains high under ambient conditions.
Black phosphorus is an atomically thin material that exhibits excellent properties for electronics applications, but these degrade in atmospheric conditions. Here, the authors demonstrate the fabrication of stable, ultra-clean and high-mobility black phosphorus sandwiched between the layers of boron nitride.
PMCID: PMC4557360  PMID: 26099721
5.  Blocking the PI3K/AKT pathway enhances mammalian reovirus replication by repressing IFN-stimulated genes 
Many host cellular signaling pathways were activated and exploited by virus infection for more efficient replication. The PI3K/Akt pathway has recently attracted considerable interest due to its role in regulating virus replication. This study demonstrated for the first time that the mammalian reovirus strains Masked Palm Civet/China/2004 (MPC/04) and Bat/China/2003 (B/03) can induce transient activation of the PI3K/Akt pathway early in infection in vitro. When UV-treated, both viruses activated PI3K/Akt signaling, indicating that the virus/receptor interaction was sufficient to activate PI3K/Akt. Reovirus virions can use both clathrin- and caveolae-mediated endocytosis, but only chlorpromazine, a specific inhibitor of clathrin-mediated endocytosis, or siRNA targeting clathrin suppressed Akt phosphorylation. We also identified the upstream molecules of the PI3K pathway. Virus infection induced phosphorylation of focal adhesion kinase (FAK) but not Gab1, and blockage of FAK phosphorylation suppressed Akt phosphorylation. Blockage of PI3K/Akt activation increased virus RNA synthesis and viral yield. We also found that reovirus infection activated the IFN-stimulated response element (ISRE) in an interferon-independent manner and up-regulated IFN-stimulated genes (ISGs) via the PI3K/Akt/EMSY pathway. Suppression of PI3K/Akt activation impaired the induction of ISRE and down-regulated the expression of ISGs. Overexpression of ISG15 and Viperin inhibited virus replication, and knockdown of either enhanced virus replication. Collectively, these results demonstrate that PI3K/Akt activated by mammalian reovirus serves as a pathway for sensing and then inhibiting virus replication/infection.
PMCID: PMC4557281  PMID: 26388843
reovirus; PI3K/Akt; endocytosis; enhancing viral replication
6.  Fibronectin type III domains engineered to bind CD40L: cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of two complexes 
Tn3 proteins, a novel class of binding molecules based on a fibronectin type III domain, have been cloned, expressed, purified and crystallized in complex with their cognate target.
Tn3 proteins are a novel class of binding molecules based on the third fibronectin type III domain of human tenascin C. Target-specific Tn3 proteins are selected from combinatorial libraries in which three surface-exposed loops have been diversified. Here, the cocrystallization of two different Tn3 proteins in complex with CD40L, a therapeutic target for immunological disease, is reported. These crystal structures are the first to be reported of Tn3 proteins and will help to reveal how these engineered molecules achieve specific recognition of a cognate target.
PMCID: PMC3758160  PMID: 23989160
fibronectin type III domains; CD40L
7.  Comparison of retinal and cerebral blood flow between continuous arterial spin labeling MRI and fluorescent microsphere techniques 
To compare basal retinal and cerebral blood flow (BF) values using continuous arterial spin labeling (CASL) MRI and fluorescent microsphere.
Materials and Methods
A total of 41 animals were used. BF was measured using an established microsphere technique (a mixture of 2.5 million 8 μm green and 0.5 million 10 μm blue fluorescent microspheres) and CASL MRI blood flow measurement in the rat retina and brain at 7T and 11.7T, respectively.
Retinal BF by MRI was 1.18±0.57 ml/g/min and choroidal BF was 8.14±1.8 ml/g/min (n=6). Microsphere retinal BF was 9.12±2.8 μl/min per tissue and choroidal BF was 73.38±44 μl/min per tissue (n=18), corresponding to a retinal BF value of 1.22±0.36 ml/g/min via a wet weight conversion. The wet-weight of the choroid could not be determined. To corroborate our findings, cerebral BF (CBF) by MRI was also analyzed. In the cerebral cortices, CBF was 0.91±0.29 ml/g/min (n=14) by CASL MRI and 1.09±0.37 ml/g/min (n=6) by microspheres. There were no significant differences found between MRI and microsphere blood flow in the retina and brain.
