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1.  A Novel Minimal Invasive Mouse Model of Extracorporeal Circulation 
Mediators of Inflammation  2015;2015:412319.
Extracorporeal circulation (ECC) is necessary for conventional cardiac surgery and life support, but it often triggers systemic inflammation that can significantly damage tissue. Studies of ECC have been limited to large animals because of the complexity of the surgical procedures involved, which has hampered detailed understanding of ECC-induced injury. Here we describe a minimally invasive mouse model of ECC that may allow more extensive mechanistic studies. The right carotid artery and external jugular vein of anesthetized adult male C57BL/6 mice were cannulated to allow blood flow through a 1/32-inch external tube. All animals (n = 20) survived 30 min ECC and subsequent 60 min observation. Blood analysis after ECC showed significant increases in levels of tumor necrosis factor α, interleukin-6, and neutrophil elastase in plasma, lung, and renal tissues, as well as increases in plasma creatinine and cystatin C and decreases in the oxygenation index. Histopathology showed that ECC induced the expected lung inflammation, which included alveolar congestion, hemorrhage, neutrophil infiltration, and alveolar wall thickening; in renal tissue, ECC induced intracytoplasmic vacuolization, acute tubular necrosis, and epithelial swelling. Our results suggest that this novel, minimally invasive mouse model can recapitulate many of the clinical features of ECC-induced systemic inflammatory response and organ injury.
doi:10.1155/2015/412319
PMCID: PMC4325217
2.  Morphology, Carbohydrate Composition and Vernalization Response in a Genetically Diverse Collection of Asian and European Turnips (Brassica rapa subsp. rapa) 
PLoS ONE  2014;9(12):e114241.
Brassica rapa displays enormous morphological diversity, with leafy vegetables, turnips and oil crops. Turnips (Brassica rapa subsp. rapa) represent one of the morphotypes, which form tubers and can be used to study the genetics underlying storage organ formation. In the present study we investigated several characteristics of an extensive turnip collection comprising 56 accessions from both Asia (mainly Japanese origin) and Europe. Population structure was calculated using data from 280 evenly distributed SNP markers over 56 turnip accessions. We studied the anatomy of turnip tubers and measured carbohydrate composition of the mature turnip tubers of a subset of the collection. The variation in 16 leaf traits, 12 tuber traits and flowering time was evaluated in five independent experiments for the entire collection. The effect of vernalization on flowering and tuber formation was also investigated. SNP marker profiling basically divided the turnip accessions into two subpopulations, with admixture, generally corresponding with geographical origin (Europe or Asia). The enlarged turnip tuber consists of both hypocotyl and root tissue, but the proportion of the two tissues differs between accessions. The ratio of sucrose to fructose and glucose differed among accessions, while generally starch content was low. The evaluated traits segregated in both subpopulations, with leaf shape, tuber colour and number of shoots per tuber explaining most variation between the two subpopulations. Vernalization resulted in reduced flowering time and smaller tubers for the Asian turnips whereas the European turnips were less affected by vernalization.
doi:10.1371/journal.pone.0114241
PMCID: PMC4256417  PMID: 25474111
3.  Gene expression profile of peripheral blood in colorectal cancer 
World Journal of Gastroenterology : WJG  2014;20(39):14463-14471.
AIM: Optimal molecular markers for detecting colorectal cancer (CRC) in a blood-based assay were evaluated.
METHODS: A matched (by variables of age and sex) case-control design (111 CRC and 227 non-cancer samples) was applied. Total RNAs isolated from the 338 blood samples were reverse-transcribed, and the relative transcript levels of candidate genes were analyzed. The training set was made of 162 random samples of the total 338 samples. A logistic regression analysis was performed, and odds ratios for each gene were determined between CRC and non-cancer. The samples (n = 176) in the testing set were used to validate the logistic model, and an inferred performance (generality) was verified. By pooling 12 public microarray datasets(GSE 4107, 4183, 8671, 9348, 10961, 13067, 13294, 13471, 14333, 15960, 17538, and 18105), which included 519 cases of adenocarcinoma and 88 controls of normal mucosa, we were able to verify the selected genes from logistic models and estimate their external generality.
RESULTS: The logistic regression analysis resulted in the selection of five significant genes (P < 0.05; MDM2, DUSP6, CPEB4, MMD, and EIF2S3), with odds ratios of 2.978, 6.029, 3.776, 0.538 and 0.138, respectively. The five-gene model performed stably for the discrimination of CRC cases from controls in the training set, with accuracies ranging from 73.9% to 87.0%, a sensitivity of 95% and a specificity of 95%. In addition, a good performance in the test set was obtained using the discrimination model, providing 83.5% accuracy, 66.0% sensitivity, 92.0% specificity, a positive predictive value of 89.2% and a negative predictive value of 73.0%. Multivariate logistic regressions analyzed 12 pooled public microarray data sets as an external validation. Models that provided similar expected and observed event rates in subgroups were termed well calibrated. A model in which MDM2, DUSP6, CPEB4, MMD, and EIF2S3 were selected showed the result in logistic regression analysis (H-L P = 0.460, R2= 0.853, AUC = 0.978, accuracy = 0.949, specificity = 0.818 and sensitivity = 0.971).
