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1.  Automated Lung Segmentation and Image Quality Assessment for Clinical 3D/4D Computed Tomography 
Four-dimensional computed tomography (4DCT) provides not only a new dimension of patient-specific information for radiation therapy planning and treatment but also a challenging scale of data volume to process and analyze. Manual analysis using existing 3D tools is unable to keep up with vastly increased 4D data volume, automated processing and analysis are thus needed to process 4DCT data effectively and efficiently. In this work, we applied ideas and algorithms from image/signal processing, computer vision and machine learning to 4DCT lung data so that lungs can be reliably segmented in a fully-automated manner, lung features can be visualized and measured on-the-fly via user interactions, and data quality classifications can be computed in a robust manner. Comparisons of our results with an established treatment planning system and calculation by experts demonstrated negligible discrepancies (within ±2%) for volume assessment but one to two orders of magnitude performance enhancement. An empirical Fourier-analysis-based quality measure delivered performances closely emulating human experts. Three machine learners are inspected to justify the viability of machine learning techniques used to robustly identify data quality of 4DCT images in the scalable manner. The resultant system provides tools that speeds up 4D tasks in the clinic and facilitates clinical research to improve current clinical practice.
PMCID: PMC4302269  PMID: 25621194
Biomedical image processing; Image analysis; Classification algorithms; Morphological operations; Machine learning algorithms; Data visualization; Computed tomography
2.  KLRG1 impairs CD4+ T cell responses via p16ink4a and p27kip1 pathways - Role in hepatitis B vaccine failure in individuals with hepatitis C virus infection 
Co-infection of hepatitis B virus (HBV) with hepatitis C virus (HCV) is quite common, leading to an increase in morbidity and mortality. As such, HBV vaccination is recommended in HCV-infected individuals. HBV vaccine responses in HCV-infected individuals, however, are often blunted when compared to uninfected populations. The mechanism for this failure of vaccine response in HCV-infected subjects remains unclear. In this study, we investigated the expression and function of an inhibitory receptor, killer cell lectin-like receptor subfamily G member 1 (KLRG1), in regulation of CD4+ T cells and HBV vaccine responses during HCV infection. We demonstrated that KLRG1 was over-expressed on CD4+ T cells from HCV-infected, HBV vaccine non-responders (HBV-NR) compared to those responders (HBV-R). The capacity of CD4+ T cell to proliferate and secrete IL-2 cytokine was inversely associated with the level of KLRG1 expression. Importantly, blocking KLRG1 signaling resulted in a significant improvement of CD4+ T cell proliferation and IL-2 production in HCV-infected, HBV-NR in response to T cell receptor (TCR) stimulation. Moreover, blockade of KLRG1 increased the phosphorylation of Akt (Ser473) and decreased the expression of cell cycle inhibitors p16ink4a and p27kip1, which subsequently enhanced CDK 2 and cyclin E expressions. These results suggest that the KLRG1 pathway impairs CD4+ T cell responses to neo-antigen and induces a state of immune senescence in individuals with HCV infection, raising the possibility that blocking this negative signaling pathway might improve HBV vaccine responses in the setting of chronic viral infection.
PMCID: PMC3894750  PMID: 24337749
CD4+ T cells; hepatitis B vaccine; hepatitis C infection; KLRG1; p16ink4a; p27kip1
3.  A method of extending the depth of focus of the high-resolution X-ray imaging system employing optical lens and scintillator: a phantom study 
BioMedical Engineering OnLine  2015;14(Suppl 1):S15.
The high-resolution X-ray imaging system employing synchrotron radiation source, thin scintillator, optical lens and advanced CCD camera can achieve a resolution in the range of tens of nanometers to sub-micrometer. Based on this advantage, it can effectively image tissues, cells and many other small samples, especially the calcification in the vascular or in the glomerulus. In general, the thickness of the scintillator should be several micrometers or even within nanometers because it has a big relationship with the resolution. However, it is difficult to make the scintillator so thin, and additionally thin scintillator may greatly reduce the efficiency of collecting photons.
In this paper, we propose an approach to extend the depth of focus (DOF) to solve these problems. We develop equation sets by deducing the relationship between the high-resolution image generated by the scintillator and the degraded blur image due to defect of focus first, and then we adopt projection onto convex sets (POCS) and total variation algorithm to get the solution of the equation sets and to recover the blur image.
By using a 20 μm thick unmatching scintillator to replace the 1 μm thick matching one, we simulated a high-resolution X-ray imaging system and got a degraded blur image. Based on the algorithm proposed, we recovered the blur image and the result in the experiment showed that the proposed algorithm has good performance on the recovery of image blur caused by unmatching thickness of scintillator.
The method proposed is testified to be able to efficiently recover the degraded image due to defect of focus. But, the quality of the recovery image especially of the low contrast image depends on the noise level of the degraded blur image, so there is room for improving and the corresponding denoising algorithm is worthy for further study and discussion.