BF values in the rat retina and cerebral cortex by MRI are in agreement with those obtained by the microsphere technique.
PMCID: PMC4019707  PMID: 24227681
MRI; microsphere; blood flow; retina; choroid; brain; rat
8.  Role of Schwann cells in the regeneration of penile and peripheral nerves 
Asian Journal of Andrology  2015;17(5):776-782.
Schwann cells (SCs) are the principal glia of the peripheral nervous system. The end point of SC development is the formation of myelinating and nonmyelinating cells which ensheath large and small diameter axons, respectively. They play an important role in axon regeneration after injury, including cavernous nerve injury that leads to erectile dysfunction (ED). Despite improvement in radical prostatectomy surgical techniques, many patients still suffer from ED postoperatively as surgical trauma causes traction injuries and local inflammatory changes in the neuronal microenvironment of the autonomic fibers innervating the penis resulting in pathophysiological alterations in the end organ. The aim of this review is to summarize contemporary evidence regarding: (1) the origin and development of SCs in the peripheral and penile nerve system; (2) Wallerian degeneration and SC plastic change following peripheral and penile nerve injury; (3) how SCs promote peripheral and penile nerve regeneration by secreting neurotrophic factors; (4) and strategies targeting SCs to accelerate peripheral nerve regeneration. We searched PubMed for articles related to these topics in both animal models and human research and found numerous studies suggesting that SCs could be a novel target for treatment of nerve injury-induced ED.
PMCID: PMC4577590  PMID: 25999359
erectile dysfunction; growth factors; prostatectomy
9.  Effect of Bone Cement Implantation on Haemodynamics in Elderly Patients and Preventive Measure in Cemented Hemiarthroplasty 
BioMed Research International  2015;2015:568019.
This study was to investigate the influence of bone cement implantation on haemodynamics and the preventive effect of epinephrine hydrochloride on pulmonary embolism in elderly patients with cemented semihip replacement. 128 patients were retrospectively analyzed. The patients were treated with (group A, 64 cases) or without (group B, 64 cases) epinephrine hydrochloride saline. The monitoring indicators included systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), and pulse oxygen saturation (SPO2). The indicators of the two groups were compared before and 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 minutes after bone cement implantation. Analysis of variance and SNK-q test were used for the statistical analysis. Blood pressure and SPO2 of group B decreased with statistical difference (P < 0.05) and HR increased without statistical significance, comparing with those of group A. In group A, SBP, DBP, MAP, HR, and SPO2 after bone cement implantation did not change significantly at each time point comparing with before implantation (P > 0.05). Bone cement implantation has significant influence on hemodynamics in elderly patients with hemiarthroplasty. Flushing the bone marrow cavity with saline epinephrine hydrochloride is an effective measure to reduce the incidence of bone cement pulmonary embolism.
PMCID: PMC4568059  PMID: 26413535
10.  Expression of Semaphorin 4A and its potential role in rheumatoid arthritis 
Semaphorin 4A (Sema4A) plays critical roles in many physiological and pathological processes including neuronal development, angiogenesis, immune response regulation, autoimmunity, and infectious diseases. The present study aimed to investigate its expression and biological activity in rheumatoid arthritis (RA).
RNA and protein were isolated from synovial tissues in RA and osteoarthritis (OA) patients. Treatment with recombinant human Sema4A (rhSema4A) or small interfering RNA (siRNA) was applied to examine its effect on the biological activity of synovial fibroblasts of RA (RASFs). Expression of Sema4A and NF-κB were measured by quantitative RT-PCR (qRT-PCR) and Western blot after lipopolysaccharide (LPS) stimulation. Chromatin immunoprecipitation (ChIP) and siRNA targeting p50 and p60 were applied to detect the regulation of Nuclear factor kappa (NF-κB) on Sema4A. Sema4A, interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) secretion were measured by ELISA-based assays.
