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1.  The structure of the symptoms of major depression: exploratory and confirmatory factor analysis in depressed Han Chinese women 
Psychological Medicine  2013;44(7):1391-1401.
The symptoms of major depression (MD) are clinically diverse. Do they form coherent factors that might clarify the underlying nature of this important psychiatric syndrome?
Symptoms at lifetime worst depressive episode were assessed at structured psychiatric interview in 6008 women of Han Chinese descent, age ⩾30 years with recurrent DSM-IV MD. Exploratory factor analysis (EFA) and confirmatoryfactor analysis (CFA) were performed in Mplus in random split-half samples.
The preliminary EFA results were consistently supported by the findings from CFA. Analyses of the nine DSM-IV MD symptomatic A criteria revealed two factors loading on: (i) general depressive symptoms; and (ii) guilt/suicidal ideation. Examining 14 disaggregated DSM-IV criteria revealed three factors reflecting: (i) weight/appetite disturbance; (ii) general depressive symptoms; and (iii) sleep disturbance. Using all symptoms (n = 27), we identified five factors that reflected: (i) weight/appetite symptoms; (ii) general retarded depressive symptoms; (iii) atypical vegetative symptoms; (iv) suicidality/hopelessness; and (v) symptoms of agitation and anxiety.
MD is a clinically complex syndrome with several underlying correlated symptom dimensions. In addition to a general depressive symptom factor, a complete picture must include factors reflecting typical/atypical vegetative symptoms, cognitive symptoms (hopelessness/suicidal ideation), and an agitated symptom factor characterized by anxiety, guilt, helplessness and irritability. Prior cross-cultural studies, factor analyses of MD in Western populations and empirical findings in this sample showing risk factor profiles similar to those seen in Western populations suggest that our results are likely to be broadly representative of the human depressive syndrome.
PMCID: PMC3967839  PMID: 23920138
Atypical symptoms; China; cognitive symptoms; depression; factor analysis
2.  Childhood sexual abuse and the risk for recurrent major depression in Chinese women 
Psychological Medicine  2011;42(2):409-417.
Studies in Western countries have repeatedly shown that women with a history of childhood sexual abuse (CSA) are at increased risk for developing major depression (MD). Would this relationship be found in China?
Three levels of CSA (non-genital, genital, and intercourse) were assessed by self-report in two groups of Han Chinese women: 1970 clinically ascertained with recurrent MD and 2597 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression and regression coefficients by linear or Poisson regression.
Any form of CSA was significantly associated with recurrent MD [OR 3.26, 95% confidence interval (CI) 1.95–5.45]. This association strengthened with increasing CSA severity: non-genital (OR 2.47, 95% CI 1.17–5.23), genital (OR 2.77, 95% CI 1.32–5.83) and intercourse (OR 13.35, 95% CI 1.83–97.42). The association between any form of CSA and MD remained significant after accounting for parental history of depression, childhood emotional neglect (CEN), childhood physical abuse (CPA) and parent–child relationship. Among the depressed women, those with CSA had an earlier age of onset, longer depressive episodes and an increased risk for generalized anxiety disorder (GAD; OR 1.92, 95% CI 1.39–2.66) and dysthymia (OR 2.16, 95% CI 1.52–3.09).
In Chinese women CSA is strongly associated with MD and this association increases with greater severity of CSA. Depressed women with CSA have an earlier age of onset, longer depressive episodes and increased co-morbidity with GAD and dysthymia. Although reporting biases cannot be ruled out, our results are consistent with the hypothesis that, as in Western countries, CSA substantially increases the risk for MD in China.
PMCID: PMC3250087  PMID: 21835095
Childhood sexual abuse; co-morbidity; major depression
3.  Cognitive trio: relationship with major depression and clinical predictors in Han Chinese women 
Psychological Medicine  2013;43(11):2265-2275.
Previous studies support Beck's cognitive model of vulnerability to depression. However, the relationship between his cognitive triad and other clinical features and risk factors among those with major depression (MD) has rarely been systematically studied.
The three key cognitive symptoms of worthlessness, hopelessness and helplessness were assessed during their lifetime worst episode in 1970 Han Chinese women with recurrent MD. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression.
Compared to patients who did not endorse the cognitive trio, those who did had a greater number of DSM-IV A criteria, more individual depressive symptoms, an earlier age at onset, a greater number of episodes, and were more likely to meet diagnostic criteria for melancholia, postnatal depression, dysthymia and anxiety disorders. Hopelessness was highly related to all the suicidal symptomatology, with ORs ranging from 5.92 to 6.51. Neuroticism, stressful life events (SLEs) and a protective parental rearing style were associated with these cognitive symptoms.
During the worst episode of MD in Han Chinese women, the endorsement of the cognitive trio was associated with a worse course of depression and an increased risk of suicide. Individuals with high levels of neuroticism, many SLEs and high parental protectiveness were at increased risk for these cognitive depressive symptoms. As in Western populations, symptoms of the cognitive trio appear to play a central role in the psychopathology of MD in Chinese women.
