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1.  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
2.  A surrogate-based metaheuristic global search method for beam angle selection in radiation treatment planning 
Physics in medicine and biology  2013;58(6):10.1088/0031-9155/58/6/1933.
An important element of radiation treatment planning for cancer therapy is the selection of beam angles (out of all possible coplanar and non-coplanar angles in relation to the patient) in order to maximize the delivery of radiation to the tumor site and minimize radiation damage to nearby organs-at-risk. This category of combinatorial optimization problem is particularly difficult because direct evaluation of the quality of treatment corresponding to any proposed selection of beams requires the solution of a large-scale dose optimization problem involving many thousands of variables that represent doses delivered to volume elements (voxels) in the patient. However, if the quality of angle sets can be accurately estimated without expensive computation, a large number of angle sets can be considered, increasing the likelihood of identifying a very high quality set. Using a computationally efficient surrogate beam set evaluation procedure based on single-beam data extracted from plans employing equally-spaced beams (eplans), we have developed a global search metaheuristic process based on the Nested Partitions framework for this combinatorial optimization problem. The surrogate scoring mechanism allows us to assess thousands of beam set samples within a clinically acceptable time frame. Tests on difficult clinical cases demonstrate that the beam sets obtained via our method are superior quality.
PMCID: PMC3652383  PMID: 23459411
3.  Taiwan Aneurysm Registry: Multivariate Analysis of Two-Month, One-Year, and Two-Year Outcomes after Endovascular and Microsurgical Treatment of Ruptured Aneurysms 
Interventional Neuroradiology  2013;19(1):35-42.
We compared the outcomes of endovascular coiling with microsurgical clipping of aneurysms in a Taiwanese population.
In an ambi-directional cohort design, patient baseline characteristics and clinical course after treatment for ruptured subarachnoid aneurysm were abstracted from medical records from three hospitals to examine and compare differences in post-operative outcomes between those treated with endovascular coiling and those treated with microsurgical clipping. Outcomes were measured, using the modified Rankin scale, two months, one year and two years postoperatively.
Of the 642 patients enrolled in the study, 281 underwent endovascular treatment and 361 underwent neurosurgery. The demographics and baseline characteristics of two groups were comparable except for a larger maximum target aneurysm lumen size (p=0.02) in the endovascular group. Patients who underwent the endovascular procedure tended to have a better quality of life than those who had neurosurgery (p<0.01). When the severity of symptom data was pooled into two groups (Rankin values 0-2 and 3-6) a statistically significant relationship was found between the severity of symptoms and age, Hunt and Hess grade, number of target aneurysms detected, and log of maximum target aneurysm lumen size (all p≤0.01). After controlling for potential confounding factors and using the lumped Rankin outcome data, no significant difference in outcome was found between the two procedures at either time point.
Our study indicated that endovascular coiling achieves results comparable to surgical clipping for patients with ruptured subarachnoid aneurysms in a Taiwanese population.
PMCID: PMC3601615  PMID: 23472721
aneurysm, hemorrhage, microsurgery, endovascular coiling, size, outcome, quality of life
4.  Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: A genome-wide association study of 13,372 participants 
Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans.
To identify novel genetic variants associated with resting heart rate in African Americans.
Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of single nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci (P ≤ 2.5 × 10−8).
Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98 × 10−15). This SNP was approximately 350 kb downstream of GJA1, a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6, which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans.
An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin.
PMCID: PMC3718037  PMID: 23183192
African Americans; Heart rate; Single nucleotide polymorphisms; Meta-analysis
5.  Genome-wide transcriptional analysis of differentially expressed genes in flagellin-pretreated mouse corneal epithelial cells in response to Pseudomonas aeruginosa: involvement of S100A8/A9 
Mucosal immunology  2013;6(5):993-1005.