Increased levels of Sema4A were detected in the synovial tissue and fluid of patients with RA compared with those with OA. Furthermore, synovial fluid level of Sema4A correlated with Disease Activity Score (DAS) in RA. Treatment with rhSema4A promoted invasion of RASFs by upregulating the expression of Matrix metallopeptidase3 (MMP3), MMP9, alpha-smooth muscle actin(α-SMA), and Vimentin, and exacerbated inflammation by promoting the production of IL-6 in RASFs, as well as IL-1β and TNF-α in THP-1 cells. The induction of IL-6 and TNF-α by Sema4A was confirmed at the protein level in fluid samples from patients with RA. Knock-down experiments showed the participation of Plexin B1 towards rhSema4A in the induction of cytokines. In addition, LPS stimulation induced Sema4A expression in RASFs in an NF-κB-dependent manner, and rhSema4A treatment could also activate NF-κB signaling.
These findings suggest an NF-κB-dependent modulation of Sema4A in the immune response. Further, increased expression of Sema4A is required to promote inflammation of RA.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0734-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4549119  PMID: 26303122
11.  Diagnostic accuracy of different body weight and height-based definitions of childhood obesity in identifying overfat among Chinese children and adolescents: a cross-sectional study 
BMC Public Health  2015;15:802.
Various body weight and height-based references are used to define obese children and adolescents. However, no study investigating the diagnostic accuracies of the definitions of obesity and overweight in Hong Kong Chinese children and adolescents has been conducted. The current study aims to investigate the diagnostic accuracy of BMI-based definitions and 1993 HK reference in screening excess body fat among Hong Kong Chinese children and adolescents.
A total of 2,134 participants (1,135 boys and 999 girls) were recruited from local schools. The foot-to-foot BIA scale was applied to assess %BF using standard methods. The criterion of childhood obesity (i.e., overfat) was defined as over 25 %BF for boys and over 30 %BF for girls. Childhood obesity was also determined from four BMI-based references and the 1993 HK reference. The diagnostic accuracy of these existing definitions for childhood obesity in screening excess body fat was evaluated using diagnostic indices.
Overall, %BF was significantly correlated with anthropometry measurements in both genders (in boys, r = 0.747 for BMI 0.766 for PWH; in girls, r = 0.930 for BMI 0.851 for PWH). The prevalence rates of overweight and obesity determined by BMI-based references were similar with the prevalence rates of obesity in the 1993 HK reference in both genders. All definitions for childhood obesity showed low sensitivity (in boys, 0.325–0.761; in girls, 0.128–0.588) in detecting overfat. Specificities were high for cut-offs among all definitions for childhood obesity (in boys, 0.862–0.980; in girls, 0.973–0.998).
In conclusion, prevalence rates of childhood obesity or overweight varied widely according to the diagnostic references applied. The diagnostic performance for weight and height-based references for obesity is poorer than expected for both genders among Hong Kong Chinese children and adolescents. In order to improve the diagnosis accuracy of childhood obesity, either cut-off values of body weight and height-based definitions of childhood obesity should be revised to increase the sensitivity or the possibility of using other indirect methods of estimating the %BF should be explored.
PMCID: PMC4545979  PMID: 26289936
12.  Lower Extremity Muscle Activation and Kinematics of Catchers When Throwing Using Various Squatting and Throwing Postures 
This study investigated the differences in joint motions and muscle activities of the lower extremities involved in various squatting postures. The motion capture system with thirty-one reflective markers attached on participants was used for motion data collection. The electromyography system was applied over the quadriceps, biceps femoris, tibialis anterior, and gastrocnemius muscles of the pivot and stride leg. The joint extension and flexion in wide squatting are greater than in general squatting (p = 0.005). Knee joint extension and flexion in general squatting are significantly greater than in wide squatting (p = 0.001). The adduction and abduction of the hip joint in stride passing are significantly greater than in step squatting (p = 0.000). Furthermore, the adduction and abduction of the knee joint in stride passing are also significantly greater than in step squatting (p = 0.000). When stride passing is performed, the muscle activation of the hamstring of the pivot foot in general squatting is significantly greater than in wide squatting (p < 0.05), and this difference continues to the stride period. Most catchers use a general or wide squatting width, exclusive of a narrow one. Therefore, the training design for strengthening the lower extremity muscles should consider the appropriateness of the common squat width to enhance squat-up performance. For lower limb muscle activation, wide squatting requires more active gastrocnemius and tibialis anterior muscles. Baseball players should extend the knee angle of the pivot foot before catching the ball.