CONCLUSION: A novel gene expression profile was associated with CRC and can potentially be applied to blood-based detection assays.
doi:10.3748/wjg.v20.i39.14463
PMCID: PMC4202375  PMID: 25339833
Colorectal cancer; Gene expression; Microarray; Internet
4.  Regulatory Network of Secondary Metabolism in Brassica rapa: Insight into the Glucosinolate Pathway 
PLoS ONE  2014;9(9):e107123.
Brassica rapa studies towards metabolic variation have largely been focused on the profiling of the diversity of metabolic compounds in specific crop types or regional varieties, but none aimed to identify genes with regulatory function in metabolite composition. Here we followed a genetical genomics approach to identify regulatory genes for six biosynthetic pathways of health-related phytochemicals, i.e carotenoids, tocopherols, folates, glucosinolates, flavonoids and phenylpropanoids. Leaves from six weeks-old plants of a Brassica rapa doubled haploid population, consisting of 92 genotypes, were profiled for their secondary metabolite composition, using both targeted and LC-MS-based untargeted metabolomics approaches. Furthermore, the same population was profiled for transcript variation using a microarray containing EST sequences mainly derived from three Brassica species: B. napus, B. rapa and B. oleracea. The biochemical pathway analysis was based on the network analyses of both metabolite QTLs (mQTLs) and transcript QTLs (eQTLs). Co-localization of mQTLs and eQTLs lead to the identification of candidate regulatory genes involved in the biosynthesis of carotenoids, tocopherols and glucosinolates. We subsequently focused on the well-characterized glucosinolate pathway and revealed two hotspots of co-localization of eQTLs with mQTLs in linkage groups A03 and A09. Our results indicate that such a large-scale genetical genomics approach combining transcriptomics and metabolomics data can provide new insights into the genetic regulation of metabolite composition of Brassica vegetables.
doi:10.1371/journal.pone.0107123
PMCID: PMC4164526  PMID: 25222144
5.  Selective IAP inhibition results in sensitization of unstimulated but not CD40-stimulated chronic lymphocytic leukaemia cells to TRAIL-induced apoptosis 
Despite recent advances in therapy, chronic lymphocytic leukaemia (CLL) remains incurable and new treatment strategies are therefore urgently required. Inhibitor of apoptosis proteins (IAPs) are over-expressed in CLL, suggesting both a role in disease pathogenesis and the potential for therapeutic targeting. To explore these questions, we evaluated the effects on primary CLL cells of AZD5582, a novel potent and selective inhibitor of IAPs. AZD5582 at nanomolar concentrations induced extensive degradation of cIAP-1 and cIAP-2, but minimally of X chromosome-linked IAP (XIAP). However, these effects of AZD5582 produced little or no direct cytotoxicity, nor did they sensitize CLL cells to p53-dependent killing by fludarabine or p53-independent killing by dexamethasone. In contrast, AZD5582 significantly enhanced apoptosis induced by the death receptor (DR) agonist tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Importantly, killing by TRAIL plus AZD5582 was independent of adverse prognostic features including TP53 deletion which is strongly associated with chemoresistance in CLL. Coculture experiments involving transfected mouse fibroblasts expressing human CD40L (CD154) to mimic the effect of T cells at sites of tissue involvement showed that CD40 stimulation almost completely prevented the killing of CLL cells by TRAIL plus AZD5582 despite up-regulating TRAIL receptors 1 and 2. In conclusion, our findings confirm the rate-limiting, upstream involvement of IAPs in the extrinsic but not intrinsic apoptotic pathway of CLL cells and suggest that drug combinations that simultaneously activate DRs and inhibit IAPs may have therapeutic potential in patients with CLL who have failed T-cell-depleting chemotherapy.
doi:10.1002/prp2.81
PMCID: PMC4186455  PMID: 25505620
Apoptosis; CD40-stimulation; CLL; IAPs; TRAIL
6.  Beyond genomic variation - comparison and functional annotation of three Brassica rapa genomes: a turnip, a rapid cycling and a Chinese cabbage 
BMC Genomics  2014;15:250.
Background
Brassica rapa is an economically important crop species. During its long breeding history, a large number of morphotypes have been generated, including leafy vegetables such as Chinese cabbage and pakchoi, turnip tuber crops and oil crops.
Results
To investigate the genetic variation underlying this morphological variation, we re-sequenced, assembled and annotated the genomes of two B. rapa subspecies, turnip crops (turnip) and a rapid cycling. We then analysed the two resulting genomes together with the Chinese cabbage Chiifu reference genome to obtain an impression of the B. rapa pan-genome. The number of genes with protein-coding changes between the three genotypes was lower than that among different accessions of Arabidopsis thaliana, which can be explained by the smaller effective population size of B. rapa due to its domestication. Based on orthology to a number of non-brassica species, we estimated the date of divergence among the three B. rapa morphotypes at approximately 250,000 YA, far predating Brassica domestication (5,000-10,000 YA).