We previously showed that pre-exposure of the cornea to Toll-like receptor 5 ligand flagellin induces profound mucosal innate protection against infections by modifying gene expression. Taking advantage of easily procurable epithelial cell population, this study is the first report to use genome-wide cDNA microarray approach to document genes associated with flagellin-induced protection against Pseudomonas aeruginosa in corneal epithelial cells (CECs). Infection altered the expression of 675 genes (497 up and 178 down), while flagellin pretreatment followed by infection resulted in a great increase in 890 gene upregulated and 37 genes downregulated. Comparing these two groups showed 209 differentially expressed genes (157 up, 52 down). Notably, among 114 genes categorized as defense related, S100A8/A9 are the two most highly induced genes by flagellin, and their expression in the corneal was confirmed by realtime PCR and immunohistochemistry. Neutralization of S100A8 and, to a less extent, A9, resulted in significantly increased bacterial burden and severe keratitis. Collectively, our study identifies many differentially expressed genes by flagellin in CECs in response to Pseudomonas. These novel gene expression signatures provide new insights and clues into the nature of protective mechanisms established by flagellin and new therapeutic targets for reducing inflammation and for controlling microbial infection.
PMCID: PMC3722258  PMID: 23340821
6.  Controllability of Vortex Domain Structure in Ferroelectric Nanodot: Fruitful Domain Patterns and Transformation Paths 
Scientific Reports  2014;4:3946.
Ferroelectric vortex domain structure which exists in low-dimensional ferroelectrics is being intensively researched for future applications in functional nanodevices. Here we demonstrate that adjusting surface charge screening in combination with temperature can provide an efficient way to gain control of vortex domain structure in ferroelectric nanodot. Systematical simulating experiments have been conducted to reveal the stability and evolution mechanisms of domain structure in ferroelectric nanodot under various conditions, including processes of cooling-down/heating-up under different surface charge screening conditions, and increasing/decreasing surface charge screening at different temperatures. Fruitful phase diagrams as functions of surface screening and temperature are presented, together with evolution paths of various domain patterns. Calculations discover up to 25 different kinds of domain patterns and 22 typical evolution paths of phase transitions. The fruitful controllability of vortex domain structure by surface charge screening in combination with temperature should shed light on prospective nanodevice applications of low-dimensional ferroelectric nanostructures.
PMCID: PMC3912473  PMID: 24492764
7.  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
8.  A common functional promoter variant links CNR1 gene expression to HDL cholesterol level 
Nature communications  2013;4:10.1038/ncomms2973.
CB1 receptor blockers increase HDL-C levels. Although genetic variation in the CB1 receptor – encoded by the CNR1 gene – is known to influence HDL-C level as well, human studies conducted to date have been limited to genetic markers such as haplotype tagging SNPs. Here we identify rs806371 in the CNR1 promoter as the causal variant. We resequenced the CNR1 gene and genotype all variants in a DNA biobank linked to comprehensive electronic medical records. By testing each variant for association with HDL-C level in a clinical practice-based setting, we localize a putative functional allele to a 100bp window in the 5′-flanking region. Assessment of variants in this window for functional impact on electrophoretic mobility shift assay identified rs806371 as a novel regulatory binding element. Reporter gene assays confirm that rs806371 reduces HDL-C gene expression, thereby linking CNR1 gene variation to HDL-C level in humans.
PMCID: PMC3873874  PMID: 23748922
9.  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
10.  Thyroid hormone receptors promote metastasis of human hepatoma cells via regulation of TRAIL 
Cell Death and Differentiation  2012;19(11):1802-1814.
Although accumulating evidence has confirmed the important roles of thyroid hormone (T3) and its receptors (TRs) in tumor progression, the specific functions of TRs in carcinogenesis remain unclear. In the present study, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was directly upregulated by T3 in TR-overexpressing hepatoma cell lines. TRAIL is an apoptotic inducer, but it can nonetheless trigger non-apoptotic signals favoring tumorigenesis in apoptosis-resistant cancer cells. We found that TR-overexpressing hepatoma cells treated with T3 were apoptosis resistant, even when TRAIL was upregulated. This apoptotic resistance may be attributable to simultaneous upregulation of Bcl-xL by T3, because (1) knockdown of T3-induced Bcl-xL expression suppressed T3-mediated protection against apoptosis, and (2) overexpression of Bcl-xL further protected hepatoma cells from TRAIL-induced apoptotic death, consequently leading to TRAIL-promoted metastasis of hepatoma cells. Moreover, T3-enhanced metastasis in vivo was repressed by the treatment of TRAIL-blocking antibody. Notably, TRAIL was highly expressed in a subset of hepatocellular carcinoma (HCC) patients, and this high-level expression was significantly correlated with that of TRs in these HCC tissues. Together, our findings provide evidence for the existence of a novel mechanistic link between increased TR and TRAIL levels in HCC. Thus, TRs induce TRAIL expression, and TRAIL thus synthesized acts in concert with simultaneously synthesized Bcl-xL to promote metastasis, but not apoptosis.
