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1.  Whole Exome Sequencing Reveals Overlap Between Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis and Familial Hemophagocytic Lymphohistiocytosis 
Macrophage activation syndrome (MAS), a life-threatening complication of systemic Juvenile Idiopathic Arthritis (SJIA), resembles Familial Hemophagocytic Lymphohistiocytosis (FHLH), a constellation of autosomal recessive immune disorders resulting from deficiency in cytolytic pathway proteins. We hypothesized that MAS predisposition in SJIA could be attributed to rare gene sequence variants affecting the cytotolytic pathway.
Whole exome sequencing (WES) was used in 14 SJIA/MAS patients and their parents to identify protein altering SNPs/indels in the known HLH-associated genes. To discover new candidate genes, the entire WES data were filtered to identify protein altering, rare recessive homozygous, compound heterozygous, and de novo variants with the potential to affect the cytolytic pathway.
Heterozygous protein-altering rare variants in the known genes (LYST, MUNC13-4, and STXBP2) were found in 5 of 14 SJIA/MAS patients (35.7%). This was in contrast to only 4 variants in 4 of 29 (13,7%) SJIA patients without MAS. Homozygosity and compound heterozygosity analysis applied to the entire WES data in SJIAMAS, revealed 3 recessive pairs in 3 genes, and 76 compound heterozygotes in 75 genes. We also identified 22 heterozygous rare protein altering variants that occurred in at least two patients. Many of the identified genes encode proteins with a role in actin and microtubule reorganization and vesicle-mediated transport. “Cellular assembly and organization” was the top cellular function category based on Ingenuity Pathways Analysis (p<3.10E-05).
WES performed in SJIA/MAS patients identified rare protein altering variants in the known HLH associated genes as well as new candidate genes.
PMCID: PMC4321811  PMID: 25047945
2.  Possible Electric-Field-Induced Superconducting States in Doped Silicene 
Scientific Reports  2015;5:8203.
Silicene has been synthesized recently, with experimental evidence showing possible superconductivity in the doped case. The noncoplanar low-buckled structure of this material inspires us to study the pairing symmetry of the doped system under a perpendicular external electric field. Our study reveals that the electric field induces an interesting quantum phase transition from the singlet chiral d + id′-wave superconducting phase to the triplet f-wave one. The emergence of the f-wave pairing results from the sublattice-symmetry-breaking caused by the electric field and the ferromagnetic-like intra-sublattice spin correlations at low dopings. Due to the enhanced density of states, the superconducting critical temperature of the system is enhanced by the electric field remarkably. Furthermore, we design a particular dc SQUID experiment to detect the quantum phase transition predicted here. Our results, if confirmed, will inject a new vitality to the familiar Si-based industry through adopting doped silicene as a tunable platform to study different types of exotic unconventional superconductivities.
PMCID: PMC4314630  PMID: 25644143
3.  Expression and function of NIK- and IKK2-binding protein (NIBP) in mouse enteric nervous system 
NIBP/TRAPPC9 is expressed in brain neurons, and human NIBP mutations are associated with neurodevelopmental disorders. The cellular distribution and function of NIBP in the enteric nervous system (ENS) remain unknown.
Western blot and RT-PCR analysis were used respectively to identify the protein and mRNA expression of NIBP and other neuronal markers. Multilabeled immunofluorescent microscopy and confocal image analysis were used to examine the cellular distribution of NIBP-like immunoreactivity (IR) in whole mount intestine. Enteric neuronal cell line (ENC) was infected with lentivirus carrying NIBP or its shRNA expression vectors and treated with vehicle or TNFα.
Key Results
NIBP is expressed at both mRNA and protein levels in different regions and layers of the mouse intestine. NIBP-like-IR was co-localized with various neuronal markers, but not with glial, smooth muscular, or ICC markers. A small population of NIBP-expressing cells and fibers in extra-ganglionic and intra-ganglionic area were negative for pan-neuronal markers HuD or Peripherin. Relatively high NIBP-like-IR was found in 35-44% of myenteric neurons and 9-10% of submucosal neurons. Approximately 98%, 87% and 43% of these relatively high NIBP-expressing neurons were positive for ChAT, nNOS and Calretinin, respectively. NIBP shRNA knockdown in ENC inhibited TNFα-induced NFkB activation and neuronal differentiation, whereas NIBP overexpression promoted it.
Conclusions & Inferences
NIBP is extensively expressed in the ENS with relatively high level in a subpopulation of enteric neurons. Various NIBP expression levels in different neurons may represent dynamic trafficking or posttranslational modification of NIBP in some functionally-active neurons and ultimately regulate ENS plasticity.
PMCID: PMC3962790  PMID: 24011459
Enteric nervous system; NFκB; TRAPPC9/NIBP; Cytokines; Immunohistochemistry; Confocal image; Enteric neuronal cell line
4.  Dormancy cycling and persistence of seeds in soil of a cold desert halophyte shrub 
Annals of Botany  2013;113(1):171-179.
Background and Aims
Formation of seed banks and dormancy cycling are well known in annual species, but not in woody species. In this study it was hypothesized that the long-lived halophytic cold desert shrub Kalidium gracile has a seed bank and dormancy cycling, which help restrict germination to a favourable time for seedling survival.
