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1.  Association between cytochrome P450 1A1 (CYP1A1) gene polymorphisms and the risk of renal cell carcinoma: a meta-analysis 
Scientific Reports  2015;5:8108.
Cytochrome P450 1A1 (CYP1A1) usually metabolizes carcinogens to their inactive derivatives but occasionally converts the chemicals to more potent carcinogens. To date, many studies have evaluated the association between the CYP1A1 MspI and Ile462Val polymorphisms and renal cell carcinoma (RCC) risk, but the results have been conflicting. To more precisely evaluate the potential association, we carried out a meta-analysis of seven published case-control studies. The meta-analysis indicated that the MspI polymorphism was associated with an increased RCC risk (allele model: OR = 1.49, 95%CI 1.03–2.16; homozygous model: OR = 1.64, 95%CI 1.13–2.40; dominant model: OR = 1.72, 95%CI 1.07–2.76). No significant associations were found for the Ile462Val polymorphism for all genetic models. When stratified by smoking status, smokers carrying the variant Vt and Val allele were more susceptible to RCC (Vt allele: OR = 3.37, 95%CI = 2.24–5.06; Val allele: OR = 2.07, 95%CI = 1.34–3.19). These data indicate that the CYP1A1 MspI polymorphism significantly increased RCC risk, while the Ile462Val polymorphism was not associated with RCC. Among smokers, individuals with the CYP1A1 Vt allele and Val allele showed a significantly increased risk of RCC. More well-designed studies with larger samples are warranted to show the underlying mechanisms of CYP1A1 in the development of RCC.
doi:10.1038/srep08108
PMCID: PMC4309971  PMID: 25630554
2.  Functional connectivity changes during a working memory task in rat via NMF analysis 
Working memory (WM) is necessary in higher cognition. The brain as a complex network is formed by interconnections among neurons. Connectivity results in neural dynamics to support cognition. The first aim is to investigate connectivity dynamics in medial prefrontal cortex (mPFC) networks during WM. As brain neural activity is sparse, the second aim is to find the intrinsic connectivity property in a feature space. Using multi-channel electrode recording techniques, spikes were simultaneously obtained from mPFC of rats that performed a Y-maze WM task. Continuous time series converted from spikes were embedded in a low-dimensional space by non-negative matrix factorization (NMF). mPFC network in original space was constructed by measuring connections among neurons. And the same network in NMF space was constructed by computing connectivity values between the extracted NMF components. Causal density (Cd) and global efficiency (E) were estimated to present the network property. The results showed that Cd and E significantly peaked in the interval right before the maze choice point in correct trials. However, the increase did not emerge in error trials. Additionally, Cd and E in two spaces displayed similar trends in correct trials. The difference was that the measures in NMF space were significantly greater than those in original space. Our findings indicated that the anticipatory changes in mPFC networks may have an effect on future WM behavioral choices. Moreover, the NMF analysis achieves a better characterization for a brain network.
doi:10.3389/fnbeh.2015.00002
PMCID: PMC4311635
working memory (WM); spikes; functional connectivity; dimensionality reduction; non-negative matrix factorization (NMF)
3.  Cardiovascular assessment of fetal mice by in utero echocardiography 
Ultrasound in medicine & biology  2008;34(5):741-752.
To establish a developmental profile of fetal mouse cardiovascular parameters, we analyzed a large body of ultrasound measurements obtained by in utero echocardiography of C57BL/6J fetal mice from embryonic day 12.5 to 19.5 (term). Measurements were obtained using 2D, spectral Doppler and M-mode imaging with standard clinical cardiac ultrasound imaging planes. As these studies were conducted as part of a large scale mouse mutagenesis screen, stringent filtering criteria were used to eliminate potentially abnormal fetuses. Our analysis showed heart rate increased from 190 to 245 bpm as the mouse fetus grew from 8 mm at embryonic day 12.5 to 18.7 mm at term. This was accompanied by increases in peak outflow velocity, E-wave, E/A ratio and ventricular dimensions. In contrast, the A-wave, myocardial performance index and isovolemic contraction time decreased gradually. Systolic function remained remarkably stable at 80% ejection fraction. Analysis of intra and interobserver variabilities showed these parameters were reproducible, with most comparing favorably to clinical ultrasound measurements in human fetuses. A comprehensive database was generated comprising 23 echocardiographic parameters delineating fetal mouse cardiovascular function from embryonic day 12.5 to term. This database can serve as a standard for evaluating cardiovascular pathophysiology in genetically altered and mutant mouse models.
doi:10.1016/j.ultrasmedbio.2007.11.001
PMCID: PMC4275222  PMID: 18328616
Fetal ultrasound; Image comparison; Mouse fetus; Development; Cardiovascular system
4.  P2X7 Mediates ATP-Driven Invasiveness in Prostate Cancer Cells 
PLoS ONE  2014;9(12):e114371.
