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1.  Immunogenicity and Tolerability to Human Papillomavirus-like Particle Vaccine in Girls and Young Women with Inflammatory Bowel Disease 
Inflammatory bowel diseases  2013;19(7):1441-1449.
Female patients receiving immunosuppressive therapy may be at increased risk for human papillomavirus (HPV) infection and cervical neoplasia.
We administered the 3-dose HPV vaccine Gardasil® to 37 females aged 9-26 years with inflammatory bowel disease (IBD) prescribed immunosuppressive therapy (prospective cohort). Geometric mean titers (GMT) in milli-Merck (mMu/mL) units were determined before dose 1 and one month after dose 3 by competitive Luminex immunoassay (cLIA) and qualitatively compared to healthy females of similar age from Merck’s database. Side effects and adverse events were evaluated. Concurrently, in 15 similar IBD patients previously vaccinated by their primary care provider we assessed antibody titers by cLIA and total IgG LIA after dose 3 of vaccine (range 0.5 to 27 months).
The mean age of prospective patients was 15 years with 51% on anti-TNF therapy and 49% on immunomodulators: 33 of 37 completed all three doses. Seropositivity after dose 3 was 100% for types 6, 11 and 16 and 96% for type 18. GMT for HPV 6, 11, 16 and 18 was 1080, 1682, 3975 and 858, respectively, and did not qualitatively differ from healthy females. No serious adverse events were attributable to the vaccine. In the previously vaccinated cohort, seropositivity was 100% for types 6, 11, and 16, and 40% for type 18 by cLIA (93% for HPV18 by IgG LIA). Titers decreased with time since dose 3.
In this small study of IBD patients prescribed immunosuppressive therapy, Gardasil® was immunogenic and there were no clinically significant vaccine-associated adverse events.
PMCID: PMC3677764  PMID: 23567780
inflammatory bowel disease; immunosuppressive therapy; human papillomavirus vaccine; immunogenicity; girls and young women
2.  Lamellar Thickness and Stretching Temperature Dependency of Cavitation in Semicrystalline Polymers 
PLoS ONE  2014;9(5):e97234.
Polybutene-1 (PB-1), a typical semicrystalline polymer, in its stable form I shows a peculiar temperature dependent strain-whitening behavior when being stretched at temperatures in between room temperature and melting temperature of the crystallites where the extent of strain-whitening weakens with the increasing of stretching temperature reaching a minima value followed by an increase at higher stretching temperatures. Correspondingly, a stronger strain-hardening phenomenon was observed at higher temperatures. The strain-whitening phenomenon in semicrystalline polymers has its origin of cavitation process during stretching. In this work, the effect of crystalline lamellar thickness and stretching temperature on the cavitation process in PB-1 has been investigated by means of combined synchrotron ultrasmall-angle and wide-angle X-ray scattering techniques. Three modes of cavitation during the stretching process can be identified, namely “no cavitation” for the quenched sample with the thinnest lamellae where only shear yielding occurred, “cavitation with reorientation” for the samples stretched at lower temperatures and samples with thicker lamellae, and “cavitation without reorientation” for samples with thinner lamellae stretched at higher temperatures. The mode “cavitation with reorientation” occurs before yield point where the plate-like cavities start to be generated within the lamellar stacks with normal perpendicular to the stretching direction due to the blocky substructure of the crystalline lamellae and reorient gradually to the stretching direction after strain-hardening. The mode of “cavitation without reorientation” appears after yield point where ellipsoidal shaped cavities are generated in those lamellae stacks with normal parallel to the stretching direction followed by an improvement of their orientation at larger strains. X-ray diffraction results reveal a much improved crystalline orientation for samples with thinner lamellae stretched at higher temperatures. The observed behavior of microscopic structural evolution in PB-1 stretched at different temperatures explains above mentioned changes in macroscopic strain-whitening phenomenon with increasing in stretching temperature and stress-strain curves.
PMCID: PMC4018252  PMID: 24820772
3.  Varicella Vaccination in Children With Inflammatory Bowel Disease Receiving Immunosuppressive Therapy 
Children with inflammatory bowel disease (IBD) are often receiving chronic immunosuppressive therapy to stay in clinical remission; however, these therapies also put patients at risk for infections. Therefore, it is important to immunize children to minimize vaccine-preventable infections. However, there is a paucity of data on immune response to vaccines in patients with IBD. Current guidelines recommend that patients with IBD receive inactivated vaccines but suggest against immunizing immunosuppressed patients having IBD with live vaccines such as varicella. Unfortunately, the recommendation to not vaccinate with varicella was not based on any data. We present a case series of children with IBD receiving immunosuppressive therapy who tolerated and had a good immune response to varicella vaccine. We also review the literature and demonstrate that studies in other immunocompromised populations suggest that varicella vaccine is generally well tolerated and immunogenic. We also argue that it is important to weigh the benefits against risks with individual patients having IBD to decide whether varicella vaccination should be considered. Additional studies evaluating the safety and immunogenicity of varicella vaccine in patients with IBD are needed.
PMCID: PMC3955715  PMID: 20639716
immunization; immunosuppression; inflammatory bowel disease; vaccine; varicella
4.  Application of the back-error propagation artificial neural network (BPANN) on genetic variants in the PPAR-γ and RXR-α gene and risk of metabolic syndrome in a Chinese Han population 
Journal of Biomedical Research  2013;28(2):114-122.
