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1.  A New PAMPA Model Proposed on the Basis of a Synthetic Phospholipid Membrane 
PLoS ONE  2015;10(2):e0116502.
The purpose of this work was to investigate the synthetic phospholipid dependence of permeability measured by parallel artificial membrane permeability assay (PAMPA) method. Three phospholipids with hydrophobic groups of different lengths and phosphorylcholine as the hydrophilic group were concisely synthesized. Ten model drug molecules were selected because of their distinct human fraction absorbed (%FA) values and various pKa characteristics. In vitro drug permeation experiments were designed to determine the effect of the incubation time (4–20 h), pH gradient (4.6–9.32) and carbon chain length (8, 10, 12) on the drug permeability through the synthetic phospholipid membrane in the PAMPA system. The results showed that intensive and significant synthetic phospholipids dependence of permeability influenced by the length of lipid’s hydrophobic carbon chain. The effective permeability constant (Pe) of each drug increased rapidly with time, then decreased slightly after reaching the maximum; the pH gradient changed the drug permeability according to the pH-partition hypothesis for drugs with diverse pKa values; and longer hydrophobic chains in the synthetic phospholipid membrane improved the drug permeability, as observed for all test drugs at almost all incubation time points. This newly proposed PAMPA model considered the synthetic phospholipid membrane and showed good Pe-%FA correlation for the passive transport of drugs, making it a helpful supplementary method for PAMPA systems.
PMCID: PMC4315410  PMID: 25647086
2.  Combined Cancer Photothermal-Chemotherapy Based on Doxorubicin/Gold Nanorod-Loaded Polymersomes 
Theranostics  2015;5(4):345-356.
Gold nanorods (GNRs) are well known in photothermal therapy based on near-infrared (NIR) laser absorption of the longitudinal plasmon band. Herein, we developed an effective stimulus system -- GNRs and doxorubicin co-loaded polymersomes (P-GNRs-DOX) -- to facilitate co-therapy of photothermal and chemotherapy. DOX can be triggered to release once the polymersomes are corrupted under local hyperthermic condition of GNRs induced by NIR laser irradiation. Also, the cytotoxicity of GNRs caused by the residual cetyltrimethylacmmonium bromide (CTAB) was reduced by shielding the polymersomes. The GNRs-loaded polymersomes (P-GNRs) can be efficiently taken up by the tumor cells. The distribution of the nanomaterial was imaged by IR-820 and quantitatively analyzed by ICP-AES. We studied the ablation of tumor cells in vitro and in vivo, and found that co-therapy offers significantly improved therapeutic efficacy (tumors were eliminated without regrowth.) compared with chemotherapy or photothermal therapy alone. By TUNEL immunofluorescent staining of tumors after NIR laser irradiation, we found that the co-therapy showed more apoptotic tumor cells than the other groups. Furthermore, the toxicity study by pathologic examination of the heart tissues demonstrated a lower systematic toxicity of P-GNRs-DOX than free DOX. Thus, the chemo-photothermal treatment based on polymersomes loaded with DOX and GNRs is a useful strategy for maximizing the therapeutic efficacy and minimizing the dosage-related side effects in the treatment of solid tumors.
PMCID: PMC4329499
polymersomes; gold nanorod; NIR; photothermal therapy; chemotherapy.
3.  Association of Genetic Polymorphisms with Warfarin Dose Requirements in Chinese Patients 
Objective: Warfarin is a commonly used anticoagulant with a narrow therapeutic range and large interindividual differences in dosing requirements. Previously, studies have identified that the interindividual variability was influenced by varieties of factors, including age, body size, vitamin K intake, interacting medications, as well as genetic variants. We aimed to investigate the effect of single-nucleotide polymorphisms (SNPs) on the interindividual variability of warfarin dose requirements in Chinese patients. Methods: The study population consisted of 300 patients with a stable maintenance dose of warfarin. We examined SNPs in eight genes involving in the biotransformation and mode of action of warfarin (i.e., CYP4F2, CYP2C19, APOE, CALU, EPHX1, PROC, CYP2C9, and GGCX) using the SNaPshot assay. Results: The mean daily warfarin dose in patients carrying CYP2C19 rs3814637CC, CYP2C9 rs1057910AA, and GGCX rs699664AA genotype was 3.39, 3.34, and 3.51 mg/day, respectively, which was higher than those carrying CYP2C19 rs3814637TT, CYP2C9 rs1057910CC, and rs699664GG genotype (2.00, 0.81, and 3.09 mg/day, respectively). Conclusion: These findings indicate that individuals carrying the CYP2C19 rs3814637CC or CYP2C9 rs1057910AA or GGCX rs699664AA genotype needed higher warfarin doses in the Chinese population.