The ATP-gated P2X7 has been shown to play an important role in invasiveness and metastasis of some tumors. However, the possible links and underlying mechanisms between P2X7 and prostate cancer have not been elucidated. Here, we demonstrated that P2X7 was highly expressed in some prostate cancer cells. Down-regulation of P2X7 by siRNA significantly attenuated ATP- or BzATP-driven migration and invasion of prostate cancer cells in vitro, and inhibited tumor invasiveness and metastases in nude mice. In addition, silencing of P2X7 remarkably attenuated ATP- or BzATP- driven expression changes of EMT/invasion-related genes Snail, E-cadherin, Claudin-1, IL-8 and MMP-3, and weakened the phosphorylation of PI3K/AKT and ERK1/2 in vitro. Similar effects were observed in nude mice. These data indicate that P2X7 stimulates cell invasion and metastasis in prostate cancer cells via some EMT/invasion-related genes, as well as PI3K/AKT and ERK1/2 signaling pathways. P2X7 could be a promising therapeutic target for prostate cancer.
doi:10.1371/journal.pone.0114371
PMCID: PMC4259308  PMID: 25486274
5.  Pim-1 kinase is a target of miR-486-5p and eukaryotic translation initiation factor 4E, and plays a critical role in lung cancer 
Molecular Cancer  2014;13(1):240.
Background
Pim-1 kinase is a proto-oncogene and its dysregulation contributes to tumorigenesis and progression of a variety of malignancies. Pim-1 was suggested as a therapeutic target of cancers. The functional relevance of Pim-1 and the mechanism underlying its dysregulation in lung tumorigenesis remained unclear. This study aimed to investigate if Pim-1 has important functions in non-small-cell lung cancer (NSCLC) by: 1) evaluating the clinicopathologic significance of Pim-1 through analysing its expression in 101 human NSCLCs tissues using quantitative PCR, Western Blot and immunohistochemical studies, 2) determining its role in NSCLC and drug resistance using in vitro assays, and 3) investigating the regulatory mechanism of Pim-1 dysregulation in lung tumorigenesis.
Results
Pim-1 was upregulated in 66.2% of the lung tumor tissues and its expression was significantly related to advanced stage (P = 0.019) and lymph node metastasis (P = 0.026). Reduced Pim-1 expression suppressed NSCLC cell growth, cell cycle progression and migration in vitro. Pim-1 was a novel target of miR-486-5p determined by luciferase report assay, and ectopic miR-486-5p expression in cancer cells reduced Pim-1 expression. Furthermore, eukaryotic translation initiation factor 4E (eIF4E) controlled the synthesis of Pim-1 in NSCLC cells, and its expression was positively associated with that of Pim-1 in NSCLC tissue specimens (r = 0.504, p < 0.001). The downregulated miR-486-5p and upregulated eIF4E in NSCLC cells led to the overexpression of Pim-1 by relieving the inhibitory effect of the 3′-UTR or 5′-UTR of Pim-1 mRNA, respectively. Moreover, Pim-1 knockdown sensitized NSCLC cells to cisplatin and EGFR tyrosine kinase inhibitor, gefitinib.
Conclusions
Pim-1 kinase could be a critical survival signaling factor in NSCLC, and regulated by miR-486-5p and eIF4E. Pim-1 kinase may provide a potential target for diagnosis and treatment for lung cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-4598-13-240) contains supplementary material, which is available to authorized users.
doi:10.1186/1476-4598-13-240
PMCID: PMC4213487  PMID: 25342548
6.  The Effects of Temperature and Anesthetic Agents on Ciliary Function in Murine Respiratory Epithelia 
Background: Mucus transport mediated by motile cilia in the airway is an important defense mechanism for prevention of respiratory infections. As cilia motility can be depressed by hypothermia or exposure to anesthetics, in this study, we investigated the individual and combined effects of dexmedetomidine (dex), fentanyl (fen), and/or isoflurane (iso) at physiologic and low temperatures on cilia motility in mouse tracheal airway epithelia. These anesthetic combinations and low temperature conditions are often used in the setting of cardiopulmonary bypass surgery, surgical repair of congenital heart disease, and cardiac intensive care.
Methods: C57BL/6J mouse tracheal epithelia were excised and cilia dynamics were captured by videomicroscopy following incubation at 15, 22–24, and 37°C with different combinations of therapeutic concentrations of dex (10 nM), fen (10 nM), and iso (0.01%). Airway ciliary motion was assessed and compared across conditions by measuring ciliary beat frequency and ciliary flow velocity. Statistical analysis was carried out using unpaired t-tests, analysis of variance, and multivariate linear regression.