PMCID: PMC3469053  PMID: 22576662
thyroid hormone receptor; TRAIL; apoptosis; metastasis
11.  Pathway-based analysis of primary biliary cirrhosis genome-wide association studies 
Genes and immunity  2013;14(3):179-186.
Genome-wide association studies (GWAS) have successfully identified several loci associated with primary biliary cirrhosis (PBC) risk. Pathway analysis complements conventional GWAS analysis. We applied the recently developed linear combination test for pathways to datasets drawn from independent PBC GWAS in Italian and Canadian subjects. Of the Kyoto Encyclopedia of Genes and Genomes and BioCarta pathways tested, 25 pathways in the Italian dataset (449 cases, 940 controls) and 26 pathways in the Canadian dataset (530 cases, 398 controls) were associated with PBC susceptibility (P < 0.05). After correcting for multiple comparisons, only the eight most significant pathways in the Italian dataset had FDR < 0.25 with tumor necrosis factor/stress-related signaling emerging as the top pathway (P = 7.38 × 10−4, FDR = 0.18). Two pathways, phosphatidylinositol signaling and hedgehog signaling, were replicated in both datasets (P < 0.05), and subjected to two additional complementary pathway tests. Both pathway signals remained significant in the Italian dataset on modified gene set enrichment analysis (P < 0.05). In both GWAS, variants nominally associated with PBC were significantly overrepresented in the phosphatidylinositol pathway (Fisher exact P < 0.05). These results point to established and novel pathway-level associations with inherited predisposition to PBC that on further independent replication and functional validation, may provide fresh insights into PBC etiology.
PMCID: PMC3780793  PMID: 23392275
linear combination test; phosphatidylinositol signaling; hedgehog signaling; autoimmune disease
12.  The epigenetic modifier trichostatin A, a histone deacetylase inhibitor, suppresses proliferation and epithelial–mesenchymal transition of lens epithelial cells 
Chen, X | Xiao, W | Chen, W | Luo, L | Ye, S | Liu, Y
Cell Death & Disease  2013;4(10):e884-.
Proliferation and epithelial–mesenchymal transition (EMT) of lens epithelium cells (LECs) may contribute to anterior subcapsular cataract (ASC) and posterior capsule opacification (PCO), which are important causes of visual impairment. Histone deacetylases (HDACs)-mediated epigenetic mechanism has a central role in controlling cell cycle regulation, cell proliferation and differentiation in a variety of cells and the pathogenesis of some diseases. However, whether HDACs are involved in the regulation of proliferation and EMT in LECs remain unknown. In this study, we evaluated the expression profile of HDAC family (18 genes) and found that class I and II HDACs were upregulated in transforming growth factor β2 (TGFβ2)-induced EMT in human LEC lines SRA01/04 and HLEB3. Tricostatin A (TSA), a class I and II HDAC inhibitor, suppressed the proliferation of LECs by G1 phase cell cycle arrest not only through inhibition of cyclin/CDK complexes and induction of p21 and p27, but also inactivation of the phosphatidylinositol-3-kinase/Akt, p38MAPK and ERK1/2 pathways. Meanwhile, TSA strongly prevented TGFβ2-induced upregulation of fibronectin, collagen type I, collagen type IV, N-cadherin, Snail and Slug. We also demonstrated that the underlying mechanism of TSA affects EMT in LECs through inhibiting the canonical TGFβ/Smad2 and the Jagged/Notch signaling pathways. Finally, we found that TSA completely prevented TGFβ2-induced ASC in the whole lens culture semi-in vivo model. Therefore, this study may provide a new insight into the pathogenesis of ASC and PCO, and suggests that epigenetic treatment with HDAC inhibitors may be a novel therapeutic approach for the prevention and treatment of ASC, PCO and other fibrotic diseases.
PMCID: PMC3920942  PMID: 24157878
histone deacetylase inhibitor; lens epithelium cells (LECs); proliferation; epithelial–mesenchymal transition (EMT); anterior subcapsular cataract (ASC); posterior capsule opacification (PCO)
13.  Anomalous interface adhesion of graphene membranes 
Scientific Reports  2013;3:2660.