PMCID: PMC4306104  PMID: 25602532
4.  Intestinal Parasite Co-infection among Pulmonary Tuberculosis Cases without Human Immunodeficiency Virus Infection in a Rural County in China 
Epidemiologic studies of co-infection with tuberculosis (TB) and intestinal parasites in humans have not been extensively investigated in China. A cross-section study was conducted in a rural county of Henan Province, China. Pulmonary TB (PTB) case-patients receiving treatment for infection with Mycobacterium tuberculosis and healthy controls matched for geographic area, age, and sex were surveyed by using questionnaires. Fecal and blood specimens were collected for detection of intestinal parasites, routine blood examination, and infection with human immunodeficiency virus. The chi-square test was used for univariate analysis and multivariate logistic regression models were used to adjust for potential confounding factors. A total of 369 persons with PTB and 366 healthy controls were included; all participants were negative for human immunodeficiency virus. The overall prevalence of intestinal parasites in persons with PTB was 14.9%, including intestinal protozoa (7.9%) and helminthes (7.6%). The infection spectrum of intestinal parasites was Entamoeba spp. (1.4%), Blastocystis hominis (6.2%), Trichomonas hominis (0.3%), Clonorchis sinensis (0.3%), Ascaris lumbricoides (0.5%), Trichuris trichiura (2.2%), and hookworm (4.6%). The prevalence of intestinal parasites showed no significant difference between persons with PTB and healthy controls after adjusting for potential confounding factors. There was no factor that affected infection rates for intestinal parasites between the two groups. Infection with intestinal parasites of persons with PTB was associated with female sex (adjusted odds ratio [AOR] = 2.05, 95% confidence interval [CI] = 1.01–4.17), body mass index ≤ 19 (AOR = 3.02, 95% CI = 1.47–6.20), and anemia (AOR = 2.43, 95% CI = 1.17–5.03). Infection of healthy controls was only associated with an annual labor time in farmlands > 2 months (AOR = 4.50, 95% CI = 2.03–10.00). In addition, there was no significant trend between rates of infection with intestinal parasites and duration of receiving treatment for infection with M. tuberculosis in persons with PTB. The prevalence of intestinal parasites was not higher in persons with PTB, and there was no evidence that PTB increased susceptibility to intestinal parasites in this study. However, for patients with PTB, women and patients with comorbidities were more likely to be infected with intestinal parasites.
PMCID: PMC3886404  PMID: 24166044
5.  Glycated hemoglobin level is significantly associated with the severity of coronary artery disease in non-diabetic adults 
To investigate relationship between glycated hemoglobin (HbA1c) level and coronary artery disease (CAD) severity.
Observational study was conducted and 573 participants were enrolled and baseline characteristics were collected. Clinical presentations in terms of stable angina, unstable angina or acute myocardial infarction were diagnosed. All participants were performed coronary angiography to figure out the numbers of coronary artery stenosis in terms of none-stenosis (< 50% stenosis), single or multiple vessels stenoses (≥ 50% stenosis). All participants were divided into subgroups according to two categories in terms of severity of clinical presentation (stable angina, unstable angina, or acute myocardial infarction) and the number of coronary artery stenosis (none, single, and multiple vessels). Primary endpoint was to evaluate relationship between baseline HbA1c value and CAD severity.
Consistent to previous studies, participants with CAD had more risk factors such as elderly, smoking, low HDL-C and high CRP levels. Notably, HbA1c level was more prominent in CAD group than that without CAD. As compared to stable angina subgroup, HbA1c levels were gradually increased in unstable angina and acute myocardial infarction groups. Similar trend was identified in another category in terms of higher HbA1c level corresponding to more vessels stenoses. Multivariate regression analyses showed that after adjusted for traditional risk factors as well as fasting blood glucose, HbA1c remained strongly associated with the severity of CAD. Nonetheless, there was no significant association when CRP was accounted for.
HbA1c may be a useful indicator for CAD risk evaluation in non-diabetic adults.
PMCID: PMC4271481  PMID: 25477191
Glycated hemoglobin; Coronary artery disease; Diabetes mellitus
6.  Expression of Angiogenesis Regulatory Proteins and Epithelial-Mesenchymal Transition Factors in Platelets of the Breast Cancer Patients 
The Scientific World Journal  2014;2014:878209.
Platelets play a role in tumor angiogenesis and growth and are the main transporters of several angiogenesis regulators. Here, we aimed to determine the levels of angiogenesis regulators and epithelial-mesenchymal transition factors sequestered by circulating platelets in breast cancer patients and age-matched healthy controls. Platelet pellets (PP) and platelet-poor plasma (PPP) were collected by routine protocols. Vascular endothelial growth factor (VEGF), platelet-derived growth factor BB (PDGF-BB), thrombospondin-1 (TSP-1), platelet factor 4 (PF4), and transforming growth factor-β1 (TGF-β1) were measured by enzyme-linked immunosorbent assay. Angiogenesis-associated expression of VEGF (2.1 pg/106 platelets versus 0.9 pg/106 platelets, P < 0.001), PF4 (21.2 ng/106 platelets versus 10.2 ng/106 platelets, P < 0.001), PDGF-BB (42.9 pg/106 platelets versus 19.1 pg/106 platelets, P < 0.001), and TGF-β1 (15.3 ng/106 platelets versus 4.3 ng/106 platelets, P < 0.001) differed in the PP samples of cancer and control subjects. In addition, protein concentrations were associated with clinical characteristics (P < 0.05). Circulating platelets in breast cancer sequester higher levels of PF4, VEGF, PDGF-BB, and TGF-β1, suggesting a possible target for early diagnosis. VEGF, PDGF, and TGF-β1 concentrations in platelets may be associated with prognosis.
