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1.  Design, Synthesis, and Osteogenic Activity of Daidzein Analogs on Human Mesenchymal Stem Cells 
ACS Medicinal Chemistry Letters  2013;5(2):143-148.
Osteoporosis is caused by an overstimulation of osteoclast activity and the destruction of the bone extracellular matrix. Without the normal architecture, osteoblast cells are unable to rebuild phenotypically normal bone. Hormone replacement therapy with estrogen has been effective in increasing osteoblast activity but also has resulted in the increased incidence of breast and uterine cancer. In this study we designed and synthesized a series of daidzein analogs to investigate their osteogenic induction potentials. Human bone marrow derived mesenchymal stem cells (MSCs) from three different donors were treated with daidzein analogs and demonstrated enhanced osteogenesis when compared to daidzein treatment. The enhanced osteogenic potential of these daidzein analogs resulted in increased osterix (Sp7), alkaline phosphatase (ALP), osteopontin (OPN), and insulin-like growth factor 1 (IGF-1), which are osteogenic transcription factors that regulate the maturation of osteogenic progenitor cells into mature osteoblast cells.
PMCID: PMC4027770  PMID: 24900787
Daidzein analogs; mesenchymal stem cells; BMSCs; osteogenesis
2.  Disrupting the Interaction of BRD4 with Di-acetylated Twist Suppresses Tumorigenesis in Basal-like Breast Cancer 
Cancer cell  2014;25(2):210-225.
Twist is a key transcription activator of epithelial-mesenchymal transition (EMT). It remains unclear how Twist induces gene expression. Here we reported a mechanism by which Twist recruits BRD4 to direct WNT5A expression in basal-like breast cancer (BLBC). Twist contains a “histone H4 mimic” GK-X-GK motif that is di-acetylated by Tip60. The di-acetylated Twist binds the second bromodomain of BRD4, whose first bromodomain interacts with acetylated H4, thereby constructs an activated Twist/BRD4/P-TEFb/RNA-PolII complex at the WNT5A promoter and enhancer. Pharmacologic inhibition of the Twist-BRD4 association reduced WNT5A expression and suppressed invasion, cancer stem cell (CSC)-like properties, and tumorigenicity of BLBC cells. Our study indicates that the interaction with BRD4 is critical for the oncogenic function of Twist in BLBC.
PMCID: PMC4004960  PMID: 24525235
3.  In Vitro and In Vivo Evidence for Amphotericin B as a P-Glycoprotein Substrate on the Blood-Brain Barrier 
Amphotericin B (AMB) has been a mainstay therapy for fungal infections of the central nervous system, but its use has been limited by its poor penetration into the brain, the mechanism of which remains unclear. In this study, we aimed to investigate the role of P-glycoprotein (P-gp) in AMB crossing the blood-brain barrier (BBB). The uptake of AMB by primary brain capillary endothelial cells in vitro was significantly enhanced after inhibition of P-gp by verapamil. The impact of two model P-gp inhibitors, verapamil and itraconazole, on brain/plasma ratios of AMB was examined in both uninfected CD-1 mice and those intracerebrally infected with Cryptococcus neoformans. In uninfected mice, the brain/plasma ratios of AMB were increased 15 min (3.5 versus 2.0; P < 0.05) and 30 min (5.2 versus 2.8; P < 0.05) after administration of verapamil or 45 min (6.0 versus 3.9; P < 0.05) and 60 min (5.4 versus 3.8; P < 0.05) after itraconazole administration. The increases in brain/plasma ratios were also observed in infected mice treated with AMB and P-gp inhibitors. The brain tissue fungal CFU in infected mice were significantly lower in AMB-plus-itraconazole or verapamil groups than in the untreated group (P < 0.005), but none of the treatments protected the mice from succumbing to the infection. In conclusion, we demonstrated that P-gp inhibitors can enhance the uptake of AMB through the BBB, suggesting that AMB is a P-gp substrate.
PMCID: PMC4136029  PMID: 24867970
4.  Rs1800625 in the receptor for advanced glycation end products gene predisposes to sepsis and multiple organ dysfunction syndrome in patients with major trauma 
Critical Care  2015;19(1):6.
The receptor for advanced glycation end products (RAGE) is a transmembrane receptor of the immunoglobulin superfamily, it plays pivotal roles in the pathogenesis of sepsis in several ways. Our previous study showed that rs1800625 (−429T/C) revealed a strong clinical relevance with sepsis morbidity rate and multiple organ dysfunction syndrome (MODS) in patients with major trauma. In this study, we enlarged the sample size, added two validation populations and examined the expression of RAGE on the surface of peripheral leukocytes to ex vivo lipopolysaccharide (LPS) stimulation in subjects with different genotypes.
Rs1800625 was genotyped using pyrosequencing in 837 Chinese Han patients with major trauma in Chongqing. We then validated the clinical relevance in 340 Zhejiang and 347 Yunnan patients. The expression of RAGE on the surface of peripheral blood mononuclear cells was measured by flow cytometric analysis.
The results indicated that rs1800625 was significantly associated with sepsis morbidity rate and MODS in patients with major trauma in the Chongqing, Zhejiang and Yunnan districts. Patients with CC genotype had lower sepsis morbidity rate and MODS after major trauma. Furthermore, patients with CC genotype had significantly higher RAGE expression (P = 0.009).
The rs1800625 polymorphism is a functional single nucleotide polymorphism and confers host susceptibility to sepsis and MODS in patients with major trauma.
PMCID: PMC4310192  PMID: 25572180
5.  MiR-217 Promotes Tumor Proliferation in Breast Cancer via Targeting DACH1 
Journal of Cancer  2015;6(2):184-191.