Conclusions
By analysing genes unique to turnip we found evidence for copy number differences in peroxidases, pointing to a role for the phenylpropanoid biosynthesis pathway in the generation of morphological variation. The estimated date of divergence among three B. rapa morphotypes implies that prior to domestication there was already considerably divergence among B. rapa genotypes. Our study thus provides two new B. rapa reference genomes, delivers a set of computer tools to analyse the resulting pan-genome and uses these to shed light on genetic drivers behind the rich morphological variation found in B. rapa.
doi:10.1186/1471-2164-15-250
PMCID: PMC4230417  PMID: 24684742
7.  Genome-wide analysis of coordinated transcript abundance during seed development in different Brassica rapa morphotypes 
BMC Genomics  2013;14(1):840.
Background
Brassica seeds are important as basic units of plant growth and sources of vegetable oil. Seed development is regulated by many dynamic metabolic processes controlled by complex networks of spatially and temporally expressed genes. We conducted a global microarray gene co-expression analysis by measuring transcript abundance of developing seeds from two diverse B. rapa morphotypes: a pak choi (leafy-type) and a yellow sarson (oil-type), and two of their doubled haploid (DH) progenies, (1) to study the timing of metabolic processes in developing seeds, (2) to explore the major transcriptional differences in developing seeds of the two morphotypes, and (3) to identify the optimum stage for a genetical genomics study in B. rapa seed.
Results
Seed developmental stages were similar in developing seeds of pak choi and yellow sarson of B. rapa; however, the colour of embryo and seed coat differed among these two morphotypes. In this study, most transcriptional changes occurred between 25 and 35 DAP, which shows that the timing of seed developmental processes in B. rapa is at later developmental stages than in the related species B. napus. Using a Weighted Gene Co-expression Network Analysis (WGCNA), we identified 47 “gene modules”, of which 27 showed a significant association with temporal and/or genotypic variation. An additional hierarchical cluster analysis identified broad spectra of gene expression patterns during seed development. The predominant variation in gene expression was according to developmental stages rather than morphotype differences. Since lipids are the major storage compounds of Brassica seeds, we investigated in more detail the regulation of lipid metabolism. Four co-regulated gene clusters were identified with 17 putative cis-regulatory elements predicted in their 1000 bp upstream region, either specific or common to different lipid metabolic pathways.
Conclusions
This is the first study of genome-wide profiling of transcript abundance during seed development in B. rapa. The identification of key physiological events, major expression patterns, and putative cis-regulatory elements provides useful information to construct gene regulatory networks in B. rapa developing seeds and provides a starting point for a genetical genomics study of seed quality traits.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-14-840) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-14-840
PMCID: PMC4046715  PMID: 24289287
Brassica rapa; Leafy vegetables; Oil-seed; Seed development; Microarray; Co-expression network analysis; Transcript abundance; cis-regulatory elements
8.  Construction of the Octose 8-Phosphate Intermediate in Lincomycin A Biosynthesis: Characterization of the Reactions Catalyzed by LmbR and LmbN 
Journal of the American Chemical Society  2012;134(42):17432-17435.
Lincomycin A is a potent antimicrobial agent noted for its unusual C1 methylmercapto-substituted eight-carbon sugar. Despite its long clinical history for the treatment of Grampositive infections, the biosynthesis of the C8-sugar, methylthiolincosamide (MTL), is poorly understood. Here, we report our studies of the two initial enzymatic steps in the MTL biosynthetic pathway leading to the identification of D-erythro-D-gluco-octose 8-phosphate as a key intermediate. Our experiments demonstrate that this intermediate is formed via a transaldol reaction catalyzed by LmbR using D-fructose 6-phosphate or D-sedoheptulose 7-phosphate as the C3 donor and D-ribose 5-phosphate as the C5 acceptor. Subsequent 1,2-isomerization catalyzed by LmbN converts the resulting 2-keto C8-sugar (octulose 8-phosphate) to octose 8-phosphate. These results provide, for the first time, in vitro evidence revealing the biosynthetic origin of the C8 backbone of MTL.
doi:10.1021/ja308221z
PMCID: PMC3486926  PMID: 22989310
9.  The Brassica rapa FLC homologue FLC2 is a key regulator of flowering time, identified through transcriptional co-expression networks 
Journal of Experimental Botany  2013;64(14):4503-4516.
The role of many genes and interactions among genes involved in flowering time have been studied extensively in Arabidopsis, and the purpose of this study was to investigate how effectively results obtained with the model species Arabidopsis can be applied to the Brassicacea with often larger and more complex genomes. Brassica rapa represents a very close relative, with its triplicated genome, with subgenomes having evolved by genome fractionation. The question of whether this genome fractionation is a random process, or whether specific genes are preferentially retained, such as flowering time (Ft) genes that play a role in the extreme morphological variation within the B. rapa species (displayed by the diverse morphotypes), is addressed. Data are presented showing that indeed Ft genes are preferentially retained, so the next intriguing question is whether these different orthologues of Arabidopsis Ft genes play similar roles compared with Arabidopsis, and what is the role of these different orthologues in B. rapa. Using a genetical–genomics approach, co-location of flowering quantitative trait loci (QTLs) and expression QTLs (eQTLs) resulted in identification of candidate genes for flowering QTLs and visualization of co-expression networks of Ft genes and flowering time. A major flowering QTL on A02 at the BrFLC2 locus co-localized with cis eQTLs for BrFLC2, BrSSR1, and BrTCP11, and trans eQTLs for the photoperiod gene BrCO and two paralogues of the floral integrator genes BrSOC1 and BrFT. It is concluded that the BrFLC2 Ft gene is a major regulator of flowering time in the studied doubled haploid population.
doi:10.1093/jxb/ert264
PMCID: PMC3808329  PMID: 24078668
Brassica rapa; candidate gene mapping; expression quantitative trait loci (eQTL); FLOWERING LOCUS C (FLC).; flowering time; gene expression networks; genome triplication.