PMCID: PMC4212629  PMID: 25379550
7.  Biogenesis of C-Glycosyl Flavones and Profiling of Flavonoid Glycosides in Lotus (Nelumbo nucifera) 
PLoS ONE  2014;9(10):e108860.
Flavonoids in nine tissues of Nelumbo nucifera Gaertner were identified and quantified by high-performance liquid chromatography with diode array detector (HPLC-DAD) and HPLC-electrospray ionization-mass spectrometry (HPLC-ESI-MSn). Thirty-eight flavonoids were identified; eleven C-glycosides and five O-glycosides were discovered for the first time in N. nucifera. Most importantly, the C-glycosyl apigenin or luteolin detected in lotus plumules proved valuable for deep elucidation of flavonoid composition in lotus tissues and for further utilization as functional tea and medicine materials. Lotus leaves possessed the significantly highest amount of flavonoids (2.06E3±0.08 mg 100 g−1 FW) and separating and purifying the bioactive compound, quercetin 3-O-glucuronide, from leaves showed great potential. In contrast, flavonoids in flower stalks, seed coats and kernels were extremely low. Simultaneously, the optimal picking time was confirmed by comparing the compound contents in five developmental phases. Finally, we proposed the putative flavonoid biosynthesis pathway in N. nucifera.
PMCID: PMC4184820  PMID: 25279809
8.  Mesothelioma of the tunica vaginalis testis with prominent adenomatoid features: a case report 
Malignant mesotheliomas of the testis arise from the tunica vaginalis, formed from the evagination of the abdominal peritoneum into the scrotum. It is an extremely rare tumor representing 0.3% to 5% of all malignant mesotheliomas. We presented an interesting case of 68-year-old male with swelling and slightly painful in the right scrotum. Histologically, the lesion were composed of small tubular, microcystic, gland lined by flattened epithelioid cells and vague signet ring cells set in a myxofibrous stroma, which is resemblance to adenomatoid tumor. But the tumor cells showed significant atypical cytologic morphology and invaded into spermatic cord tissue, which indicated the diagnosis of malignant tumor. Immunohistochemistry study showed positive expression of CK, CK5/6, CK7, Calretinin, D2-40 and Vimentin which indicated the diagnosis of malignant mesothelioma. This case of mesothelioma should be classified as epithelial in type. To our knowledge, the mesothelioma of the tunica vaginalis testis with adenomatoid tumor-like microscopic features is very rare.
PMCID: PMC4230092  PMID: 25400801
Mesothelioma; tunica vaginalis testis; histology; adenomatoid
9.  Development of Contrast-Induced Acute Kidney Injury after Elective Contrast Media Exposure in Patients with Type 2 Diabetes Mellitus: Effect of Albuminuria 
PLoS ONE  2014;9(9):e106454.
The influence of albuminuria and urinary pH on the development of contrast-induced acute kidney disease (CI-AKI) in patients with type 2 diabetes mellitus (T2DM) after elective coronary angiography (CAG) or percutaneous coronary intervention (PCI) is unknown.
CI-AKI was defined as an increase in serum creatinine >26.4 µmol/L or ≥50% of baseline value within 48 hours after contrast media exposure. Demographics, traditional risk factors, clinical outcomes and CI-AKI incidence were compared between groups. Univariate analysis and multivariate logistic regression were performed to assess risk factors of CI-AKI.
We observed 597 patients with T2DM after CAG or PCI. Patients were divided into 3 groups based on early morning urinary albumin: negative group (urine dipstick negative, n = 483), trace group (urine dipstick trace, n = 60), and positive group (urine dipstick ≥1+, n = 54). CI-AKI occurred in 33 (5.5%) patients, including 19 (3.9%) in the negativealbuminuria group, 4 (6.7%) in the trace group, and 10 (18.5%) in the positive group (p< 0.001), respectively. After adjusting for potential confounding risk factors, positive albuminuria (OR = 3.8, 95% CI: 1.5 to 9.2, p = 0.004) and urinary pH<6 (OR = 2.4, 95% CI: 1.1 to 5.1, p = 0.020) remained significantly associated with CI-AKI.
Preprocedural albuminuria and urinary pH <6 are independent risk factors of CI-AKI in patients with T2DM undergoing elective cardiac catheterization, and may be used to identify patients at high risk of post-procedural CI-AKI.