This study was aimed to explore the associations between the combined effects of several polymorphisms in the PPAR-γ and RXR-α gene and environmental factors with the risk of metabolic syndrome by back-error propagation artificial neural network (BPANN). We established the model based on data gathered from metabolic syndrome patients (n = 1012) and normal controls (n = 1069) by BPANN. Mean impact value (MIV) for each input variable was calculated and the sequence of factors was sorted according to their absolute MIVs. Generalized multifactor dimensionality reduction (GMDR) confirmed a joint effect of PPAR-γ and RXR-α based on the results from BPANN. By BPANN analysis, the sequences according to the importance of metabolic syndrome risk factors were in the order of body mass index (BMI), serum adiponectin, rs4240711, gender, rs4842194, family history of type 2 diabetes, rs2920502, physical activity, alcohol drinking, rs3856806, family history of hypertension, rs1045570, rs6537944, age, rs17817276, family history of hyperlipidemia, smoking, rs1801282 and rs3132291. However, no polymorphism was statistically significant in multiple logistic regression analysis. After controlling for environmental factors, A1, A2, B1 and B2 (rs4240711, rs4842194, rs2920502 and rs3856806) models were the best models (cross-validation consistency 10/10, P = 0.0107) with the GMDR method. In conclusion, the interaction of the PPAR-γ and RXR-α gene could play a role in susceptibility to metabolic syndrome. A more realistic model is obtained by using BPANN to screen out determinants of diseases of multiple etiologies like metabolic syndrome.
PMCID: PMC3968282  PMID: 24683409
back-error propagation artificial neural network (BPANN); metabolic syndrome; peroxisome proliferators activated receptor-γ (PPAR) gene; retinoid X receptor-α (RXR-α) gene; adiponectin
5.  Performance of four computer-coded verbal autopsy methods for cause of death assignment compared with physician coding on 24,000 deaths in low- and middle-income countries 
BMC Medicine  2014;12:20.
Physician-coded verbal autopsy (PCVA) is the most widely used method to determine causes of death (CODs) in countries where medical certification of death is uncommon. Computer-coded verbal autopsy (CCVA) methods have been proposed as a faster and cheaper alternative to PCVA, though they have not been widely compared to PCVA or to each other.
We compared the performance of open-source random forest, open-source tariff method, InterVA-4, and the King-Lu method to PCVA on five datasets comprising over 24,000 verbal autopsies from low- and middle-income countries. Metrics to assess performance were positive predictive value and partial chance-corrected concordance at the individual level, and cause-specific mortality fraction accuracy and cause-specific mortality fraction error at the population level.
The positive predictive value for the most probable COD predicted by the four CCVA methods averaged about 43% to 44% across the datasets. The average positive predictive value improved for the top three most probable CODs, with greater improvements for open-source random forest (69%) and open-source tariff method (68%) than for InterVA-4 (62%). The average partial chance-corrected concordance for the most probable COD predicted by the open-source random forest, open-source tariff method and InterVA-4 were 41%, 40% and 41%, respectively, with better results for the top three most probable CODs. Performance generally improved with larger datasets. At the population level, the King-Lu method had the highest average cause-specific mortality fraction accuracy across all five datasets (91%), followed by InterVA-4 (72% across three datasets), open-source random forest (71%) and open-source tariff method (54%).
On an individual level, no single method was able to replicate the physician assignment of COD more than about half the time. At the population level, the King-Lu method was the best method to estimate cause-specific mortality fractions, though it does not assign individual CODs. Future testing should focus on combining different computer-coded verbal autopsy tools, paired with PCVA strengths. This includes using open-source tools applied to larger and varied datasets (especially those including a random sample of deaths drawn from the population), so as to establish the performance for age- and sex-specific CODs.
PMCID: PMC3912488  PMID: 24495855
Causes of death; Computer-coded verbal autopsy (CCVA); InterVA-4; King-Lu; Physician-certified verbal autopsy (PCVA); Random forest; Tariff method; Validation; Verbal autopsy
6.  Comparison of physician-certified verbal autopsy with computer-coded verbal autopsy for cause of death assignment in hospitalized patients in low- and middle-income countries: systematic review 
BMC Medicine  2014;12:22.
Computer-coded verbal autopsy (CCVA) methods to assign causes of death (CODs) for medically unattended deaths have been proposed as an alternative to physician-certified verbal autopsy (PCVA). We conducted a systematic review of 19 published comparison studies (from 684 evaluated), most of which used hospital-based deaths as the reference standard. We assessed the performance of PCVA and five CCVA methods: Random Forest, Tariff, InterVA, King-Lu, and Simplified Symptom Pattern.
The reviewed studies assessed methods’ performance through various metrics: sensitivity, specificity, and chance-corrected concordance for coding individual deaths, and cause-specific mortality fraction (CSMF) error and CSMF accuracy at the population level. These results were summarized into means, medians, and ranges.