Fresh seeds were buried in November 2009 and exhumed and tested for germination monthly from May 2010 to December 2011 over a range of temperatures and salinities. Germination recovery and viability were determined after exposure to salinity and water stress. Seedling emergence and dynamics of the soil seed bank were investigated in the field.
Key Results
Seeds of K. gracile had a soil seed bank of 7030 seeds m−2 at the beginning of the growing season. About 72 % of the seeds were depleted from the soil seed bank during a growing season, and only 1·4 % of them gave rise to seedlings that germinated early enough to reach a stage of growth at which they could survive to overwinter. About 28 % of the seeds became part of a persistent soil seed bank. Buried seeds exhibited an annual non-dormancy/conditional dormancy (ND/CD) cycle, and germination varied in sensitivity to salinity during the cycle. Dormancy cycling is coordinated with seasonal environmental conditions in such a way that the seeds germinate in summer, when there is sufficient precipitation for seedling establishment.
Kalidium gracile has three life history traits that help ensure persistence at a site: a polycarpic perennial life cycle, a persistent seed bank and dormancy cycling. The annual ND/CD cycle in seeds of K. gracile contributes to seedling establishment of this species in the unpredictable desert environment and to maintenance of a persistent soil seed bank. This is the first report of a seed dormancy cycle in a cold desert shrub.
PMCID: PMC3864727  PMID: 24249808
Cold desert habitat; dormancy cycling; halophyte; Kalidium gracile; salt tolerance; seed germination; seedling recruitment; soil seed bank
5.  Doxorubicin, DNA torsion, and chromatin dynamics 
Biochimica et biophysica acta  2013;1845(1):84-89.
Doxorubicin is one of the most important anti-cancer chemotherapeutic drugs, being widely used for the treatment of solid tumors and acute leukemias. The action of doxorubicin and other anthracycline drugs has been intensively investigated during the last several decades, but the mechanisms that have been proposed for cell killing remain disparate and controversial. In this review, we examine the proposed models for doxorubicin action from the perspective of the chromatin landscape, which is altered in many types of cancer due to recurrent mutations in chromatin modifiers. We highlight recent evidence for effects of anthracyclines on DNA torsion and chromatin dynamics that may underlie basic mechanisms of doxorubicin-mediated cell death and suggest new therapeutic strategies for cancer treatment.
PMCID: PMC3927826  PMID: 24361676
doxorubicin; anthracycline; cancer; DNA torsion; chromatin dynamics; chemotherapy
6.  AtROP1 negatively regulates potato resistance to Phytophthora infestans via NADPH oxidase-mediated accumulation of H2O2 
BMC Plant Biology  2014;14:392.
Small GTPases are monomeric guanine nucleotide-binding proteins. In plants, ROPs regulate plant cell polarity, plant cell differentiation and development as well as biotic and abiotic stress signaling pathways.
We report the subcellular localization of the AtRop1 protein at the plasma membrane in tobacco epidermal cells using GFP fusions. Additionally, transient and stable expression of a dominant negative form (DN) of the Arabidopsis AtRop1 in potato led to H2O2 accumulation associated with the reduced development of Phytophthora infestans Montagne de Bary and smaller lesions on infected potato leaves. The expression of the Strboh-D gene, a NADPH oxidase homologue in potato, was analyzed by RT-PCR. Expression of this gene was maintained in DN-AtRop1 transgenic plants after infection with P. infestans. In transgenic potato lines, the transcript levels of salicylic acid (SA) and jasmonic acid (JA) marker genes (Npr1 and Lox, respectively) were analyzed. The Lox gene was induced dramatically whereas expression of Npr1, a gene up-regulated by SA, decreased slightly in DN-AtRop1 transgenic plants after infection with P. infestans.
In conclusion, our results indicate that DN-AtROP1 affects potato resistance to P. infestans. This is associated with increased NADPH oxidase-mediated H2O2 production and JA signaling.
PMCID: PMC4323192  PMID: 25547733
AtRop1; Potato; Resistance; NADPH oxidase; H2O2 production; Jasmonic acid
7.  Efficacy of GP referral of insufficiently active patients for expert physical activity counseling: protocol for a pragmatic randomized trial (The NewCOACH trial) 
BMC Family Practice  2014;15(1):218.
Physical inactivity is fourth in the list of risk factors for global mortality. General practitioners are well placed to offer physical activity counseling but insufficient time is a barrier. Although referral to an exercise specialist is an alternative, in Australia, these allied health professionals are only publicly funded to provide face-to-face counseling to patients who have an existing chronic illness. Accordingly, this trial aims to determine the efficacy of GP referral of insufficiently active patients (regardless of their chronic disease status) for physical activity counseling (either face-to-face or predominately via telephone) by exercise specialists, based on patients’ objectively assessed physical activity levels, compared with usual care. If the trial is efficacious, the equivalence and cost-effectiveness of face-to-face counseling versus telephone counseling will be assessed.