PMCID: PMC4156370  PMID: 25192238
10.  Buckwheat Rutin Inhibits AngII-induced Cardiomyocyte Hypertrophy via Blockade of CaN-dependent Signal Pathway  
Buckwheat rutin has been found to be able to inhibit angiotensin II (AngII) - induced hypertrophy in cultured neonatal rat cardiomyocytes, but the mechanism remains uncertain. In this study, myocardial hypertrophy model was made by adding AngII to the medium of cardiac myocytes of neonatal rats; meanwhile, different concentrations of buckwheat rutin were applied to observe their effects. Intracellular Ca2+ level was detected by Hitachi - 850 fluorospectrophotometer, calcineurin (CaN) activity was measured by colorimetric method, the expression of CaN protein was observed with immunocytochemistry, and the proto - oncogene c - fos mRNA expression was assessed with reverse transcription polymerase chain reaction (RT - PCR). Compared with control group, AngII could greatly stimulate the increase of intracellular Ca2+ level, the activities and protein expression of cardiomyocytes CaN, and the expression of proto - oncogene c - fos mRNA in cultured neonatal rat cardiomyocytes, which could be effectively decreased by buckwheat rutin. Our results demonstrated that buckwheat rutin exhibited inhibitory effect on AngII - induced hypertrophy in cultured neonatal rat cardiomyocytes via Ca2+ antagonism action thus block the CaN - dependent signal pathway.
PMCID: PMC4232801  PMID: 25587324
Rutin; Buckwheat; Angiotensin II; Cardiac hypertrophy; Calcineurin
11.  Targeting of the β6 gene to suppress degradation of ECM via inactivation of the MAPK pathway in breast adenocarcinoma cells 
Oncology Reports  2014;32(5):1787-1795.
Integrin ανβ6 has emerged as a potential novel target for anticancer and plays a major role in promoting malignant tumor progression. Recent studies indicate that integrin ανβ6 occurs in many cancers. However, whether and how ανβ6 is regulated by genetic and epigenetic mechanisms in breast cancer remain unknown. In the present study, two different short hairpin RNAs (shRNAs) targeting the β6 gene were designed and constructed into pSUPER, respectively, which were transfected into the MCF-7 human breast adenocarcinoma cell line. The β6-shRNA stably transfected cells were successfully established, and significant lower levels of ανβ6 mRNA and protein expression were confirmed. Furthermore, inhibition of integrin ανβ6 markedly downregulated the expression of matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase-3 (MMP-3) and urokinase plasminogen activator (uPA) in tumor conditioned medium. Furthermore, β6-shRNA-mediated silencing of the ανβ6 gene obviously decreased the expression of ERK1/2. In particular, supression of integrin ανβ6 caused significant downregulation of the degradation of basement membrane type IV collagen secretion via modulation of the plasminogen activation cascade. Our results thus indicate that ανβ6 plays a fundamental role in promoting invasion and growth of breast adenocarcinoma cells. Taken together, this study revealed that targeting of the β6 gene by RNA interference (RNAi) could efficiently downregulate ανβ6 expression and suppress the ERK1/2-dependent extracellular matrix degradation in vitro, which is dependent upon inactivation of the mitogen-activated protein kinase (MAPK) pathway. These findings may offer a useful therapeutic approach to block invasion and migration of breast cancer cells.
PMCID: PMC4203328  PMID: 25176506
breast adenocarcinoma; β6 gene; RNA interference; matrix metalloproteinase; ERK; neoplasm invasion
12.  Risk and predictors for early radiation pneumonitis in patients with stage III non-small cell lung cancer treated with concurrent or sequential chemoradiotherapy 
The rate of radiation pneumonitis (RP) for patients receiving chemoradiotherapy has been various across studies. Whether it is related to different chemotherapy schedules used in combination with radiation therapy were evaluated in this study. New factors associated with RP were also investigated.
Methods and materials
A total of 369 consecutive patients with Stage III non small cell lung cancer treated with chemoradiotherapy were followed after radiotherapy (RT). Among them 262 patients received concurrent chemoradiotherapy followed by consolidation chemotherapy and 107 patients received only sequential chemotherapy after RT. RP was graded according to Common Terminology Criteria for Adverse Events version 4.0.
The rate of grade ≥ 2 were 39.7%, 31% and 33.6% in the concurrent DP (docetaxel/cisplatin), concurrent NP (vinorelbine/cisplatin) and sequential group, and grade ≥ 3 RP were 18.4%, 9.5%, and 11.2% respectively. The rate of grade ≥ 3 RP was significantly higher in concurrent DP group than that in concurrent NP group (p = 0.04). RP occurred earlier in concurrent DP group than that in the other two groups. There were no significant differences in response rate among the three groups. In the multivariate analysis, age (OR = 1.99, p = 0.038 and OR = 8.90, p < 0.001), chemotherapy schedule (OR = 1.45, p = 0.041 and OR = 1.98, p = 0.013), mean lung dose(OR = 1.42, p < 0.001 and OR = 1.64, p < 0.001), and planning target volume(OR = 1.004, p = 0.001 and OR = 1.005, p = 0.021) were predictors for both grade ≥ 2 and grade ≥ 3 RP. Response to treatment was a new predictor for grade ≥ 3 RP only (OR = 4.39, p = 0.034).