The 19 studies ranged from 200 to 50,000 deaths per study (total over 116,000 deaths). Sensitivity of PCVA versus hospital-assigned COD varied widely by cause, but showed consistently high specificity. PCVA and CCVA methods had an overall chance-corrected concordance of about 50% or lower, across all ages and CODs. At the population level, the relative CSMF error between PCVA and hospital-based deaths indicated good performance for most CODs. Random Forest had the best CSMF accuracy performance, followed closely by PCVA and the other CCVA methods, but with lower values for InterVA-3.
There is no single best-performing coding method for verbal autopsies across various studies and metrics. There is little current justification for CCVA to replace PCVA, particularly as physician diagnosis remains the worldwide standard for clinical diagnosis on live patients. Further assessments and large accessible datasets on which to train and test combinations of methods are required, particularly for rural deaths without medical attention.
PMCID: PMC3912516  PMID: 24495312
Causes of death; Computer-coded verbal autopsy; InterVA; King and Lu; Physician-certified verbal autopsy; Random forest; Simplified symptom pattern; Tariff; Validity; Verbal autopsy
7.  Platelet IKKβ Deficiency Increases Mouse Arterial Neointima Formation via Delayed Glycoprotein Ibα Shedding 
On the luminal surface of injured arteries, platelet activation and leukocyte-platelet interactions are critical for the initiation and progression of arterial restenosis. The transcription factor nuclear factor kappa B (NF-κB) is a critical molecule in platelet activation. Here, we investigated the role of the platelet NF-κB pathway in forming arterial neointima after arterial injury.
Methods and Results
We performed carotid artery wire injuries in LDL receptor-deficient (LDLR–/–) mice with a platelet-specific deletion of IκB kinase beta (IKKβ) (IKKβfl/fl/PF4cre/LDLR–/–) and in control mice (IKKβfl/fl/LDLR–/–). The size of the arterial neointima was 61% larger in the IKKβfl/fl/PF4cre/LDLR–/– mice compared to the littermate control IKKβfl/fl/LDLR–/– mice. Compared to the control mice, the IKKβfl/fl/PF4cre/LDLR–/– mice exhibited more leukocyte adhesion at the injured area. The extent of GPIbα shedding after platelet activation was compromised in the IKKβ-deficient platelets. This effect was associated with a low level of the active form of A Disintegrin And Metalloproteinase 17 (ADAM17), the key enzyme involved in mediating GPIbα shedding in activated IKKβ-deficient platelets.
Platelet IKKβ deficiency increases the formation of injury-induced arterial neointima formation. Thus, NF-κB-related inhibitors should be carefully evaluated for use in patients after an arterial intervention.
PMCID: PMC3755353  PMID: 23241410
restenosis; arterial injury; platelets; leukocytes; NF-κB
8.  Activation, Immune Polarization, and Graft-versus-Leukemia Activity of Donor T-cells are Regulated by Specific Subsets of Donor Bone Marrow Antigen-Presenting Cells in Allogeneic Hematopoietic Stem Cell Transplantation1 
We investigated the roles of specific subsets of donor APCs purified from bone marrow in donor T cell activation and graft-vs-leukemia (GvL) activity in murine models of hemopoietic stem cell transplantation. Lineage−CD11c+ APC precursors were separated from donor bone marrow based on expression of CD11b. Transplanting lineage−CD11c+CD11b− APC (CD11b− APC) in combination with c-kit+Sca-1+lineage− hemopoietic stem cells (HSC) and congenic donor T cells led to increased donor CD4+ and CD8+ T cell proliferation and higher donor T cell chimerism than with transplanting grafts containing HSC, T cells, and lineage−CD11c+CD11b+ APCs (CD11b+ APC), or grafts containing only HSC and T cells. Transplanting CD11b− APCs induced Th1/type 1 cytotoxic T lymphocyte donor T cell immune polarization and enhanced GvL activity of donor T cells without increased graft-vs-host disease in both MHC- and minor histocompatibility Ag-mismatched murine hemopoietic stem cell transplantation models, whereas CD11b+ APCs led to Th2/type 2 cytotoxic T lymphocyte donor T cell immune polarization. Donor CD11b− APCs were plasmacytoid dendritic cell progenitors (>90% CD317; PDCA-1+) and up-regulated CD80, CD86, and IL-12 during alloantigen presentation, whereas CD11b+ APCs expressed Gr-1 and up-regulated expression of programmed death ligands-1 and 2 after activation. These results are the first to show that manipulation of the content of donor APCs in allogeneic HSC grafts can regulate donor T cell immunity and enhance GvL without increasing graft-vs-host disease activity.
PMCID: PMC3908652  PMID: 19933853
Antigen presenting cells; Dendritic Cells; T-cells; Graft versus Host Disease; Cell Activity; Tumor Immunity
9.  Proper PIN1 Distribution Is Needed for Root Negative Phototropism in Arabidopsis 
PLoS ONE  2014;9(1):e85720.
Plants can be adapted to the changing environments through tropic responses, such as light and gravity. One of them is root negative phototropism, which is needed for root growth and nutrient absorption. Here, we show that the auxin efflux carrier PIN-FORMED (PIN) 1 is involved in asymmetric auxin distribution and root negative phototropism. In darkness, PIN1 is internalized and localized to intracellular compartments; upon blue light illumination, PIN1 relocalize to basal plasma membrane in root stele cells. The shift of PIN1 localization induced by blue light is involved in asymmetric auxin distribution and root negative phototropic response. Both blue-light-induced PIN1 redistribution and root negative phototropism is mediated by a BFA-sensitive trafficking pathway and the activity of PID/PP2A. Our results demonstrate that blue-light-induced PIN1 redistribution participate in asymmetric auxin distribution and root negative phototropism.