PMCID: PMC3865618  PMID: 23941071
4.  CD24 expression predicts poor prognosis for patients with cutaneous malignant melanoma 
Cutaneous malignant melanoma represents the major cause of mortality among skin cancers. Metastasis-associated protein CD24 is a small, heavily glycosylated cell surface protein that is overexpressed in various human malignancies. The present study was designed to determine the roles of CD24 in cutaneous malignant melanoma. The levels of CD24 mRNA and protein in cutaneous malignant melanoma tissues were detected by RT-PCR, Western blot and IHC. In patient samples, the levels of CD24 mRNA and protein were higher in cancer tissues than that in normal tissues. CD24 expression decreased the survival time of the patients with melanoma. Taken together, these results suggest that CD24 may be used as a new drug target for cutaneous malignant melanoma.
PMCID: PMC4276209  PMID: 25550951
CD24; melanoma; prognosis
5.  The Glasgow Prognostic Score Predicts Poor Survival in Cisplatin-Based Treated Patients with Metastatic Nasopharyngeal Carcinoma 
PLoS ONE  2014;9(11):e112581.
Several inflammation-based prognostic scoring systems, including Glasgow Prognostic Score (GPS), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) have been reported to predict survival in many malignancies, whereas their role in metastatic nasopharyngeal carcinoma (NPC) remains unclear. The aim of this study is to evaluate the clinical value of these prognostic scoring systems in a cohort of cisplatin-based treated patients with metastatic NPC.
Two hundred and eleven patients with histologically proven metastatic NPC treated with first-line cisplatin-based chemotherapy were retrospectively evaluated. Demographics, disease-related characteristics and relevant laboratory data before treatment were recorded. GPS, NLR and PLR were calculated as described previously. Response to first-line therapy and survival data were also collected. Survival was analyzed in Cox regressions and stability of the models was examined by bootstrap resampling. The area under the receiver operating characteristics curve (AUC) was calculated to compare the discriminatory ability of each scoring system.
Among the above three inflammation-based prognostic scoring systems, GPS (P<0.001) and NLR (P = 0.019) were independently associated with overall survival, which showed to be stable in a bootstrap resampling study. The GPS consistently showed a higher AUC value at 6-month (0.805), 12-month (0.705), and 24-month (0.705) in comparison with NLR and PLR. Further analysis of the association of GPS with progression-free survival showed GPS was also associated independently with progression-free survival (P<0.001).
Our study demonstrated that the GPS may be of prognostic value in metastatic NPC patients treated with cisplatin-based palliative chemotherapy and facilitate individualized treatment. However a prospective study to validate this prognostic model is still needed.
PMCID: PMC4230992  PMID: 25393117
6.  Expression of serotonin receptors in human lower esophageal sphincter 
Serotonin (5-HT) is a neurotransmitter and vasoactive amine that is involved in the regulation of a large number of physiological functions. The wide variety of 5-HT-mediated functions is due to the existence of different classes of serotonergic receptors in the mammalian gastrointestinal tract and nervous system. The aim of this study was to explore the expression of multiple types of 5-HT receptor (5-HT1AR, 5-HT2AR, 5-HT3AR, 5-HT4R, 5-HT5AR, 5-HT6R and 5-HT7R) in sling and clasp fibers from the human lower esophageal sphincter (LES). Muscle strips of sling and clasp fibers from the LES were obtained from patients undergoing esophagogastrectomy, and circular muscle strips from the esophagus and stomach were used as controls. Reverse transcription-polymerase chain reaction (RT-PCR), quantitative PCR and western blotting were used to investigate the expression of the various 5-HT receptor types. Messenger RNA for all seven 5-HT receptor types was identified in the sling and clasp fibers of the LES. At the mRNA level, the expression levels were highest for 5-HT3AR and 5-HT4R, and lowest for 5-HT5AR, 5-HT6R and 5-HT7R. At the protein level, the expression levels were highest for 5-HT3AR and 5-HT4R, followed by 5-HT1AR and 5-HT2AR; 5-HT7R was also detected at a low level. The expression of 5-HT5AR and 5-HT6R proteins was not confirmed. The results indicate that a variety of 5-HT receptor types can be detected in the human LES and probably contribute to LES function.
PMCID: PMC4247306  PMID: 25452775
serotonin receptors; human; lower esophageal sphincter; sling fibers; clasp fibers
7.  HREM Analysis of Graphite-Encapsulated Metallic Nanoparticles for Possible Medical Applications 
Ultramicroscopy  2013;134:167-174.