Response to treatment was found to be a new predictor for grade ≥ 3 RP. Compared to concurrent NP schedule, concurrent DP schedule achieved similar response to treatment but resulted in a higher risk of grade ≥ 3 RP.
PMCID: PMC4120001  PMID: 25074618
Non-small cell lung cancer; Radiation pneumonitis; Predictor; Concurrent chemoradiotherapy; Sequential chemoradiotherapy
13.  Liver fibrosis evaluation by ARFI and APRI in chronic hepatitis C 
AIM: To explore the value of liver fibrosis assessment by acoustic radiation force impulse (ARFI) and the AST/PLT ratio index (APRI) in chronic hepatitis C patients.
METHODS: One hundred and twenty eight patients with chronic hepatitis C were examined using ARFI elastometry and APRI, calculated according to known formulae. The gold standard of liver biopsy was referred; ROC curve analysis was used to assess all ARFI and APRI values. The corresponding cut-off values, sensitivities, and specificities were calculated and compared. In addition, the correlation of liver fibrosis stages in chronic hepatitis C patients with ARFI measurements and APRI were also tested to evaluate significant data.
RESULTS: The values of ARFI in S1-S4 were 1.23 ± 0.34 m/s, 1.48 ± 0.43 m/s, 2.06 ± 0.45 m/s, and 2.30 ± 0.87 m/s. The values of APRI in S1-S4 were 0.31 ± 0.45 m/s, 0.28 ± 0.38 m/s, 0.58 ± 0.59 m/s and 0.65 ± 0.34 m/s. ARFI (r = 0.649, P < 0.05) showed a better correlation with liver fibrosis stages in chronic hepatitis C than APRI (r = 0.478, P < 0.05). The areas under the ROC curves for ARFI and APRI were 0.775 and 0.721 for stages ≥ S2, 0.901 and 0.787 for stages ≥ S3, and 0.792 and 0.780 for S = 4, respectively.
CONCLUSION: Both ARFI and APRI could evaluate liver fibrosis stages in chronic hepatitis C. ARFI is more accurate than the APRI index.
PMCID: PMC4110585  PMID: 25071348
Liver fibrosis; Chronic hepatitis C; Acoustic radiation force impulse; AST/PLT ratio index; Sensitivity; Specificity
14.  Increased leukemia-associated gene expression in benzene-exposed workers 
Scientific Reports  2014;4:5369.
Long-term exposure to benzene causes several adverse health effects, including an increased risk of acute myeloid leukemia. This study was to identify genetic alternations involved in pathogenesis of leukemia in benzene-exposed workers without clinical symptoms of leukemia. This study included 33 shoe-factory workers exposed to benzene at levels from 1 ppm to 10 ppm. These workers were divided into 3 groups based on the benzene exposure time, 1- < 7, 7- < 12, and 12- < 24 years. 17 individuals without benzene exposure history were recruited as controls. Cytogenetic analysis using Affymetrix Cytogenetics Array found copy-number variations (CNVs) in several chromosomes of benzene-exposed workers. Expression of targeted genes in these altered chromosomes, NOTCH1 and BSG, which play roles in leukemia pathogenesis, was further examined using real-time PCR. The NOTCH1 mRNA level was significantly increased in all 3 groups of workers, and the NOTCH1 mRNA level in the 12- < 24 years group was significantly higher than that in 1- < 7 and 7- < 12 years groups. Compared to the controls, the BSG mRNA level was significantly increased in 7- < 12 and 12- < 24 years groups, but not in the 1- < 7 years group. These results suggest that CNVs and leukemia-related gene expression might play roles in leukemia development in benzene-exposed workers.
PMCID: PMC4081871  PMID: 24993241
15.  MRI Study of Cerebral, Retinal and Choroidal Blood Flow Responses to Acute Hypertension 
Experimental eye research  2013;112:118-124.
Blood flow (BF) in many tissues is stable during significant fluctuations in systemic arterial blood pressure or perfusion pressure under normal conditions. The regulatory mechanisms responsible for this non-passive BF behavior include both local and neural control mechanisms. This study evaluated cerebral BF (CBF), retinal BF (RBF) and choroidal BF (ChBF) responses to acute blood pressure increases in rats using magnetic resonance imaging (MRI). A transient increase in blood pressure inside the MRI scanner was achieved by mechanically inflating a balloon catheter to occlude the descending aorta near the diaphragm. We verified the rat model of mechanical occlusion and MRI approach by first measuring blood-flow regulatory responses to changing BP in the brain under normoxia and hypercapnia where the phenomenon is well documented. Retinal and choroidal blood-flow responses to transient increased arterial pressure were then investigated. In response to an acute increase in blood pressure, RBF exhibited autoregulatory behavior and ChBF exhibited baroregulation similar to that seen in the cerebral circulation. This approach may prove useful to investigate retinal and choroidal vascular dysregulation in rat models of retinal diseases with suspected vascular etiology.