10.  Testing the annual nature of speleothem banding 
Scientific Reports  2013;3:2633.
Speleothem laminae have been postulated to form annually, and this lamina-chronology is widely applied to high-resolution modern and past climate reconstructions. However, this argument has not been directly supported by high resolution dating methods. Here we present contemporary single-lamina 230Th dating techniques with 2σ precision as good as ±0.5 yr on a laminated stalagmite with density couplets from Xianren Cave, China, that covers the last 300 years. We find that the layers do not always deposit annually. Annual bands can be under- or over-counted by several years during different multi-decadal intervals. The irregular formation of missing and false bands in this example indicates that the assumption of annual speleothem laminae in a climate reconstruction should be approached carefully without a robust absolute-dated chronology.
doi:10.1038/srep02633
PMCID: PMC3773624  PMID: 24037594
11.  Mefloquine induces cell death in prostate cancer cells and provides a potential novel treatment strategy in vivo 
Oncology Letters  2013;5(5):1567-1571.
Mefloquine (MQ) is currently in clinical use as a prophylactic treatment for malaria. Previous studies have shown that MQ induces oxidative stress in vitro. The present study investigated the anticancer effects of MQ treatment in PC3 cells. The cell viability was evaluated using sulphorhodamine-B (SRB) staining, while annexin V and propidium iodide (PI) were used as an assay for cell death. Reactive oxygen species (ROS) formation was detected with 2′,7′-dichlorofluorescein-diacetate (DCFH-DA), a sensitive intracellular probe, and the alteration of cellular status was defined by trypan blue staining. The results of the present study indicated that MQ has a high cytotoxicity that causes cell death in PC3 cells. MQ markedly inhibited the PC3 cells through non-apoptotic cell death. MQ also induced significant ROS production. The MQ treatment mediated G1 cell cycle arrest and cyclin D1 accumulation through p21 upregulation in the PC3 cells. Moreover, the use of MQ improved the survival of the treatment group compared with the control group in the experimental mice. The present study indicates that MQ possesses potential therapeutic efficacy for the treatment of prostate cancer (PCa) in vivo. These findings provide insights that may aid the further optimization and application of new and existing therapeutic options.
doi:10.3892/ol.2013.1259
PMCID: PMC3678863  PMID: 23759954
mefloquine; prostate cancer; reactive oxygen species; glutathione
12.  Mefloquine exerts anticancer activity in prostate cancer cells via ROS-mediated modulation of Akt, ERK, JNK and AMPK signaling 
Oncology Letters  2013;5(5):1541-1545.
Mefloquine (MQ) is a prophylactic anti-malarial drug. Previous studies have shown that MQ induces oxidative stress in vitro. Evidence indicates that reactive oxygen species (ROS) may be used as a therapeutic modality to kill cancer cells. This study investigated whether MQ also inhibits prostate cancer (PCa) cell growth. We used sulforhodamine B (SRB) staining to determine cell viability. MQ has a highly selective cytotoxicity that inhibits PCa cell growth. The antitumor effect was most significant when examined using a colony formation assay. MQ also induces hyperpolarization of the mitochondrial membrane potential (MMP), as well as ROS generation. The blockade of MQ-induced anticancer effects by N-acetyl cysteine (NAC) pre-treatment confirmed the role of ROS. This indicates that the MQ-induced anticancer effects are caused primarily by increased ROS generation. Moreover, we observed that MQ-mediated ROS simultaneously downregulated Akt phosphorylation and activated extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and adenosine monophosphate-activated protein kinase (AMPK) signaling in PC3 cells. These findings provide insights for further anticancer therapeutic options.
doi:10.3892/ol.2013.1211
PMCID: PMC3678889  PMID: 23760395
mefloquine; prostate cancer; reactive oxygen species; mitochondrial membrane potential; hyperpolarization; N-acetyl cysteine
13.  Preliminary Report on Use of 3-Dimensional Computed Tomographic Images in a Disease-Based Transesophageal Echocardiographic Simulation System 
Texas Heart Institute Journal  2013;40(3):250-255.
We used 3-dimensional computed tomographic images to create a disease-based transesophageal echocardiographic simulation system for complex congenital heart defects.
We enrolled 7 pediatric patients with complex congenital heart defects in this proof-of-concept study. Preoperative computed tomographic images and intraoperative transesophageal echocardiographic images were acquired for all patients. Two- and 3-dimensional computed tomographic cross-sectional images were created to simulate the process of transesophageal echocardiographic image acquisition. Computed tomographic images simulating the midesophageal 4- and 5-chamber views, aortic valve short-axis views, long-axis views, and ascending aortic short-axis views were created to correspond with the actual transesophageal echocardiographic images from each patient. Four reviewers then evaluated the image quality of the computed tomographic images, the agreement between the echocardiographic and tomographic images, and the ability of the 3-dimensional computed tomographic full-volume and cross-sectional images to yield the spatial and temporal congruence of transesophageal echocardiograms.