PMCID: PMC3807662  PMID: 23425530
Cognitive trio; Han Chinese women; major depression; suicide; symptoms
4.  Evaluation of dose reduction and image quality in chest CT using adaptive statistical iterative reconstruction with the same group of patients 
The British Journal of Radiology  2012;85(1018):e906-e911.
The objective of this study was to compare the image quality and radiation dose of chest CT images reconstructed with a blend of adaptive statistical iterative reconstruction (ASIR) and filtered back-projection (FBP) with images generated using conventional FBP.
Patients with chest CT re-examinations were alternately assigned to two scanners with different reconstruction techniques. The study groups included noise index (NI) 11 with 30% ASIR (A30), NI 13 with 40% ASIR (A40), NI 15 with 50% ASIR (A50) and NI 17 with 60% ASIR (A60), sequentially changed every 2 months. The control images were obtained using FBP and NI 11. All acquisitions were performed with automatic dose modulation. Paired t-test and non-parameter test were applied to compare the difference.
The radiation doses were significantly lower in the examinations that used ASIR (p<0.001). The mean dose reduction rate was 27.7%, 45.2%, 57.1% and 71.8% for Groups A30, A40, A50 and A60, respectively. The image quality of Groups A30–A50 was not inferior to that of the control examinations. The image noise of Group A60 was greater and subjective image quality was inferior to that of the control.
ASIR enabled the use of a higher NI with automatic dose modulation. With 50% ASIR and a NI of 15, the effective radiation dose was reduced by 57%, without compromising image quality.
PMCID: PMC3474005  PMID: 22595496
5.  Drug-mediated inhibition of Fli-1 for the treatment of leukemia 
Blood Cancer Journal  2012;2(1):e54-.
The Ets transcription factor, Fli-1 is activated in murine erythroleukemia and overexpressed in various human malignancies including Ewing's sarcoma, induced by the oncogenic fusion protein EWS/Fli-1. Recent studies by our group and others have demonstrated that Fli-1 plays a key role in tumorigenesis, and disrupting its oncogenic function may serve as a potential treatment option for malignancies associated with its overexpression. Herein, we describe the discovery of 30 anti-Fli-1 compounds, characterized into six functional groups. Treatment of murine and human leukemic cell lines with select compounds inhibits Fli-1 protein or mRNA expression, resulting in proliferation arrest and apoptosis. This anti-cancer effect was mediated, at least in part through direct inhibition of Fli-1 function, as anti-Fli-1 drug treatment inhibited Fli-1 DNA binding to target genes, such as SHIP-1 and gata-1, governing hematopoietic differentiation and proliferation. Furthermore, treatment with select Fli-1 inhibitors revealed a positive relationship between the loss of DNA-binding activity and Fli-1 phosphorylation. Accordingly, anti-Fli-1 drug treatment significantly inhibited leukemogenesis in a murine erythroleukemia model overexpressing Fli-1. This study demonstrates the ability of this drug-screening strategy to isolate effective anti-Fli-1 inhibitors and highlights their potential use for the treatment of malignancies overexpressing this oncogene.
PMCID: PMC3270256  PMID: 22829238
erythroleukemia; Fli-1; drug inhibition
6.  Common genetic variability in ESR1 and EGF in relation to endometrial cancer risk and survival 
British Journal of Cancer  2009;100(8):1358-1364.
We investigated common genetic variation in the entire ESR1 and EGF genes in relation to endometrial cancer risk, myometrial invasion and endometrial cancer survival. We genotyped a dense set of single-nucleotide polymorphisms (SNPs) in both genes and selected haplotype tagging SNPs (tagSNPs). The tagSNPs were genotyped in 713 Swedish endometrial cancer cases and 1567 population controls and the results incorporated into logistic regression and Cox proportional hazards models. We found five adjacent tagSNPs covering a region of 15 kb at the 5′ end of ESR1 that decreased the endometrial cancer risk. The ESR1 variants did not, however, seem to affect myometrial invasion or endometrial cancer survival. For the EGF gene, no association emerged between common genetic variants and endometrial cancer risk or myometrial invasion, but we found a five-tagSNP region that covered 51 kb at the 5′ end of the gene where all five tagSNPs seemed to decrease the risk of dying from endometrial cancer. One of the five tagSNPs in this region was in strong linkage disequilibrium (LD) with the untranslated A61G (rs4444903) EGF variant, earlier shown to be associated with risk for other forms of cancer.
PMCID: PMC2676544  PMID: 19319135
ESR1; EGF; polymorphism; endometrial cancer; survival
7.  A novel semiconductor compatible path for nano-graphene synthesis using CBr4 precursor and Ga catalyst 
Scientific Reports  2014;4:4653.
We propose a novel semiconductor compatible path for nano-graphene synthesis using precursors containing C-Br bonding and liquid catalyst. The unique combination of CBr4 as precursor and Ga as catalyst leads to efficient C precipitation at a synthesis temperature of 200°C or lower. The non-wetting nature of liquid Ga on tested substrates limits nano-scale graphene to form on Ga droplets and substrate surfaces at low synthesis temperatures of T ≤ 450°C and at droplet/substrate interfaces by C diffusion via droplet edges when T ≥ 400°C. Good quality interface nano-graphene is demonstrated and the quality can be further improved by optimization of synthesis conditions and proper selection of substrate type and orientation. The proposed method provides a scalable and transfer-free route to synthesize graphene/semiconductor heterostructures, graphene quantum dots as well as patterned graphene nano-structures at a medium temperature range of 400–700°C suitable for most important elementary and compound semiconductors.