High resolution electron microscopy has been applied to study the structure of metallic nanoparticles. These have sparked considerable interest as contrast agents in the field of biological imaging, including in magnetic resonance imaging (MRI) and computed tomography (CT). Here, we describe a method of synthesizing sub-10nm superparamagnetic metal and alloy nanoparticles by reduction of metallic salts. Annealing at 900°C in a methane/hydrogen environment forms a thin graphitic-carbon shell which is expected to improve stability, biocompatibility, and functionalization. Subsequent high resolution electron microscopy verifies graphitization and allows for crystallographic analysis. Most particles consist of single crystals in the phase predicted for the bulk material at the annealing temperature. Electron energy loss spectroscopy, energy dispersive X-ray spectroscopy and lattice constant measurements show large variation in composition for alloy nanoparticles from a single synthesis. The magnetization relaxation time (T2) measurements demonstrate that Fe and AuFe nanoparticles compete with commercially available iron oxide MRI contrast agents. X-ray attenuation measurements of an AuFe alloy nanoparticle solution gave a relative radiodensity of 280 Hounsfield Units, demonstrating promise as a dual-purpose contrast agent in CT and MRI. Long term stability in an atmospheric environment was also tested, with no signs of corrosion or oxidation after several years of storage.
PMCID: PMC3769614  PMID: 23809196
Metallic nanoparticles; HREM; Computed tomography; Magnetic resonance imaging
8.  Prepubertal Exposure to Genistein Alleviates Di-(2-ethylhexyl) Phthalate Induced Testicular Oxidative Stress in Adult Rats 
BioMed Research International  2014;2014:598630.
Di-(2-ethylhexyl) phthalate (DEHP) is the most widely used plastizer in the world and can suppress testosterone production via activation of oxidative stress. Genistein (GEN) is one of the isoflavones ingredients exhibiting weak estrogenic and potentially antioxidative effects. However, study on reproductive effects following prepubertal multiple endocrine disrupters exposure has been lacking. In this study, DEHP and GEN were administrated to prepubertal male Sprague-Dawley rats by gavage from postnatal day 22 (PND22) to PND35 with vehicle control, GEN at 50 mg/kg body weight (bw)/day (G), DEHP at 50, 150, 450 mg/kg bw/day (D50, D150, D450) and their mixture (G + D50, G + D150, G + D450). On PND90, general morphometry (body weight, AGD, organ weight, and organ coefficient), testicular redox state, and testicular histology were studied. Our results indicated that DEHP could significantly decrease sex organs weight, organ coefficient, and testicular antioxidative ability, which largely depended on the dose of DEHP. However, coadministration of GEN could partially alleviate DEHP-induced reproductive injuries via enhancement of testicular antioxidative enzymes activities, which indicates that GEN has protective effects on DEHP-induced male reproductive system damage after prepubertal exposure and GEN may have promising future in its curative antioxidative role for reproductive disorders caused by other environmental endocrine disruptors.
PMCID: PMC4228721  PMID: 25530965
9.  Anticancer drug-loaded multifunctional nanoparticles to enhance the chemotherapeutic efficacy in lung cancer metastasis 
Inhalation of chemotherapeutic drugs directly into the lungs augments the drug exposure to lung cancers. The inhalation of free drugs however results in over exposure and causes severe adverse effect to normal cells. In the present study, epidermal growth factor (EGF)-modified gelatin nanoparticles (EGNP) was developed to administer doxorubicin (DOX) to lung cancers.
The EGNP released DOX in a sustained manner and effectively internalized in EGFR overexpressing A549 and H226 lung cancer cells via a receptor-mediated endocytosis. In vitro cytotoxicity assay showed that EGNP effectively inhibited the growth of A549 and H226 cells in a dose-dependent manner. In vivo biocompatibility study showed that both GNP and EGNP did not activate the inflammatory response and had a low propensity to cause immune response. Additionally, EGNP maintained a high therapeutic concentration in lungs throughout up to 24 h comparing to that of free drug and GNP, implying the effect of ligand-targeted tumor delivery. Mice treated with EGNP remarkably suppressed the tumor growth (~90% tumor inhibition) with 100% mice survival rate. Furthermore, inhalation of EGNP resulted in elevated levels of cleaved caspase-3 (apoptotic marker), while MMP-9 level significantly reduced comparing to that of control group.
Overall, results suggest that EGF surface-modified nanocarriers could be delivered to lungs via inhalation and controlled delivery of drugs in the lungs will greatly improve the therapeutic options in lung cancer therapy. This ligand-targeted nanoparticulate system could be promising for the lung cancer treatment.