Results: There was a linear correlation between cilia motility and temperature. Fen exerted cilia stimulatory effects, while dex and iso each had ciliodepressive effects. When added together, fen + iso, dex + iso, and dex + fen + iso were all cilia inhibitory. In contrast fenl + dex did not significantly alter ciliary function.
Conclusion: We show that ciliary motility is stimulated by fen, but depressed by dex or iso. However, when used in combination, ciliary motility showed changes indicative of complex drug–drug and drug–temperature interactions not predicted by simple summation of their individual effects. Similar studies are needed to examine the human airway epithelia and its response to anesthetics.
doi:10.3389/fped.2014.00111
PMCID: PMC4199259  PMID: 25360434
ciliary beat frequency; dexmedetomidine; fentanyl; isoflurane; hypothermia
7.  Rapid donor T-cell engraftment increases the risk of chronic graft-versus-host disease following salvage allogeneic peripheral blood hematopoietic cell transplantation for bone marrow failure syndromes 
American journal of hematology  2013;88(10):874-882.
The risk of graft-rejection after allogeneic hematopoietic cell transplantation using conventional cyclophosphamide-based conditioning is increased in patients with bone marrow failure syndromes (BMFS) who are heavily transfused and often HLA-alloimmunized. Fifty-six patients with BMFS underwent fludarabine-based reduced-intensity conditioning and allogeneic peripheral blood progenitor cell (PBPC) transplantation at a single institution. The conditioning regimen consisted of intravenous cyclophosphamide, fludarabine, and equine antithymocyte globulin. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine A alone or in combination with either mycophenolate mofetil or methotrexate. To reduce the risk of graft-rejection/failure, unmanipulated G-CSF mobilized PBPCs obtained from an HLA-identical or single HLA-antigen mismatched relative were transplanted rather than donor bone marrow. Despite a high prevalence of pretransplant HLA-alloimmunization (41%) and a heavy prior transfusion burden, graft-failure did not occur with all patients having sustained donor lympho-hematopoietic engraftment. The cumulative incidence of grade II–IV acute-GVHD and chronic-GVHD was 51.8% and 72%, respectively; with 87.1% surviving at a median follow-up of 4.5 years. A multivariate analysis showed pretransplant alloimmunization and rapid donor T-cell engraftment (≥95% donor by day 30) were both significantly (P < 0.05) associated with the development of chronic-GVHD (adjusted HR 2.13 and 2.99, respectively). These data show fludarabine-based PBPC transplantation overcomes the risk of graft-failure in patients with BMFS, although rapid donor T-cell engraftment associated with this approach appears to increase the risk of chronic-GVHD.
doi:10.1002/ajh.23526
PMCID: PMC4171745  PMID: 23813900
8.  Docosahexaenoic acid has an anti-diabetic effect in streptozotocin-induced diabetic mice 
Consumption of fish oil-rich foods containing docosahexaenoic acid (DHA) can result in a low incidence of diabetes. The underlying mechanisms of these anti-hyperglycemic effects are ambiguous. This study aims to investigate the role of DHA in the prevention and treatment of type 1 diabetes in a murine model. Forty streptozotocin-induced diabetic mice were divided into control with diabetes, diabetes prevention (500 μg/kg DHA orally for 5 days) or diabetes treatment groups (DHA solvent in DMSO into the colon for 5 days). The groups were observed for 25 days after administration of DHA. Mice in the prevention and treatment group had shinier fur, increased body weight, significantly lower food and water intake and were more active compared with the control group with diabetes. Elevated insulin and liver SOD and T-AOC levels were also observed. Furthermore, islet cell apoptosis was reduced and islet cell GLP-1R expression increased.
PMCID: PMC4211827  PMID: 25356177
Docosahexaenoic acid (DHA); diabetes; glucagon-like peptide-1 receptor
9.  Childhood Renal Tumor: A Report from a Chinese Children's Cancer Group 
BioMed Research International  2014;2014:894341.
Here we investigated the establishment of multicenter cooperative treatment groups in China, as well as radiotherapy compliance and effectiveness among children with renal tumors. Medical records were reviewed for 316 children with renal tumors diagnosed by a multicenter cooperative group from 14 hospitals in China from 1998 to 2012. Median patient age was 29.5 months (range, 2–173 months old), and male-to-female ratio was 1.4 : 1. After a median follow-up of 22 months (range, 1–177 months), five-year event-free survival rates were 72% overall; 76.1% for favorable histology (251 cases); 59% for unfavorable histology (27 cases); and 91%, 75%, 71%, 53%, and 48.5%, respectively for Stages I, II, III, IV, and V. Following standardized criteria, radiation therapy was indicated for 153 patients, among whom five-year event-free survival was 72.8% for the 95 who received radiation and 24% for the 58 patients who did not. Our results are reasonable but can be further improved and show the feasibility of a multicenter cooperative group model for childhood renal tumor treatment in China. Radiation therapy is important for stage III and IV patients but remains difficult to implement in some parts of China. Government management departments and medical professionals must pay attention to this situation. This clinical trial is registered with ChiCTR-PRCH-14004372.