Key pointsCommon squatting width can enhance squat-up performance through strengthening lower body muscle.Wide squatting width might improve lower body muscle activation, leading to more effective communication between the brain and the muscle group. The benefit might be improved coordination of lower body muscle.Common and wide squatting width might be cycled through training to enhance the strengthen and coordination of the lower body muscle, respectively.
PMCID: PMC4541110  PMID: 26336333
Baseball; biomechanics; stride; electromyography; motion; kinetic chain
13.  High-throughput sequencing of 16S rDNA amplicons characterizes bacterial composition in cerebrospinal fluid samples from patients with purulent meningitis 
Purulent meningitis (PM) is a severe infectious disease that is associated with high rates of morbidity and mortality. It has been recognized that bacterial infection is a major contributing factor to the pathogenesis of PM. However, there is a lack of information on the bacterial composition in PM, due to the low positive rate of cerebrospinal fluid bacterial culture. Herein, we aimed to discriminate and identify the main pathogens and bacterial composition in cerebrospinal fluid sample from PM patients using high-throughput sequencing approach. The cerebrospinal fluid samples were collected from 26 PM patients, and were determined as culture-negative samples. The polymerase chain reaction products of the hypervariable regions of 16S rDNA gene in these 26 samples of PM were sequenced using the 454 GS FLX system. The results showed that there were 71,440 pyrosequencing reads, of which, the predominant phyla were Proteobacteria and Firmicutes; and the predominant genera were Streptococcus, Acinetobacter, Pseudomonas, and Neisseria. The bacterial species in the cerebrospinal fluid were complex, with 61.5% of the samples presenting with mixed pathogens. A significant number of bacteria belonging to a known pathogenic potential was observed. The number of operational taxonomic units for individual samples ranged from six to 75 and there was a comparable difference in the species diversity that was calculated through alpha and beta diversity analysis. Collectively, the data show that high-throughput sequencing approach facilitates the characterization of the pathogens in cerebrospinal fluid and determine the abundance and the composition of bacteria in the cerebrospinal fluid samples of the PM patients, which may provide a better understanding of pathogens in PM and assist clinicians to make rational and effective therapeutic decisions.
PMCID: PMC4535540  PMID: 26300628
Bioinformatics; cerebrospinal fluid sample; OTU
14.  Phage nanofibers induce vascularized osteogenesis in 3D printed bone scaffolds 
PMCID: PMC4122615  PMID: 24711251
nanofibers; 3D printing; scaffolds; phage display; bone regeneration
15.  Meta-analysis of postoperative adjuvant chemotherapy without radiotherapy in early stage non-small cell lung cancer 
OncoTargets and therapy  2015;8:2033-2043.
Many clinical trials have confirmed that postoperative adjuvant therapy can prolong survival of non-small cell lung cancer. However, the efficiency of postoperative chemotherapy without radiotherapy is unclear, especially in early stage (stages I and II). We aimed to assess the effect of postoperative chemotherapy without radiotherapy in early stage patients.
Databases and manual searches were adopted to identify eligible randomized control trials. Hazard ratio (HR) was used to assess the advantage of disease-free survival (DFS) and overall survival (OS) by fixed or random-effects models.
Fourteen trials with 3,923 patients were included based on inclusion criteria. Compared with surgery alone, postoperative chemotherapy significantly improved DFS and OS with HR of 0.71 (P=0.005) and 0.74 (P<0.00001), respectively. Subgroup analysis showed both cisplatin-based (HR: 0.75, P<0.0001) and single tegafur–uracil (UFT) chemotherapy (HR: 0.72, P=0.002) yielded significant survival benefits, but the latter did not improve DFS (HR: 1.04, P=0.81). Indirect treatment comparison showed cisplatin-based chemotherapy was superior to single UFT in DFS, but comparable in OS. The benefits of postoperative chemotherapy were maintained in patients in stage I (HR: 0.74, P<0.00001) and IB (HR: 0.74, P=0.0003), but not in stage IA, although the trend supported chemotherapy (HR: 0.76, P=0.43).
This meta-analysis demonstrates that postoperative chemotherapy without radiotherapy improves survival of stage I–II, I, and IB non-small cell lung cancer patients, but not for IA. Meanwhile, efficacy of cisplatin-based chemotherapy is comparable to single UFT in OS, but better in DFS, which should be paid more attention in future clinical practice.