PMCID: PMC4190288  PMID: 25266303
Doxorubicin; EGF; EGFR; Gelatin nanoparticles; Lung cancer; Inhalation; Ligand targeting; Controlled release
10.  Mitochondrial Gene Expression Profiles and Metabolic Pathways in the Amygdala Associated with Exaggerated Fear in an Animal Model of PTSD 
The metabolic mechanisms underlying the development of exaggerated fear in post-traumatic stress disorder (PTSD) are not well defined. In the present study, alteration in the expression of genes associated with mitochondrial function in the amygdala of an animal model of PTSD was determined. Amygdala tissue samples were excised from 10 non-stressed control rats and 10 stressed rats, 14 days post-stress treatment. Total RNA was isolated, cDNA was synthesized, and gene expression levels were determined using a cDNA microarray. During the development of the exaggerated fear associated with PTSD, 48 genes were found to be significantly upregulated and 37 were significantly downregulated in the amygdala complex based on stringent criteria (p < 0.01). Ingenuity pathway analysis revealed up- or downregulation in the amygdala complex of four signaling networks – one associated with inflammatory and apoptotic pathways, one with immune mediators and metabolism, one with transcriptional factors, and one with chromatin remodeling. Thus, informatics of a neuronal gene array allowed us to determine the expression profile of mitochondrial genes in the amygdala complex of an animal model of PTSD. The result is a further understanding of the metabolic and neuronal signaling mechanisms associated with delayed and exaggerated fear.
PMCID: PMC4172054  PMID: 25295026
PTSD; amygdala; mitochondrial genes; stress; fear; Bcl-2; microarray
11.  Inhibition of EZH2 reverses chemotherapeutic drug TMZ chemosensitivity in glioblastoma 
Glioblastoma remains among the most devastating cancers with a median survival of less than 15 months and virtually no survival beyond five years. Currently, the treatment of glioma includes surgery, radiation therapy, chemotherapy, and comprehensive treatment. Intrinsic or acquired resistance to TMZ, is one of the greatest obstacles in successful GB treatment, and is thought to be influenced by a variety of mechanisms. The EZH2 gene, which is expressed in various solid tumors, can regulate gene transcription and promote the generation and progression of tumors. Our aim was to investigate the relationship between EZH2 and multidrug-resistance of human glioblastoma cells. In this study, we established TMZ-resistant U251 and U87 clones (U251/TMZ and U87/TMZ cells), which expressed high level of EZH2. Using RNA interference, we demonstrated that the downregulation of Ezh2 expression in U251/TMZ and U87/TMZ cells resulted in apoptosis and a cell cycle arrest in the G1/S phase. Furthermore, the reduced expression of Ezh2 altered the MDR, MRP and BCRP mRNA and protein levels. These findings suggest that EZH2 plays an important part in the development of multidrug resistance and may represent a novel therapeutic target for multidrug-resistant glioblastoma.
PMCID: PMC4230130  PMID: 25400745
Glioblastoma; EZH2; multidrug-resistance; therapeutic target
12.  Differential Expression of Brain Cannabinoid Receptors between Repeatedly Stressed Males and Females may Play a Role in Age and Gender-Related Difference in Traumatic Brain Injury: Implications from Animal Studies 
Inconsistent gender differences in the outcome of TBI have been reported. The mechanism is unknown. In a recent male animal study, repeated stress followed by TBI had synergistic effects on brain gene expression and caused greater behavioral deficits. Because females are more likely to develop anxiety after stress and because anxiety is mediated by cannabinoid receptors (CBRs) (CB1 and CB2), there is a need to compare CB1 and CB2 expression in stressed males and females. CB1 and CB2 mRNA expression was determined in the amygdala, hippocampus, prefrontal cortex (PFC), and hypothalamus of adolescent male and female rats after 3 days of repeated tail-shock stress using qPCR. PFC CB1 and CB2 protein levels were determined using Western blot techniques. Both gender and stress had significant effects on brain CB1 mRNA expression levels. Overall, females showed significantly higher CB1 and CB2 mRNA levels in all brain regions than males (p < 0.01). Repeated stress reduced CB1 mRNA levels in the amygdala, hippocampus, and PFC (p < 0.01, each). A gender × stress interaction was found in CB1 mRNA level in the hippocampus (p < 0.05), hypothalamus (p < 0.01), and PFC (p < 0.01). Within-sex one-way ANOVA analysis showed decreased CB1 mRNA in the hippocampus, hypothalamus, and PFC of stressed females (p < 0.01, each) but increased CB1 mRNA levels in the hypothalamus of stressed males (p < 01). There was a gender and stress interaction in prefrontal CB1 receptor protein levels (p < 0.05), which were decreased in stressed females only (p < 0.05). Prefrontal CB2 protein levels were decreased in both male and female animals after repeated stress (p < 0.05, each). High basal levels of CBR expression in young naïve females could protect against TBI damage whereas stress-induced CBR deficits could predict a poor outcome of TBI in repeatedly stressed females. Further animal studies could help evaluate this possibility.
PMCID: PMC4147999  PMID: 25221540
stress; anxiety; brain cannabinoid receptors; sex dimorphism; TBI outcome
13.  Acute acalculous cholecystitis immediately after gastric operation: Case report and literatures review 
World Journal of Gastroenterology : WJG  2014;20(30):10642-10650.