This three arm pragmatic randomized trial will involve the recruitment of 261 patients from primary care clinics in metropolitan and regional areas of New South Wales, Australia. Insufficiently active (less than 7000 steps/day) consenting adult patients will be randomly assigned to: 1) five face-to-face counseling sessions, 2) one face-to-face counseling session followed by four telephone calls, or 3) a generic mailed physical activity brochure (usual care). The interventions will operationalize social cognitive theory via a behavior change counseling framework. Participants will complete a survey and seven days of pedometry at baseline, and at three and 12 months post-randomization. The primary analyses will be based on intention-to-treat principles and will compare: (i) mean change in average daily step counts between baseline and 12 months for the combined intervention group (Group 1: face-to-face, and Group 2: telephone) and usual care (Group 3); (ii) step counts at 3 months post-randomization. Secondary outcomes include: self-reported physical activity, sedentary behavior, quality of life, and depression.
If referral of primary care patients to exercise specialists increases physical activity, this process offers the prospect of systematically and sustainably reaching a large proportion of insufficiently active adults. If shown to be efficacious this trial provides evidence to expand public funding beyond those with a chronic disease and for delivery via telephone as well as face-to-face consultations.
Trial registration
Australian New Zealand Clinical Trials Registry ACTRN12611000884909.
PMCID: PMC4305254  PMID: 25543688
Physical activity; Primary care; Referral; Pedometry
8.  Clinical trial with traditional Chinese medicine intervention ''tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment'' for chronic hepatitis B-associated liver failure 
World Journal of Gastroenterology : WJG  2014;20(48):18458-18465.
AIM: To study the clinical efficacy of traditional Chinese medicine (TCM) intervention “tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment” (“TTK”) for treating liver failure due to chronic hepatitis B.
METHODS: We designed the study as a randomized controlled clinical trial. Registration number of Chinese Clinical Trial Registry is ChiCTR-TRC-12002961. A total of 144 patients with liver failure due to infection with chronic hepatitis B virus were enrolled in this randomized controlled clinical study. Participants were randomly assigned to the following three groups: (1) a modern medicine control group (MMC group, 36 patients); (2) a “tonifying qi and detoxification” (“TQD”) group (72 patients); and (3) a “tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment” (“TTK”) group (36 patients). Patients in the MMC group received general internal medicine treatment; patients in the “TQD” group were given a TCM formula “tonifying qi and detoxification” and general internal medicine treatment; patients in the “TTK” group were given a TCM formula of “TTK” and general internal medicine treatment. All participants were treated for 8 wk and then followed at 48 wk following their final treatment. The primary efficacy end point was the patient fatality rate in each group. Measurements of various virological and biochemical indicators served as secondary endpoints. The one-way analysis of variance and the t-test were used to compare patient outcomes in the different treatment groups.
RESULTS: At the 48-wk post-treatment time point, the patient fatality rates in the MMC, “TQD”, and “TTK” groups were 51.61%, 35.38%, and 16.67%, respectively, and the differences between groups were statistically significant (P < 0.05). However, there were no significant differences in the levels of hepatitis B virus DNA or prothrombin activity among the three groups (P > 0.05). Patients in the “TTK” group had significantly higher levels of serum total bilirubin compared to MMC subjects (339.40 μmol/L ± 270.09 μmol/L vs 176.13 μmol/L ± 185.70 μmol/L, P = 0.014). Serum albumin levels were significantly increased in both the “TQD” group and “TTK” group as compared with the MMC group (31.30 g/L ± 4.77 g/L, 30.72 g/L ± 2.89 g/L vs 28.57 g/L ± 4.56 g/L, P < 0.05). There were no significant differences in levels of alanine transaminase among the three groups (P > 0.05). Safety data showed that there was one case of stomachache in the “TQD” group and one case of gastrointestinal side effect in the “TTK” group.
CONCLUSION: Treatment with “TTK” improved the survival rates of patients with liver failure due to chronic hepatitis B. Additionally, liver tissue was regenerated and liver function was restored.
PMCID: PMC4277987  PMID: 25561817
Clinical study; “Tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment” (“TTK”); Liver regeneration; Treatment with integrated traditional and Western medicine; Chronic hepatitis B-associated liver failure
9.  Fabrication and investigation of the optoelectrical properties of MoS2/CdS heterojunction solar cells 
Nanoscale Research Letters  2014;9(1):662.
Molybdenum disulfide (MoS2)/cadmium sulfide (CdS) heterojunction solar cells were successfully synthesized via chemical bath deposition (CBD) and chemical vapor deposition (CVD). The as-grown CdS film on a fluorine tin oxide (FTO) substrate deposited by CBD is continuous and compact. The MoS2 film deposited by CVD is homogeneous and continuous, with a uniform color and a thickness of approximately 10 nm. The optical absorption range of the MoS2/CdS heterojunction covers the visible and near-infrared spectral regions of 350 to 800 nm, which is beneficial for the improvement of solar cell efficiency. Moreover, the MoS2/CdS solar cell exhibits good current-voltage (I-V) characteristics and pronounced photovoltaic behavior, with an open-circuit voltage of 0.66 V and a short-circuit current density of 0.227 × 10-6 A/cm2, comparable to the results obtained from other MoS2-based solar cells. This research is critical to investigate more efficient and stable solar cells based on graphene-like materials in the future.