PMCID: PMC4531011  PMID: 26346974
postoperative chemotherapy; disease-free survival; overall survival
16.  MyoR Modulates Cardiac Conduction by Repressing Gata4 
Molecular and Cellular Biology  2014;35(4):649-661.
The cardiac conduction system coordinates electrical activation through a series of interconnected structures, including the atrioventricular node (AVN), the central connection point that delays impulse propagation to optimize cardiac performance. Although recent studies have uncovered important molecular details of AVN formation, relatively little is known about the transcriptional mechanisms that regulate AV delay, the primary function of the mature AVN. We identify here MyoR as a novel transcription factor expressed in Cx30.2+ cells of the AVN. We show that MyoR specifically inhibits a Cx30.2 enhancer required for AVN-specific gene expression. Furthermore, we demonstrate that MyoR interacts directly with Gata4 to mediate transcriptional repression. Our studies reveal that MyoR contains two nonequivalent repression domains. While the MyoR C-terminal repression domain inhibits transcription in a context-dependent manner, the N-terminal repression domain can function in a heterologous context to convert the Hand2 activator into a repressor. In addition, we show that genetic deletion of MyoR in mice increases Cx30.2 expression by 50% and prolongs AV delay by 13%. Taken together, we conclude that MyoR modulates a Gata4-dependent regulatory circuit that establishes proper AV delay, and these findings may have wider implications for the variability of cardiac rhythm observed in the general population.
PMCID: PMC4301724  PMID: 25487574
17.  Identification of immunohistochemical markers for distinguishing lung adenocarcinoma from squamous cell carcinoma 
Journal of Thoracic Disease  2015;7(8):1398-1405.
Immunohistochemical staining has been widely used in distinguishing lung adenocarcinoma (LUAD) from lung squamous cell carcinoma (LUSC), which is of vital importance for the diagnosis and treatment of lung cancer. Due to the lack of a comprehensive analysis of different lung cancer subtypes, there may still be undiscovered markers with higher diagnostic accuracy.
Herein first, we systematically analyzed high-throughput data obtained from The Cancer Genome Atlas (TCGA) database. Combining differently expressed gene screening and receiver operating characteristic (ROC) curve analysis, we attempted to identify the genes which might be suitable as immunohistochemical markers in distinguishing LUAD from LUSC. Then we detected the expression of six of these genes (MLPH, TMC5, SFTA3, DSG3, DSC3 and CALML3) in lung cancer sections using immunohistochemical staining.
A number of genes were identified as candidate immunohistochemical markers with high sensitivity and specificity in distinguishing LUAD from LUSC. Then the staining results confirmed the potentials of the six genes (MLPH, TMC5, SFTA3, DSG3, DSC3 and CALML3) in distinguishing LUAD from LUSC, and their sensitivity and specificity were not less than many commonly used markers.
The results revealed that the six genes (MLPH, TMC5, SFTA3, DSG3, DSC3 and CALML3) might be suitable markers in distinguishing LUAD from LUSC, and also validated the feasibility of our methods for identification of candidate markers from high-throughput data.
PMCID: PMC4561256  PMID: 26380766
Lung cancer; immunohistochemical marker; receiver operating characteristic (ROC) curve analysis; The Cancer Genome Atlas (TCGA)
18.  The edaravone and 3-n-butylphthalide ring-opening derivative 10b effectively attenuates cerebral ischemia injury in rats 
Acta Pharmacologica Sinica  2015;36(8):917-927.
Compound 10b is a hybrid molecule of edaravone and a ring-opening derivative of 3-n-butylphthalide (NBP). The aim of this study was to examine the effects of compound 10b on brain damage in rats after focal cerebral ischemia.
SD rats were subjected to 2-h-middle cerebral artery occlusion (MCAO). At the onset of reperfusion, the rats were orally treated with NBP (60 mg/kg), edaravone (3 mg/kg), NBP (60 mg/kg)+edaravone (3 mg/kg), or compound 10b (70, 140 mg/kg). The infarct volume, motor behavior deficits, brain water content, histopathological alterations, and activity of GSH, SOD, and MDA were analyzed 24 h after reperfusion. The levels of relevant proteins in the ipsilateral striatum were examined using immunoblotting.