Acute acalculous cholecystitis (AAC) is a rare complication of gastric surgery. The most commonly accepted concepts regarding its pathogenesis are bile stasis, sepsis and ischemia, but it has not been well described how to identify and manage this disease in the early stage. We report three cases of AAC in elderly patients immediately after gastric surgery, which were treated with three different strategies. One patient died 42 d after emergency cholecystectomy, and the other two finally recovered through timely cholecystostomy and percutaneous transhepatic gallbladder drainage, respectively. These cases informed us of the value of early diagnosis and proper treatment for perioperative AAC after gastric surgery. We further reviewed reported cases of AAC immediately after gastric operation, which may expand our knowledge of this disease.
PMCID: PMC4130878  PMID: 25132787
Acute acalculous cholecystitis; Postoperative complication; Gastric surgery
14.  Lactobacillus casei reduces susceptibility to type 2 diabetes via microbiota-mediated body chloride ion influx 
Scientific Reports  2014;4:5654.
Gut microbiota mediated low-grade inflammation is involved in the onset of type 2 diabetes (T2DM). In this study, we used a high fat sucrose (HFS) diet-induced pre-insulin resistance and a low dose-STZ HFS rat models to study the effect and mechanism of Lactobacillus casei Zhang in protecting against T2DM onset. Hyperglycemia was favorably suppressed by L. casei Zhang treatment. Moreover, the hyperglycemia was connected with type 1 immune response, high plasma bile acids and urine chloride ion loss. This chloride ion loss was significantly prevented by L. casei via upregulating of chloride ion-dependent genes (ClC1-7, GlyRα1, SLC26A3, SLC26A6, GABAAα1, Bestrophin-3 and CFTR). A shift in the caecal microflora, particularly the reduction of bile acid 7α-dehydroxylating bacteria, and fecal bile acid profiles also occurred. These change coincided with organ chloride influx. Thus, we postulate that the prevention of T2DM onset by L. casei Zhang may be via a microbiota-based bile acid-chloride exchange mechanism.
PMCID: PMC4135721  PMID: 25133590
15.  The association of PTPN22 rs2476601 polymorphism and CTLA-4 rs231775 polymorphism with LADA risks: a systematic review and meta-analysis 
Acta Diabetologica  2014;51(5):691-703.
Although the polymorphisms of PTPN22 and the variants of CTLA-4 have been reported to be the susceptibility genes, which increased risk of latent autoimmune diabetes in adults (LADA), the results remained inconclusive. The aim of this meta-analysis was to evaluate the association between the polymorphisms of two genes and LADA. We performed a systematic review by identifying relevant studies and applied meta-analysis to pool gene effects. Data from ten studies published between 2001 and 2013 were pooled for two polymorphisms: rs2476601 in the PTPN22 gene and rs231775 in the CTLA-4 gene. Data extraction and assessments for risk of bias were independently performed by two reviewers. Fixed-effect model and random-effect model were used to pool the odds ratios; meanwhile, heterogeneity test, publication bias and sensitive analysis were explored. The minor T allele at rs2476601 and the minor G at rs231775 carried estimated relative risks (odds ratio) of 1.52 (95 % CI 1.29–1.79) and 1.39 (95 % CI 1.11–1.74), respectively. These alleles contributed to an absolute lowering of the risk of all LADA by 4.88 and 14.93 % when individuals do not carry these alleles. The estimated lambdas were 0.49 and 0.63, suggesting a codominant model of effects was most likely for two genes. In summary, our systematic review has demonstrated that PTPN22 rs2476601 and CTLA-4 rs231775 are potential risk factors for LADA. An updated meta-analysis is required when more studies are published to increase the power of these polymorphisms and LADA.
Electronic supplementary material
The online version of this article (doi:10.1007/s00592-014-0613-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4176954  PMID: 25005490
PTPN22; CTLA-4; Polymorphism; LADA; Systematic review; Meta-analysis
16.  Different Patterns of White Matter Disruption among Amnestic Mild Cognitive Impairment Subtypes: Relationship with Neuropsychological Performance 
Amnestic mild cognitive impairment (aMCI) is recognized as the prodromal phase of Alzheimer’s disease (AD). Evidence showed that patients with multiple-domain (MD) aMCI were at higher risk of converting to dementia and exhibited more severe gray matter atrophy than single-domain (SD) aMCI. The investigation of the microstructural abnormalities of white matter (WM) among different subtypes of aMCI and their relations with cognitive performances can help to understand the variations among aMCI subtypes and to construct potential imaging based biomarkers to monitor the progression of aMCI. Diffusion-weighted MRI data were acquired from 40 patients with aMCI (aMCI-SD: n = 19; aMCI-MD: n= 21) and 37 healthy controls (HC). Voxel-wise and atlas-based analyses of whole-brain WM were performed among three groups. The correlations between the altered diffusion metrics of the WM tracts and the neuropsychological scores in each subtype of aMCI were assessed. The aMCI-MD patients showed disrupted integrity in multiple WM tracts across the whole-brain when compared with HCs or with aMCI-SD. In contrast, only few WM regions with diffusion changes were found in aMCI-SD as compared to HCs and with less significance. For neuropsychological correlations, only aMCI-MD patients exhibited significant associations between disrupted WM connectivity (in the body of the corpus callosum and the right anterior internal capsules) and cognitive impairments (MMSE and Digit Symb-Coding scores), whereas no such correlations were found in aMCI-SD. These findings indicate that the degeneration extensively exists in WM tracts in aMCI-MD that precedes the development of AD, whereas underlying WM pathology in aMCI-SD is imperceptible. The results are consistent with the view that aMCI is not a uniform disease entity and presents heterogeneity in the clinical progression.