doi:10.1155/2014/894341
PMCID: PMC4131417  PMID: 25147822
10.  Gene profiling analysis for patients with oral verrucous carcinoma and oral squamous cell carcinoma 
Oral verrucous carcinoma (OVC) is one malignant tumor which was carved out from the oral squamous cell carcinoma (OSCC). However, the clinical and pathological features as well as the treatment strategies of OVC are different from OSCC. Here, global transcript abundance of tumor tissues from five patients with primary OVC and six patients with primary OSCC including their matched adjacently normal oral mucosa were profiled using the Affymetrix HGU133 Plus 2.0. Ingenuity Systems IPA software was used to analyse the gene function and biological pathways. There were 109 differentially expressed genes (more than 2-fold) between OVC and the adjacently normal tissue, among them 66 were up-regulated and 43 were down-regulated; 1172 differentially expressed genes (more than 2-fold) between OSCC and the adjacently normal tissue, among them 608 were up-regulated and 564 were down-regulated. There were 39 common differentially expressed genes in OVC and OSCC compared with their matched normal oral mucosa, among them 22 up-regulated and 17 down-regulated, and 8 of them different between OVC and OSCC. In addition, the gene expression profile was further validated by quantitative real-time PCR (Q-RT-PCR) analysis for four of those 39 selected genes.
PMCID: PMC4132153  PMID: 25126189
Oral verrucous carcinoma; oral squamous cell carcinoma; biological pathways; expression profile; quantitative real-time PCR
11.  Evaluation of the effects of comprehensive reform on primary healthcare institutions in Anhui Province 
Background
In 2009, the Chinese Central Communist Party and the China State Council started to implement comprehensive healthcare reforms. The first round of reforms, involving Anhui province, was from 2009 to 2011, and focused on primary healthcare institutions. This study conducts an initial assessment of the effects of specific parts of the reforms in Anhui.
Methods
Mixed quantitative and qualitative methods were adopted for data collection. Seven hundred and three health institutions from 15 counties were randomly chosen. The practices, development, effects, problems, and other relevant information related to the reform were classified into four aspects: medicine management; personnel systems and income distribution mechanisms; compensation mechanisms for primary healthcare institutions; and strengthening the primary healthcare system. The effects of reform were analyzed by evaluating changes in compensation channels, visit costs, diagnosis and treatment structure, hardware, structures, efficiency, and behavior.
Results
A new system for authorizing drugs resulted in a total of 857 new drugs being accessible at agreed prices through primary healthcare institutions in Anhui. The cost of the average outpatient visit decreased from 35.29 RMB to 31.64 RMB, although for inpatients, the average cost increased from 799.05 RMB to 992.60 RMB. The number of healthcare personnel decreased, but their workloads increased. The total revenue from government sources increased by 41.09%, and the proportion of revenue from drugs decreased by 25.19%. The rate of diagnosis and treatment visits and outpatient visits to primary healthcare institutions increased. Finally, between 2008 and 2010, 1,195 standardized township hospitals, 14,134 village clinics, and 1,234 community health service institutions were constructed.
Conclusion
The reform of primary healthcare institutions in Anhui has improved the personnel structures surrounding frontline healthcare workers, increased their incomes, improved work efficiency, and changed the compensation patterns of primary healthcare institutions, improved hardware, reduced drug prices, and, to some extent, improved the diagnosis and treatment structure. However, the reforms have not radically changed the behavior of medical workers or the visit patterns of patients. Approaches such as strengthening performance evaluation, and carrying out initiatives to further mobilize frontline healthcare workers, enhance rational drug use through improved training and educate patients, should be undertaken in the future.
doi:10.1186/1472-6963-14-268
PMCID: PMC4105389  PMID: 24942901
Health reform; Primary healthcare institutions; Anhui province
12.  Current approaches to enhance CNS delivery of drugs across the brain barriers 
Although many agents have therapeutic potentials for central nervous system (CNS) diseases, few of these agents have been clinically used because of the brain barriers. As the protective barrier of the CNS, the blood–brain barrier and the blood–cerebrospinal fluid barrier maintain the brain microenvironment, neuronal activity, and proper functioning of the CNS. Different strategies for efficient CNS delivery have been studied. This article reviews the current approaches to open or facilitate penetration across these barriers for enhanced drug delivery to the CNS. These approaches are summarized into three broad categories: noninvasive, invasive, and miscellaneous techniques. The progresses made using these approaches are reviewed, and the associated mechanisms and problems are discussed.
doi:10.2147/IJN.S61288
PMCID: PMC4026551  PMID: 24872687
drug delivery system; blood–brain barrier (BBB); central nervous system; brain-targeted therapy; cerebrospinal fluid (CSF)
13.  Chinese SLE Treatment and Research Group Registry: III. Association of Autoantibodies with Clinical Manifestations in Chinese Patients with Systemic Lupus Erythematosus 
Journal of Immunology Research  2014;2014:809389.