In most of the patients, computed tomography yielded images of good-to-excellent quality. Strong agreement was noted between the computed tomographic and transesophageal echocardiographic images acquired in the same patients. The ability of 3-dimensional computed tomography to yield the spatial and temporal congruence of transesophageal echocardiography in selected planes was also good to excellent.
We found that 3-dimensional computed tomographic images can simulate the process of transesophageal echocardiography in acquiring the echocardiographic image clearly. This imaging method has the potential to be applied successfully to a disease-based transesophageal echocardiographic simulation system.
PMCID: PMC3709216  PMID: 23914013
Adult health personnel/education; computer graphics; echocardiography, transesophageal/instrumentation; heart defects, congenital/ultrasonography; image processing, computer-assisted/methods; imaging, three-dimensional/methods; tomography, x-ray computed/methods
14.  Perventricular Device Closure of Residual Muscular Ventricular Septal Defects after Repair of Complex Congenital Heart Defects in Pediatric Patients 
Texas Heart Institute Journal  2013;40(5):534-540.
Residual muscular ventricular septal defects are surgical challenges, especially after the repair of complex congenital heart defects. We investigated perventricular device closure as a salvage technique in pediatric patients who had postoperative residual muscular ventricular septal defects.
From February 2009 through June 2011, 14 pediatric patients at our hospital had residual muscular ventricular septal defects after undergoing surgical repair of complex congenital heart defects. Ten patients met our criteria for perventricular device closure of the residual defects: significant left-to-right shunting (Qp/Qs >1.5) or substantial hemodynamic instability (a defect ≥2 mm in size). The patients' mean age was 20.4 ± 13.5 months, and their mean body weight was 10 ± 3.1 kg. The median diameter of the residual defects was 4.2 mm (range, 2.5–5.1 mm).
We deployed a total of 11 SQFDQ-II Muscular VSD Occluders (Shanghai Shape Memory Alloy Co., Ltd.; Shanghai, China) in the 10 patients, in accord with conventional techniques of perventricular device closure. The mean procedural duration was 31.1 ±9.1 min. We recorded the closure and complication rates perioperatively and during a 12-month follow-up period. Complete closure was achieved in 8 patients; 2 patients had persistent trivial residual shunts. No deaths, conduction block, device embolism, or other complications occurred throughout the study period.
We conclude that perventricular device closure is a safe, effective salvage treatment for postoperative residual muscular ventricular septal defects in pediatric patients. Long-term studies with larger cohorts might further confirm this method's feasibility.
PMCID: PMC3853845  PMID: 24391313
Cardiac surgical procedures/instrumentation/methods; equipment design; heart defects, congenital/adverse effects; heart septal defects, ventricular/complications/pathology/therapy; hemodynamics; postoperative complications; prostheses and implants; surgical procedures, minimally invasive/methods; treatment outcome
15.  Changes in the intestinal absorption mechanism of icariin in the nanocavities of cyclodextrins 
Icariin is a bioactive herbal ingredient isolated from Herba epimedii, which has been widely used for the treatment of osteoporosis and male sexual dysfunction in traditional Chinese medicine. The major objective of this work is to investigate the different enhancing effects of β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) on the intestinal absorption of icariin, and to identify the molecular mechanisms of this action. Host–guest-type interactions of icariin with cyclodextrins nanocavities were unambiguously demonstrated by the phase-solubility diagram, ultraviolet spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray powder diffractometry, and two dimensional proton nuclear magnetic resonance rotating-frame Overhauser effect spectroscopy. These results were further supported using molecular modeling studies. The rat single-pass intestinal perfusion model showed that the absorption of icariin was affected by P-glycoprotein (Pgp). The icariin/HP-β-CD inclusion complex provided greater enhancement in the intestinal absorption than the icariin/β-CD inclusion complex. Therefore, the enhancing effect was involved in a solubilizing effect and/or Pgp inhibitory effect. Finally, fluorescence anisotropy measurements and Pgp adenosine triphosphatase (ATPase) assay demonstrated that β-CD exhibited no effect on Pgp, while HP-β-CD showed inhibition by restraining the Pgp ATPase activity rather than changing the fluidity of cell membrane.
doi:10.2147/IJN.S33014
PMCID: PMC3418075  PMID: 22904630
icariin; cyclodextrin; inclusion complex; molecular modeling; P-glycoprotein (Pgp); intestinal absorption
16.  Clinical Analysis of 10 AIDS Patients with Malignant Lymphoma 
Cancer Biology & Medicine  2012;9(2):115-119.
Objective
This work summarizes the clinical features and treatment of 10 AIDS patients with malignant lymphoma.
Methods
A total of 10 AIDS patients with malignant lymphoma seen in Beijing Ditan Hospital since 2009 were enrolled. Clinical manifestations, pathological examinations, immunity levels, Epstein-Barr virus antibody examinations, complications, treatments, and outcomes were retrospectively analyzed.