PMCID: PMC4085483  PMID: 23603396
Amnestic mild cognitive impairment; diffusion tensor imaging; multiple-domain; single-domain; TBSS; white matter
17.  Reconstruction for the distal urethral end incorrectly anastomosed to the proximal false passage in the treatment of urethral stricture 
Patient: Male, 24
Final Diagnosis: Urethral stricture
Symptoms: —
Medication: —
Clinical Procedure: —
Specialty: Urology
Unusual or unexpected effect of treatment
The most dependable management of anterior urethral stricture is the complete excision of the area of fibrosis, with a primary reanastomosis of the normal ends of the anterior urethra.
Case Report:
A 24-year-old man had urethral stricture in the penoscrotal junction caused by catheterization approximately 3 years ago. After the resection of the urethral stricture segment and the end-to-end anastomosis were performed, in addition to stricture, urethrocutaneous fistula formation as another complication in the penoscrotal junction was confirmed. The direct vision internal urethrotomy did not improve all the above symptoms. The retrograde urethrogram and voiding cysto-urethrogram showed complete obliteration in the penile urethra, urethrocutaneous fistula, and proximal urethral bifurcation singularity. Intraoperatively, we found that the distal urethral end had been anastomosed to the proximal false passage in the initial surgery and the proximal urethra was located in the dorsal side of the false passage. Then, tubularized preputial flap urethroplasty was performed. The patient was followed up for 10 months. His peak urinary flow was 18.3 milliliter per second.
We would remind urologists that urethral end intraoperatively anastomosed to the false passage is a rare, serious, avoidable, and elementary medical error. Urethroplasty is one of the curative choices for treatment of this unexpected condition.
PMCID: PMC4049976  PMID: 24917901
Urethra – surgery; Urethroplasty; False passage; Urethral Stricture – surgery; Urinary Fistula – surgery
18.  A Novel Recombinant BCG Vaccine Encoding Eimeria tenella Rhomboid and Chicken IL-2 Induces Protective Immunity Against Coccidiosis 
A novel recombinant Bacille Calmette-Guerin (rBCG) vaccine co-expressed Eimeria tenella rhomboid and cytokine chicken IL-2 (chIL-2) was constructed, and its efficacy against E. tenella challenge was observed. The rhomboid gene of E. tenella and chIL-2 gene were subcloned into integrative expression vector pMV361, producing vaccines rBCG pMV361-rho and pMV361-rho-IL2. Animal experiment via intranasal and subcutaneous route in chickens was carried out to evaluate the immune efficacy of the vaccines. The results indicated that these rBCG vaccines could obviously alleviate cacal lesions and oocyst output. Intranasal immunization with pMV361-rho and pMV361-rho-IL2 elicited better protective immunity against E. tenella than subcutaneous immunization. Splenocytes from chickens immunized with either rBCG pMV361-rho and pMV361-rho-IL2 had increased CD4+ and CD8+ cell production. Our data indicate recombinant BCG is able to impart partial protection against E. tenella challenge and co-expression of cytokine with antigen was an effective strategy to improve vaccine immunity.
PMCID: PMC4096635  PMID: 25031464
Eimeria tenella; recombinant BCG; rhomboid; chIL-2; immunity
19.  Passive Smoking Exposure from Partners as a Risk Factor for ER+/PR+ Double Positive Breast Cancer in Never-Smoking Chinese Urban Women: A Hospital-Based Matched Case Control Study 
PLoS ONE  2014;9(5):e97498.
The relationship between passive smoking exposure (PSE) and breast cancer risk is of major interest.
To evaluate the relationship between PSE from partners and breast cancer risk stratified by hormone-receptor (HR) status in Chinese urban women population.
Hospital-based matched case control study.
Chinese urban breast cancer patients without current or previous active smoking history in China Medical University 1st Hospital, Liaoning Province, China between Jan 2009 and Nov 2009.