Objective: The expression of DACH1 was frequently lost in human breast cancer, which significantly correlated with poor prognosis. Herein, we aim to investigate its underlying mechanisms.
Methods: The expression of miR-217 was detected by Taqman PCR. The mRNA and protein level of DACH1 were investigated by real time PCR and western blot. The dual-luciferase reporter system was used to determine the direct interaction between miR-217 and DACH1. A series of gain&loss of function assays were performed to measure the affects of miR-217 on tumor proliferation and cell cycle distribution.
Results: Compared to that in normal breast samples, the expression of miR-217 was significantly upregulated in breast cancer tissues. High level of miR-217 was notably correlated with highly histological grade, the triple negative subtype and advanced tumor stage. Moreover, the expression of miR-217 was negatively correlated with the expression of DACH1. The results of dual-luciferase reporter assay demonstrated that miR-217 directly targets and inhibits the transcriptive activity of DACH1. In vitro, treatment with miR-217 mimics significantly suppressed the proliferation of MCF-7 cells, induced G1 phase arrest and inhibited the expression of cyclin D1; while these effects were significantly reversed by the restoration of DACH1. In MDA-MB-231 cells, treatment with miR-217 inhibitors enhanced the cellular proliferation, promoted cell cycle progression and upregulated the expression of cyclin D1, which were neutralized by the pre-treatment of siRNA-DACH1. In vivo, inhibition of miR-217 significantly suppressed the xenografts growth and downregulated the expression of cyclin D1.
Conclusion: We found that miR-217 was commonly overexpressed in breast cancer, which could enhance tumor proliferation via promoting cell cycle progression. Moreover, the DACH1 (the cell fate determination factor) was identified as a novel target of miR-217. Our results proposed inhibiting miR-217 to be a potent therapeutic strategy for breast cancer.
PMCID: PMC4314667  PMID: 25653720
DACH1; miR-217; breast cancer; proliferation; cell cycle
6.  Incomplete Radiofrequency Ablation Enhances Invasiveness and Metastasis of Residual Cancer of Hepatocellular Carcinoma Cell HCCLM3 via Activating β-Catenin Signaling 
PLoS ONE  2014;9(12):e115949.
Radiofrequency ablation (RFA) is one of the curative therapies for hepatocellular carcinoma (HCC), however, accelerated progression of residual HCC after incomplete RFA has been reported more frequently. The underlying molecular mechanism of this phenomenon remains to be elucidated. In this study, we used an incomplete RFA orthotopic HCC nude mouse model to study the invasive and metastatic potential of residual cancer as well as the correlated mechanism.
The incomplete RFA orthotopic nude mouse models were established using high metastatic potential HCC cell line HCCLM3 and low metastatic potential HCC cell line HepG2, respectively. The changes in cellular morphology, motility, metastasis and epithelial–mesenchymal transition (EMT), and HCC cell molecular markers after in vitro and in vivo incomplete RFA intervention were observed.
Pulmonary and intraperitoneal metastasis were observed in an in vivo study. The underlying pro-invasive mechanism of incomplete RFA appeared to be associated with promoting EMT, including down-regulation of E-cadherin and up-regulation of N-cadherin and vimentin. These results were in accordance with the in vitro response of HCC cells to heat intervention. Further studies demonstrated that β-catenin was a pivotal factor during this course and blocking β-catenin reduced metastasis and EMT phenotype changes in heat-treated HCCLM3 cells in vitro.
Incomplete RFA enhanced the invasive and metastatic potential of residual cancer, accompanying with EMT-like phenotype changes by activating β-catenin signaling in HCCLM3 cells.
PMCID: PMC4277411  PMID: 25542041
7.  Nanoscale Drug Delivery Platforms Overcome Platinum-Based Resistance in Cancer Cells Due to Abnormal Membrane Protein Trafficking 
ACS nano  2013;7(12):10452-10464.
The development of cellular resistance to platinum-based chemotherapies is often associated with reduced intracellular platinum concentrations. In some models, this reduction is due to abnormal membrane protein trafficking, resulting in reduced uptake by transporters at the cell surface. Given the central role of platinum drugs in the clinic, it is critical to overcome cisplatin resistance by bypassing the plasma membrane barrier to significantly increase the intracellular cisplatin concentration enough to inhibit the proliferation of cisplatin-resistant cells. Therefore, rational design of appropriate nanoscale drug delivery platforms (nDDPs) loaded with cisplatin or other platinum analogs as payloads is a possible strategy to solve this problem. This review will focus on the known mechanism of membrane trafficking in cisplatin-resistant cells, and the development and employment of nDDPs to improve cell uptake of cisplatin.
PMCID: PMC3907077  PMID: 24219825
cancer; cisplatin; drug resistance; nanoscale drug delivery platforms; membrane trafficking; nanotechnology; chemotherapy; abnormal membrane proteins
8.  Motif mining based on network space compression 
BioData Mining  2014;8:29.
A network motif is a recurring subnetwork within a network, and it takes on certain functions in practical biological macromolecule applications. Previous algorithms have focused on the computational efficiency of network motif detection, but some problems in storage space and searching time manifested during earlier studies. The considerable computational and spacial complexity also presents a significant challenge. In this paper, we provide a new approach for motif mining based on compressing the searching space. According to the characteristic of the parity nodes, we cut down the searching space and storage space in real graphs and random graphs, thereby reducing the computational cost of verifying the isomorphism of sub-graphs. We obtain a new network with smaller size after removing parity nodes and the “repeated edges” connected with the parity nodes. Random graph structure and sub-graph searching are based on the Back Tracking Method; all sub-graphs can be searched for by adding edges progressively. Experimental results show that this algorithm has higher speed and better stability than its alternatives.