Administration of compound 10b (70 or 140 mg/kg) significantly reduced the infarct volume and neurological deficits in MCAO rats. The neuroprotective effects of compound 10b were more pronounced compared to NBP, edaravone or NBP+edaravone. Furthermore, compound 10b significantly upregulated the protein levels of the cytoprotective molecules Bcl-2, HO-1, Nrf2, Trx, P-NF-κB p65, and IκB-α, while decreasing the expression of Bax, caspase 3, caspase 9, Txnip, NF-κB p65, and P-IκB-α.
Oral administration of compound 10b effectively attenuates rat cerebral ischemia injury.
PMCID: PMC4564877  PMID: 26073328
cerebral ischemia; middle cerebral artery occlusion; 3-n-butylphthalide; edaravone; edaravone and 3-n-butylphthalide ring-opening derivative
19.  Design and performance of a sericin-alginate interpenetrating network hydrogel for cell and drug delivery 
Scientific Reports  2015;5:12374.
Although alginate hydrogels have been extensively studied for tissue engineering applications, their utilization is limited by poor mechanical strength, rapid drug release, and a lack of cell adhesive ability. Aiming to improve these properties, we employ the interpenetrating hydrogel design rationale. Using alginate and sericin (a natural protein with many unique properties and a major component of silkworm silk), we develop an interpenetrating polymer network (IPN) hydrogel comprising interwoven sericin and alginate double networks. By adjusting the sericin-to-alginate ratios, IPNs’ mechanical strength can be adjusted to meet stiffness requirements for various tissue repairs. The IPNs with high sericin content show increased stability during degradation, avoiding pure alginate’s early collapse. These IPNs have high swelling ratios, benefiting various applications such as drug delivery. The IPNs sustain controlled drug release with the adjustable rates. Furthermore, these IPNs are adhesive to cells, supporting cell proliferation, long-term survival and migration. Notably, the IPNs inherit sericin’s photoluminescent property, enabling bioimaging in vivo. Together, our study indicates that the sericin-alginate IPN hydrogels may serve as a versatile platform for delivering cells and drugs, and suggests that sericin may be a building block broadly applicable for generating IPN networks with other biomaterials for diverse tissue engineering applications.
PMCID: PMC4513302  PMID: 26205586
20.  Elevated Serum Gas6 Is a Novel Prognostic Biomarker in Patients with Oral Squamous Cell Carcinoma 
PLoS ONE  2015;10(7):e0133940.
This study explored the level and clinical significance of serum Gas6 in patients with oral squamous cell carcinoma (OSCC).
A total of 128 OSCC patients and 145 normal controls were selected. Enzyme-linked immunosorbent assay was used to detect Gas6 concentration in sera from the OSCC patients and controls. The correlations of serum Gas6 concentration and clinicopathological characteristics of OSCC patients were assessed, and the prognostic significance of serum Gas6 was evaluated with a Kaplan–Meier curve and log-rank test.
The results showed that serum Gas6 concentration was significantly higher in OSCC patients than in controls (P < 0.05). OSCC patients with late TNM stage (III, IV) had a relatively high serum Gas6 concentration compared with those with early stage (I, II) (P < 0.01) and patients with poorly differentiated tumors had a higher level of serum Gas6 than those with well-differentiated tumors (P < 0.01). Multivariate logistic regression analysis demonstrated that high serum Gas6 was an independent risk factor for lymph nodal metastases in OSCC patients (OR = 2.79, 95% CI: 1.72–4.48). For predicting OSCC development, ROC curve analysis showed a sensitivity of 0.63 with a specificity of 0.92 (AUC = 0.79, 95% CI: 0.74–0.85). Cox analysis revealed that high serum Gas6 was an independent biomarker for predicting poor overall survival in OSCC patients (HR = 2.07, 95% CI: 1.79–3.62). In addition, we found that Gas6 expression was increased in OSCC tissues and it may significantly decrease E-cadherin expression, and increase P-cadherin and N-cadherin expression, in OSCC cells. Further, Gas6 could promote the migratory and invasive ability of OSCC cells in vitro.
Taken together, these results suggest that Gas6 increases the metastatic capacity of OSCC cells and serum Gas6 could be a candidate biomarker for diagnostic and prognostic use in OSCC patients.
PMCID: PMC4514879  PMID: 26207647
21.  Molecular evidence of Ebola Reston virus infection in Philippine bats 
Virology Journal  2015;12:107.