PMCID: PMC3983675  PMID: 24722194
8.  The effective dose assessment of C-arm CT in hepatic arterial embolisation therapy 
The British Journal of Radiology  2013;86(1024):20120551.
To assess the effective dose of the liver C-arm computed tomography (CT) scan during hepatic arterial embolisation surgery with clinical dose–area product (DAP) data from Taiwan.
The experiment used two kinds of phantoms: RANDO® Man and RANDO Woman (The Phantom Laboratory, Salem, NY), embedded with thermoluminescent dosemeters at locations according to the International Commission on Radiological Protection 103 report. The conversion factors of DAP to effective doses for males and females, respectively, were obtained. The clinical DAP data of liver C-arm CT scan during hepatic arterial embolisation surgery were collected in a hospital in Taiwan.
There were 125 liver transarterial embolisation therapy cases, including 94 males and 31 females, from February 2009 to June 2010. C-arm CT was used 38 times for males and 17 times for females. The corresponding average and standard deviation of clinical DAP were 61.0±6.6 Gy cm2 and 52.2±8.3 Gy cm2, respectively.
The DAP of RANDO Man and RANDO Woman phantoms simply scanned by C-arm CT are much lower than that of patients. After consideration of the clinical DAP of patients, the effective doses of a liver C-arm CT scan recommended for males and females in Taiwan are 11.5±2.3 mSv and 11.3±3.0 mSv, respectively.
Advances in knowledge:
The conversion factors of DAP to effective doses for males and females are 0.19±0.03 mSv Gy−1 cm−2 and 0.22±0.05 mSv Gy−1 cm−2. Only if the actual DAP value of a patient scan is multiplied by the conversion factor can the correct effective dose be determined.
PMCID: PMC3635788  PMID: 23403454
9.  IL-1α Stimulates Cathepsin K Expression in Osteoclasts via the Tyrosine Kinase-NF-κB Pathway 
Journal of dental research  2004;83(10):791-796.
Interleukin-1α(IL-1α) is a powerful activator of osteoclast cells. However, the underlying mechanism for this activation is unknown. In this study, we reveal that IL-1α up-regulates the expression of cathepsin K protein, a key protease in bone resorption, by five-fold. Northern blot analysis and promoter analysis show that this induction occurs at the transcriptional level, in a dose-responsive and time-dependent manner. No increase in expression occurs in the presence of either pyrrolidine dithiocarbamate (PDTC), a selective inhibitor of NF-κB, or Genistein, a protein tyrosine kinase inhibitor, suggesting that IL-1α up-regulation may be via the tyrosine kinase-NF-κB pathway to regulate cathepsin K expression. Antisense oligonucleotides to p65, but not the p50 subunit of NF-κB, suppress the IL-1α-induced expression of cathepsin K. We therefore conclude that IL-1α up-regulates cathepsin K gene expression at the transcription level, and this regulation may be via the tyrosine-kinase-NF-κB pathway.
PMCID: PMC3966556  PMID: 15381721
interleukin-1alpha; cathepsin K; osteoclast; NF-κB; tyrosine kinase
10.  Protein tyrosine phosphatase SHP2 regulates TGF-β1 production in airway epithelia and asthmatic airway remodeling in mice 
Allergy  2012;67(12):1547-1556.
Transforming growth factor (TGF)-β1 produced in airway epithelia has been suggested as a contributor to the airway remodeling observed in asthma patients. The protein tyrosine phosphatase SHP2 is a demonstrable modulator of TGF-β1 production and thus a potential regulator of airway remodeling.
To define the signal event by which SHP2 regulates asthmatic responses in airway epithelial cells by using a mouse model of experimental OVA-induced airway remodeling.
The airways of Shp2flox/flox mice were infected with recombinant adenovirus vectors expressing a Cre recombinase–green fluorescence protein (GFP) fusion protein as part of allergen provocation studies using mice sensitized with ovalbumin (OVA) and repeatedly challenged with OVA. Several endpoint pathologies were assessed, including airway hyper-responsiveness (AHR), lung inflammatory score, peribronchial collagen deposition, and α-smooth muscle actin (SMA) hyperplasia. In vitro studies using airway epithelial cells (BEAS-2B) were used to investigate the role of SHP2 in the regulation of pulmonary remodeling events, including the expression of collagen, α-SMA, and TGF-β1.
Chronic OVA challenges in wild-type mice resulted in airway remodeling and lung dysfunction (e.g., increased inflammatory scores, collagen deposition (fibrosis), smooth muscle hyperplasia, and a significant increase in AHR). These endpoint pathology metrics were each significantly attenuated by conditional shp2 gene knockdown in airway epithelia. In vitro studies using BEAS-2B cells also demonstrated that the level of TGF-β1 production by these cells correlated with the extent of shp2 gene expression.
SHP2 activities in airway epithelial cells appear to modulate TGF-β1 production and, in turn, regulate allergic airway remodeling following allergen provocation.