PMCID: PMC4269098  PMID: 25525470
Associated matrix; Space compression; Sub-graph mark; Parity nodes
9.  Feasibility Study of Perfusion Imaging Using Flat Detector CT with an Intra-Arterial Injection Protocol Compared to Conventional Multi-Slice Perfusion CT with an Intravenous Injection Protocol 
Interventional Neuroradiology  null;19(4):409-415.
This study investigated the feasibility of using intra-arterial injection-based cerebral blood volume (CBV) imaging with flat detector computed tomography (CT, IAFD-CBV). It is proven that this new method could provide comparable physiologic information as standard intravenous injection-based multi-slice computed tomography CBV imaging (IVCT-CBV).
Twelve patients were examined using both IAFD-CBV and IVCT-CBV. An experienced neuroradiologist read both sets of generated CBV maps. If a physiologic perfusion disorder was detected in standard IVCT-CBV, the focus was to check whether IAFD-CBV indicated the same disorder or not. Otherwise, if no disorder was detected, relative CBV (rCBV) values at different basal ganglia regions were measured for both CBV maps and then compared.
For three patients with lesions, IAFD-CBV and IVCT-CBV showed similar perfusion disorders in the corresponding regions. For nine patients without lesions, both CBV maps showed good symmetry of contrast agent (CA) distribution for left/right hemisphere, the total average of rCBV was found to be 0.94 −/+0.18 and 1.01 −/+0.14 (1.0 for perfect symmetry) in IAFD-CBV and IVCT-CBV, respectively. However, compared to IVCT-CBV, IAFD-CBV imaging required 70% less contrast agent (CA).
In general, a good correlation between IAFD-CBV and IVCT-CBV was found for all 12 patients. Minor deviations of IAFD-CBV were only detected at regions supplied by the middle cerebral artery. IAFD-CBV imaging, which can be directly performed in a catheterization laboratory, was proven to be technically feasible for real-time CBV assessment of the whole brain with good accuracy, and minimized CA usage.
PMCID: PMC3902738  PMID: 24355143
flat detector CT; cerebral blood volume; perfusion
10.  Molecular Signaling Network Motifs Provide a Mechanistic Basis for Cellular Threshold Responses 
Environmental Health Perspectives  2014;122(12):1261-1270.
Background: Increasingly, there is a move toward using in vitro toxicity testing to assess human health risk due to chemical exposure. As with in vivo toxicity testing, an important question for in vitro results is whether there are thresholds for adverse cellular responses. Empirical evaluations may show consistency with thresholds, but the main evidence has to come from mechanistic considerations.
Objectives: Cellular response behaviors depend on the molecular pathway and circuitry in the cell and the manner in which chemicals perturb these circuits. Understanding circuit structures that are inherently capable of resisting small perturbations and producing threshold responses is an important step towards mechanistically interpreting in vitro testing data.
Methods: Here we have examined dose–response characteristics for several biochemical network motifs. These network motifs are basic building blocks of molecular circuits underpinning a variety of cellular functions, including adaptation, homeostasis, proliferation, differentiation, and apoptosis. For each motif, we present biological examples and models to illustrate how thresholds arise from specific network structures.
Discussion and Conclusion: Integral feedback, feedforward, and transcritical bifurcation motifs can generate thresholds. Other motifs (e.g., proportional feedback and ultrasensitivity)produce responses where the slope in the low-dose region is small and stays close to the baseline. Feedforward control may lead to nonmonotonic or hormetic responses. We conclude that network motifs provide a basis for understanding thresholds for cellular responses. Computational pathway modeling of these motifs and their combinations occurring in molecular signaling networks will be a key element in new risk assessment approaches based on in vitro cellular assays.
Citation: Zhang Q, Bhattacharya S, Conolly RB, Clewell HJ III, Kaminski NE, Andersen ME. 2014. Molecular signaling network motifs provide a mechanistic basis for cellular threshold responses. Environ Health Perspect 122:1261–1270;
PMCID: PMC4256703  PMID: 25117432
11.  Gallstone ectopia in the lungs: case report and literature review 
Gallstone ectopia in the lungs is relatively rare, which accounts for its frequent misdiagnosis. This paper reports a case found in a suspicious lung cancer surgery. The patient received intrahepatic duct stone removal surgery and partial hepatectomy five months prior to the report. He started showing symptoms of cough and hemoptysis without any apparent cause one month before this report. Enhanced computed tomography showed a solid mass in the lower lobe of the right lung, which was considered as hamartoma or lung cancer. A wedge-shaped excision was then performed in the lower lobe of the right lung. After the surgery, postoperative findings and pathological examination results showed gallstone ectopia in the lung. This case reminds us that gallstones that overflow into the intraperitoneal section can enter the thoracic cavity through diaphragmatic weakness and travel to the lung, thus forming an inflammatory mass. The case also reminds us of the following points in clinical diagnosis: 1) remove gallstones to the greatest extent during cholelithiasis surgery to prevent the stones from migrating from the intraperitoneal area, which causes intraperitoneal and thoracic cavity complications; 2) conduct routine chest imaging examination after cholelithiasis surgery during the clinical follow-up period to facilitate early detection and timely treatment of intrathoracic complications; 3) inquire whether the patients suffering from a solid mass of the lower lobe of right lung, have cholelithiasis history to facilitate clinical diagnosis and avoid misdiagnosis, mistreatment, and treatment delay.