PMCID: PMC3700615  PMID: 23623996
cASL MRI; retina; choroid; blood pressure; blood flow; baroregulation; autoregulation
16.  Optimization of Large-Scale Culture Conditions for the Production of Cordycepin with Cordyceps militaris by Liquid Static Culture 
The Scientific World Journal  2014;2014:510627.
Cordycepin is one of the most important bioactive compounds produced by species of Cordyceps sensu lato, but it is hard to produce large amounts of this substance in industrial production. In this work, single factor design, Plackett-Burman design, and central composite design were employed to establish the key factors and identify optimal culture conditions which improved cordycepin production. Using these culture conditions, a maximum production of cordycepin was 2008.48 mg/L for 700 mL working volume in the 1000 mL glass jars and total content of cordycepin reached 1405.94 mg/bottle. This method provides an effective way for increasing the cordycepin production at a large scale. The strategies used in this study could have a wide application in other fermentation processes.
PMCID: PMC4094858  PMID: 25054182
17.  Spatial patterns of the congenital heart disease prevalence among 0- to 14-year-old children in Sichuan Basin, P. R China, from 2004 to 2009 
BMC Public Health  2014;14:595.
Congenital heart disease (CHD) is the most common type of major birth defects in Sichuan, the most populous province in China. The detailed etiology of CHD is unknown but some environmental factors are suspected as the cause of this disease. However, the geographical variations in CHD prevalence would be highly valuable in providing a clue on the role of the environment in CHD etiology. Here, we investigate the spatial patterns and geographic differences in CHD prevalence among 0- to 14-year-old children, discuss the possible environmental risk factors that might be associated with CHD prevalence in Sichuan Basin from 2004 to 2009.
The hierarchical Bayesian model was used to estimate CHD prevalence at the township level. Spatial autocorrelation statistics were performed, and a hot-spot analysis with different distance thresholds was used to identify the spatial pattern of CHD prevalence. Distribution and clustering maps were drawn using geographic information system tools.
CHD prevalence was significantly clustered in Sichuan Basin in different spatial scale. Typical hot/cold clusters were identified, and possible CHD causes were discussed. The association between selected hypothetical environmental factors of maternal exposure and CHD prevalence was evaluated.
The largest hot-spot clustering phenomena and the CHD prevalence clustering trend among 0- to 14-year-old children in the study area showed a plausibly close similarity with those observed in the Tuojiang River Basin. The high ecological risk of heavy metal(Cd, As, and Pb)sediments in the middle and lower streams of the Tuojiang River watershed and ammonia–nitrogen pollution may have contribution to the high prevalence of CHD in this area.
PMCID: PMC4073187  PMID: 24924350
Congenital heart disease(CHD); Hierarchical Bayesian model(HB); Spatial autocorrelation; Hot-spot analysis; Sichuan Basin
18.  Hydrothermal growth of TiO2 nanowire membranes sensitized with CdS quantum dots for the enhancement of photocatalytic performance 
Nanoscale Research Letters  2014;9(1):270.
In this paper, TiO2 nanowires (NWs) on Ti foils were prepared using a simple hydrothermal approach and annealing treatment. CdS quantum dots (QDs) were assembled onto the crystallized TiO2 NWs by sequential chemical bath deposition. Ultraviolet-visible absorption spectra showed that CdS adds bands in the visible to the TiO2 absorption and exhibited a broad absorption band in the visible region, which extended the scope of absorption spectrum and helped improve the photocatalytic degradation efficiency. The results of photocatalytic experiment revealed that CdS-TiO2 NWs possessed higher photocatalytic activities toward methyl orange than pure TiO2 nanowires. The degradation efficiency of 96.32% after ten cycles indicated that the as-prepared CdS-TiO2 composite exhibited excellent long-time recyclable ability and can be reused for the degradation of contaminants.
PMCID: PMC4046152  PMID: 24936164
Hydrothermal; S-CBD; CdS-TiO2 NWs; Photocatalytic activity
19.  KLRG1 Negatively Regulates Natural Killer Cell Functions through the Akt Pathway in Individuals with Chronic Hepatitis C Virus Infection 
Journal of Virology  2013;87(21):11626-11636.