We investigated the characteristics of Chinese SLE patients by analyzing the association between specific autoantibodies and clinical manifestations of 2104 SLE patients from registry data of CSTAR cohort. Significant (P < 0.05) associations were found between anti-Sm antibody, anti-rRNP antibody, and malar rash; between anti-RNP antibody, anti-SSA antibody, and pulmonary arterial hypertension (PAH); between anti-SSB antibody and hematologic involvement; and between anti-dsDNA antibody and nephropathy. APL antibody was associated with hematologic involvement, interstitial lung disease, and a lower prevalence of oral ulcerations (P < 0.05). Associations were also found between anti-dsDNA antibody and a lower prevalence of photosensitivity, and between anti-SSA antibody and a lower prevalence of nephropathy (P < 0.05). Most of these findings were consistent with other studies in the literature but this study is the first report on the association between anti-SSA and a lower prevalence of nephropathy. The correlations of specific autoantibodies and clinical manifestations could provide clues for physicians to predict organ damages in SLE patients. We suggest that a thorough screening of autoantibodies should be carried out when the diagnosis of SLE is established, and repeated echocardiography annually in SLE patients with anti-RNP or anti-SSA antibody should be performed.
doi:10.1155/2014/809389
PMCID: PMC4017718  PMID: 24864270
14.  Hemodynamic Predictors of Mortality in Adults with Sickle Cell Disease 
Background: Pulmonary hypertension (PH) in adults with sickle cell disease (SCD) is associated with early mortality, but no prior studies have evaluated quantitative relationships of mortality to physiological measures of pre- and postcapillary PH.
Objectives: To identify risk factors associated with mortality and to estimate the expected survival in a cohort of patients with SCD with PH documented by right heart catheterization.
Methods: Nine-year follow-up data (median, 4.7 yr) from the National Institutes of Health SCD PH screening study are reported. A total of 529 adults with SCD were screened by echocardiography between 2001 and 2010 with no exclusion criteria. Hemodynamic data were collected from 84 patients. PH was defined as mean pulmonary artery pressure (PAP) ≥ 25 mm Hg. Survival rates were estimated by the Kaplan-Meier method, and mortality risk factors were analyzed by the Cox proportional hazards regression.
Measurements and Main Results: Specific hemodynamic variables were independently related to mortality: mean PAP (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.05–2.45 per 10 mm Hg increase; P = 0.027), diastolic PAP (HR, 1.83; 95% CI, 1.09–3.08 per 10 mm Hg increase; P = 0.022), diastolic PAP − pulmonary capillary wedge pressure (HR, 2.19; 95% CI, 1.23–3.89 per 10 mm Hg increase; P = 0.008), transpulmonary gradient (HR, 1.78; 95% CI, 1.14–2.79 per 10 mm Hg increase; P = 0.011), and pulmonary vascular resistance (HR, 1.44; 95% CI, 1.09–1.89 per Wood unit increase; P = 0.009) as risk factors for mortality.
Conclusions: Mortality in adults with SCD and PH is proportional to the physiological severity of precapillary PH, demonstrating its prognostic and clinical relevance despite anemia-induced high cardiac output and less severely elevated pulmonary vascular resistance.
doi:10.1164/rccm.201207-1222OC
PMCID: PMC3707372  PMID: 23348978
sickle cell; pulmonary hypertension; mortality; autopsy
15.  Biomass Allocation Patterns across China’s Terrestrial Biomes 
PLoS ONE  2014;9(4):e93566.
Root to shoot ratio (RS) is commonly used to describe the biomass allocation between below- and aboveground parts of plants. Determining the key factors influencing RS and interpreting the relationship between RS and environmental factors is important for biological and ecological research. In this study, we compiled 2088 pairs of root and shoot biomass data across China’s terrestrial biomes to examine variations in the RS and its responses to biotic and abiotic factors including vegetation type, soil texture, climatic variables, and stand age. The median value of RS (RSm) for grasslands, shrublands, and forests was 6.0, 0.73, and 0.23, respectively. The range of RS was considerably wide for each vegetation type. RS values for all three major vegetation types were found to be significantly correlated to mean annual precipitation (MAP) and potential water deficit index (PWDI). Mean annual temperature (MAT) also significantly affect the RS for forests and grasslands. Soil texture and forest origin altered the response of RS to climatic factors as well. An allometric formula could be used to well quantify the relationship between aboveground and belowground biomass, although each vegetation type had its own inherent allometric relationship.
doi:10.1371/journal.pone.0093566
PMCID: PMC3977935  PMID: 24710503
16.  Functional Connectivity among Spikes in Low Dimensional Space during Working Memory Task in Rat 
PLoS ONE  2014;9(3):e91481.