PMCID: PMC4276240  PMID: 25550982
Gallstone; intrathoracic complications; ectopia
12.  Illumina Amplicon Sequencing of 16S rRNA Tag Reveals Bacterial Community Development in the Rhizosphere of Apple Nurseries at a Replant Disease Site and a New Planting Site 
PLoS ONE  2014;9(10):e111744.
We used a next-generation, Illumina-based sequencing approach to characterize the bacterial community development of apple rhizosphere soil in a replant site (RePlant) and a new planting site (NewPlant) in Beijing. Dwarfing apple nurseries of ‘Fuji’/SH6/Pingyitiancha trees were planted in the spring of 2013. Before planting, soil from the apple rhizosphere of the replant site (ReSoil) and from the new planting site (NewSoil) was sampled for analysis on the Illumina MiSeq platform. In late September, the rhizosphere soil from both sites was resampled (RePlant and NewPlant). More than 16,000 valid reads were obtained for each replicate, and the community was composed of five dominant groups (Proteobacteria, Acidobacteria, Bacteroidetes, Gemmatimonadetes and Actinobacteria). The bacterial diversity decreased after apple planting. Principal component analyses revealed that the rhizosphere samples were significantly different among treatments. Apple nursery planting showed a large impact on the soil bacterial community, and the community development was significantly different between the replanted and newly planted soils. Verrucomicrobia were less abundant in RePlant soil, while Pseudomonas and Lysobacter were increased in RePlant compared with ReSoil and NewPlant. Both RePlant and ReSoil showed relatively higher invertase and cellulase activities than NewPlant and NewSoil, but only NewPlant soil showed higher urease activity, and this soil also had the higher plant growth. Our experimental results suggest that planting apple nurseries has a significant impact on soil bacterial community development at both replant and new planting sites, and planting on new site resulted in significantly higher soil urease activity and a different bacterial community composition.
PMCID: PMC4216118  PMID: 25360786
13.  Absence of Gamma-Interferon-Inducible Lysosomal Thiol Reductase (GILT) Is Associated with Poor Disease-Free Survival in Breast Cancer Patients 
PLoS ONE  2014;9(10):e109449.
Tumor immunosurveillance is known to be of critical importance in controlling tumorigenesis and progression in various cancers. The role of gamma-interferon-inducible lysosomal thiol reductase (GILT) in tumor immunosurveillance has recently been studied in several malignant diseases, but its role in breast cancer remains to be elucidated. In the present study, we found GILT as a significant different expressed gene by cDNA microarray analysis. To further determine the role of GILT in breast cancer, we examined GILT expression in breast cancers as well as noncancerous breast tissues by immunohistochemistry and real-time PCR, and assessed its association with clinicopathologic characteristics and patient outcome. The absence of GILT expression increased significantly from 2.02% (2/99) in noncancerous breast tissues to 15.6% (34/218) in breast cancer tissues (P<0.001). In accordance with its proliferation inhibiting function, GILT expression was inversely correlated with Ki67 index (P<0.05). In addition, absence of GILT was positively correlated with adverse characteristics of breast cancers, such as histological type, tumor size, lymph nodes status, and pTNM stage (P<0.05). Consistently, breast cancers with reduced GILT expression had poorer disease-free survival (P<0.005). Moreover, significantly decreased expression of GILT was found in both primary and metastatic breast cancer cells, in contrast to normal epithelial cells. These findings indicate that GILT may act as a tumor suppressor in breast cancer, in line with its previously suggested role in anti-tumor immunity. Thus, GILT has the potential to be a novel independent prognostic factor in breast cancer and further studies are needed to illustrate the underlying mechanism of this relationship.
PMCID: PMC4204821  PMID: 25333930
14.  N-methyl-D-aspartate receptor antagonist MK-801 prevents apoptosis in rats that have undergone fetal spinal cord transplantation following spinal hemisection 
Spinal cord injury is the main cause of paraplegia, but effective therapies for it are lacking. Embryonic spinal cord transplantation is able to repair spinal cord injury, albeit with a large amount of neuronal apoptosis remaining in the spinal cord. MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, is able to reduce cell death by decreasing the concentration of excitatory amino acids and preventing extracellular calcium ion influx. In this study, the effect of MK-801 on the apoptosis of spinal cord neurons in rats that have received a fetal spinal cord (FSC) transplant following spinal hemisection was investigated. Wistar rats were divided into three groups: Spinal cord hemisection injury with a combination of FSC transplantation and MK-801 treatment (group A); spinal cord hemisection injury with FSC transplantation (group B); and spinal cord injury with insertion of a Gelfoam pledget (group C). The rats were sacrificed 1, 3, 7 and 14 days after the surgery. Apoptosis in spinal slices from the injured spinal cord was examined by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling reaction, and the expression of B-cell lymphoma-2 (Bcl-2) was measured by immunohistochemistry. The positive cells were quantitatively analyzed using a computer image analysis system. The rate of apoptosis and the positive expression of Bcl-2 protein in the spinal cord neurons in the three groups decreased in the following order: C>B>A (P<0.05) and A>B>C (P<0.05), respectively. This indicates that treatment with the NMDA receptor antagonist MK-801 prevents apoptosis in the spinal cord neurons of rats that have undergone FSC transplantation following spinal hemisection.
PMCID: PMC4218703  PMID: 25371724
spinal cord injury; MK-801; fetal spinal cord; graft; apoptosis
15.  Assessment of Risk Factors for Delayed Colonic Post-Polypectomy Hemorrhage: A Study of 15553 Polypectomies from 2005 to 2013 
PLoS ONE  2014;9(10):e108290.