PMCID: PMC4273683  PMID: 25593552
Molybdenum disulfide; CdS; Solar cells; CVD; CBD; I-V behaviors
10.  Mutant MCP-1 Protein Delivery from Layer-by-Layer Coatings on Orthopaedic Implants to Modulate Inflammatory Response 
Biomaterials  2013;34(38):10287-10295.
Total joint replacement (TJR) is a common and effective surgical procedure for hip or knee joint reconstruction. However, the production of wear particles is inevitable for all TJRs, which activates macrophages and initiates an inflammatory cascade often resulting in bone loss, prosthetic loosening and eventual TJR failure. Macrophage Chemoattractant Protein-1 (MCP-1) is one of the most potent cytokines responsible for macrophage cell recruitment, and previous studies suggest that mutant MCP-1 proteins such as 7ND may be used as a decoy drug to block the receptor and reduce inflammatory cell recruitment. Here we report the development of a biodegradable, layer-by-layer (LBL) coating platform that allows efficient loading and controlled release of 7ND proteins from the surface of orthopaedic implants using as few as 14 layers. Scanning electron microscopy and fluorescence imaging confirmed effective coating using the LBL procedure on titanium rods. 7ND protein loading concentration and release kinetics can be modulated by varying the polyelectrolytes of choice, the polymer chemistry, the pH of the polyelectrolyte solution, and the degradation rate of the LBL assembly. The released 7ND from LBL coating retained its bioactivity and effectively reduced macrophage migration towards MCP-1. Finally, the LBL coating remained intact following a femoral rod implantation procedure as determined by immunostaining of the 7ND coating. The LBL platform reported herein may be applied for in situ controlled release of 7ND protein from orthopaedic implants, to reduce wear particle-induced inflammatory responses in an effort to prolong the lifetime of implants.
PMCID: PMC4018195  PMID: 24075408
11.  Carbon sandwich preparation preserves quality of two-dimensional crystals for cryo-electron microscopy 
Microscopy  2013;62(6):597-606.
Received 7 June 2013; accepted 21 June 2013Abstract
Electron crystallography is an important method for determining the structure of membrane proteins. In this paper, we show the impact of a carbon sandwich preparation on the preservation of crystalline sample quality, using characteristic examples of two-dimensional (2D) crystals from gastric H+,K+-ATPase and their analyzed images. Compared with the ordinary single carbon support film preparation, the carbon sandwich preparation dramatically enhanced the resolution of images from flat sheet 2D crystals. As water evaporation is restricted in the carbon-sandwiched specimen, the improvement could be due to the strong protective effect of the retained water against drastic changes in the environment surrounding the specimen, such as dehydration and increased salt concentrations. This protective effect by the carbon sandwich technique helped to maintain the inherent and therefore best crystal conditions for analysis. Together with its strong compensation effect for the image shift due to beam-induced specimen charging, the carbon sandwich technique is a powerful method for preserving crystals of membrane proteins with larger hydrophilic regions, such as H+,K+-ATPase, and thus constitutes an efficient and high-quality method for collecting data for the structural analysis of these types of membrane proteins by electron crystallography.
PMCID: PMC4030762  PMID: 23883606
cryo-electron microscopy; electron crystallography; H+,K+-ATPase; two-dimensional crystals; membrane proteins
12.  Enhanced local bioavailability of single or compound drugs delivery to the inner ear through application of PLGA nanoparticles via round window administration 
In this paper, the potential of poly(d,l-lactide-co-glycolide acid) (PLGA) nanoparticles (NPs) for carrying single or compound drugs traversing the round window membrane (RWM) was examined after the round window (RW) administration of different NPs to guinea pigs. First, coumarin-6 was incorporated into PLGA NPs as a fluorescent probe to investigate its ability to cross the RWM. Then, PLGA NPs with salvianolic acid B (Sal B), tanshinone IIA (TS IIA), and total panax notoginsenoside (PNS) including notoginsenoside R1 (R1), ginsenoside Rg1 (Rg1), and ginsenoside Rb1 (Rb1) were developed to evaluate whether NPs loaded with compound drugs would pass through the RWM and improve the local bioavailability of these agents. PLGA NPs loaded with single or compound drugs were prepared by the emulsification solvent evaporation method, and their particle size distribution, particle morphology, and encapsulation efficiency were characterized. In vitro release study showed sustained-release profiles of Sal B, TS IIA, and PNS from the NPs. The pharmacokinetic results showed that NPs applied to the RWM significantly improved drug distribution within the inner ear. The AUC0–t of coumarin-6 in the perilymph (PL) following RW administration of NPs was 4.7-fold higher than that of coumarin-6 solution, and the Cmax was 10.9-fold higher. Furthermore, the AUC0–t of R1, Rg1, and Rb1 were 4.0-, 3.1-, and 7.1-fold greater, respectively, after the application of NPs compared to the compound solution, and the Cmax were, respectively, 14.4-, 10.0-, and 16.7-fold higher. These findings suggest that PLGA NPs with unique properties at the nanoscale dimensions have a powerful ability to transport single or compound drugs into the PL through the RWM and remarkably enhance the local bioavailability of the encapsulated drugs in the inner ear. The use of PLGA NPs as nanoscale delivery vehicles to carry drugs across the RWM may be a promising strategy for the treatment of inner ear diseases.