Each breast cancer patient was matched 1∶1 with healthy controls by gender and age (±2 years) from the same hospital.
The authors used unconditional logistic regression analyses to estimate odds ratio for women with PSE from partners and breast cancer risk.
312 pairs were included in the study. Women who endured PSE had significantly increased risk of breast cancer (adjusted OR: 1.46; 95% CI: 1.05–2.03; P = 0.027), comparing with unexposed women. Women who exposed to >5 cigarettes/day also had significant increased risk (adjusted OR: 1.99; 95% CI: 1.28–3.10; P = 0.002), as were women exposed to passive smoke for 16–25 years (adjusted OR: 1.87 95% CI: 1.22–2.86; P = 0.004), and those exposed to > 4 pack-years (adjusted OR: 1.71 95% CI: 1.17–2.50; P = 0.004). Similar trends were significant for estrogen receptor (ER)/progesterone receptor (PR) double positive subgroup(adjusted OR: 1.71; 2.20; 1.99; 1.92, respectively), but not for ER+/PR−, ER−/PR+, or ER−/PR− subgroups.
limitations of the hospital-based retrospective study, lack of information on entire lifetime PSE and low statistical power.
Our findings provide further evidence that PSE from partners contributes to increased risk of breast cancer, especially for ER/PR double positive breast cancer, in Chinese urban women.
PMCID: PMC4035255  PMID: 24866166
20.  Synthesis of Rosin Acid Starch Catalyzed by Lipase 
BioMed Research International  2014;2014:647068.
Rosin, an abundant raw material from pine trees, was used as a starting material directly for the synthesis of rosin acid starch. The esterification reaction was catalyzed by lipase (Novozym 435) under mild conditions. Based on single factor experimentation, the optimal esterification conditions were obtained as follows: rosin acid/anhydrous glucose unit in the molar ratio 2 : 1, reaction time 4 h at 45°C, and 15% of lipase dosage. The degree of substitution (DS) reaches 0.098. Product from esterification of cassava starch with rosin acid was confirmed by FTIR spectroscopy and iodine coloration analysis. Scanning electron microscopy and X-ray diffraction analysis showed that the morphology and crystallinity of the cassava starch were largely destroyed. Thermogravimetric analysis indicated that thermal stability of rosin acid starch decreased compared with native starch.
PMCID: PMC4055620  PMID: 24977156
21.  Intravoxel incoherent motion MRI: emerging applications for nasopharyngeal carcinoma at the primary site 
European Radiology  2014;24(8):1998-2004.
We compared pure molecular diffusion (D), perfusion-related diffusion (D*), perfusion fraction (f) and apparent diffusion coefficient (ADC) based on intravoxel incoherent motion (IVIM) theory in patients with nasopharyngeal carcinoma (NPC).
Sixty-five consecutive patients (48 men) with suspected NPC were examined using a 3.0-T MR system. Diffusion-weighted imaging (DWI) was performed with 13 b values (range, 0–800 s/mm2). We regarded the result of endoscopy and biopsy as the gold standard for detection. D, D* and f were compared between patients with primary NPC and enlarged adenoids.
IVIM DWI was successful in 37 of 40 NPC and 23 of 25 enlarged adenoids cases. D (P = 0.001) and f (P < 0.0001) were significantly lower in patients with NPC than in patients with enlarged adenoids, whereas D* was significantly higher (P < 0.0001). However, the ADC was not significantly different between the two groups (P > 0.05). The area under the ROC curve (AUC) for D was 0.849 and was significantly larger than that for ADC (P < 0.05).
IVIM DWI is a feasible technique for investigating primary NPC. D was significantly decreased in primary NPC, and increased D* reflected increased blood vessel generation and parenchymal perfusion in primary NPC.
Key Points
• Intravoxel incoherent motion (IVIM) analysis permits separate quantification of diffusion and perfusion.
• IVIM DWI is a feasible technique for investigating primary NPC.
• IVIM suggests that primary NPC tissue voxels exhibit both perfusion and diffusion.
PMCID: PMC4082649  PMID: 24838795
Intravoxel incoherent motion; MRI; Nasopharyngeal carcinoma; DWI; Enlarged adenoids
22.  Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren’s syndrome 
Nature genetics  2013;45(11):10.1038/ng.2792.
Sjögren’s syndrome is a common autoimmune disease (~0.7% of European Americans) typically presenting as keratoconjunctivitis sicca and xerostomia. In addition to strong association within the HLA region at 6p21 (Pmeta=7.65×10−114), we establish associations with IRF5-TNPO3 (Pmeta=2.73×10−19), STAT4 (Pmeta=6.80×10−15), IL12A (Pmeta =1.17×10−10), FAM167A-BLK (Pmeta=4.97×10−10), DDX6-CXCR5 (Pmeta=1.10×10−8), and TNIP1 (Pmeta=3.30×10−8). Suggestive associations with Pmeta<5×10−5 were observed with 29 regions including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2, and PHIP amongst others. These results highlight the importance of genes involved in both innate and adaptive immunity in Sjögren’s syndrome.