Background and Aim
Delayed colonic postpolypectomy bleeding is the commonest serious complication after polypectomy. This study aimed to utilize massive sampling data of polypectomy to analyze risk factors for delayed postpolypectomy bleeding.
Patients and Methods
The endoscopic data of 5600 patients with 15553 polyps removed (2005 to 2013) were analyzed retrospectively through univariate analysis and multiple logistic regression analysis to evaluate the risk factors for delayed bleeding.
Delayed postpolypectomy bleeding occurred in 99 polyps (0.6%). The rates of bleeding for different polypectomy methods including hot biopsy forcep, biopsy forcep, Argon Plasma Coagulation (APC), Endoscopy piecemeal mucosal resection (EPMR), Endoscopic Mucosal Resection (EMR), and snare polypectomy were 0.1%, 0.0%, 0.0%, 6.9%, 0.9% and 1.0%, respectively. The risk factors for delayed bleeding were the size of polyps over 10 mm (odds ratio [OR] = 4.6, 95% CI, 2.9–7.2), pathology of colonic polyps (inflammatory/hyperplastic, OR = 1; adenomatous, OR = 1.4, 95% CI, 0.7–2.6; serrated, OR = 1.5, 95% CI, 0.2–11.9; juvenile, OR = 4.3, 95% CI, 1.8–11.0; Peutz-Jegher, OR = 3.3, 95% CI, 1.0–10.7), and immediate postpolypectomy bleeding (OR = 2.9, 95% CI, 1.4–5.9). In addition, although polypectomy method was not a risk factor, compared with hot biopsy forcep, snare polypectomy, EMR, and EPMR had increased risks of delayed bleeding, with ORs of 3.2 (0.4–23.3), 2.8 (0.4–21.7) and 5.1 (0.5–47.7), respectively.
Polyp size over 10 mm, pathology of colonic polyps (especially juvenile, Peutz-Jegher), and immediate postpolypectomy bleeding were significant risk factors for delayed postpolypectomy bleeding.
PMCID: PMC4182718  PMID: 25271734
16.  A New Method for Motif Mining in Biological Networks 
Network motifs are overly represented as topological patterns that occur more often in a given network than in random networks, and take on some certain functions in practical biological applications. Existing methods of detecting network motifs have focused on computational efficiency. However, detecting network motifs also presents huge challenges in computational and spatial complexity. In this paper, we provide a new approach for mining network motifs. First, all sub-graphs can be enumerated by adding edges and nodes progressively, using the backtracking method based on the associated matrix. Then, the associated matrix is standardized and the isomorphism sub-graphs are marked uniquely in combination with symmetric ternary, which can simulate the elements (−1,0,1) in the associated matrix. Taking advantage of the combination of the associated matrix and the backtracking method, our method reduces the complexity of enumerating sub-graphs, providing a more efficient solution for motif mining. From the results obtained, our method has shown higher speed and more extensive applicability than other similar methods.
PMCID: PMC4196890  PMID: 25336896
sub-graphs mark; associated matrix; backtracking; symmetric ternary
17.  Role of MR-DWI and MR-PWI in the radiotherapy of implanted pulmonary VX-2 carcinoma in rabbits 
To detect the activity of tumor cells and tumor blood flow before and after the radiotherapy of implanted pulmonary VX-2 carcinoma in rabbit models by using magnetic resonance diffusion-weighted imaging (MR-DWI) and magnetic resonance perfusion weighted imaging (MR-PWI), and to evaluate the effectiveness and safety of the radiotherapy based on the changes in the MR-DWI and MR-PWI parameters at different treatment stages.
A total of 56 rabbit models with implanted pulmonary VX-2 carcinoma were established, and then equally divided into treatment group and control group. MR-DWI and MR-PWI were separately performed using a Philips Acheiva 1.5T MRI machine (Philips, Netherland). MRI image processing was performed using special perfusion software and the WORKSPACE advanced workstation for MRI. MR-DWI was applied for the observation of tumor signals and the measurement of apparent diffusion coefficient (ADC) values; whereas MR-PWI was used for the measurement of wash in rate (WIR), wash out rate (WOR), and maximum enhancement rate (MER). The radiation treatment was performed using Siemens PRIMUS linear accelerator. In the treatment group, the radiotherapy was performed 21 days later on a once weekly dosage of 1,000 cGy to yield a total dosage of 5,000 cGy.