PMCID: PMC4257110  PMID: 25489245
inner ear administration; nanoparticles; perilymph; local bioavailability; poly(d,l-lactide-co-glycolide acid)
13.  STAT5 programs a distinct subset of GM-CSF-producing T helper cells that is essential for autoimmune neuroinflammation 
Cell Research  2014;24(12):1387-1402.
T helper (TH)-cell subsets, such as TH1 and TH17, mediate inflammation in both peripheral tissues and central nervous system. Here we show that STAT5 is required for T helper-cell pathogenicity in autoimmune neuroinflammation but not in experimental colitis. Although STAT5 promotes regulatory T cell generation and immune suppression, loss of STAT5 in CD4+ T cells resulted in diminished development of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Our results showed that loss of encephalitogenic activity of STAT5-deficient autoreactive CD4+ T cells was independent of IFN-γ or interleukin 17 (IL-17) production, but was due to the impaired expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), a crucial mediator of T-cell pathogenicity. We further showed that IL-7-activated STAT5 promotes the generation of GM-CSF-producing CD4+ T cells, which were preferentially able to induce more severe EAE than TH17 or TH1 cells. Consistent with GM-CSF-producing cells being a distinct subset of TH cells, the differentiation program of these cells was distinct from that of TH17 or TH1 cells. We further found that IL-3 was secreted in a similar pattern as GM-CSF in this subset of TH cells. In conclusion, the IL-7-STAT5 axis promotes the generation of GM-CSF/IL-3-producing TH cells. These cells display a distinct transcriptional profile and may represent a novel subset of T helper cells which we designate as TH-GM.
PMCID: PMC4260352  PMID: 25412660
T helper cell; experimental autoimmune encephalomyelitis; GM-CSF; IL-7; STAT5
14.  Aaptamine Derivatives with Antifungal and Anti-HIV-1 Activities from the South China Sea Sponge Aaptos aaptos 
Marine Drugs  2014;12(12):6003-6013.
Five new alkaloids of aaptamine family, compounds (1–5) and three known derivatives (6–8), have been isolated from the South China Sea sponge Aaptos aaptos. The structures of all compounds were unambiguously elucidated by spectroscopic analyses, as well as by comparison with the literature data. Compounds 1–2 are characterized with triazapyrene lactam skeleton, whereas compounds 4–5 share an imidazole-fused aaptamine moiety. These compounds were evaluated in antifungal and anti-HIV-1 assays. Compounds 3, 7, and 8 showed antifungal activity against six fungi, with MIC values in the range of 4 to 64 μg/mL. Compounds 7–8 exhibited anti-HIV-1 activity, with inhibitory rates of 88.0% and 72.3%, respectively, at a concentration of 10 μM.
PMCID: PMC4278215  PMID: 25532563
Aaptos aaptos; aaptamine; antifungal; anti-HIV-1 activity
15.  Association between Tissue Characteristics of Coronary Plaque and Distal Embolization after Coronary Intervention in Acute Coronary Syndrome Patients: Insights from a Meta-Analysis of Virtual Histology-Intravascular Ultrasound Studies 
PLoS ONE  2014;9(11):e106583.
Background and Objectives
The predictive value of plaque characteristics assessed by virtual histology-intravascular ultrasound (VH-IVUS) including fibrous tissue (FT), fibrofatty (FF), necrotic core (NC) and dense calcium (DC) in identifying distal embolization after percutaneous coronary intervention (PCI) is still controversial. We performed a systematic review and meta-analysis to summarize the association of pre-PCI plaque composition and post-PCI distal embolization in acute coronary syndrome patients.
Studies were identified in PubMed, OVID, EMBASE, the Cochrane Library, the Current Controlled Trials Register, reviews, and reference lists of relevant articles. A meta-analysis using both fixed and random effects models with assessment of study heterogeneity and publication bias was performed.
Of the 388 articles screened, 10 studies with a total of 872 subjects (199 with distal embolization and 673 with normal flow) met the eligibility of our study. Compared with normal flow groups, significant higher absolute volume of NC [weighted mean differences (WMD): 5.79 mm3, 95% CI: 3.02 to 8.55 mm3; p<0.001] and DC (WMD: 2.55 mm3, 95% CI: 0.22 to 4.88 mm3; p = 0.03) were found in acute coronary syndrome patients with distal embolization. Further subgroup analysis demonstrated that the predictive value of tissue characteristics in determining distal embolization was correlated to clinical scenario of the patients, definition of distal embolization, and whether the percutaneous aspiration thrombectomy was applied.
Our study that pooled current evidence showed that plaque components were closely related to the distal embolization after PCI, especially the absolute volume of NC and DC, supporting further studies with larger sample size and high-methodological quality.