PMCID: PMC3897508  PMID: 24465665
10.  Health Supervision in the Management of Children and Adolescents With IBD: NASPGHAN Recommendations 
Ulcerative colitis (UC) and Crohn disease (CD), collectively referred to as inflammatory bowel disease (IBD), are chronic inflammatory disorders that can affect the gastrointestinal tract of children and adults. Like other autoimmune processes, the cause(s) of these disorders remain unknown but likely involves some interplay between genetic vulnerability and environmental factors. Children, in particular with UC or CD, can present to their primary care providers with similar symptoms, including abdominal pain, diarrhea, weight loss, and bloody stool. Although UC and CD are more predominant in adults, epidemiologic studies have demonstrated that a significant percentage of these patients were diagnosed during childhood. The chronic nature of the inflammatory process observed in these children and the waxing and waning nature of their clinical symptoms can be especially disruptive to their physical, social, and academic development. As such, physicians caring for children must consider these diseases when evaluating patients with compatible symptoms. Recent research efforts have made available a variety of more specific and effective pharmacologic agents and improved endoscopic and radiologic assessment tools to assist clinicians in the diagnosis and interval assessment of their patients with IBD; however, as the level of complexity of these interventions has increased, so too has the need for practitioners to become familiar with a wider array of treatments and the risks and benefits of particular diagnostic testing. Nonetheless, in most cases, and especially when frequent visits to subspecialty referral centers are not geographically feasible, primary care providers can be active participants in the management of their pediatric patients with IBD. The goal of this article is to educate and assist pediatricians and adult gastroenterology physicians caring for children with IBD, and in doing so, help to develop more collaborative care plans between primary care and subspecialty providers.
PMCID: PMC3895471  PMID: 22516861
Crohn disease; health supervision; inflammatory bowel disease; preventive care; primary care; ulcerative colitis
11.  Proteome Differences Between Male and Female Fetal Cells in Amniotic Fluid 
In mammals, sex development is genetically and hormonally regulated. The process starts with the establishment of chromosomal structures (XY or XX), followed by the expression of sex-dependent genes. In order to elucidate the differential protein profiles between male and female amniocytes, a proteomic approach has been performed in this study. Here, we utilized a proteomics-based approach including 2D-DIGE and MALDI-TOF MS analysis to obtain differentially expressed proteins between male and female amniocytes. After resolving protein samples with 2D-DIGE technique, 45 proteins corresponding to 28 unique proteins were differentially expressed between male and female amninocytes from three independent batches of amniotic fluid. Of all of these unique identified spots, five of them (annexin A1, cathepsin D, cytoskeletal 19, protein disulfide-isomerase, and vimentin) exhibited more than 1.5-fold upregulation or downregulation in at least two independent experiments. Importantly, the identified proteins involved in protein degradation and protein folding display upregulated in male amniocytes, implying the differential regulations of protein degradation and protein folding during sex development. In conclusion, the identified differentially expressed proteins may be employed as potential signatures for the sex development. Moreover, the established proteomic platform might further utilize to discover the potential biomarkers for the prenatal genetic disorders in fetus.
PMCID: PMC3545359  PMID: 22404150
12.  Role of ROS and auxin in plant response to metal-mediated stress 
Plant Signaling & Behavior  2013;8(7):e24671.
Being unable to move away from their places of germination, in order to avoid excess metal-induced damages, plants have to evolve different strategies and complex regulatory mechanisms to survive harsh conditions. While both ROS and auxin are documented to be important in plant response to metal stress, the mechanisms underlying the crosstalk between ROS and auxin in metal stress are poorly understood. In this review, we provide an update on the regulation of plant responses to metal-stress by ROS and auxin signaling pathways, primarily, with a focus on the copper, aluminum and cadmium stress. We aim at surveying the mechanisms underlying how metal stress modulates the changes in auxin distribution and the network of ROS and auxin in plant response to metal stress based on recent studies.
PMCID: PMC3906317  PMID: 23603941
abiotic stress; aluminium; auxin; cadmium; metal stress; copper; heavy metal stress; ROS
13.  Effects of HLEC on the secreted proteins of epithelial ovarian cancer cells prone to metastasize to lymph nodes 
Cancer Biology & Medicine  2013;10(4):221-226.
To study explores the effect of HLEC on the secreted proteins of epithelial ovarian cancer (EOC) cells (SKOV3-PM4) with directional highly lymphatic metastasis.
Supernatants of four groups of cultured cells, namely, SKOV3 (A), SKOV3+HLEC (B), SKOV3-PM4 (C), SKOV3-PM4+HLEC (D), were collected, and their proteins were detected by antibody arrays and iTRAQ-2D-LC-MALDI-TOF/TOF/MS. Significantly differential proteins were further analyzed via bioinformatics and validated in human serums and cell media via ELISA.