Results
The main clinical manifestations of these patients included intermittent fever in 2 cases, neck masses and fever in 3 cases, auxiliary lymph node enlargement in 2 cases, and abdominal pain and bloating with fever in 3 cases. Up to 7 patients were pathologically diagnosed with diffuse large B cell lymphoma (DLBCL), and 3 patients were pathologically diagnosed with Burkitt’s lymphoma. Up to 8 patients had CD4 cell counts below 200/µL, and 2 patients had a level of more than 200/µL. Up to 7 patients were negative for EBV-IgM antibodies and 3 patients were not examined. Six patients underwent different chemotherapy and their prognoses were different. One patient with Burkitt’s lymphoma alternatively took CODOXM and IVAC for 3 turns after VP chemotherapy; 1 patient with liver metastasis took R-CHOP 5 times, then changed therapy regimen to R-MINE and MINE. One patient with adrenal DLBCL took CHOP 6 times. Three patients with DLBCL took CHOP 1 or 2 times. Four patients gave up treatment. Various infections and side effects occurred, including bone marrow suppression, gastrointestinal bleeding, and renal dysfunction during chemotherapy. Six patients took HAART, and 4 did not. Six patients died, whereas 3 patients got improved; and 1 patient was discharged.
Conclusions
AIDS patients with malignant lymphoma had various clinical manifestations, were immunocompromised, and had multiple metastases when they were admitted; they were already in the interim or late stage of lymphoma. Chemotherapy was not effective, and additional complications occurred. HAART failed to improve patient prognosis, and the overall prognosis was poor.
doi:10.3969/j.issn.2095-3941.2012.02.006
PMCID: PMC3643651  PMID: 23691465
acquired immunodeficiency syndrome (AIDS); malignant lymphoma; chemotherapy; HAART; prognosis
17.  Biased Gene Fractionation and Dominant Gene Expression among the Subgenomes of Brassica rapa 
PLoS ONE  2012;7(5):e36442.
Polyploidization, both ancient and recent, is frequent among plants. A “two-step theory" was proposed to explain the meso-triplication of the Brassica “A" genome: Brassica rapa. By accurately partitioning of this genome, we observed that genes in the less fractioned subgenome (LF) were dominantly expressed over the genes in more fractioned subgenomes (MFs: MF1 and MF2), while the genes in MF1 were slightly dominantly expressed over the genes in MF2. The results indicated that the dominantly expressed genes tended to be resistant against gene fractionation. By re-sequencing two B. rapa accessions: a vegetable turnip (VT117) and a Rapid Cycling line (L144), we found that genes in LF had less non-synonymous or frameshift mutations than genes in MFs; however mutation rates were not significantly different between MF1 and MF2. The differences in gene expression patterns and on-going gene death among the three subgenomes suggest that “two-step" genome triplication and differential subgenome methylation played important roles in the genome evolution of B. rapa.
doi:10.1371/journal.pone.0036442
PMCID: PMC3342247  PMID: 22567157
18.  Risk Assessment of Hemorrhagic Transformation of Acute Middle Cerebral Artery Stroke Using Multimodal CT 
Journal of Neuroimaging  2010;22(2):160-166.
PURPOSE
Multimodal CT with CT angiography (CTA) and CT perfusion (CTP) are increasingly used in stroke triage. Our aim was to identify parameters most predictive of hemorrhagic transformation (HT), especially symptomatic intracerebral hemorrhage (SICH).
METHODS
This retrospective study included patients evaluated by baseline multimodal CT ≤ 9hours from ictus with acute nonlacunar middle cerebral artery (MCA) territory infarction. Two readers independently evaluated CTP maps for ischemic severity and CTA source images (CTA-SI) for infarct extent (as measured by ASPECTS). Presence of proximal occlusion (ICA or M1) and degree of collateralization (collateral score) were also assessed on CTA. HT was defined as SICH if associated with deterioration ≥ 4-points on NIHSS. Multivariate logistic regression analysis identified independent predictors of SICH. ROC curves selected optimal thresholds.
RESULTS
Of 84 patients reviewed, HT occurred in 22 (26.2%) and SICH in 8 (9.5%). Univariate predictors for SICH were proximal occlusion (OR = 8.65, P = .049), collateral score (OR = .34, P = .017), ASPECTS (OR = .46, P = .001), and CBV (OR = .001, P = .005). Multivariate analysis revealed ASPECTS as the only independent predictor with optimal threshold ≤ 5 and sensitivity and specificity of 75.0% and 85.5%, respectively.
CONCLUSION
For acute MCA infarcts ≤ 9 hours, the strongest predictor of SICH on multimodal CT was ASPECTS on CTA-SI.
doi:10.1111/j.1552-6569.2010.00562.x
PMCID: PMC3175503  PMID: 21143549
Alberta Stroke Program Early CT Score; CT perfusion; CT angiography; hemorrhagic transformation; acute stroke
19.  Dietary Blue Pigments Derived from Genipin, Attenuate Inflammation by Inhibiting LPS-Induced iNOS and COX-2 Expression via the NF-κB Inactivation 
PLoS ONE  2012;7(3):e34122.