PMCID: PMC3867192  PMID: 24097067
23.  Dimerization Interface of 3-Hydroxyacyl-CoA Dehydrogenase Tunes the Formation of Its Catalytic Intermediate 
PLoS ONE  2014;9(4):e95965.
3-hydroxyacyl-CoA dehydrogenase (HAD, EC is a homodimeric enzyme localized in the mitochondrial matrix, which catalyzes the third step in fatty acid β-oxidation. The crystal structures of human HAD and subsequent complexes with cofactor/substrate enabled better understanding of HAD catalytic mechanism. However, numerous human diseases were found related to mutations at HAD dimerization interface that is away from the catalytic pocket. The role of HAD dimerization in its catalytic activity needs to be elucidated. Here, we solved the crystal structure of Caenorhabditis elegans HAD (cHAD) that is highly conserved to human HAD. Even though the cHAD mutants (R204A, Y209A and R204A/Y209A) with attenuated interactions on the dimerization interface still maintain a dimerization form, their enzymatic activities significantly decrease compared to that of the wild type. Such reduced activities are in consistency with the reduced ratios of the catalytic intermediate formation. Further molecular dynamics simulations results reveal that the alteration of the dimerization interface will increase the fluctuation of a distal region (a.a. 60–80) that plays an important role in the substrate binding. The increased fluctuation decreases the stability of the catalytic intermediate formation, and therefore the enzymatic activity is attenuated. Our study reveals the molecular mechanism about the essential role of the HAD dimerization interface in its catalytic activity via allosteric effects.
PMCID: PMC3999109  PMID: 24763278
24.  Independent Adipogenic and Contractile Properties of Fibroblasts in Graves’ Orbitopathy: An In Vitro Model for the Evaluation of Treatments 
PLoS ONE  2014;9(4):e95586.
Graves’ orbitopathy (GO) is a disfiguring and sometimes blinding disease, characterised by inflammation and swelling of orbital tissues, with fibrosis and adipogenesis being predominant features. Little is known about the disease aetiology and the molecular mechanisms driving the phenotypic changes in orbital fibroblasts are unknown. Using fibroblasts isolated from the orbital fat of undiseased individuals or GO patients, we have established a novel in vitro model to evaluate the dual profile of GO cells in a three-dimensional collagen matrix; this pseudo-physiological 3D environment allows measurement of their contractile and adipogenic properties. GO cells contracted collagen matrices more efficiently than control cells following serum or TGFβ1 stimulation, and showed a slightly increased ability to proliferate in the 3D matrix, in accordance with a fibro-proliferative phenotype. GO cells, unlike controls, also spontaneously differentiated into adipocytes in 3D cultures - confirming an intrinsic adipogenic profile. However, both control and GO cells underwent adipogenesis when cultured under pathological pressure levels. We further demonstrate that a Thy-1-low population of GO cells underlies the adipogenic - but not the contractile - phenotype and, using inhibitors, confirm that the contractile and adipogenic phenotypes are regulated by separate pathways. In view of the current lack of suitable treatment for GO, we propose that this new model testing the duality of the GO phenotype could be useful as a preclinical evaluation for the efficacy of potential treatments.
PMCID: PMC3994071  PMID: 24751986
25.  Application of Ultrasound on Monitoring the Evolution of the Collagen Fiber Reinforced nHAC/CS Composites In Vivo 
BioMed Research International  2014;2014:418302.
To date, fiber reinforce scaffolds have been largely applied to repair hard and soft tissues. Meanwhile, monitoring the scaffolds for long periods in vivo is recognized as a crucial issue before its wide use. As a consequence, there is a growing need for noninvasive and convenient methods to analyze the implantation remolding process in situ and in real time. In this paper, diagnostic medical ultrasound was used to monitor the in vivo bone formation and degradation process of the novel mineralized collagen fiber reinforced composite which is synthesized by chitosan (CS), nanohydroxyapatite (nHA), and collagen fiber (Col). To observe the impact of cells on bone remodeling process, the scaffolds were planted into the back of the SD rats with and without rat bone mesenchymal stem cells (rBMSCs). Systematic data of scaffolds in vivo was extracted from ultrasound images. Significant consistency between the data from the ultrasound and DXA could be observed (P < 0.05). This indicated that ultrasound may serve as a feasible alternative for noninvasive monitoring the evolution of scaffolds in situ during cell growth.
PMCID: PMC4009107  PMID: 24822206

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