Results of antibody arrays and mass spectrometry demonstrated that GRN and VEGFA were upregulated in group C (compared with group A), whereas IGFBP7 and SPARC were downregulated in group D (compared with group C). Comprehensive bioinformatics analysis results showed that IGFBP7 and VEGFA were closely linked to each other. Further validation with serums showed statistical significance in VEGFA and IGFBP7 levels among groups of patients with ovarian cancers, benign tumors, and control groups. Two proteins were upegulated in the first group. VEGFA in the control group was downregulated. For IGFBP, upregulation in the control group and down-regulation in the first group were also observed.
The HLEC microenvironment is closely associated with directional metastasis to lymph nodes and with differential proteins including cell stromal proteins and adhesion factors. The upregulation of VEGFA and GRN and the downregulation of SPARC and IGFBP7 are closely associated with directional metastasis to lymph nodes in EOC cells.
PMCID: PMC3860345  PMID: 24349832
Ovarian cancer; tumor microenvironment; lymphatic metastasis; human lymphatic capillary endothelial cells; secreted proteins
14.  SCF-Mediated Cdh1 Degradation Defines a Negative Feedback System that Coordinates Cell-Cycle Progression 
Cell reports  2013;4(4):10.1016/j.celrep.2013.07.031.
Proper cell-cycle transitions are driven by waves of ubiquitin-dependent degradation of key regulators by the anaphase-promoting complex (APC) and Skp1-Cullin1-F-box (SCF) E3 ubiquitin ligase complexes. But precisely how APC and SCF activities are coordinated to regulate cell-cycle progression remains largely unclear. We previously showed that APC/Cdh1 earmarks the SCF component Skp2 for degradation. Here, we continue to report that SCFβ-TRCP reciprocally controls APC/Cdh1 activity by governing Cdh1 ubiquitination and subsequent degradation. Furthermore, we define both cyclin A and Plk1, two well-known Cdh1 substrates, as upstream modifying enzymes that promote Cdh1 phosphorylation to trigger Cdh1 ubiquitination and subsequent degradation by SCFβ-TRCP. Thus, our work reveals a negative repression mechanism for SCF to control APC, thereby illustrating an elegant dual repression system between these two E3 ligase complexes to create the ordered cascade of APC and SCF activities governing timely cell-cycle transitions.
PMCID: PMC3839583  PMID: 23972993
15.  TIME FOR COFFEE controls root meristem size by changes in auxin accumulation in Arabidopsis  
Journal of Experimental Botany  2013;65(1):275-286.
Reduced root meristem length in tic mutant is due to the repressed expression of PIN genes for decreased acropetal auxin transport, leading to low auxin accumulation. MYC2-mediated JA-signaling pathway may not be involved in this process
Roots play important roles in plant survival and productivity as they not only anchor the plants in the soil but are also the primary organ for the uptake of nutrients from the outside. The growth and development of roots depend on the specification and maintenance of the root meristem. Here, we report a previously unknown role of TIME FOR COFFEE (TIC) in controlling root meristem size in Arabidopsis. The results showed that loss of function of TIC reduced root meristem length and cell number by decreasing the competence of meristematic cells to divide. This was due to the repressed expression of PIN genes for decreased acropetal auxin transport in tic-2, leading to low auxin accumulation in the roots responsible for reduced root meristem, which was verified by exogenous application of indole-3-acetic acid. Downregulated expression of PLETHORA1 (PLT1) and PLT2, key transcription factors in mediating the patterning of the root stem cell niche, was also assayed in tic-2. Similar results were obtained with tic-2 and wild-type plants at either dawn or dusk. We also suggested that the MYC2-mediated jasmonic acid signalling pathway may not be involved in the regulation of TIC in controlling the root meristem. Taken together, these results suggest that TIC functions in an auxin–PLTs loop for maintenance of post-embryonic root meristem.
PMCID: PMC3883298  PMID: 24277277
Arabidopsis thaliana; auxin; circadian clock; jasmonic acid; MYC2; PIN; root meristem; TIME FOR COFFEE.
16.  SUMOylation of PPARγ by Rosiglitazone Prevents LPS-Induced NCoR Degradation Mediating Down Regulation of Chemokines Expression in Renal Proximal Tubular Cells 
PLoS ONE  2013;8(11):e79815.
Rosiglitazone (RGL), a synthetic agonist for peroxisome proliferator activated receptor γ (PPARγ), exhibits a potent anti-inflammatory activity by attenuating local infiltration of neutrophils and monocytes in the renal interstitium. To evaluate the mechanisms that account for inhibiting inflammatory cells infiltration, we investigated the effect of RGL on chemokines secretion and nuclear factor-kappa B (NF-κB) activation in human renal proximal tubular cells (PTCs). We demonstrated that RGL significantly inhibited lipopolysaccharide (LPS)-induced interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) production in a dose-dependent manner, without appreciable cytotoxicity. Chromatin immunoprecipitation (ChIP) assays clearly revealed that, RGL inhibited p65 binding to IL-8/MCP-1 gene promoters in LPS-stimulated PTCs. Interestingly, further experiments showed RGL reversed LPS-induced nuclear receptor corepressor (NCoR) degradation. In addition, knockdown of protein inhibitor of activated STAT1 (PIAS1), an indispensable small ubiquitin-like modifier (SUMO) ligase, abrogated the effects of RGL on antagonizing LPS-induced IL-8/MCP-1 overexpression and NCoR degradation. These findings suggest that, RGL activates PPARγ SUMOylation, inhibiting NCoR degradation and NF-κB activation in LPS-stimulated PTCs, which in turn decrease chemokines expression. The results unveil a new mechanism triggered by RGL for prevention of tubular inflammatory injury.