The ADC parameters in the region of interest on DWI were as follows: on the treatment day for the implanted pulmonary VX-2 carcinoma, the t values at the center and the edge of the lesions were 1.352 and 1.461 in the treatment group and control group (P>0.05). During weeks 0-1 after treatment, the t values at the center and the edge of the lesions were 1.336 and 1.137 (P>0.05). During weeks 1-2, the t values were 1.731 and 1.736 (P<0.05). During weeks 2-3, the t values were 1.742 and 1.749 (P<0.05). During weeks 3-4, the t values were 2.050 and 2.127 (P<0.05). During weeks 4-5, the t values were 2.764 and 2.985 (P<0.05). The ADC values in the treatment group were significantly higher than in the control group. After the radiotherapy (5,000 cGy), the tumors remarkably shrank, along with low signal on DWI, decreased signal on ADC map, and remarkably increased ADC values. As shown on PWI, on the treatment day for the implanted pulmonary VX-2 carcinoma, the t values of the WIR, WOR, and MER at the center of the lesions were 1.05, 1.31, and 1.33 in the treatment group and control group (P>0.05); in addition, the t values of the WIR, WOR, and MER at the edge of the lesions were 1.35, 1.07, and 1.51 (P>0.05). During weeks 0-1 after treatment, the t values of the WIR, WOR, and MER at the center of the lesions were 1.821, 1.856, and 1.931 (P<0.05); in addition, the t values of the WIR, WOR, and MER at the edge of the lesions were 1.799, 2.016, and 2.137 (P<0.05). During weeks 1-1 after treatment, the t values of the WIR, WOR, and MER at the center of the lesions were 2.574, 2.156, and 2.059 (P<0.05) and the t values of the WIR, WOR, and MER at the edge of the lesions were 1.869, 2.058, and 2.057 (P<0.05). During weeks 2-3 after treatment, the t values of the WIR, WOR, and MER at the center of the lesions were 2.461, 2.098, and 2.739 (P<0.05) and the t values of the WIR, WOR, and MER at the edge of the lesions were 2.951, 2.625, and 2.154 (P<0.05). During weeks 3-4 after treatment, the t values of the WIR, WOR, and MER at the center of the lesions were 2.584, 2.107, and 2.869 (P<0.05) and the t values of the WIR, WOR, and MER at the edge of the lesions were 2.057, 2.637, and 2.951 (P<0.05). During weeks 4-5 after treatment, the t values of the WIR, WOR, and MER at the center of the lesions were 2.894, 2.827, and 3.285 (P<0.05) and the t values of the WIR, WOR, and MER at the edge of the lesions were 3.45, 3.246, and 3.614 (P<0.05). After the radiotherapy (500 cGy), the tumors shrank on the T1WI, WIR, WOR, and MER; meanwhile, the PWI parameter gradually decreased and reached its minimum value.
MR-DWI and MR-PWI can accurately and directly reflect the inactivation of tumor cells and the tumor hemodynamics in rabbit models with implanted pulmonary VX-2 carcinoma, and thus provide theoretical evidences for judging the clinical effectiveness of radiotherapy for the squamous cell carcinoma of the lung.
PMCID: PMC4220250  PMID: 25400418
Magnetic resonance diffusion-weighted imaging (MR-DWI); magnetic resonance perfusion weighted imaging (MR-PWI); implanted pulmonary VX-2 carcinoma in rabbits; radiotherapy
18.  Breast cancer awareness among women in Eastern China: a cross-sectional study 
BMC Public Health  2014;14(1):1004.
High breast cancer mortality has been attributed to lack of public awareness, which leads to late diagnoses. As little is known about the level of knowledge and awareness of breast cancer in China, this study was designed to explore it among women in Eastern China.
We conducted a cross-sectional survey covering 122,058 females around Shandong, Hebei, Jiangsu and Tianjin, in Eastern China, using in-person interviews based on a self-designed structured questionnaire. Student’s t-test, Pearson’s χ2 test, reliability analysis, exploratory factor analysis, univariate and multivariate logistic regression analyses were performed in the statistical analysis.
The results showed poor awareness of breast cancer among women aged 25–70 years in Eastern China. Only 18.6% of women were highly aware in the study, whereas 81.4% were poorly aware. Among all participants, family history of breast cancer was the best accepted risk factor for breast cancer (awareness rate 31.5%), followed by menarche at age before 12 (11.2%), no parity or late childbirth (13.9%), menopause at a late age (13.7%), high-fat diets (19.1%), long time drinking (19.5%) and long-term use of estrogen drugs (20.7%). Multivariate logistic regression analysis (α = 0.05) identified nine variables that predicted awareness of breast cancer: age (OR = 0.975, 95% CI: 0.960–0.990), location (OR = 1.675, 95% CI: 1.602–1.752), occupation (OR = 4.774, 95% CI: 4.316–5.281), family history of breast cancer (OR = 1.234, 95% CI: 1.073–1.420), household annual income (OR = 0.418, 95% CI: 0.400–0.436), behavioral prevention score (OR = 4.137, 95% CI: 3.991–4.290), no smoking (OR = 2.113, 95% CI: 1.488–2.999), no drinking (OR = 1.427, 95% CI: 1.018–2.000), overall life satisfaction (OR = 0.707, 95% CI: 0.683–0.731).
Our study indicates insufficient awareness of breast cancer among women in Eastern China, and an urgent need for health education programs on this subject.
PMCID: PMC4180963  PMID: 25257142
Breast cancer; Knowledge; Chinese women; Cancer awareness
19.  Identification of a novel polyprenylated acylphloroglucinol-derived SIRT1 inhibitor with cancer-specific anti-proliferative and invasion-suppressing activities 
International Journal of Oncology  2014;45(5):2128-2136.
SIRT1, a class III histone deacetylase, plays a critical role in regulating cancer cell growth, migration and invasion, which makes it a potential target for cancer therapeutics. In this study, we screened derivatives of several groups of natural products and identified a novel SIRT1 inhibitor JQ-101, a synthetic derivative of the polyprenylated acylphloroglucinol (PPAP) natural products, with an IC50 for SIRT1 of 30 μM in vitro, with 5-fold higher activity for SIRT1 vs. SIRT2. Exposure of tumor cells to JQ-101 significantly enhanced acetylation of p53 and histone H4K16 at known sites of SIRT1 deacetylation, validating SIRT1 as its cellular target. JQ-101 suppressed cancer cell growth and survival by targeting SIRT1, and also exhibited selective cytotoxicity towards a panel of human tumor cell lines, while producing no toxicity in two normal human cell types at comparable concentrations. JQ-101 induced both apoptosis and cell senescence, and suppressed cancer cell invasion in vitro. In summary, we have identified JQ-101 as a new SIRT1 inhibitor which may have potential application in cancer treatment through its ability to induce tumor cell apoptosis and senescence and suppress cancer cell invasion.