Working memory (WM) is critically important in cognitive tasks. The functional connectivity has been a powerful tool for understanding the mechanism underlying the information processing during WM tasks. The aim of this study is to investigate how to effectively characterize the dynamic variations of the functional connectivity in low dimensional space among the principal components (PCs) which were extracted from the instantaneous firing rate series. Spikes were obtained from medial prefrontal cortex (mPFC) of rats with implanted microelectrode array and then transformed into continuous series via instantaneous firing rate method. Granger causality method is proposed to study the functional connectivity. Then three scalar metrics were applied to identify the changes of the reduced dimensionality functional network during working memory tasks: functional connectivity (GC), global efficiency (E) and casual density (CD). As a comparison, GC, E and CD were also calculated to describe the functional connectivity in the original space. The results showed that these network characteristics dynamically changed during the correct WM tasks. The measure values increased to maximum, and then decreased both in the original and in the reduced dimensionality. Besides, the feature values of the reduced dimensionality were significantly higher during the WM tasks than they were in the original space. These findings suggested that functional connectivity among the spikes varied dynamically during the WM tasks and could be described effectively in the low dimensional space.
doi:10.1371/journal.pone.0091481
PMCID: PMC3962371  PMID: 24658291
17.  Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease 
Nature genetics  2013;45(9):1004-1012.
Kidney cysts occur following inactivation of polycystins in otherwise intact cilia or following complete removal of cilia by inactivation of intraflagellar transport-related proteins. We investigated the mechanisms of cyst formation in these two distinct processes by combining conditional inactivation of polycystins with concomitant ablation of cilia in developing and adult kidney and liver. We found that loss of intact cilia suppresses cyst growth following inactivation of polycystins and that the severity of cystic disease was directly related to the length of time between the initial loss of the polycystin proteins and the subsequent involution of cilia. This cilia-dependent cyst growth was not explained by activation of the MAPK/ERK, mTOR or cAMP pathways and is likely to be distinct from the mechanism of cyst growth following complete loss of cilia. The data establish the existence of a novel pathway defined by polycystin-dependent inhibition and cilia-dependent activation that promotes rapid cyst growth.
doi:10.1038/ng.2715
PMCID: PMC3758452  PMID: 23892607
18.  Contribution of Baicalin on the Plasma Protein Binding Displacement and CYP3A Activity Inhibition to the Pharmacokinetic Changes of Nifedipine in Rats In Vivo and In Vitro 
PLoS ONE  2014;9(1):e87234.
Baicalin purified from the root of Radix scutellariae is widely used in clinical practices. This study aimed to evaluate the effect of baicalin on the pharmacokinetics of nifedipine, a CYP3A probe substrate, in rats in vivo and in vitro. In a randomised, three-period crossover study, significant changes in the pharmacokinetics of nifedipine (2 mg/kg) were observed after treatment with a low (0.225 g/kg) or high (0.45 g/kg) dose of baicalin in rats. In the low- and high-dose groups of baicalin-treated rats, Cmax of total nifedipine decreased by 40%±14% (P<0.01) and 65%±14% (P<0.01), AUC0–∞ decreased by 41%±8% (P<0.01) and 63%±7% (P<0.01), Vd increased by 85%±43% (P<0.01) and 224%±231% (P<0.01), and CL increased by 97%±78% (P<0.01) and 242%±135% (P<0.01), respectively. Plasma protein binding experiments in vivo showed that Cmax of unbound nifedipine significantly increased by 25%±19% (P<0.01) and 44%±29% (P<0.01), respectively, and there was a good correlation between the unbound nifedipine (%) and baicalin concentrations (P<0.01). Furthermore, in vitro results revealed that baicalin was a competitive displacer of nifedipine from plasma proteins. In vitro incubation experiments demonstrated that baicalin could also competitively inhibit CYP3A activity in rat liver microsomes in a concentration-dependent manner. In conclusion, the pharmacokinetic changes of nifedipine may be modulated by the inhibitory effects of baicalin on plasma protein binding and CYP3A–mediated metabolism.