PMCID: PMC3832667  PMID: 24260304
17.  Immune response to influenza vaccine in children with inflammatory bowel disease 
Patients with inflammatory bowel disease (IBD) frequently receive immunosuppressive therapy. The immune response in these patients to vaccines has not been well studied. We conducted a prospective, open label study to evaluate the serologic response to influenza vaccine in children with IBD.
Serum was obtained from 146 children and young adults with IBD (96 CD, 47 UC, 3 IC) for baseline influenza titer, immediately followed by immunization with trivalent [A/Solomon Islands/3/2006 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004 (B)] inactivated influenza vaccine. Subjects returned for repeat titers 3-9 weeks later. Seroprotection against each influenza strain was defined as hemagglutination inhibition (HAI) titer ≥40. Patients were categorized as non-immunosuppressed [(NIS), aminosalicylates only, antibiotics only, or no therapy] or immunosuppressed [(IS), any immunosuppressive agent]. IS patients were further subcategorized as: (1) tacrolimus; (2) TNF-alpha inhibitor; (3) immunomodulator; and (4) corticosteroids only.
More patients were seroprotected against strains A/H1N1 and A/H3N2 than B strain (p<0.02), regardless of immunosuppression status. The proportion seroprotected and geometric mean titers at post-vaccination were similar between NIS and IS groups for all three strains. Subanalysis of patients not seroprotected at baseline showed that those receiving anti-TNF therapy were less likely seroprotected against strain B (14%) compared to patients in the NIS group (39%, p=0.025). There were no serious vaccine-associated adverse events.
Influenza vaccination produces a high prevalence of seroprotection in IBD patients, particularly against A strains. The vaccine is well tolerated. Routine influenza vaccination in IBD patients is recommended, irrespective of whether patients receive immunosuppressive medications.
PMCID: PMC3805272  PMID: 19174786
18.  Neuroprotective Effect of Ginkgolide B on Bupivacaine-Induced Apoptosis in SH-SY5Y Cells 
Local anesthetics are used routinely and effectively. However, many are also known to activate neurotoxic pathways. We tested the neuroprotective efficacy of ginkgolide B (GB), an active component of Ginkgo biloba, against ROS-mediated neurotoxicity caused by the local anesthetic bupivacaine. SH-SY5Y cells were treated with different concentrations of bupivacaine alone or following preincubation with GB. Pretreatment with GB increased SH-SY5Y cell viability and attenuated intracellular ROS accumulation, apoptosis, mitochondrial dysfunction, and ER stress. GB suppressed bupivacaine-induced mitochondrial depolarization and mitochondria complex I and III inhibition and increased cleaved caspase-3 and Htra2 expression, which was strongly indicative of activation of mitochondria-dependent apoptosis with concomitantly enhanced expressions of Grp78, caspase-12 mRNA, protein, and ER stress. GB also improved ultrastructural changes indicative of mitochondrial and ER damage induced by bupivacaine. These results implicate bupivacaine-induced ROS-dependent mitochondria, ER dysfunction, and apoptosis, which can be attenuated by GB through its antioxidant property.
PMCID: PMC3818975  PMID: 24228138
19.  De novo combined lamivudine and adefovir dipivoxil therapy vs entecavir monotherapy for hepatitis B virus-related decompensated cirrhosis 
AIM: To compare efficacy of combined lamivudine (LAM) and adefovir dipivoxil (ADV) therapy with that of entecavir (ETV) monotherapy for hepatitis B virus (HBV)-related decompensated liver cirrhosis.
METHODS: A total of 120 naïve patients with HBV-related decompensated cirrhosis participated in this study. Sixty patients were treated with combined LAM and ADV therapy (LAM + ADV group), while the other 60 were treated with ETV monotherapy (ETV group) for two years. Tests for liver and kidney function, alpha-fetoprotein, HBV serum markers, HBV DNA load, prothrombin time (PT), and ultrasonography or computed tomography scan of the liver were performed every 1 to 3 mo. Repeated measure ANOVA and the χ2 test were performed to compare the efficacy, side effects, and the cumulative survival rates at 48 and 96 wk.
RESULTS: Forty-five patients in each group were observed for 96 wk. No significant differences in HBV DNA negative rates and alanine aminotransferase (ALT) normalization rates at weeks 48 (χ2 = 2.12 and 2.88) and 96 (χ2 = 3.21 and 3.24) between the two groups were observed. Hepatitis B e antigen seroconversion rate in the LAM + ADV group at week 96 was significantly higher in the ETV group (43.5% vs 36.4%, χ2 = 4.09, P < 0.05). Viral breakthrough occurred in 2 cases (4.4%) by week 48 and in 3 cases (6.7%) by week 96 in the LAM + ADV group, and no viral mutation was detected. In the ETV group, viral breakthrough occurred in 1 case (2.2%) at the end of week 96. An increase in albumin (F = 18.9 and 17.3), decrease in total bilirubin and in ALT (F = 16.5, 17.1 and 23.7, 24.8), reduced PT (F = 22.7 and 24.5), and improved Child-Turcotte-Pugh and the model for end-stage liver disease scores (F = 18.5, 17.8, and 24.2, 23.8) were observed in both groups. The cumulative rates of mortality and liver transplantation were 16.7% (10/60) and 18.3% (11/60) in the LAM + ADV and ETV groups, respectively.