PMCID: PMC4203335  PMID: 25189993
SIRT1 inhibitor; polyprenylated acylphloroglucinol; cancer cell growth; cancer cell invasion
20.  Divergent effects of Sulforaphane on Basal and Glucose-Stimulated Insulin Secretion in β-Cells: Role of Reactive Oxygen Species and Induction of Endogenous Antioxidants 
Pharmaceutical research  2013;30(9):2248-2259.
Oxidative stress is implicated in pancreatic β-cell dysfunction, yet clinical outcomes of antioxidant therapies on diabetes are inconclusive. Since reactive oxygen species (ROS) can function as signaling intermediates for glucose-stimulated insulin secretion (GSIS), we hypothesize that exogenously boosting cellular antioxidant capacity dampens signaling ROS and GSIS.
To test the hypothesis, we formulated a mathematical model of redox homeostatic control circuit comprising known feedback and feedforward loops and validated model predictions with plant-derived antioxidant sulforaphane (SFN).
SFN acutely (30-min treatment) stimulated basal insulin secretion in INS-1(832/13) cells and cultured mouse islets, which could be attributed to SFN-elicited ROS as N-acetylcysteine or glutathione ethyl ester suppressed SFN-stimulated insulin secretion. The mathematical model predicted an adapted redox state characteristic of strong induction of endogenous antioxidants but marginally increased ROS under prolonged SFN exposure, a state that attenuates rather than facilitates glucose-stimulated ROS and GSIS. We validated the prediction by demonstrating that although 24-h treatment of INS-1(832/13) cells with low, non-cytotoxic concentrations of SFN (2-10 μM) protected the cells from cytotoxicity by oxidative insult, it markedly suppressed insulin secretion stimulated by 20 mM glucose.
Our study indicates that adaptive induction of endogenous antioxidants by exogenous antioxidants, albeit cytoprotective, inhibits GSIS in β-cells.
PMCID: PMC3718872  PMID: 23468051
sulforaphane; insulin secretion; ROS; Nrf2; antioxidant; computational model
21.  Sensitization of pancreatic cancer to chemoradiation by the Chk1 inhibitor, MK8776 
The combination of radiation with chemotherapy is the most effective therapy for unresectable pancreatic cancer. To improve upon this regimen, we combined the selective Chk1 inhibitor, MK8776 with gemcitabine-based chemoradiation in preclinical pancreatic cancer models.
Experimental Design
We tested the ability of MK8776 to sensitize to gemcitabine-radiation in homologous recombination repair (HRR)- proficient and deficient pancreatic cancer cells and assessed Rad51 focus formation. In vivo, we investigated the efficacy, tumor cell selectivity, and pharmacodynamic biomarkers of sensitization by MK8776.
We found that MK8776 significantly sensitized HRR-proficient (AsPC-1, MiaPaCa-2, BxPC-3) but not deficient (Capan-1) pancreatic cancer cells to gemcitabine-radiation and inhibited Rad51 focus formation in HRR-proficient cells. In vivo, MiaPaCa-2 xenografts were significantly sensitized to gemcitabine-radiation by MK8776 without significant weight loss or observable toxicity in the small intestine, the dose limiting organ for chemoradiation therapy in pancreatic cancer. We also assessed pChk1 (S345), a pharmacodynamic biomarker of DNA damage in response to Chk1 inhibition in both tumor and small intestine and found that MK8776 combined with gemcitabine or gemcitabine-radiation produced a significantly greater increase in pChk1 (S345) in tumor relative to small intestine, suggesting greater DNA damage in tumor than in normal tissue. Furthermore, we demonstrated the utility of an ex vivo platform for assessment of pharmacodynamic biomarkers of Chk1 inhibition in pancreatic cancer.
Together, our results suggest that MK8776 selectively sensitizes HRR-proficient pancreatic cancer cells and xenografts to gemcitabine-radiation and support the clinical investigation of MK8776 in combination with gemcitabine-radiation in locally advanced pancreatic cancer.
PMCID: PMC3745540  PMID: 23804422
pancreatic cancer; Chk1; radiosensitization; homologous recombination repair; gemcitabine; cell cycle checkpoint
22.  Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission 
Psychopharmacology  2014;232:605-621.
Schizophrenia remains among the most prevalent neuropsychiatric disorders, and current treatment options are accompanied by unwanted side effects. New treatments that better address core features of the disease with minimal side effects are needed.
As a new therapeutic approach, 1-(4-fluoro-phenyl)-4-((6bR, 10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) is currently in human clinical trials for the treatment of schizophrenia. Here, we characterize the preclinical functional activity of ITI-007.
ITI-007 is a potent 5-HT2A receptor ligand (Ki = 0.5 nM) with strong affinity for dopamine (DA) D2 receptors (Ki = 32 nM) and the serotonin transporter (SERT) (Ki = 62 nM) but negligible binding to receptors (e.g., H1 histaminergic, 5-HT2C, and muscarinic) associated with cognitive and metabolic side effects of antipsychotic drugs. In vivo it is a 5-HT2A antagonist, blocking (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)-induced headtwitch in mice with an inhibitory dose 50 (ID50) = 0.09 mg/kg, per oral (p.o.), and has dual properties at D2 receptors, acting as a postsynaptic D2 receptor antagonist to block D-amphetamine hydrochloride (D-AMPH) hyperlocomotion (ID50 = 0.95 mg/kg, p.o.), yet acting as a partial agonist at presynaptic striatal D2 receptors in assays measuring striatal DA neurotransmission. Further, in microdialysis studies, this compound significantly and preferentially enhances mesocortical DA release. At doses relevant for antipsychotic activity in rodents, ITI-007 has no demonstrable cataleptogenic activity. ITI-007 indirectly modulates glutamatergic neurotransmission by increasing phosphorylation of GluN2B-type N-methyl-d-aspartate (NMDA) receptors and preferentially increases phosphorylation of glycogen synthase kinase 3β (GSK-3β) in mesolimbic/mesocortical dopamine systems.