PMCID: PMC4222782  PMID: 25375841
16.  NUP98-PHF23 is a chromatin modifying oncoprotein that causes a wide array of leukemias sensitive to inhibition of PHD domain histone reader function 
Cancer discovery  2014;4(5):564-577.
In this report, we show that expression of a NUP98-PHF23 (NP23) fusion, associated with acute myeloid leukemia (AML) in humans, leads to myeloid, erythroid, T-cell, and B-cell leukemia in mice. The leukemic and pre-leukemic tissues display a stem cell-like expression signature including Hoxa, Hoxb, and Meis1 genes. The PHF23 PHD domain is known to bind H3K4me3 residues, and chromatin immunoprecipitation experiments demonstrated that the NP23 protein bound chromatin at a specific subset of H3K4me3 sites, including Hoxa, Hoxb, and Meis1. Treatment of NP23 cells with disulfiram, which inhibits the binding of PHD domains to H3K4me3 residues, rapidly and selectively killed NP23 myeloblasts; cell death was preceded by decreased expression of Hoxa, Hoxb, and Meis1. Furthermore, AML driven by a related fusion gene, NUP98-JARID1A (NJL), was also sensitive to disulfiram. Thus, the NP23 mouse provides a platform to evaluate compounds that disrupt binding of oncogenic PHD proteins to H3K4me3.
PMCID: PMC4018760  PMID: 24535671
NUP98-PHF23; AML; HOXA9; disulfiram; BAHCC1; NUP98-JARID1A; epigenetic therapy
17.  A novel synthetic derivative of the natural product berbamine inhibits cell viability and induces apoptosis of human osteosarcoma cells, associated with activation of JNK/AP-1 signaling 
Cancer Biology & Therapy  2013;14(11):1024-1031.
Osteosarcoma is the most common primary bone tumor in children and adolescents. There is a critical need to find more potent drugs for patients with metastatic or recurrent disease. Berbamine (BBM) is a natural compound derived from the Berberis amurensis plants. BBM and its derivatives have been shown to have antitumor effects in several cancers. Here, we report that a novel synthetic berbamine derivative, BBMD3, inhibits cell viability and induces apoptosis of G292, KHOS, and MG-63 human osteosarcoma cells. Induction of apoptosis in these tumor cells depends on activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). Since pan-caspase inhibitor (Z-VAD-FMK) and caspase-9 inhibitor (Z-LEHD-FMK) could block the cleavage of PARP, the apoptosis induced by BBMD3 is through intrinsic signaling pathway. BBMD3 increased phosphorylation of c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK), resulting in increase of phosphorylated c-Jun and total c-Fos, the major components of transcriptional factor AP-1. JNK inhibitor could partially suppress antitumor effect of BBMD3 on osteosarcoma cells. BBMD3 increased the production of reactive oxygen species (ROS) and ROS scavenger, N-acetylcysteine (NAC), could block the phosphorylation of JNK and c-Jun induced by BBMD3. BBMD3 increased the expression of the pro-apototic gene Bad, associated with apoptosis induction. Finally, BBMD3 also decreased the expression of cyclin D1 and D2, the positive cell cycle regulators, which is correlated with growth inhibition in osteosarcoma cells. Collectively, these findings indicate that BBMD3 is a potentially promising drug for the treatment of human osteosarcoma.
PMCID: PMC3925657  PMID: 24025361
berbamine derivative; osteosarcoma; apoptosis; JNK; AP-1; natural product
19.  Y-chromosomal haplotyping of single sperm cells isolated from semen mixtures – a successful identification of three perpetrators in a multi-suspect sexual assault case 
Croatian Medical Journal  2014;55(5):537-541.
To obtain individual Y-short tandem repeat (STR) profiles in a multi-suspect sexual assault case.
We used laser cut microdissection to capture the single sperm cell in the multi-contributor semen sample, combined with the low volume polymerase chain reaction (LV-PCR) method to genotype the single sperm cell profiles using the Yfiler® kit. Consensus DNA profiles were generated from 5 replicate experiments.
Ninety-four parallel LV-PCRs were performed and 41 reactions (44%) produced Y-STR profiles with more than nine loci. Three individual Y-STR profiles were successfully obtained.
The three Y haplotype units matched three known perpetrators’ genotypes. Our results showed that single sperm cells Y-STR analysis was a powerful method for analyzing multi-donor semen mixture sample.
PMCID: PMC4228287  PMID: 25358887
20.  Perspectives on Screening Winter-Flood-Tolerant Woody Species in the Riparian Protection Forests of the Three Gorges Reservoir 
PLoS ONE  2014;9(9):e108725.