Clinical Implications
Our findings identify SHP2 as a previously underappreciated contributor to the airway remodeling and lung dysfunction associated with allergen challenge. As such, SHP2 represents a potentially novel therapeutic target for the treatment of asthmatics.
PMCID: PMC3942166  PMID: 23057634
airway epithelia; asthma; mice; protein tyrosine phosphatase SHP2; remodeling
11.  Defining the roles of inflammatory and anabolic cytokines in cartilage metabolism 
Annals of the rheumatic diseases  2008;67(0 3):iii75-iii82.
In osteoarthritis (OA), adult articular chondrocytes undergo phenotypic modulation in response to alterations in the environment owing to mechanical injury and inflammation. These processes not only stimulate the production of enzymes that degrade the cartilage matrix but also inhibit repair. With the use of in vitro and in vivo models, new genes, not known previously to act in cartilage, have been identified and their roles in chondrocyte differentiation during development and in dysregulated chondrocyte function in OA have been examined. These new genes include growth arrest and DNA damage (GADD)45β and the epithelial-specific ETS (ESE)-1 transcription factor, induced by bone morpho-genetic protein (BMP)-2 and inflammatory cytokines, respectively. Both genes are induced by NF-κB, suppress COL2A1 and upregulate matrix meatalloproteinase-13 (MMP-13) expression. These genes have also been examined in mouse models of OA, in which discoidin domain receptor 2 is associated with MMP-13-mediated remodelling, in order to understand their roles in physiological cartilage homoeostasis and joint disease.
PMCID: PMC3939701  PMID: 19022820
12.  Notch1 induced brain tumor models the sonic hedgehog subgroup of human medulloblastoma 
Cancer research  2013;73(17):5381-5390.
While activation of the Notch pathway is observed in many human cancers, it is unknown whether elevated Notch1 expression is sufficient to initiate tumorigenesis in most tissues. To test the oncogenic potential of Notch1 in solid tumors, we expressed an activated form of NOTCH1 (N1ICD) in the developing mouse brain. N1ICD;hGFAP-cre mice were viable but developed severe ataxia and seizures, and died by weaning age. Analysis of transgenic embryonic brains revealed that N1ICD expression induced p53-dependent apoptosis. When apoptosis was blocked by genetic deletion of p53, 30~40% of N1ICD;GFAP-cre;p53+/− and N1ICD;GFAP-cre;p53−/− mice developed spontaneous medulloblastomas. Interestingly, Notch1-induced medulloblastomas most closely resembled the sonic hedgehog (SHH) subgroup of human medulloblastoma at the molecular level. Surprisingly, N1ICD-induced tumors do not maintain high levels of the Notch pathway gene expression, except for Notch2, demonstrating that initiating oncogenic events may not be decipherable by analyzing growing tumors in some cases. In summary, this study demonstrates that Notch1 has an oncogenic potential in the brain when combined with other oncogenic hits, such as p53 loss, and provides a novel mouse model of medulloblastoma.
PMCID: PMC3766480  PMID: 23852537
13.  Inhibition of APE1/Ref-1 redox activity rescues human retinal pigment epithelial cells from oxidative stress and reduces choroidal neovascularization 
Redox Biology  2014;2:485-494.
The effectiveness of current treatment for age related macular degeneration (AMD) by targeting one molecule is limited due to its multifactorial nature and heterogeneous pathologies. Treatment strategy to target multiple signaling pathways or pathological components in AMD pathogenesis is under investigation for better clinical outcome. Inhibition of the redox function of apurinic endonuclease 1/redox factor-1 (APE1) was found to suppress endothelial angiogenesis and promote neuronal cell recovery, thereby may serve as a potential treatment for AMD. In the current study, we for the first time have found that a specific inhibitor of APE1 redox function by a small molecule compound E3330 regulates retinal pigment epithelium (RPEs) cell response to oxidative stress. E3330 significantly blocked sub-lethal doses of oxidized low density lipoprotein (oxLDL) induced proliferation decline and senescence advancement of RPEs. At the same time, E3330 remarkably decreased the accumulation of intracellular reactive oxygen species (ROS) and down-regulated the productions of monocyte chemoattractant protein-1 (MCP-1) and vascular endothelial growth factor (VEGF), as well as attenuated the level of nuclear factor-κB (NF-κB) p65 in RPEs. A panel of stress and toxicity responsive transcription factors that were significantly upregulated by oxLDL was restored by E3330, including Nrf2/Nrf1, p53, NF-κB, HIF1, CBF/NF-Y/YY1, and MTF-1. Further, a single intravitreal injection of E3330 effectively reduced the progression of laser-induced choroidal neovascularization (CNV) in mouse eyes. These data revealed that E3330 effectively rescued RPEs from oxidative stress induced senescence and dysfunctions in multiple aspects in vitro, and attenuated laser-induced damages to RPE–Bruch׳s membrane complex in vivo. Together with its previously established anti-angiogenic and neuroprotection benefits, E3330 is implicated for potential use for AMD treatment.