The combination of in vitro and in vivo activities of this compound support its development for the treatment of schizophrenia and other psychiatric and neurologic disorders.
PMCID: PMC4302236  PMID: 25120104
Schizophrenia; Dopamine D2 receptor; NMDA receptors; Serotonin 5-HT2A receptor; Social defeat; Nucleus accumbens; Microdialysis; Mesocortical; Nigrostriatal; Serotonin transporter
23.  A prospective study of biomarker-guided chemotherapy in patients with non-small cell lung cancer 
To assess the therapeutic value of biomarker-guided chemotherapy in patients with advanced non-small cell lung cancer (NSCLC).
Eighty-five NSCLC patients at stage IIIb or IV were divided into two groups based on the feasibility of biomarker analysis. Group A included patients with biomarker data (n = 41); Group B were patients without biomarker results (n = 44). Tumor samples obtained by fiberoptic bronchoscopy and computerized tomography-guided needle biopsy were analyzed by immunohistochemistry for intratumoral level of excision repair cross-complementing gene 1 (ERCC1), ribonucleotide reductase M1 (RRM1), and β-tubulin III. Chemotherapy regimens in Group A were determined according to the status of molecular signatures, whereas a standard gemcitabine plus cisplatin regimen was used for Group B. Tumor response, patient survival, and adverse effects were monitored for both groups.
The overall response rate, defined as complete response plus partial response, was 56.1 % for Group A, significantly higher than that in Group B (31.8 %; P = 0.024). The median progression-free survival (PFS) time was 5.2 months for Group A, significantly longer than that of Group B (4.1 months; P = 0.026). The 1-year survival rate of Group A was 65.9 %, significantly higher than that of Group B (40.9 %; P = 0.021), whereas the median overall survival times were 13.5 versus 12.5 months for Groups A and B, respectively (P = 0.483). The adverse effects in the two groups were essentially the same.
Biomarker-tailored chemotherapy based on ERCC1, RRM1, and β-tubulin III expression showed significantly increased response rate, median PFS time, and 1-year survival rate in patients with NSCLC.
PMCID: PMC4175041  PMID: 25119181
Chemotherapy; Non-small cell lung cancer; Molecular biomarkers; Efficacy
24.  TGF-β mediated DNA methylation in prostate cancer 
Almost all tumors harbor a defective negative feedback loop of signaling by transforming growth factor-β (TGF-β). Epigenetic mechanisms of gene regulation, including DNA methylation, are fundamental to normal cellular function and also play a major role in carcinogenesis. Recent evidence demonstrated that TGF-β signaling mediates cancer development and progression. Many key events in TGF-β signaling in cancer included auto-induction of TGF-β1 and increased expression of DNA methyltransferases (DNMTs), suggesting that DNA methylation plays a significant role in cancer development and progression. In this review, we performed an extensive survey of the literature linking TGF-β signaling to DNA methylation in prostate cancer. It appeared that almost all DNA methylated genes detected in prostate cancer are directly or indirectly related to TGF-β signaling. This knowledge has provided a basis for our future directions of prostate cancer research and strategies for prevention and therapy for prostate cancer.
PMCID: PMC4131550  PMID: 25133096
TGF-β; DNA methylation; prostate cancer; DNMT; Erk activation; tumor development and progression
25.  Gene Expression Analysis Suggests Bone Development-Related Genes GDF5 and DIO2 Are Involved in the Development of Kashin-Beck Disease in Children Rather than Adults 
PLoS ONE  2014;9(7):e103618.
To investigate the differences in gene expression between children and adults with Kashin-Beck disease (KBD).
12 children with KBD and 12 healthy children were selected and divided into 4 KBD vs. control pairs matched according to age and gender, with each pair having 3 KBD children and 3 healthy children. Additionally, 15 adults with KBD and 15 healthy adults were selected and divided into 5 KBD vs. control pairs matched according to age and gender, with each pair having 3 KBD adults and 3 healthy adults. Total RNA was isolated from peripheral blood mononuclear cells (PBMCs) respectively. A total of 367 target genes were selected based on previous genome-wide gene expression profile analysis. Expression levels of the 367 genes were evaluated by customized oligonucleotide microarray and the differentially expressed genes were identified. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was conducted to validate the microarray data.
A total of 95 (25.9%) genes in KBD children and 158 (43.1%) genes in KBD adults were found to exhibit more than two-fold change in gene expression level relative to healthy controls. By comparing differentially expressed genes identified in KBD children to those of KBD adults, 42 genes were found to be differentially expressed only in KBD children. And 105 genes were found to be differentially expressed only in KBD adults. Further, 16 differentially expressed genes common to both KBD children and adults were found to be asynchronously expressed in KBD children compared to KBD adults.
Significant differences in gene expression pattern were identified between KBD children and KBD adults, indicating different molecular mechanisms underlying cartilage lesions of KBD children and KBD adults. In addition, bone development-related genes GDF5 (expression ratio = 2.14±0.02) and DIO2 (expression ratio = 0.11±0.05) may contribute to the development of KBD in children rather than in adults.
PMCID: PMC4114804  PMID: 25072641

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