In this study, we demonstrate that killer cell lectin-like receptor subfamily G member 1 (KLRG1), a transmembrane protein preferentially expressed on T cells, is highly expressed on CD56+ NK cells, which are significantly reduced in their numbers and functions in the peripheral blood of patients with chronic hepatitis C virus (HCV) infection compared to subjects without infection. KLRG1 expression is also upregulated on healthy NK cells exposed to Huh-7 hepatocytes infected with HCV in vitro. Importantly, the expression levels of KLRG1 are inversely associated with the capacity of NK cells to proliferate and to produce gamma interferon (IFN-γ) but positively associated with apoptosis of NK cells in response to inflammatory cytokine stimulation. KLRG1+ NK cells, including CD56bright and CD56dim subsets, exhibit impaired cell activation and IFN-γ production but increased apoptosis compared to KLRG1− NK cells, particularly in HCV-infected individuals. Importantly, blockade of KLRG1 signaling significantly recovered the impaired IFN-γ production by NK cells from HCV-infected subjects. Blockade of KLRG1 also enhanced the impaired phosphorylation of Akt (Ser473) in NK cells from HCV-infected subjects. Taken together, these results indicate that KLRG1 negatively regulates NK cell numbers and functions via the Akt pathway, thus providing a novel marker and therapeutic target for HCV infection.
PMCID: PMC3807337  PMID: 23966413
20.  Tim-3 alters the balance of IL-12/IL-23 and drives TH17 cells: role in hepatitis B vaccine failure during hepatitis C infection 
Vaccine  2013;31(18):2238-2245.
Hepatitis B virus (HBV) vaccination is recommended for individuals with hepatitis C virus (HCV) infection given their shared risk factors and increased liver-related morbidity and mortality upon super-infection. Vaccine responses in this setting are often blunted, with poor response rates to HBV vaccinations in chronically HCV-infected individuals compared to healthy subjects. In this study, we investigated the role of T cell immunoglobulin mucin domain-3 (Tim-3)-mediated immune regulation in HBV vaccine responses during HCV infection. We found that Tim-3, a marker for T cell exhaustion, was over-expressed on monocytes, leading to a differential regulation of IL-12/IL-23 production with in turn TH17 cell accumulation, in HCV-infected HBV vaccine non-responders compared to HCV-infected HBV vaccine responders or healthy subjects (HS). Importantly, ex vivo blockade of Tim-3 signaling corrected the imbalance of IL-12/IL-23 as well as the IL-17 bias observed in HBV vaccine non-responders during HCV infection. These results suggest that Tim-3-mediated dysregulation of innate to adaptive immune responses is involved in HBV vaccine failure in individuals with chronic HCV infection, raising the possibility that blocking this negative signaling pathway might improve the success rate of HBV immunization in the setting of chronic viral infection.
PMCID: PMC3667544  PMID: 23499521
Tim-3; IL-12; IL-23; IL-17; hepatitis B vaccine; hepatitis C infection
21.  Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of cancer cell internalization in vivo 
Biomaterials  2013;34(12):2980-2990.
The cell membrane is a critical barrier to effective delivery for many therapeutics, including those which are nanoparticle-based. Improving nanoparticle transport across the cell membrane remains a fundamental challenge. Cancer cells preferentially internalized pegylated calcium phosphate nanoparticles over normal epithelial cells. Furthermore, non-cytotoxic levels of doxorubicin markedly amplified this difference by increasing free unbound caveolin-1 and resulted in enhanced caveolin-mediated nanoparticle endocytosis in cancer cells. Engineered pegylated siRNA-loaded triple-shell calcium phosphate nanoconstructs incorporating ultra-low levels of doxorubicin recapitulated these effects and delivered increased numbers of siRNA into cancer cells with target-specific results. Systemic administration of nanoparticles in vivo demonstrated highly preferential entry into tumors, little bystander organ biodistribution, and significant tumor growth arrest. In conclusion, siRNA-loaded calcium phosphate nanoparticles incorporating non-cytotoxic amounts of doxorubicin markedly enhances nanoparticle internalization and results in increased payload delivery with concomitant on-target effects.
PMCID: PMC3633203  PMID: 23369215
Nanoparticle; Calcium phosphate; In vivo delivery; Endocytosis; Cancer; siRNA
22.  Field comparison of circulating antibody assays versus circulating antigen assays for the detection of schistosomiasis japonica in endemic areas of China 
Parasites & Vectors  2014;7:138.
Schistosomiasis remains a serious public health problem in affected countries, and routine, highly sensitive and cost-effective diagnostic methods are lacking. We evaluated two immunodiagnostic techniques for the detection of Schistosoma japonicum infections: circulating antibody and circulating antigen assays.
A total of 1864 individuals (between 6 and 72 years old) residing in five administrative villages in Hubei province were screened by serum examination with an indirect hemagglutination assay (IHA). The positive individuals (titer ≥20 in IHA) were reconfirmed by stool examination with the Kato-Katz method (three slides from a single stool specimen). Samples of good serum quality and a volume above 0.5 ml were selected for further testing with two immunodiagnostic antibody (DDIA and ELISA) and two antigen (ELISA) assays.
The average antibody positive rate in the five villages was 12.7%, while the average parasitological prevalence was 1.50%; 25 of the 28 egg-positive samples were also circulating antigen-positive. Significant differences were observed between the prevalence according to the Kato-Katz method and all three immunodiagnostic antibody assays (P-value <0.0001). Similar differences were observed between the Kato-Katz method and the two immunodiagnostic antigen assays (P-value <0.0001) and between the antigen and antibody assays (P-value <0.0001).