CONCLUSION: Both LAM + ADV combination therapy and ETV monotherapy can effectively inhibit HBV replication, improve liver function, and decrease mortality.
PMCID: PMC3787360  PMID: 24115827
Chronic hepatitis B; Decompensated liver cirrhosis; Lamivudine; Adefovir dipivoxil; Combination therapy; Entecavir
20.  Gallbladder Gallstone Disease Is Associated with Newly Diagnosed Coronary Artery Atherosclerotic Disease: A Cross-Sectional Study 
PLoS ONE  2013;8(9):e75400.
Background and Aims
The association between gallstone disease and coronary artery atherosclerotic disease (CAD) remains unclear. To clarify their relationship, patients with CAD newly diagnosed by coronary angiography were investigated in this cross-sectional study.
The study cohort consisted of 1,270 patients undergoing coronary angiography for the first time between January 2007 and September 2011. Patients with ≥50% diameter stenosis in any major coronary artery on coronary angiography were defined as being CAD positive (n = 766) and those with no stenosis as CAD negative (n = 504). Multivariate logistic regression was used to investigate the relationship between gallstone disease and CAD. The odds ratios (OR) of factors associated with CAD were calculated. In addition, CAD-positive and CAD-negative patients were matched one-to-one by age, gender and metabolic syndrome (MetS), and the association between gallbladder disease and CAD was determined.
The prevalence of gallstone disease was significantly higher in CAD-positive than in CAD negative patients (149/766 [19.5%] vs 57/504 [11.3%], P<0.01). Gallstone disease was significantly associated with CAD (adjusted OR = 1.59, 95% confidence interval [CI] 1.10–2.31). Following matched pairing of 320 patients per group, gallstone disease remained significantly associated with CAD (adjusted OR = 1.69, 95% CI: 1.08–2.65).
Gallstone disease is strongly associated with CAD diagnosed by coronary angiography.
PMCID: PMC3776774  PMID: 24058685
21.  Overexpression of Arginine Transporter CAT-1 Is Associated with Accumulation of L-Arginine and Cell Growth in Human Colorectal Cancer Tissue 
PLoS ONE  2013;8(9):e73866.
We previously showed that L-arginine (Arg) accumulates in colorectal cancer tissues. The aim of this study was to investigate the mechanism by which Arg accumulates and determine its biological significance. The concentration of Arg and Citrulline (Cit) in sera and tumor tissues from colorectal cancer (CRC) patients was analyzed by high-performance liquid chromatography (HPLC). The expression of Arg transporters was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemical analysis of tissue microarray. We also transfected the colon cancer cell line HCT-116 with siRNA specific for the Arg transporter CAT-1 and measured the induction of apoptosis by flow cytometry and cell proliferation by MTT assay. Consistent with our previous results, serum Arg and Cit concentrations in colorectal cancer patients were significantly lower than those in normal volunteers, while Arg and Cit concentrations in colorectal cancer tissues were significantly higher than in matched adjacent normal colon tissues. Quantitative RT-PCR showed that the CAT-1 gene was highly overexpressed in 70.5% of colorectal cancer tissue samples relative to adjacent normal colon tissues in all 122 patients with colorectal cancer. Immunohistochemical analysis of tissue microarray confirmed that the expression of CAT-1 was higher in all 25 colorectal cancer tissues tested. CAT-1 siRNA significantly induced apoptosis of HCT-116 cells and subsequently inhibited cell growth by 20–50%. Our findings indicate that accumulation of L-Arg and Cit and cell growth in colorectal cancer tissues is associated with over-expression of the Arg transporter gene CAT-1. Our results may be useful for the development of molecular diagnostic tools and targeted therapy for colorectal cancer.
PMCID: PMC3765253  PMID: 24040099
22.  De Novo Transcriptome of Brassica juncea Seed Coat and Identification of Genes for the Biosynthesis of Flavonoids 
PLoS ONE  2013;8(8):e71110.
Brassica juncea, a worldwide cultivated crop plant, produces seeds of different colors. Seed pigmentation is due to the deposition in endothelial cells of proanthocyanidins (PAs), end products from a branch of flavonoid biosynthetic pathway. To elucidate the gene regulatory network of seed pigmentation in B. juncea, transcriptomes in seed coat of a yellow-seeded inbred line and its brown-seeded near- isogenic line were sequenced using the next-generation sequencing platform Illumina/Solexa and de novo assembled. Over 116 million high-quality reads were assembled into 69,605 unigenes, of which about 71.5% (49,758 unigenes) were aligned to Nr protein database with a cut-off E-value of 10−5. RPKM analysis showed that the brown-seeded testa up-regulated 802 unigenes and down-regulated 502 unigenes as compared to the yellow-seeded one. Biological pathway analysis revealed the involvement of forty six unigenes in flavonoid biosynthesis. The unigenes encoding dihydroflavonol reductase (DFR), leucoantho-cyanidin dioxygenase (LDOX) and anthocyanidin reductase (ANR) for late flavonoid biosynthesis were not expressed at all or at a very low level in the yellow-seeded testa, which implied that these genes for PAs biosynthesis be associated with seed color of B. juncea, as confirmed by qRT-PCR analysis of these genes. To our knowledge, it is the first time to sequence the transcriptome of seed coat in Brassica juncea. The unigene sequences obtained in this study will not only lay the foundations for insight into the molecular mechanisms underlying seed pigmentation in B.juncea, but also provide the basis for further genomics research on this species or its allies.