Background and Purpose
The edible blue pigments produced by gardenia fruits have been used as value-added colorants for foods in East Asia for 20 years. However, the biological activity of the blue pigments derived from genipin has not been reported.
Methodology/Principal Findings
The anti-inflammatory effect of blue pigments was studied in lipopolysaccharide (LPS) stimulated RAW 264.7 macrophage in vitro. The secretions of nitric oxide (NO) and prostaglandin E2 (PGE2) were inhibited in concentration-dependent manner by blue pigments. Real-time reverse-transcription polymerase chain reaction (Real-time RT-PCR) analyses demonstrated that the mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin (IL)-6, and tumor necrosis factor alpha (TNF-α) was inhibited, moreover, ELISA results showed that the productions of IL-6 and TNF-α were inhibited. Cell-based ELISA revealed the COX-2 protein expression was inhibited. The proteome profiler array showed that 12 cytokines and chemokines involved in the inflammatory process were down-regulated by blue pigments. Blue pigments inhibited the nuclear transcription factor kappa-B (NF-κB) activation induced by LPS, and this was associated with decreasing the DNA-binding activity of p65 and p50. Furthermore, blue pigments suppressed the degradation of inhibitor of κB (IκB) α, Inhibitor of NF-κB Kinase (IKK) α, IKK-β, and phosphorylation of IκB-α. The anti-inflammatory effect of blue pigments in vivo was studied in carrageenan-induced paw edema and LPS-injecting ICR mice. Finally, blue pigments significantly inhibited paw swelling and reduced plasma TNF-α and IL-6 production in vivo.
Conclusions and Implications
These results suggest that the anti-inflammatory properties of blue pigments might be the results from the inhibition of iNOS, COX-2, IL-6, IL-1β, and TNF-α expression through the down-regulation of NF-κB activation, which will provide strong scientific evidence for the edible blue pigments to be developed as a new health-enhancing nutritional food for the prevention and treatment of inflammatory diseases.
doi:10.1371/journal.pone.0034122
PMCID: PMC3316609  PMID: 22479539
20.  ProRepeat: an integrated repository for studying amino acid tandem repeats in proteins 
Nucleic Acids Research  2011;40(Database issue):D394-D399.
ProRepeat (http://prorepeat.bioinformatics.nl/) is an integrated curated repository and analysis platform for in-depth research on the biological characteristics of amino acid tandem repeats. ProRepeat collects repeats from all proteins included in the UniProt knowledgebase, together with 85 completely sequenced eukaryotic proteomes contained within the RefSeq collection. It contains non-redundant perfect tandem repeats, approximate tandem repeats and simple, low-complexity sequences, covering the majority of the amino acid tandem repeat patterns found in proteins. The ProRepeat web interface allows querying the repeat database using repeat characteristics like repeat unit and length, number of repetitions of the repeat unit and position of the repeat in the protein. Users can also search for repeats by the characteristics of repeat containing proteins, such as entry ID, protein description, sequence length, gene name and taxon. ProRepeat offers powerful analysis tools for finding biological interesting properties of repeats, such as the strong position bias of leucine repeats in the N-terminus of eukaryotic protein sequences, the differences of repeat abundance among proteomes, the functional classification of repeat containing proteins and GC content constrains of repeats’ corresponding codons.
doi:10.1093/nar/gkr1019
PMCID: PMC3245022  PMID: 22102581
21.  TNFR2 interposes the proliferative and NF-κB-mediated inflammatory response by podocytes to TNF-α 
The development of proliferative podocytopathies has been linked to ligation of TNFR2 expressed on the renal parenchyma; however, the TNFR2 positive cells within the kidney responsible for podocyte injury are unknown. We detected de novo expression of TNFR2 on podocytes prior to hyperplastic injury in crescentic glomerulonephritis of mice with nephrotoxic nephritis, and in collapsing glomerulopathy of Tg26HIV/nl mice, kd/kd mice, and humans. We further found that serum levels of soluble TNF-α and TNFR2 correlated significantly with renal injury in Tg26HIV/nl mice. Thus, we asked whether ligand binding of TNFR2 on podocytes ex vivo precipitates the characteristic proliferative and pro-inflammatory diseased podocyte phenotypes. Soluble TNF-α activated NF-κB and dose-dependently induced podocyte proliferation, marked by expression of the podocyte G1 cyclin and NF-κB target gene, cyclin D1. Microarray gene and chemokine protein expression profiling showed a marked pro-inflammatory NF-κB signature, and activated podocytes secreting CCL2 and CCL5 induced macrophage migration in transwell assays. Neutralization of TNFR2 on podocytes with blocking antibodies abrogated NF-κB activation and the induction of cyclin D1 by TNF-α, and identified TNFR2 as the primary receptor that induced IκBα degradation, the initiating event in NF-κB activation. These results suggest that TNFR2 expressed on podocytes and its canonical NF-κB signaling may directly interpose the compound pathogenic responses by podocytes to TNF-α, absent other TNFR2 positive renal cell-types in proliferative podocytopathies.