The establishment of riparian protection forests in the Three Gorges Reservoir (TGR) is an ideal measure to cope with the eco-environmental problems of the water-level fluctuation zone (WLFZ). Thus, the information for screening winter-flood-tolerant woody plant species is useful for the recovery and re-establishment of the riparian protection forests in the TGR WLFZ. Therefore, we discussed the possibilities of constructing and popularizing riparian protection forests in the TGR WLFZ from several aspects, including the woody plant species distribution in the WLFZ, the survival rate analyses of suitable candidate woody species under controlled flooding conditions, the survival rate investigation of some woody plant species planted in the TGR WLFZ, and the physiological responses of some woody plant species during the recovery stage after winter floods. The results of woody species investigation showed that most woody plant species that existed as annual seedlings in the TGR WLFZ are not suitable candidates for the riparian protection forests. However, arbor species (e.g., Salix matsudana, Populus×canadensis, Morus alba, Pterocarya stenoptera, Taxodium ascendens, and Metasequoia glyptostroboides) and shrub species (e.g., Salix variegata, Distylium chinensis, Lycium chinense, Myricaria laxiflora, and Rosa multiflora) might be considered suitable candidates for the riparian protection forests in the TGR WLFZ by survival rate analyses under controlled winter flooding conditions, and survival rate investigations of woody plant species planted in the TGR WLFZ, respectively. Physiological analyses showed that P.×canadensis, M. alba, L. chinense, and S. variegata could develop specific self-repairing mechanisms to stimulate biomass accumulation and carbohydrate synthesis via the increases in chlorophyll pigments and photosynthesis during recovery after winter floods. Our results suggested these woody plant species could endure the winter flooding stress and recover well, and be used as candidate for the construction of riparian protection forests in the TGR WLFZ.
PMCID: PMC4181873  PMID: 25265326
21.  Increased expressions of integrin subunit β1, β2 and β3 in patients with venous thromboembolism: new markers for venous thromboembolism 
Objective: To investigate the core proteins (integrin subunits β1, β2 and β3) in the acute venous thrombi and validate the specificity and sensitivity of increased expression of integrin subunits β1, β2 and β3 in patients with venous thromboembolism. Methods: A total of 120 patients (73 females) with clinically proven acute VTE and aged between 24-90 years, and 120 non-VTE patients and healthy controls receiving physical examination matched in the sex and age were recruited. Flow cytometry was done to measure the expressions of blood integrin β1, β2 and β3. The receiver-operator characteristic (ROC) curve analysis was conducted to evaluate the diagnostic accuracy of integrin β1, β2 and β3. Results: The median levels of integrin β1, β2 and β3 were significantly higher in VTE patients than in non-VTE patients (P=0.000, 0.000 and 0.000, respectively) and healthy controls (P=0.000, 0.000 and 0.000, respectively). The ROC curves showed that integrin β1, β2 and β3 were specific diagnostic predictors of VTE with an area under the curve (AUC) of 0.870, 0.821, and 0.731, respectively. When three integrins were combined for diagnosis, the AUC of ROC curve was 0.916, and the sensitivity, specificity, positive and negative predictive values were 84.6%, 90.8%, 81.7% and 92.0%, respectively. Conclusion: The increased integrin β1, β2 and β3, as the core protein of venous thrombosis, have relatively high specificity and sensitivity for VTE and thus may serve as useful new biomarkers for the diagnoses of VTE.
PMCID: PMC4211762  PMID: 25356112
Antigens; CD29; antigens; CD18; integrin beta3; venous thromboembolism; biomarker
22.  Risk factors of recurrence for resected T1aN0M0 invasive lung adenocarcinoma: a clinicopathologic study of 177 patients 
This study aimed at identifying risk factors of recurrence for completely resected pathologic T1aN0M0 lung adenocarcinomas.
We reviewed the records of 177 T1aN0M0 invasive adenocarcinoma patients, and re-classified achieved surgical specimens according to the new International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) lung adenocarcinoma classification. Impact on recurrence-free survival (RFS) for age, gender, smoking history, lymphovascular invasion (LVI) and new classification was analyzed by log-rank test and Cox regression. Two existing prognostic grouping schemes of new classification were compared, and subsequently, the correlation of high-grade group in the better prognostic grouping model with clinical data was investigated statistically.
The 5-year recurrence-free rate was 83.7%. The LVI and new adenocarcinoma classification were significantly associated with 5-year RFS (P = 0.012; P = 0.022, respectively). The designation of papillary predominant subtype in the low-grade group, along with lepidic- and acinar predominant subtype had more prognostic significance than the model of combining papillary-, solid- and micropapillary predominant subtypes as the high-grade group (P = 0.005 versus P = 0.181). This high-grade group has increased risk of recurrence in a multivariate Cox regression (adjusted HR 2.815, 95% CI: 1.239 to 6.397, P = 0.013), and is associated significantly more with male gender (adjusted OR 2.214, 95% CI: 1.050 to 4.668, P = 0.037), and, with borderline significance, the presence of LVI (adjusted OR 2.091, 95% CI: 0.938 to 4.662, P = 0.071).
Our results showed that the solid- and micropapillary predominant subtype of IASLC/ATS/ERS classification remains the only risk factor for post-operative recurrence of T1aN0M0 adenocarcinomas, suggesting that they can be indicators of aggressive tumor behaviors.