PMCID: PMC3747200  PMID: 23990927
23.  Synthesis and Cell Adhesive Properties of Linear and Cyclic RGD Functionalized Polynorbornene Thin Films 
Biomacromolecules  2012;13(8):2546-2553.
Described herein is the efficient synthesis and evaluation of bioactive arginine-glycine-aspartic acid (RGD) functionalized polynorbornene based materials for cell adhesion and spreading. Polynorbornenes containing either linear or cyclic RGD peptides were synthesized by ring-opening metathesis polymerization (ROMP) using the well-defined ruthenium initiator [(H2IMes)(pyr)2(Cl)2Ru=CHPh]. The random copolymerization of three separate norbornene monomers allowed for the incorporation of water-soluble polyethylene glycol (PEG) moieties, RGD cell recognition motifs, and primary amines for post-polymerization cross-linking. Following polymer synthesis, thin-film hydrogels were formed by cross-linking with bis(sulfosuccinimidyl) suberate (BS3), and the ability of these materials to support human umbilical vein endothelial cell (HUVEC) adhesion and spreading was evaluated and quantified. When compared to control polymers containing either no peptide or a scrambled RDG peptide, polymers with linear or cyclic RGD at varying concentrations displayed excellent cell adhesive properties in both serum-supplemented and serum-free media. Polymers with cyclic RGD side chains maintained cell adhesion and exhibited comparable integrin binding at a 100-fold lower concentration than those carrying linear RGD peptides. The precise control of monomer incorporation enabled by ROMP allows for quantification of the impact of RGD structure and concentration on cell adhesion and spreading. The results presented here will serve to guide future efforts for the design of RGD functionalized materials with applications in surgery, tissue engineering, and regenerative medicine.
PMCID: PMC3442365  PMID: 22783892
polynorbornenes; ROMP; RGD; thin films; HUVEC; cell adhesion
24.  Lactobacillus plantarum MYL26 induces endotoxin tolerance phenotype in Caco-2 cells 
BMC Microbiology  2013;13:190.
Crohn's disease and ulcerative colitis are the major types of chronic inflammatory bowel disease occurring in the colon and small intestine. A growing body of research has proposed that probiotics are able to attenuate the inflammatory symptoms of these diseases in vitro and in vivo. However, the mechanism of probiotic actions remains unclear.
Our results suggested Lactobacillus plantarum MYL26 inhibited inflammation in Caco-2 cells through regulation of gene expressions of TOLLIP, SOCS1, SOCS3, and IκBα, rather than SHIP-1 and IRAK-3.
We proposed that live/ heat-killed Lactobacillus plantarum MYL26 and bacterial cell wall extract treatments impaired TLR4-NFκb signal transduction through Tollip, SOCS-1 and SOCS-3 activation, thus inducing LPS tolerance. Our findings suggest that either heat-killed probiotics or probiotic cell wall extracts are able to attenuate inflammation through pathways similar to that of live bacteria.
PMCID: PMC3751156  PMID: 23937116
Lactobacillus plantarum MYL26; Lipopolysaccharide; Caco-2 cells
25.  Automatic functional analysis of left ventricle in cardiac cine MRI 
Rationale and objectives
A fully automated left ventricle segmentation method for the functional analysis of cine short axis (SAX) magnetic resonance (MR) images was developed, and its performance evaluated with 133 studies of subjects with diverse pathology: ischemic heart failure (n=34), non-ischemic heart failure (n=30), hypertrophy (n=32), and healthy (n=37).
Materials and methods
The proposed automatic method locates the left ventricle (LV), then for each image detects the contours of the endocardium, epicardium, papillary muscles and trabeculations. Manually and automatically determined contours and functional parameters were compared quantitatively.
There was no significant difference between automatically and manually determined end systolic volume (ESV), end diastolic volume (EDV), ejection fraction (EF) and left ventricular mass (LVM) for each of the four groups (paired sample t-test, α=0.05). The automatically determined functional parameters showed high correlations with those derived from manual contours, and the Bland-Altman analysis biases were small (1.51 mL, 1.69 mL, –0.02%, –0.66 g for ESV, EDV, EF and LVM, respectively).
The proposed technique automatically and rapidly detects endocardial, epicardial, papillary muscles’ and trabeculations’ contours providing accurate and reproducible quantitative MRI parameters, including LV mass and EF.
PMCID: PMC3759139  PMID: 24040616
Left ventricular ejection fraction; left ventricular mass (LVM); cardiac magnetic resonance imaging; automated border detection; image processing

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