doi:10.1038/labinvest.2010.199
PMCID: PMC3075956  PMID: 21221075
collapsing glomerulopathy; gene expression; glomerulonephritis; HIV-1; inflammation; podocytes; proliferation; tumor necrosis factor
22.  HLA polymorphism of the Zhuang population reflects the common HLA characteristics among Zhuang-Dong language-speaking populations*  
A study of the human leukocyte antigen (HLA) genetic characteristics in the Zhuang, the largest ethnic population in China, would provide insight into Zhuang history and give a useful tool for disease associations, transplantation, and anthropology. In the present study, we report the comprehensive HLA-A, HLA-B, HLA-C, and HLA-DRB1 alleles and haplotypes in the Zhuang population of southern China for the first time. A total of 13 HLA-A, 24 HLA-B, 22 HLA-C, and 18 HLA-DRB1 were identified in 104 Zhuang individuals. The frequencies of HLA-A*11:01, A*02:07, A*24:02, A*02:03, and A*33:03 on A loci, B*15:02, B*58:01, B*46:01, and B*13:01 on B loci, C*03:04, C*08:01, C*01:02, C*03:02, and C*07:02 on C loci, and DRB1*15:01, DRB1*16:02, DRB1*14:01, DRB1*15:02, and DRB1*03:01 on the DRB1 loci were >10%. The A*33:03-C*03:02-B*58:01-DRB1*03:01 and A*02:07-C*01:02-B*46:01-DRB1*14:01 haplotypes were predominant in the Zhuang. The phylogenetic tree, as well as the analysis of haplotypes, suggested that the Zhuang are genetically similar to southern Chinese populations, especially the Zhuang-Dong language-speaking populations, such as the Bouyei, Dai, and Maonan. Even though the Zhuang and southern Chinese populations shared common alleles and haplotypes, the Zhuang has maintained its unique genetic characteristics.
doi:10.1631/jzus.B1000285
PMCID: PMC3109144  PMID: 21634035
Human leukocyte antigen (HLA) alleles; Haplotypes; Zhuang population
23.  CAG-repeat variant in the polymerase γ gene and male infertility in the Chinese population: a meta-analysis 
Asian Journal of Andrology  2010;13(2):298-304.
Several studies have reported a relationship between the length of the CAG-repeat in the polymerase γ (POLG) gene and male infertility. However, other studies have not reproduced this result. In our study, the POLG-CAG-repeat length was analyzed in 535 healthy individuals from six Chinese Han populations living in different provinces. The frequencies of 10-CAG alleles and genotypes were high (97.38 and 94.13%, respectively), with no significant difference among the six Chinese Han populations. Furthermore, we determined the distribution of the POLG-CAG-repeat in 150 infertile men and 126 fertile men. Our study suggested that the distributions of POLG-CAG-repeat alleles and genotypes were not significantly different between infertile (95.67 and 92.67%, respectively) and fertile men (97.22 and 94.44%, respectively). In a subsequent meta-analysis, combining our data with data from previous studies, a comparison of the CAG-repeat alleles in fertile versus infertile men showed no obvious risk for male infertility associated with any particular allele (pooled odds ratio (OR)=0.94; 95% confidence interval (CI): 0.60–1.48). The significance level was not attained with any of the following genetic models: homozygote comparison (not 10/not 10 versus 10/10: OR=1.34; 95% CI: 0.66–2.72), heterozygote comparison (10/not 10 versus 10/10: OR=1.04; 95% CI: 0.78–1.38), dominant model comparison (not 10/not 10+10/not 10 versus 10/10: OR=1.08; 95% CI: 0.79–1.47) and recessive genetic comparison (not 10/not 10 versus 10/not 10+10/10: OR=1.31; 95% CI: 0.68–2.55). In conclusion, there is no significant difference of the frequencies of POLG-CAG-repeat variants among six Chinese Han populations, and this polymorphism may not be associated with Chinese male infertility. On the basis of a meta-analysis, there is no obvious association between CAG-repeat variants of the POLG gene and male infertility.
doi:10.1038/aja.2010.91
PMCID: PMC3739217  PMID: 21102476
case–control study; male infertility; meta-analysis; POLG-CAG-repeat
24.  ProGMap: an integrated annotation resource for protein orthology 
Nucleic Acids Research  2009;37(Web Server issue):W428-W434.
Current protein sequence databases employ different classification schemes that often provide conflicting annotations, especially for poorly characterized proteins. ProGMap (Protein Group Mappings, http://www.bioinformatics.nl/progmap) is a web-tool designed to help researchers and database annotators to assess the coherence of protein groups defined in various databases and thereby facilitate the annotation of newly sequenced proteins. ProGMap is based on a non-redundant dataset of over 6.6 million protein sequences which is mapped to 240 000 protein group descriptions collected from UniProt, RefSeq, Ensembl, COG, KOG, OrthoMCL-DB, HomoloGene, TRIBES and PIRSF. ProGMap combines the underlying classification schemes via a network of links constructed by a fast and fully automated mapping approach originally developed for document classification. The web interface enables queries to be made using sequence identifiers, gene symbols, protein functions or amino acid and nucleotide sequences. For the latter query type BLAST similarity search and QuickMatch identity search services have been incorporated, for finding sequences similar (or identical) to a query sequence. ProGMap is meant to help users of high throughput methodologies who deal with partially annotated genomic data.
doi:10.1093/nar/gkp462
PMCID: PMC2703891  PMID: 19494185

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