PMCID: PMC4168167  PMID: 25216551
Lung adenocarcinoma; Recurrence; New classification; Solid predominant adenocarcinoma; Micropapillary predominant adenocarcinoma
23.  NR4A1 is associated with chronic low-grade inflammation in patients with type 2 diabetes 
Type 2 diabetes (T2D) is a common disorder characterized by chronic low-grade inflammation. In the present study, the expression levels of nuclear receptor subfamily 4 group A member 1 (NR4A1) and the correlation with inflammatory cytokine production and free fatty acids (FFAs) in patients with T2D and healthy participants were investigated. NR4A1 expression levels in peripheral blood mononuclear cells (PBMCs) from patients with T2D (n=30) and healthy controls (n=34) were analyzed. In addition, the levels of fasting blood glucose (FBG), fasting plasma insulin (FIN), FFAs, total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C) were analyzed, and the homeostasis model assessment (HOMA) was used to estimate the insulin resistance (IR). Additionally, PBMCs from healthy subjects were cultured with or without 250 μM palmitic acid (PA). Levels of NR4A1, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the PBMCs were also analyzed. The basal expression levels of NR4A1, TNF-α and IL-6 were higher in the T2D patients when compared with the controls. In addition, the levels of FFAs, TG and LDL-C, as well as the HOMA-IR, were higher in T2D patients. Furthermore, NR4A1 expression was demonstrated to positively correlate with the HOMA-IR and the levels of FFAs, TNF-α, IL-6, FIN and FBG. Furthermore, 250 μM PA stimulation was shown to increase NR4A1 expression and the secretion of inflammatory cytokines in the cultured PBMCs. Therefore, increased NR4A1 expression levels are correlated with a chronic low-grade inflammatory state and the disorder of lipid metabolism in patients with T2D.
PMCID: PMC4186321  PMID: 25289075
diabetes; inflammation; nuclear receptor subfamily 4 group A member 1; nuclear factor-κB; IκBα
24.  Mutant monocyte chemoattractant protein 1 protein attenuates migration of and inflammatory cytokine release by macrophages exposed to orthopedic implant wear particles 
Wear particles generated from total joint replacements can stimulate macrophages to release chemokines, such as monocyte chemoattractant protein 1 (MCP-1), which is the most important chemokine regulating systemic and local cell trafficking and infiltration of monocyte/macrophages in chronic inflammation. One possible strategy to curtail the adverse events associated with wear particles is to mitigate migration and activation of monocyte/macrophages. The purpose of this study is to modulate the adverse effects of particulate biomaterials and inflammatory stimuli such as endotoxin by interfering with the biological effects of the chemokine MCP-1. In the current study, the function of MCP-1 was inhibited by the mutant MCP-1 protein called 7ND, which blocks its receptor, the C–C chemokine receptor type 2 (CCR2) on macrophages. Addition of 7ND decreased MCP-1-induced migration of THP-1 cells in cell migration experiments in a dose-dependent manner. Conditioned media from murine macrophages exposed to clinically relevant polymethylmethacrylate (PMMA) particles with/without endotoxin [lipopolysaccharide (LPS)] had a chemotactic effect on human macrophages, which was decreased dramatically by 7ND. 7ND demonstrated no adverse effects on the viability of macrophages, and the capability of mesenchymal stem cells (MSCs) to form bone at the doses tested. Finally, proinflammatory cytokine production was mitigated when macrophages were exposed to PMMA particles with/without LPS in the presence of 7ND. Our studies confirm that the MCP-1 mutant protein 7ND can decrease macrophage migration and inflammatory cytokine release without adverse effects at the doses tested. Local delivery of 7ND at the implant site may provide a therapeutic strategy to diminish particle-associated periprosthetic inflammation and osteolysis.
PMCID: PMC4035458  PMID: 24123855
macrophages; chemotaxis; inflammation; particles; cytokines
25.  The catalytic region and PEST domain of PTPN18 distinctly regulate the HER2 phosphorylation and ubiquitination barcodes 
Cell Research  2014;24(9):1067-1090.
The tyrosine phosphorylation barcode encoded in C-terminus of HER2 and its ubiquitination regulate diverse HER2 functions. PTPN18 was reported as a HER2 phosphatase; however, the exact mechanism by which it defines HER2 signaling is not fully understood. Here, we demonstrate that PTPN18 regulates HER2-mediated cellular functions through defining both its phosphorylation and ubiquitination barcodes. Enzymologic characterization and three crystal structures of PTPN18 in complex with HER2 phospho-peptides revealed the molecular basis for the recognition between PTPN18 and specific HER2 phosphorylation sites, which assumes two distinct conformations. Unique structural properties of PTPN18 contribute to the regulation of sub-cellular phosphorylation networks downstream of HER2, which are required for inhibition of HER2-mediated cell growth and migration. Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY1112, the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop. In agreement with the negative regulatory role of PTPN18 in HER2 signaling, the HER2/PTPN18 ratio was correlated with breast cancer stage. Taken together, our study presents a structural basis for selective HER2 dephosphorylation, a previously uncharacterized mechanism for HER2 degradation and a novel function for the PTPN18 PEST domain. The new regulatory role of the PEST domain in the ubiquitination pathway will broaden our understanding of the functions of other important PEST domain-containing phosphatases, such as LYP and PTPN12.
PMCID: PMC4152746  PMID: 25081058
phosphatase; receptor; ubiquitination; HER2; PTPN18; EGFR

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