In 2008–09, evidence of Reston ebolavirus (RESTV) infection was found in domestic pigs and pig workers in the Philippines. With species of bats having been shown to be the cryptic reservoir of filoviruses elsewhere, the Philippine government, in conjunction with the Food and Agriculture Organization of the United Nations, assembled a multi-disciplinary and multi-institutional team to investigate Philippine bats as the possible reservoir of RESTV.
The team undertook surveillance of bat populations at multiple locations during 2010 using both serology and molecular assays.
A total of 464 bats from 21 species were sampled. We found both molecular and serologic evidence of RESTV infection in multiple bat species. RNA was detected with quantitative PCR (qPCR) in oropharyngeal swabs taken from Miniopterus schreibersii, with three samples yielding a product on conventional hemi-nested PCR whose sequences differed from a Philippine pig isolate by a single nucleotide. Uncorroborated qPCR detections may indicate RESTV nucleic acid in several additional bat species (M. australis, C. brachyotis and Ch. plicata). We also detected anti-RESTV antibodies in three bats (Acerodon jubatus) using both Western blot and ELISA.
The findings suggest that ebolavirus infection is taxonomically widespread in Philippine bats, but the evident low prevalence and low viral load warrants expanded surveillance to elaborate the findings, and more broadly, to determine the taxonomic and geographic occurrence of ebolaviruses in bats in the region.
PMCID: PMC4504098  PMID: 26184657
Reston; Ebolavirus; Filovirus; Philippine; Bat; Molecular; Serology
22.  Utility of C-Reactive Protein Levels for Early Prediction of Dengue Severity in Adults 
BioMed Research International  2015;2015:936062.
Dengue has broad clinical presentation with unpredictable clinical evolution and outcome. We aimed to evaluate the utility of C-reactive protein (CRP) levels for distinguishing between mild and severe cases in the early phase of the dengue illness. We retrospectively evaluated adults with dengue from 2006 to 2014, according to 1997 and 2009 World Health Organization (WHO) criteria for severity. Of 191 included patients, 32.9% had nonshock dengue hemorrhagic fever (DHF), 3.1% dengue shock syndrome (DSS), and 7.9% severe dengue. The risk of DHF/DSS and severe dengue is significantly related to the increasing levels of CRP. Of 191 patients, 97 had CRP levels measured during the febrile (days 1–3); 85 during the critical (days 4–6); and 9 during the convalescent (days 7–10) illness phases. During the febrile phase, there was significant higher CRP level for DSS versus DF/nonshock DHF and severe dengue versus nonsevere dengue, with CRP cutoff level 30.1 mg/L (area under the receiver operating characteristic curve (AUC), 0.938; 100% sensitivity, 76.3% specificity) and 24.2 mg/L (AUC, 0.717; 70% sensitivity, 71.3% specificity), respectively. Our study highlights the utility of the CRP levels in early prediction of DSS and severe dengue in adult patients.
PMCID: PMC4515279  PMID: 26247033
23.  Notch-dependent repression of miR-155 in the bone marrow niche regulates hematopoiesis in an NF-κB dependent manner 
Cell stem cell  2014;15(1):51-65.
MicroRNA (miR)-155 has been implicated in regulating inflammatory responses and tumorigenesis, but its precise role in linking inflammation and cancer has remained elusive. Here, we identify a connection between miR-155 and Notch signaling in this context. Loss of Notch signaling in the bone marrow (BM) niche alters hematopoietic homeostasis and leads to lethal myeloproliferative-like disease. Mechanistically, Notch signaling represses miR-155 expression by promoting binding of RBPJ to the miR-155 promoter. Loss of Notch/RBPJ-signaling upregulates miR-155 in BM endothelial cells, leading to miR-155-mediated targeting of the NF-κB inhibitor κB-Ras1, NF-κB activation and increased proinflammatory cytokine production. Deletion of miR-155 in the stroma of RBPJ-/- mice prevented the development of myeloproliferative-like disease and cytokine induction. Analysis of BM from patients carrying myeloproliferative neoplasia also revealed elevated expression of miR-155. Thus, the Notch/miR155/kB-Ras1/NF-kB axis regulates the inflammatory state of the BM niche and affects the development of myeloproliferative disorders.