Both circulating antibody and circulating antigen assays had acceptable performance characteristics. Immunodiagnostic techniques to detect circulating antigens have potential to be deployed for schistosomiasis japonica screening in the endemic areas.
PMCID: PMC3978087  PMID: 24684924
Schistosoma japonicum; Circulating antibody; Circulating antigen; China
23.  Association of glycogen synthase kinase-3β with Parkinson’s disease (Review) 
Molecular Medicine Reports  2014;9(6):2043-2050.
Glycogen synthase kinase-3 (GSK-3) is a pleiotropic serine/threonine protein kinase found in almost all eukaryotes. It is structurally highly conserved and has been identified as a multifaceted enzyme affecting a wide range of biological functions, including gene expression and cellular processes. There are two closely related isoforms of GSK-3; GSK-3α and GSK-3β. The latter appears to play crucial roles in regulating the pathogenesis of diverse diseases, including neurodegenerative disease. The present review focuses on the involvement of this protein in Parkinson’s disease (PD), a common neurodegenerative disorder characterized by the gradually progressive and selective loss of dopaminergic neurons, and by intracellular inclusions known as Lewy bodies (LBs) expressed in surviving neurons of the substantia nigra (SN). GSK-3β is involved in multiple signaling pathways and has several phosphorylation targets. Numerous apoptotic conditions can be facilitated by the GSK-3β signaling pathways. Studies have shown that GSK-3β inhibition protects the dopaminergic neurons from various stress-induced injuries, indicating the involvement of GSK-3β in PD pathogenesis. However, the underlying mechanisms of the protective effect of GSK-3β inhibition on dopaminergic neurons in PD is not completely understood. Multiple pathological events have been recognized to be responsible for the loss of dopaminergic neurons in PD, including mitochondrial dysfunction, oxidative stress, protein aggregation and neuroinflammation. The present review stresses the regulatory roles of GSK-3β in these events and in dopaminergic neuron degeneration, in an attempt to gain an improved understanding of the underlying mechanisms and to provide a potential effective therapeutic target for PD.
PMCID: PMC4055480  PMID: 24681994
Parkinson’s disease; glycogen synthase kinase-3β; regulation
24.  RNAi screening with shRNAs against histone methylation-related genes reveals determinants of sorafenib sensitivity in hepatocellular carcinoma cells 
Sorafenib is the first drug currently approved to treat advanced hepatocellular carcinoma (HCC). However, very low response rate and acquired drug resistance makes rare patients benefit from sorafenib therapy, therefore it is urgent to find biomarkers for sorafenib sensitivity. Histone modifications, including histone methylation, have been demonstrated to influence the initiation and progression of HCC. It is of great interest to elicit the possibility whether histone methylation plays a role in regulation of sorafenib sensitivity. In present work, a high throughput RNAi screening with 176 shRNA pools against 88 histone methyltransferases (HMTs) and histone demethyltransferases genes was applied to HepG2 cells. Silencing of 3 genes (ASH1L, C17ORF49 and SETD4) was validated to specifically promote HepG2 cells sensitivity to sorafenib. Western blotting results showed that those 3 HMT genes knockdown alone or sorafenib treatments alone both induce AKT/ERK activation. However, combination treatment with sorafenib and silencing of C17ORF49 or SETD4 downregulated AKT phosphorylation and hence induced HCC cells death. Our work may provide potential biomarkers for sorafenib sensitivity and therapeutic combination for sorafenib treatment in HCC patients.
PMCID: PMC3971312  PMID: 24696725
Hepatocellular carcinoma; sorafenib; histone methylation; ASH1L; C17ORF49; SETD4; AKT
25.  Enhanced Virus-Specific CD8+ T Cell Responses by Listeria monocytogenes-Infected Dendritic Cells in the Context of Tim-3 Blockade 
PLoS ONE  2014;9(1):e87821.
In this study, we engineered Listeria monocytogens (Lm) by deleting the LmΔactA/ΔinlB virulence determinants and inserting HCV-NS5B consensus antigens to develop a therapeutic vaccine against hepatitis C virus (HCV) infection. We tested this recombinant Lm-HCV vaccine in triggering of innate and adaptive immune responses in vitro using immune cells from HCV-infected and uninfected individuals. This live-attenuated Lm-HCV vaccine could naturally infect human dendritic cells (DC), thereby driving DC maturation and antigen presentation, producing Th1 cytokines, and triggering CTL responses in uninfected individuals. However, vaccine responses were diminished when using DC and T cells derived from chronically HCV-infected individuals, who express higher levels of inhibitory molecule Tim-3 on immune cells. Notably, blocking Tim-3 signaling significantly improved the innate and adaptive immune responses in chronically HCV-infected patients, indicating that novel strategies to enhance the potential of antigen presentation and cellular responses are essential for developing an effective therapeutic vaccine against HCV infection.
PMCID: PMC3909257  PMID: 24498204

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