Graphical abstract
•Specific inhibition of APE1/Ref-1 redox function with E3330 blocked RPE proliferation decline and senescence-like phenotype advancement induced by oxLDL.•E3330 suppressed intracellular ROS, down-regulated the MCP-1 and VEGF production, and reduced nuclear NF-κB p65 in RPEs.•E3330 repressed the redox sensitive transcription factors Nrf2/Nrf1, p53, NF-κB, HIF1, CBF/NF-Y/YY1, and MTF-1 that stimulated by oxLDL in RPEs.•Intravitreal injection of E3330 markedly reduced the laser-induced CNV in mouse eyes.•E3330 holds great potential for the management of AMD.
PMCID: PMC3949093  PMID: 24624338
AhR, aryl hydrocarbon receptor; AMD, age related macular degeneration; AP-1, activator protein 1; APE1, apurinic endonuclease 1/redox factor-1; ApoE, apolipoprotein E; CBF/NF-Y/YY1, CCAAT binding factor/nuclear factor-Y/Yin Yang 1; CECs, choroidal endothelial cells; CNV, choroidal neovascularization; DCFH-DA, dichlorodihydrofluorescin diacetate; DMSO, dimethylsulphoxide; Fluc, firefly luciferase; HIF-1α, hypoxia inducible factor-1α; HSF1, heat-shock factor 1; IκB-α, inhibitory NF-κB-α; MCP-1, monocyte chemoattractant protein-1; MTF1, metal regulatory transcription factor 1; NF-κB, nuclear factor-κB; Nox, NADPH oxidase; Nrf, nuclear factor erythroid-2-related factor; oxLDL, oxidized low density lipoprotein; redox, reduction/oxidation; Rluc, renilla luciferase; RNV, retinal neovascularization; ROS, reactive oxygen species; RPE, retinal pigment epithelium; RVECs, retinal vascular endothelial cells; SA-β-gal, senescence associated β-gal; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; TUNEL, TdT mediated dUTP-fluorescein nick end-labeling; VEGF, vascular endothelial growth factor; APE1/Ref-1redox function; E3330; Oxidative stress; Retinal pigment epithelial cell; Transcription factor; Age-related macular degeneration.
14.  Enhanced tumor suppression in vitro and in vivo by co-expression of survivin-specific siRNA and wild-type p53 protein 
Shao, Y | Liu, Y | Shao, C | Hu, J | Li, X | Li, F | Zhang, L | Zhao, D | Sun, L | Zhao, X | Kopecko, DJ | Kalvakolanu, DV | Li, Y | Xu, DQ
Cancer gene therapy  2010;17(12):844-854.
The development of malignant prostate cancer involves multiple genetic alterations. For example, alterations in both survivin and p53 are reported to have crucial roles in prostate cancer progression. However, little is known regarding the interrelationships between p53 and survivin in prostate cancer. Our data demonstrate that the expression of survivin is inversely correlated with that of wtp53 protein (rs=0.548) in prostate cancer and in normal prostate tissues. We have developed a therapeutic strategy, in which two antitumor factors, small interfering RNA-survivin and p53 protein, are co-expressed from the same plasmid, and have examined their effects on the growth of PC3, an androgen-independent prostate cancer cell line. When p53 was expressed along with a survivin-specific short hairpin RNA (shRNA), tumor cell proliferation was significantly suppressed and apoptosis occurred. In addition, this combination also abrogated the expression of downstream target molecules such as cyclin-dependent kinase 4 and c-Myc, while enhancing the expression of GRIM19. These changes in gene expression occurred distinctly in the presence of survivin-shRNA/wtp53 compared with control or single treatment groups. Intratumoral injection of the co-expressed construct inhibited the growth and survival of tumor xenografts in a nude mouse model. These studies revealed evidence of an interaction between p53 and survivin proteins plus a complex signaling network operating downstream of the wtp53-survivin pathway that actively controls tumor cell proliferation, survival and apoptosis.
PMCID: PMC3915357  PMID: 20706288
prostate cancer; p53; survivin; siRNA
15.  Inhibiting Periapical Lesions through AAV-RNAi Silencing of Cathepsin K 
Journal of Dental Research  2013;92(2):180-186.
Dental caries, one of the most prevalent infectious diseases worldwide, affects approximately 80% of children and the majority of adults. Dental caries may result in endodontic disease, leading to dental pulp necrosis, periapical inflammation and bone resorption, severe pain, and tooth loss. Periapical inflammation may also increase inflammation in other parts of the body. Although many studies have attempted to develop therapies for this disease, there is still an urgent need for effective treatments. In this study, we applied a novel gene therapeutic approach using recombinant adeno-associated virus (AAV)-mediated RNAi knockdown of Cathepsin K (Ctsk) gene expression, to target osteoclasts and periapical bone resorption in a mouse model. We found that AAV-sh-Cathepsin K (AAV-sh-Ctsk) impaired osteoclast function in vivo and furthermore reduced bacterial infection-stimulated bone resorption by 88%. Reduced periapical lesion size was accompanied by decreases in mononuclear leukocyte infiltration and inflammatory cytokine expression. Our study shows that AAV-RNAi silencing of Cathepsin K in periapical tissues can significantly reduce endodontic disease development, bone destruction, and inflammation in the periapical lesion. This is the first demonstration that AAV-mediated RNAi knockdown gene therapy may significantly reduce the severity of endodontic disease.