In order to understand the anomalous interface adhesion properties between graphene membranes and their substrates, we have developed a theoretical method to calibrate the interface adhesion energy of monolayer and multilayer graphene on substrates based on the bond relaxation consideration. Four kinds of interfaces, including graphene/SiO2, graphene/Cu, graphene/Cu/Ni and Cu/graphene/Ni, were taken into account. It was found that the membrane thickness and the interface confinement condition determine the adhesion energy. The relationship between the critical interface separation and the graphene thickness showed that the interface separation in the self-equilibrium state drops with decreasing membrane thickness. The size-dependent Young's modulus of graphene membrane and the interfacial condition were responsible for the novel interface adhesion energy. The proposed theory was expected to be applied to the design of graphene-based devices.
PMCID: PMC3773622  PMID: 24036502
14.  Social Support Mediates the Relationship between HIV Stigma and Depression/Quality of Life among People Living with HIV in Beijing, China 
Stigma toward people living with HIV is pervasive in China and related to poor service utilization, psychosocial distress, and diminished quality of life. In an effort to identify mechanisms to reduce HIV stigma and its negative consequences, we examined whether social support mediates the relation between enacted stigma and both depressive symptoms and quality of life among 120 HIV outpatients in Beijing, China. Generally, perceived social support was associated with less stigma, less depressive symptomatology, and better quality of life. Using multivariable regression models, we found that social support was a full mediator of the impact of stigma on both depressive symptomatology and quality of life. The findings suggest social support may be an important target of interventions to reduce the impact of stigma on poor psychosocial health outcomes.
PMCID: PMC3408622  PMID: 22844001
15.  Anti-TCRβ mAb induces long-term allograft survival by reducing antigen-reactive T-cells and sparing regulatory T-cells 
American Journal of Transplantation  2012;12(6):1409-1418.
TCR specific antibodies may modulate the TCR engagement with antigen-MHC complexes, and in turn regulate in vivo T-cell responses to allo-antigens. Herein, we found that in vivo administration of mAbs specific for mouse TCRβ (H57-597), TCRα, or CD3 promptly reduced the number of CD4+ and CD8+ T-cells in normal mice, but H57-597 mAb most potently increased the frequency of CD4+Foxp3+ Treg cells. When mice were injected with staphylococcal enterotoxin B (SEB) superantigen and H57-597 mAb, the expansion of SEB-reactive Vβ8+ T-cells was completely abrogated while SEB-non-reactive Vβ2+ T-cells remained unaffected. More importantly, transient H57-597 mAb treatment exerted long-lasting effect in preventing T-cell responses to allo-antigens, and produced long-term cardiac allograft survival (>100 days) in 10 out of 11 recipients. While Treg cells were involved in maintaining donor-specific long-term graft survival, T-cell homeostasis recovered over time and immunity was retained against third party allografts. Moreover, transient H57-597 mAb treatment significantly prolonged survival of skin allografts in naïve recipients as well as heart allografts in skin-sensitized recipients. Thus, transient modulation of the TCRβ chain by H57-597 mAb exhibits potent, long-lasting therapeutic effects to control allo-immune responses.
PMCID: PMC3365620  PMID: 22420295
tolerance; T-cell receptor; T regulatory cells; allograft survival
16.  Radiofrequency ablation for hepatocellular carcinoma: use of low vs maximal radiofrequency power 
The British Journal of Radiology  2012;85(1014):e102-e109.
To investigate whether radiofrequency (RF) ablation with low power (LP) or maximal power (MP) for hepatocellular carcinoma (HCC) can achieve optimal ablation and fewer adverse effects.
RF ablation was performed with MP in 101 patients (129 tumours) and with LP in 46 patients (61 tumours). MP RF ablation used power of >120 W. RF power below this was designated as LP. Clinical outcomes were also analysed in subgroups of high-risk tumours near the bile duct and blood vessels.