PMCID: PMC4398997  PMID: 24996169
Neuro-Oncology  2014;16(Suppl 3):iii16-iii17.
BACKGROUND: Oncogenic EGFR-Akt signaling is aberrantly activated in human glioblastomas. Discoid, CUC and LCCL domain containing protein 2 (DCBLD2, also known as CLCP1 and ESDN) is a neuropilin-like membrane protein that is up-regulated in vascular injury and metastatic lung cancers. However, the role of DCBLD2 in cancer is unclear. METHODS: We examined the expression of DCBLD2 in TCGA and other data bases of clinical glioma specimens. We assessed the effects of knockdown of endogenous DCBLD2 and re-express mutated DCBLD2 in glioma cells expressing EGFRvIII in vitro and in vivo. We performed IP-WB analyses to examine EGFR-induced tyrosine phosphorylation and DCBLD2 association with TRAF6. We also examined the impact of TRAF6 in EGFRvIII_driven tumorigenesis and association of p-Y EGFR and p-Y750 of DCBLD2 with tumor prognosis. We used patient-derived glioma stem cells, primary shortern culture GBM cells and established glioma cell lines in vitro, orthotopic brain glioma xenografts, various biochemical methods and IHC analysis of de-identified clinical tumor specimens of glioma samples and HNC smaples in our study. RESULTS: We found that DCBLD2 is up-regulated gene in glioblastomas and head and neck cancers (HNCs) and is required for EGFR-stimulated tumorigenesis. EGFR induces tyrosine phosphorylation (p-Y) of DCBLD2 including in a Y750 residue within a binding motif for TNF receptor-associated factor 6 (TRAF6). Consequently, the induced p-DCBLD2Y750 recruits TRAF6 to DCBLD2. This association causes increased TRAF6 E3 ligase activity and subsequent activation of Akt, thereby enhancing EGFR-driven tumorigenesis. CONCLUSIONS: Our findings uncover a novel pathway by which DCBLD2 functions as a signal relay for oncogenic EGFR signaling in promoting tumorigenesis, a conclusion that is supported by the association of EGFR activation and DCBLD2 phosphorylation with poor prognoses for gliomas and HNCs. These data also nominate DCBLD2 and TRAF6 as attractive therapeutic targets for human cancers that are associated with EGFR activation. SECONDARY CATEGORY: n/a.
PMCID: PMC4144529
25.  Gallbladder neuroendocrine carcinoma: report of 10 cases and comparision of clinicopathologic features with gallbladder adenocarcinoma 
Few cases of neuroendocrine carcinoma (NEC) of the gallbladder (GB-NEC) have been reported. Data obtained from the 10 patients with GB-NEC treated in our hospital between January 2008 and December 2012 were retrospectively analyzed and compared with those of 377 patients with gallbladder adenocarcinoma. GB-NEC accounted for 2.2% of all gallbladder cancers. The patients (8 females and 2 males) were 59.0 ± 10.0 years old. Four patients presented mixed adenocarcinoma, while six had pure NEC. Immunohistochemical examinations showed a positive rate of 100% for CgA, NSE, and CK; the positive rates for Syn, EMA, and CD56 were 88.9, 87.5, and 75%, respectively. TNM grades II, IVA, and IVB were found in 1, 2, and 7 patients, respectively. GB-NEC patients showed significantly higher N2 lymphatic metastasis rates than gallbladder adenocarcinoma patients (70.0 vs. 34.0%; P < 0.05). Two patients were treated with radical resection and the remaining 8 with palliative operation. The 1-, 2-, and 3-year survival rates were 20, 10, and 0%, respectively (median survival time, 3.0 m); the 1-, 2-, 3-, and 5-year survival rates for all gallbladder adenocarcinoma patients were 38.0, 31.0, 30.1, and 28.4%, respectively (median survival time, 6.0 m), the difference was statistically significant (P = 0.038). The results demonstrate that GB-NEC was mainly found in aged females and shows high malignancy. Its prognosis is poorer than that of gallbladder adenocarcinoma, and surgical resection combined with TACE, radiotherapy, and chemotherapy could increase patient survival.
PMCID: PMC4555718  PMID: 26339390
Gallbladder carcinoma; neuroendocrine carcinoma; gallbladder adenocarcinoma; clinical feature; surgery

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