PMCID: PMC3545691  PMID: 23166044
endodontic disease; inflammation; bone resorption; dental caries; osteoclast; gene therapy
16.  Activation of TAK1 by MYD88 L265P drives malignant B-cell Growth in non-Hodgkin lymphoma 
Blood Cancer Journal  2014;4(2):e183-.
Massively parallel sequencing analyses have revealed a common mutation within the MYD88 gene (MYD88L265P) occurring at high frequencies in many non-Hodgkin lymphomas (NHLs) including the rare lymphoplasmacytic lymphoma, Waldenström's macroglobulinemia (WM). Using whole-exome sequencing, Sanger sequencing and allele-specific PCR, we validate the initial studies and detect the MYD88L265P mutation in the tumor genome of 97% of WM patients analyzed (n=39). Due to the high frequency of MYD88 mutation in WM and other NHL, and its known effects on malignant B-cell survival, therapeutic targeting of MYD88 signaling pathways may be clinically useful. However, we are lacking a thorough characterization of the role of intermediary signaling proteins on the biology of MYD88L265P-expressing B cells. We report here that MYD88L265P signaling is constitutively active in both WM and diffuse large B-cell lymphoma cells leading to heightened MYD88L265P, IRAK and TRAF6 oligomerization and NF-κB activation. Furthermore, we have identified the signaling protein, TAK1, to be an essential mediator of MYD88L265P-driven signaling, cellular proliferation and cytokine secretion in malignant B cells. Our studies highlight the biological significance of MYD88L265P in NHL and reveal TAK1 inhibition to be a potential therapeutic strategy for the treatment of WM and other diseases characterized by MYD88L265P.
PMCID: PMC3944662  PMID: 24531446
MYD88; Waldenstrom; lymphoma; TAK1
17.  Identification of serum CCL15 in hepatocellular carcinoma 
Li, Y | Wu, J | Zhang, W | Zhang, N | Guo, H
British Journal of Cancer  2013;108(1):99-106.
Early serum detection is of critical importance to improve the therapy for hepatocellular carcinoma (HCC), one of the most deadly cancers. Hepatitis infection is a leading cause of HCC.
In the present study, we collected total serum samples with informed consent from 80 HCC patients with HBV (+)/cirrhosis (+), 80 patients with benign diseases (50 liver cirrhosis patients and 30 HBV-infected patients) and 60 healthy controls. Analysis was by using surface-enhanced laser desorption/ionisation-time-of-flight mass spectroscopy (SELDI-TOF-MS) to find new serum markers of HCC. SELDI peaks were isolated by SDS–PAGE, identified by LC-MS/MS and validated by immunohistochemistry (IHC) in liver tissues. Migration and invasion assay were performed to test the ability of cell migration and invasion in vitro.
SELDI-TOF-MS revealed a band at 7777 M/Z in the serum samples from HCC patients but not from healthy controls or patients with benign diseases. The protein (7777.27 M/Z) in the proteomic signature was identified as C-C motif chemokine 15 (CCL15) by peptide mass fingerprinting. A significant increase in serum CCL15 was detected in HCC patients. Functional analysis showed that HCC cell expressed CCL15, which in turn promoted HCC cell migration and invasion.
CCL15 may be a specific proteomic biomarker of HCC, which has an important role in tumorigenesis and tumour invasion.
PMCID: PMC3553511  PMID: 23321514
CCL15; biomarker; HCC; migration; invasion
18.  Targeted therapy via oral administration of attenuated Salmonella expression plasmid-vectored Stat3-shRNA cures orthotopically transplanted mouse HCC 
Cancer gene therapy  2012;19(6):393-401.
The development of RNA interference-based cancer gene therapies has been delayed due to the lack of effective tumor-targeting delivery systems. Attenuated Salmonella enterica serovar Typhimurium (S. Typhimurium) has a natural tropism for solid tumors. We report here the use of attenuated S. Typhimurium as a vector to deliver shRNA directly into tumor cells. Constitutively activated signal transducer and activator of transcription 3 (Stat3) is a key transcription factor involved in both hepatocellular carcinoma (HCC) growth and metastasis. In this study, attenuated S. Typhimurium was capable of delivering shRNA-expressing vectors to the targeted cancer cells and inducing RNA interference in vivo. More importantly, a single oral dose of attenuated S. Typhimurium carrying shRNA-expressing vectors targeting Stat3 induced remarkably delayed and reduced HCC (in 70% of mice). Cancer in these cured mice did not recur over 2 years following treatment. These data demonstrated that RNA interference combined with Salmonella as a delivery system may offer a novel clinical approach for cancer gene therapy.
PMCID: PMC3891655  PMID: 22555509
HCC; immune response; RNA interference; Stat3
19.  Genomic prediction in CIMMYT maize and wheat breeding programs 
Heredity  2013;112(1):48-60.