Primary effectiveness was achieved in 91.8% in the LP group and 89.9% in the MP group (p=0.795). 1 and 2-year local tumour progression rates were 28% and 30%, respectively, in the LP group, and 24% and 29%, respectively, in the MP group (p=0.70). 1 and 2-year survival rates were 98% and 98%, respectively, in the LP group, and 93% and 90%, respectively, in the MP group (p=0.216). The MP group had more adverse effects, with post-RF ablation syndrome, asymptomatic pleural effusion and ascites, than the LP group (20% vs 39% in the MP group; p=0.027); however, there was no significant difference in major complication rates (6% in the MP and LP groups; p=0.497). Among the patients with high-risk tumours, RF ablation using MP vs LP was comparable in primary effectiveness (91.7% vs 95.2%; p=0.618), local tumour progression (42.9% vs 29.2%; p=0.304) and overall complications (5% vs 8%; p=0.618).
RF ablation with LP and MP are comparable in clinical outcomes but considerably fewer adverse effects were encountered in the LP group.
PMCID: PMC3474107  PMID: 21427178
17.  IL-10 Treatment Is Associated with Prohibitin Expression in the Crohn's Disease Intestinal Fibrosis Mouse Model 
Mediators of Inflammation  2013;2013:617145.
Prohibitin, which can inhibit oxidative stress and mitochondrial dysfunction, has been shown to have significant anti-inflammatory activities. Here, we investigate the effects of altering prohibitin levels in affected tissues in the interleukin-10 knockout (IL-10KO) mouse model with intestinal fibrosis. The aim of this study is to investigate the effects of IL-10 on prohibitin and the role of prohibitin in intestinal fibrosis of murine colitis. After the mice were treated with IL-10, prohibitin expression and localization were evaluated in IL-10KO and wild-type (WT, 129/SvEv) mice. The colon tissue was then investigated and the potential pathogenic molecular mechanisms were further studied. Fluorescence-based quantitative polymerase chain reaction (FQ-PCR) and immunohistochemistry assays revealed a significant upregulation of prohibitin with IL-10 treatment. Furthermore, IL-10 decreases inflammatory cytokines and TGF-β1 in the IL-10KO model of Crohn's disease and demonstrates a promising trend in decreasing tissue fibrosis. In conclusion, we hypothesize that IL-10 treatment is associated with increased prohibitin and would decrease inflammation and fibrosis in an animal model of Crohn's disease. Interestingly, prohibitin may be a potential target for intestinal fibrosis associated with inflammatory bowel disease (IBD).
PMCID: PMC3649775  PMID: 23690666
18.  MEK Inhibition Enhances ABT-737-Induced Leukemia Cell Apoptosis via Prevention of ERK activated MCL-1 induction and Modulation of MCL-1/BIM Complex 
Leukemia  2011;26(4):778-787.
Recently, strategies for AML therapy have been developed that target anti-apoptotic BCL2 family members using BH3 mimetic drugs such as ABT-737. Though effective against BCL2 and BCL-XL, ABT-737 poorly inhibits MCL-1. Here we report that, unexpectedly, ABT-737 induces activation of ERK and induction of MCL-1 in AML cells. MEK inhibitors such as PD0325901 and CI-1040 have been used successfully to suppress MCL-1. We report that PD0325901 blocked ABT-737 –induced MCL-1 expression and when combined with ABT-737 resulted in potent synergistic killing of AML derived cell lines, primary AML blast and CD34+38−123+ progenitor/stem cells. Finally, we tested the combination of ABT-737 and CI-1040 in a murine xenograft model using MOLM-13 human leukemia cells. While control and CI-1040 treated mice exhibited progressive leukemia growth, ABT-737 and, to a significantly greater extent, ABT-737 + CI-1040 exerted major anti-leukemia activity. Collectively, results demonstrate unexpected anti-apoptotic interaction between the BCL2 family-targeted BH3 mimetic ABT-737 and MAPK signaling in AML cells: the BH3 mimetic is not only restrained in its activity by MCL-1, but also induces it’s expression. However, concomitant inhibition by BH3 mimetics and MEK inhibitors could abrogate this effect and may be developed into a novel and effective therapeutic strategy for patients with AML.