doi:10.1371/journal.pone.0087234
PMCID: PMC3907542  PMID: 24498050
19.  How can nanotechnology help membrane vesicle-based cancer immunotherapy development? 
Exosomes are nanosized vesicles originating from endosomal compartments and secreted by most living cells. In the past decade, exosomes have emerged as potent tools for cancer immunotherapy due to their important roles in modulation of immune responses, and promising results have been achieved in exosome-based immunotherapy. The recent rapid progress of nanotechnology, especially on tailored design of nanocarriers for drug delivery based on both passive and active targeting strategies, sheds light on re-engineering native membrane vesicles for enhanced immune regulation and therapy. Applications of nanotechnology toolkits might provide new opportunity not only for value-added therapeutic or diagnostic strategies based on exosomes in cancer immunotherapy, but also new insights for biogenesis and biological relevance of membrane vesicles. This commentary focuses on the recent development and limitations of using exosomes in cancer immunotherapy and our perspectives on how nanomaterials with potential immune regulatory effects could be introduced into exosome-based immunotherapy.
doi:10.4161/hv.22130
PMCID: PMC3667943  PMID: 23108359
immunotherapy; exosome; nanotechnology; dendritic cell; cancer vaccine
20.  Incoordination between spikes and LFPs in Aβ1−42-mediated memory deficits in rats 
Alzheimer's disease (AD) is a neurodegenerative disease that gradually induces cognitive deficits. Impairments of working memory have been typically observed in AD. It is well known that spikes and local field potentials (LFPs) as well as the coordination between them encode information in normal brain function. However, the abnormal coordination between spikes and LFPs in the cognitive deficits of AD has remained largely unexplored. As amyloid-β peptide (Aβ) is a causative factor for the cognitive impairments of AD, developing a mechanistic understanding of the contribution of Aβ to cognitive impairments may yield important insights into the pathophysiology of AD. In the present study, we simultaneously recorded spikes and LFPs from multiple electrodes implanted in the prefrontal cortex of rats (control and intra-hippocampal Aβ injection group) that performed a Y-maze working memory task. The information changes in spikes and LFPs during the task were assessed by calculation of entropy. Then the coordination between spikes and LFPs was estimated by the correlation of LFP entropy and spike entropy. Compared with the control group, the Aβ group showed significantly weaker coordination between spikes and LFPs. Our results indicate that the incoordination between spikes and LFPs may provide a potential mechanism for the cognitive deficits in working memory of AD.
doi:10.3389/fnbeh.2014.00411
PMCID: PMC4245911  PMID: 25505877
Alzheimer's disease (AD); working memory; spike-LFP coordination; entropy correlation; rat
21.  Inhibition of Propofol Anesthesia on Functional Connectivity between LFPs in PFC during Rat Working Memory Task 
PLoS ONE  2013;8(12):e83653.
Working memory (WM) refers to the temporary storage and manipulation of information necessary for performance of complex cognitive tasks. There is a growing interest in whether and how propofol anesthesia inhibits WM function. The aim of this study is to investigate the possible inhibition mechanism of propofol anesthesia based on the functional connections of multi-local field potentials (LFPs) and behavior during WM tasks. Adult SD rats were randomly divided into 3 groups: pro group (0.5 mg·kg−1·min−1,2 h), PRO group (0.9 mg·kg−1·min−1, 2 h) and control group. The experimental data were 16-channel LFPs obtained at prefrontal cortex with implanted microelectrode array in SD rats during WM tasks in Y-maze at 24, 48, 72, 96, 120 hours (day 1-day 5) after propofol anesthesia, and the behavior results of WM were recoded at the same time. Directed transfer function (DTF) method was applied to analyze the connections among LFPs directly. Furthermore, the causal networks were identified by DTF. The clustering coefficient (C), network density (D) and global efficiency (Eglobal) were selected to describe the functional connectivity quantitatively. The results show that: comparing with the control group, the LFPs functional connectivity in pro group were no significantly difference (p>0.05); the connectivity in PRO group were significantly decreased (p<0.05 at 24 hours, p<0.05 at 48 hours), while no significant difference at 72, 96 and 120 hours for rats (p>0.05), which were consistent with the behavior results. These findings could lead to improved understanding the mechanism of inhibition of anesthesia on WM functions from the view of connections among LFPs.
doi:10.1371/journal.pone.0083653
PMCID: PMC3873953  PMID: 24386243
22.  Association Study of Germline Variants in CCNB1 and CDK1 with Breast Cancer Susceptibility, Progression, and Survival among Chinese Han Women 
PLoS ONE  2013;8(12):e84489.