Genomic selection (GS) has been implemented in animal and plant species, and is regarded as a useful tool for accelerating genetic gains. Varying levels of genomic prediction accuracy have been obtained in plants, depending on the prediction problem assessed and on several other factors, such as trait heritability, the relationship between the individuals to be predicted and those used to train the models for prediction, number of markers, sample size and genotype × environment interaction (GE). The main objective of this article is to describe the results of genomic prediction in International Maize and Wheat Improvement Center's (CIMMYT's) maize and wheat breeding programs, from the initial assessment of the predictive ability of different models using pedigree and marker information to the present, when methods for implementing GS in practical global maize and wheat breeding programs are being studied and investigated. Results show that pedigree (population structure) accounts for a sizeable proportion of the prediction accuracy when a global population is the prediction problem to be assessed. However, when the prediction uses unrelated populations to train the prediction equations, prediction accuracy becomes negligible. When genomic prediction includes modeling GE, an increase in prediction accuracy can be achieved by borrowing information from correlated environments. Several questions on how to incorporate GS into CIMMYT's maize and wheat programs remain unanswered and subject to further investigation, for example, prediction within and between related bi-parental crosses. Further research on the quantification of breeding value components for GS in plant breeding populations is required.
PMCID: PMC3860161  PMID: 23572121
Bayesian LASSO; International Maize and Wheat Improvement Center; genomic selection; genotype × environment interaction; reproducing kernel Hilbert space regression
20.  Synergistic cytotoxicity of gemcitabine, clofarabine and edelfosine in lymphoma cell lines 
Blood Cancer Journal  2014;4(1):e171-.
Treatments for lymphomas include gemcitabine (Gem) and clofarabine (Clo) which inhibit DNA synthesis. To improve their cytotoxicity, we studied their synergism with the alkyl phospholipid edelfosine (Ed). Exposure of the J45.01 and SUP-T1 (T-cell) and the OCI-LY10 (B-cell) lymphoma cell lines to IC10–IC20 levels of the drugs resulted in strong synergistic cytotoxicity for the 3-drug combination based on various assays of cell proliferation and apoptosis. Cell death correlated with increased phosphorylation of histone 2AX and KAP1, decreased mitochondrial transmembrane potential, increased production of reactive oxygen species and release of pro-apoptotic factors. Caspase 8-negative I9.2 cells were considerably more resistant to [Gem+Clo+Ed] than caspase 8-positive cells. In all three cell lines [Gem+Clo+Ed] decreased the level of phosphorylation of the pro-survival protein AKT and activated the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) stress signaling pathway, which in J45.01 cells resulted in the phosphorylation and heterodimerization of the transcription factors ATF2 and c-Jun. The observed rational mechanism-based efficacy of [Gem+Clo+Ed] based on the synergistic convergence of several pro-death and anti-apoptotic signaling pathways in three very different cell backgrounds provides a powerful foundation for undertaking clinical trials of this drug combination for the treatment of lymphomas.
PMCID: PMC3913938  PMID: 24413065
edelfosine; gemcitabine; clofarabine; synergism; apoptosis; lymphoma
21.  RNAi-mediated knockdown of FANCF suppresses cell proliferation, migration, invasion, and drug resistance potential of breast cancer cells 
Fanconi anemia complementation group F protein (FANCF) is a key factor, which maintains the function of FA/BRCA, a DNA damage response pathway. However, the functional role of FANCF in breast cancer has not been elucidated. We performed a specific FANCF-shRNA knockdown of endogenous FANCF in vitro. Cell viability was measured with a CCK-8 assay. DNA damage was assessed with an alkaline comet assay. Apoptosis, cell cycle, and drug accumulation were measured by flow cytometry. The expression levels of protein were determined by Western blot using specific antibodies. Based on these results, we used cell migration and invasion assays to demonstrate a crucial role for FANCF in those processes. FANCF shRNA effectively inhibited expression of FANCF. We found that proliferation of FANCF knockdown breast cancer cells (MCF-7 and MDA-MB-435S) was significantly inhibited, with cell cycle arrest in the S phase, induction of apoptosis, and DNA fragmentation. Inhibition of FANCF also resulted in decreased cell migration and invasion. In addition, FANCF knockdown enhanced sensitivity to doxorubicin in breast cancer cells. These results suggest that FANCF may be a potential target for molecular, therapeutic intervention in breast cancer.
PMCID: PMC3932970  PMID: 24345874
Fanconi anemia complementation group F protein; Breast neoplasms; Tumor cell line
22.  Enterprise Stent-Assisted Coiling of Wide-Necked Intracranial Aneurysms: Clinical and Angiographic Follow-up 
Jia, J. | Lv, X. | Liu, A. | Wu, Z. | Li, Y.
Interventional Neuroradiology  2012;18(4):426-431.
We evaluate and report our clinical and angiographic outcomes associated with stent-assisted coil embolization of wide-necked intracranial aneurysms using the Enterprise stent.
One hundred sixty-nine patients diagnosed with 182 wide-necked intracranial aneurysms underwent placement of the Enterprise stent between April 2009 and October 2011. Demographic information, procedural data, procedure-related complications, angiographic results, and clinical outcomes were reviewed and evaluated.