PMCID: PMC3604791  PMID: 22064351
MCL-1; ABT-737; BH3 mimetic; AML; ERK; Apoptosis
19.  Electroacupuncture and Acupuncture Promote the Rat's Transected Median Nerve Regeneration 
Background. Acupuncture and electroacupuncture treatments of damaged nerves may aid nerve regeneration related to hindlimb function, but the effects on the forelimb-related median nerve were not known. Methods. A gap was made in the median nerve of each rat by suturing the stumps into silicone rubber tubes. The influences of acupuncture and electroacupuncture treatments on transected median nerve regeneration were evaluated from morphological, electrophysiological, and functional angles. Results. Morphologically, the group receiving acupuncture and electroacupuncture treatments had larger total nerve area and blood vessel number compared with the controls. Electrophysiologically, the group receiving electroacupuncture had significantly larger amplitude and larger area of the evoked muscle action potentials compared with the controls. Functionally, the acupuncture and electroacupuncture treatments enhanced the injured paw's ability to regain its grasping power and resulted in a faster efficiency to a new bilateral balance. Conclusion. Our findings provide multiapproach evidence of the efficacy of acupuncture and electroacupuncture treatments to the regeneration of median nerve. Indeed, acupuncture and electroacupuncture appear to have positive effects on the regeneration processes. This platform is beneficial to further study the clinical application of acupuncture and electroacupuncture alternative treatments on nerve-injured patients.
PMCID: PMC3610348  PMID: 23573131
20.  CT and MRI findings correlate with the time-course of unresectable cavernous haemangioma of the liver after fractionated radiotherapy 
The British Journal of Radiology  2012;85(1011):e049-e052.
We present the case of a 79-year-old female with symptomatic cavernous haemangioma of the liver. The patient had experienced progressive right lateral abdominal pain for years despite increased painkiller use. Surgical resection or transarterial embolisation was not recommended because of the patient’s age, cardiovascular comorbidities and large tumour size. Therefore, the patient was treated with 3-dimensional conformal radiotherapy (RT) with a total dose of 30 Gy in 15 fractions. Following RT, the painkillers were tapered from the third month, and complete symptomatic remission was achieved after the ninth month. The measured tumour volume from serial images pre-RT and 3, 9 and 15 months post-RT was 400 ml, 372 ml, 185 ml and 140 ml, respectively. The most dramatic volumetric reduction was found between 3 and 9 months post-RT, whereas the change before or after this period was minimal. The time course of the radiological volumetric changes correlated with that of the clinical symptoms. In addition, the observed vascular changes on serial imaging studies were consistent with the assumed radiobiological effects after fractionated RT.
PMCID: PMC3473995  PMID: 22391499
21.  Dialysis Modality for Patients with Turner Syndrome and Renal Failure 
PMCID: PMC3525405  PMID: 22383732
Turner syndrome; renal failure; dialysis modality
22.  Fabrication and Evaluation of Curcumin-loaded Nanoparticles Based on Solid Lipid as a New Type of Colloidal Drug Delivery System 
Curcumin has very broad spectrum of biological activities; however, photodegradation, short half-life and low bioavailability have limited its clinical application. Curcumin-loaded solid lipid nanoparticles were studied to overcome these problems. The aim of this study was to optimize the best formulation on curcumin-loaded solid lipid nanoparticles. Emulsion-evaporation and low temperature-solidification technique was applied with monostearin as lipid carriers. The single factor analysis and orthogonal design were used to optimize formulation and various parameters were investigate. By the optimisation of a single factor analysis and orthogonal test, the particles size, polydispersity index, zeta potential, encapsulation efficiency and drug loading capacity of the optimised formulation were 99.99 nm, 0.158, −19.9 mV, 97.86%, and 4.35%, respectively. The differential scanning calorimetry and X-ray diffraction analysis results demonstrated new structure was formed in nanoparticles. The release kinetics in vitro demonstrated curcumin-loaded solid lipid nanoparticles can control drug release. These studies confirmed that curcumin-loaded solid lipid nanoparticles could be prepared successfully with high drug entrapment efficiency and loading capacity. Curcumin-loaded solid lipid nanoparticles may be a promising drug delivery system to control drug release and improve bioavailability.