The CCNB1 and CDK1 genes encode the proteins of CyclinB1 and CDK1 respectively, which interact with each other and are involved in cell cycle regulation, centrosome duplication and chromosome segregation. This study aimed to investigate whether the genetic variants in these two genes may affect breast cancer (BC) susceptibility, progression, and survival in Chinese Han population using haplotype-based analysis. A total of ten tSNPs spanning from 2kb upstream to 2kb downstream of these genes were genotyped in 1204 cases and 1204 age-matched cancer-free controls. The haplotype blocks were determined according to our genotyping data and linkage disequilibrium (LD) status of these SNPs. For CCNB1, rs2069429 was significantly associated with increased BC susceptibility under recessive model (OR=2.352, 95%CI=1.480-3.737), so was the diplotype TAGT/TAGT (OR=1.947 95%CI=1.154-3.284, P=0.013). In addition, rs164390 was associated with Her2-negative BC. For CDK1, rs2448343 and rs1871446 were significantly associated with decreased BC risk under dominant models, so was the haplotype ATATT. These two SNPs also showed a dose-dependent effect on BC susceptibility. Using stratified association analysis, we found that women with the heterozygotes or minor allele homozygotes of rs2448343 had much less BC susceptibility among women with BMI<23. In CDK1, three closely located SNPs, rs2448343, rs3213048 and rs3213067, were significantly associated with tumor’s PR status: the heterozygotes of rs2448343 were associated with PR-positive tumors, while the minor allele homozygotes of rs3213048 and heterozygotes of rs3213067 were associated with PR-negative BC tumors. In survival analysis, rs1871446 was associated with unfavorable event-free survival under recessive model, so was the CDK1 diplotype ATATG/ATATG, which carried the minor allele homozygote of rs1871446. Our study indicates that genetic polymorphisms of CCNB1 and CDK1 are related to BC susceptibility, progression, and survival in Chinese Han women. Further studies need to be performed in other populations as an independent replication to verify these results.
doi:10.1371/journal.pone.0084489
PMCID: PMC3873991  PMID: 24386390
23.  Scanning pattern of diffusion tensor tractography and an analysis of the morphology and function of spinal nerve roots 
Neural Regeneration Research  2013;8(33):3159-3166.
Radiculopathy, commonly induced by intervertebral disk bulging or protrusion, is presently diagnosed in accordance with clinical symptoms because there is no objective quantitative diagnostic criterion. Diffusion tensor magnetic resonance imaging and diffusion tensor tractography revealed the characterization of anisotropic diffusion and displayed the anatomic form of nerve root fibers. This study included 18 cases with intervertebral disc degeneration-induced unilateral radiculopathy. Magnetic resonance diffusion tensor imaging was creatively used to reveal the scanning pattern of fiber tracking of the spinal nerve root. A scoring system of nerve root morphology was used to quantitatively assess nerve root morphology and functional alteration after intervertebral disc degeneration. Results showed that after fiber tracking, compared with unaffected nerve root, fiber bundles gathered together and interrupted at the affected side. No significant alteration was detected in the number of fiber bundles, but the cross-sectional area of nerve root fibers was reduced. These results suggest that diffusion tensor magnetic resonance imaging-based tractography can be used to quantitatively evaluate nerve root function according to the area and morphology of fiber bundles of nerve roots.
doi:10.3969/j.issn.1673-5374.2013.33.010
PMCID: PMC4158705  PMID: 25206637
neural regeneration; spinal cord injury; magnetic resonance; diffusion imaging; tracking; nerve injury; nerve root; degenerative disease; grants-supported paper; neuroregeneration
24.  Gastrointestinal complications of systemic sclerosis 
Systemic sclerosis is an autoimmune disease characterized by progressive skin thickening and tightness. Pulmonary interstitial fibrosis and kidney damage are the most important indicators for mortality; however, the gastrointestinal tract is the most commonly damaged system. Virtually all parts of the gastrointestinal (GI) tract can be involved, although the esophagus is the most frequently reported. The mechanisms that cause such extensive damage are generally unclear, but vascular changes, immunological abnormalities, excessive accumulation of collagen in the submucosa, smooth muscle atrophy and neuropathy may participate because these are the most common histological findings in biopsies and autopsies. Most patients with GI tract involvement complain about dyspepsia, nausea, vomiting, abdominal bloating/distension, and fecal incontinence. These symptoms are generally mild during the early stage of the disease and are likely ignored by physicians. As the disease becomes more advanced, however, patient quality of life is markedly influenced, whereby malnutrition and shortened survival are the usual consequences. The diagnosis for systemic sclerosis is based on manometry measurements and an endoscopy examination. Supportive and symptomatic treatment is the main therapeutic strategy; however, an early diagnosis is critical for successful management.
doi:10.3748/wjg.v19.i41.7062
PMCID: PMC3819541  PMID: 24222949
Systemic sclerosis; Gastrointestinal tract; Manometry; Endoscopy; Diagnosis; Treatment
25.  Correction: Evaluation of a Novel Thermosensitive Heparin-Poloxamer Hydrogel for Improving Vascular Anastomosis Quality and Safety in a Rabbit Model 
PLoS ONE  2013;8(10):10.1371/annotation/9ba3d2e7-10c6-4e5c-96a8-ac331b4c2a83.
doi:10.1371/annotation/9ba3d2e7-10c6-4e5c-96a8-ac331b4c2a83
PMCID: PMC3795082

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