Stent deployment was successful in 166 out of 169 procedures (98.2%). Four patients had acute procedure-related complications, including thromboembolism in three patients and aneurysm perforation resulting in the death of one patient. Immediate angiographic results showed complete occlusion in 101 aneurysms (56.4%) and near-complete occlusion in 55 aneurysms (30.7%). Follow-up angiography was performed in 108 patients with 119 aneurysms at a mean of 8.1 months: complete occlusion was observed in 95 aneurysms (79.8%) and near-complete occlusion was found in 12 aneurysms (10.1%). Delayed intra-stent thromboses were observed in two patients, and asymptomatic in-stent stenosis was observed in one patient. Ten aneurysms (8.4%, 10/119) demonstrated recanalization, all of which were subsequently recoiled successfully. Clinical follow-up was obtained for 132 patients at a mean of 11.4 months, out of which 118 (89.4%) had favorable clinical outcomes as determined using a modified Rankin Scale (mRS) ≤1. The rates of procedure-related mortality and permanent morbidity were 0.6% (1/169) and 2.3% (3/132), respectively.
This study adds to the current body of evidence supporting the Enterprise stent as an effective and safe tool for the treatment of wide-necked intracranial aneurysms because it results in more complete occlusion and lower complication rates.
PMCID: PMC3520556  PMID: 23217637
Enterprise stent, stent-assisted coiling, wide-necked intracranial aneurysms
23.  A Reproducible Oral Microcosm Biofilm Model for Testing Dental Materials 
Journal of applied microbiology  2012;113(6):1540-1553.
Most studies of biofilm effects on dental materials use single-species biofilms, or consortia. Microcosm biofilms grown directly from saliva or plaque are much more diverse, but difficult to characterize. We used the Human Oral Microbial Identification Microarray (HOMIM) to validate a reproducible oral microcosm model.
Methods and Results
Saliva and dental plaque were collected from adults and children. Hydroxyapatite and dental composite disks were inoculated with either saliva or plaque, and microcosm biofilms were grown in a CDC biofilm reactor. In later experiments, the reactor was pulsed with sucrose. DNA from inoculums and microcosms were analyzed by HOMIM for 272 species. Microcosms included about 60% of species from the original inoculum. Biofilms grown on hydroxyapatite and composites were extremely similar. Sucrose-pulsing decreased diversity and pH, but increased the abundance of Streptococcus and Veilonella. Biofilms from the same donor, grown at different times, clustered together.
This model produced reproducible microcosm biofilms that were representative of the oral microbiota. Sucrose induced changes associated with dental caries.
Significance and Impact of the Study
This is the first use of HOMIM to validate an oral microcosm model that can be used to study the effects of complex biofilms on dental materials.
PMCID: PMC3501590  PMID: 22925110
oral microbiota; oral microcosms; biofilm reactors; dental materials; composite resin restorations; human oral microbial identification microarray
24.  Epigenetic silencing of miR-34a in human prostate cancer cells and tumor tissue specimens can be reversed by BR-DIM treatment 
Androgen Receptor (AR) signaling is critically important during the development and progression of prostate cancer (PCa). The AR signaling is also important in the development of castrate resistant prostate cancer (CRPC) where AR is functional even after androgen deprivation therapy (ADT); however, little is known regarding the transcriptional and functional regulation of AR in PCa. Moreover, treatment options for primary PCa for preventing the occurrence of CRPC is limited; therefore, novel strategy for direct inactivation of AR is urgently needed. In this study, we found loss of miR-34a, which targets AR, in PCa tissue specimens, especially in patients with higher Gleason grade tumors, consistent with increased expression of AR. Forced over-expression of miR-34a in PCa cell lines led to decreased expression of AR and prostate specific antigen (PSA) as well as the expression of Notch-1, another important target of miR-34a. Most importantly, BR-DIM intervention in PCa patients prior to radical prostatectomy showed reexpression of miR-34a, which was consistent with decreased expression of AR, PSA and Notch-1 in PCa tissue specimens. Moreover, BR-DIM intervention led to nuclear exclusion both in PCa cell lines and in tumor tissues. PCa cells treated with BR-DIM and 5-aza-dC resulted in the demethylation of miR-34a promoter concomitant with inhibition of AR and PSA expression in LNCaP and C4-2B cells. These results suggest, for the first time, epigenetic silencing of miR-34a in PCa, which could be reversed by BR-DIM treatment and, thus BR-DIM could be useful for the inactivation of AR in the treatment of PCa.
PMCID: PMC3853430  PMID: 24349627
BR-DIM; miR-34a; androgen receptor (AR); PSA; methylation
25.  Gradient Confinement Induced Uniform Tensile Ductility in Metallic Glass 
Scientific Reports  2013;3:3319.
Metallic glass (MG) generally fails in a brittle manner under uniaxial tension loading at room temperature. The lack of plastic strain of MG is due to the severe plastic instability via the easily formed one dominate shear band. There have been several approaches to improve the ductility in MG, but achieving uniform tensile ductility for monolithic MG in bulk size remains a challenge. Here we demonstrate a uniform tensile ductility of 12% achieved in a micrometer scale Ni-P amorphous film coated on a Ni substrate with gradient structure. Instead of a single run-away shear band, such a gradient structure generates massive extensive multiple shear bands in the film, leading to a record high tensile ductility in MG. The present finding highlights a novel route for achieving uniform tensile ductility in monolithic metallic glass with bulk size.
PMCID: PMC3839029  PMID: 24270980

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