PMCID: PMC3757856  PMID: 24019566
Curcumin; preparation; release; solid lipid nanoparticles
23.  Differential regulation of simultaneous anti-tumor and alloreactive CD8+ T cell responses in the same host by rapamycin 
Rapamycin is an immunosuppressive agent routinely used in organ transplantation, but also paradoxically, exerts antiviral and anti-tumor activities. Pathogen-specific memory CD8+ T cell (TCD8) responses were recently found to be augmented by rapamycin. However, whether rapamycin influences the magnitude and quality of anticancer TCD8 responses is unknown. Importantly, how rapamycin may regulate simultaneous virus/tumor-specific and alloreactive TCD8 in the same host remains unexplored. To answer these questions, we primed wild-type mice with allogeneic cells concomitantly expressing simian virus 40 large tumor antigen (T Ag), a viral oncoprotein with well-defined epitopes. Rapamycin selectively enhanced the cross-priming of TCD8 specific for T Ag’s most immunodominant epitope called site IV but not TCD8 alloreactivity. Rapamycin-treated mice also had a high percentage of splenic CD127highKLRG1low TCD8 as well as an increased frequency of site IV-specific T cells long after the peak of their primary response. When site IV was presented as a cytosolic minigene encoded by a recombinant vaccinia virus, rapamycin failed to boost the site IV-specific response. Therefore, the nature and presentation mode of antigen determine the susceptibility to the adjuvant effect of rapamycin. Our findings reveal the unexpected benefit of rapamycin treatment in recipients of allografts co-expressing tumor/viral Ags.
PMCID: PMC3520512  PMID: 22026814
Rapamycin; mTOR; CD8+ T cells; alloreactivity; anti-tumor response; memory
24.  Steroidogenic Factor 1 (NR5A1) resides in centrosomes and maintains genomic stability by controlling centrosome homeostasis 
Cell Death and Differentiation  2011;18(12):1836-1844.
SF-1 (Steroidogenic Factor 1, NR5A1) is a tissue-specific transcription factor critical for the growth, development and differentiation of steroidogenic and a few other endocrine tissues. But how SF-1 regulates cell growth is not entirely clear. Here we found that SF-1 was localized to the centrosome in addition to the nucleus, and SF-1 depletion by shRNA caused centrosome over-duplication, aberrant mitosis and genomic instability, leading to a reduction of cell number. Centrosome amplification defect was rescued by both wild-type SF-1 and transcription-defective SF-1-G35E, suggesting a non-genomic activity of SF-1 involved in centrosome homeostasis. In addition, we identified in SF-1 a centrosome localization signal, whose overexpression led to reduced localization of both SF-1 and γ-tubulin to the centrosome. Our results uncover a novel role of SF-1 in the control of centrosome homeostasis and genomic stability.
PMCID: PMC3214907  PMID: 21566663
adrenal growth; centrosome amplification; NR5A1; γ-tubulin; centrosome localization signal
25.  Grainyhead-like 2 (GRHL2) inhibits keratinocyte differentiation through epigenetic mechanism 
Cell Death & Disease  2012;3(12):e450-.
We recently identified Grainyhead-like 2 (GRHL2), a mammalian homolog of Grainyhead in Drosophila, to be a novel transcription factor that regulates hTERT gene expression and enhances proliferation of normal human epidermal keratinocytes (NHEK). In the current study, we show that GRHL2 impairs keratinocyte differentiation through transcriptional inhibition of the genes clustered at the epidermal differentiation complex (EDC), located at chromosome 1q21. Gene expression profiling and subsequent in vitro assays revealed consistent downregulation of EDC genes, for example, IVL, KRT1, FLG, LCEs, and SPRRs, in NHEK expressing exogenous GRHL2. In vivo binding assay by chromatin immunoprecipitation revealed GRHL2 association at the promoter regions of its target genes, many of which belong to EDC. Exogenous GRHL2 expression also inhibited recruitment of histone demethylase Jmjd3 to the EDC gene promoters and enhanced the level of histone 3 Lys 27 trimethylation enrichment at these promoters. Survey of GRHL2 expression in human skin tissues demonstrated enhanced protein and mRNA levels in chronic skin lesions with impaired keratinocyte differentiation, for example, atopic dermatitis and psoriasis, compared with normal epidermis. These data indicate that GRHL2 impairs epidermal differentiation by inhibiting EDC gene expression through epigenetic mechanisms and support its role in the hyperproliferative skin diseases.
PMCID: PMC3542624  PMID: 23254293
epidermal differentiation complex; epigenetic; GRHL2; histone methylation; keratinocyte

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