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1.  Relation between ADIPOQ gene polymorphisms and type 2 diabetes in a Chinese population 
Objective: We aimed to investigate the relation between adiponectin gene (ADIPOQ) polymorphisms and type 2 diabetes mellitus (T2DM) in a Chinese population. Methods: The present study included 510 subjects with normal glucose tolerant (NGT) and 510 patients with type 2 diabetic. Five SNPs (rs2241767, rs3821799, rs182052, rs1501299 and rs7627128) were genotyped by TaqMan methods. Results: Of these 5 SNPs, three SNPs (rs1501299, rs182052, and rs7627128) were found to be significantly associated with T2DM. The haplotypes AAT (Construction of rs1501299, rs182052, and rs7627128) was frequent in T2DM patients (OR=2.051, 95% CI: 1.439~2.923, P<0.001), but GAT (Construction of rs1501299, rs182052, and rs7627128) was frequent in the control group (OR=0.65, 95% CI: 0.540~0.805, P<0.001). Conclusion: The ADIPOQ gene variants and haplotype were associated with the risk for development of type 2 diabetes.
PMCID: PMC4483972  PMID: 26131215
ADIPOQ; diabetes; genetic polymorphism; case-control study
2.  Application of metagenomics in the human gut microbiome 
There are more than 1000 microbial species living in the complex human intestine. The gut microbial community plays an important role in protecting the host against pathogenic microbes, modulating immunity, regulating metabolic processes, and is even regarded as an endocrine organ. However, traditional culture methods are very limited for identifying microbes. With the application of molecular biologic technology in the field of the intestinal microbiome, especially metagenomic sequencing of the next-generation sequencing technology, progress has been made in the study of the human intestinal microbiome. Metagenomics can be used to study intestinal microbiome diversity and dysbiosis, as well as its relationship to health and disease. Moreover, functional metagenomics can identify novel functional genes, microbial pathways, antibiotic resistance genes, functional dysbiosis of the intestinal microbiome, and determine interactions and co-evolution between microbiota and host, though there are still some limitations. Metatranscriptomics, metaproteomics and metabolomics represent enormous complements to the understanding of the human gut microbiome. This review aims to demonstrate that metagenomics can be a powerful tool in studying the human gut microbiome with encouraging prospects. The limitations of metagenomics to be overcome are also discussed. Metatranscriptomics, metaproteomics and metabolomics in relation to the study of the human gut microbiome are also briefly discussed.
PMCID: PMC4299332  PMID: 25624713
Human gut microbiome; Metabolomics; Metagenomics; Metaproteomics; Metatranscriptomics
3.  Phosphorylation and arginine methylation mark histone H2A prior to deposition during Xenopus laevis development 
Stored, soluble histones in eggs are essential for early development, in particular during the maternally controlled early cell cycles in the absence of transcription. Histone post-translational modifications (PTMs) direct and regulate chromatin-templated transactions, so understanding the nature and function of pre-deposition maternal histones is essential to deciphering mechanisms of regulation of development, chromatin assembly, and transcription. Little is known about histone H2A pre-deposition modifications nor known about the transitions that occur upon the onset of zygotic control of the cell cycle and transcription at the mid-blastula transition (MBT).
We isolated histones from staged Xenopus laevis oocytes, eggs, embryos, and assembled pronuclei to identify changes in histone H2A modifications prior to deposition and in chromatin. Soluble and chromatin-bound histones from eggs and embryos demonstrated distinct patterns of maternal and zygotic H2A PTMs, with significant pre-deposition quantities of S1ph and R3me1, and R3me2s. We observed the first functional distinction between H2A and H4 S1 phosphorylation, as we showed that H2A and H2A.X-F (also known as H2A.X.3) serine 1 (S1) is phosphorylated concomitant with germinal vesicle breakdown (GVBD) while H4 serine 1 phosphorylation occurs post-MBT. In egg extract H2A/H4 S1 phosphorylation is independent of the cell cycle, chromatin assembly, and DNA replication. H2AS1ph is highly enriched on blastula chromatin during repression of zygotic gene expression while H4S1ph is correlated with the beginning of maternal gene expression and the lengthening of the cell cycle, consistent with distinct biological roles for H2A and H4 S1 phosphorylation. We isolated soluble H2A and H2A.X-F from the egg and chromatin-bound in pronuclei and analyzed them by mass spectrometry analysis to quantitatively determine abundances of S1ph and R3 methylation. We show that H2A and H4 S1ph, R3me1 and R3me2s are enriched on nucleosomes containing both active and repressive histone PTMs in human A549 cells and Xenopus embryos.
Significantly, we demonstrated that H2A phosphorylation and H4 arginine methylation form a new class of bona fide pre-deposition modifications in the vertebrate embryo. We show that S1ph and R3me containing chromatin domains are not correlated with H3 regulatory PTMs, suggesting a unique role for phosphorylation and arginine methylation.
PMCID: PMC4191874  PMID: 25302076
Histones; H2A; Xenopus laevis; Histone arginine methylation; Histone phosphorylation; Histone deposition; Early development
4.  Chromatin remodeling enzyme Brg1 is required for mouse lens fiber cell terminal differentiation and its denucleation 
Brahma-related gene 1 (Brg1, also known as Smarca4 and Snf2β) encodes an adenosine-5'-triphosphate (ATP)-dependent catalytical subunit of the (switch/sucrose nonfermentable) (SWI/SNF) chromatin remodeling complexes. SWI/SNF complexes are recruited to chromatin through multiple mechanisms, including specific DNA-binding factors (for example, heat shock transcription factor 4 (Hsf4) and paired box gene 6 (Pax6)), chromatin structural proteins (for example, high-mobility group A1 (HMGA1)) and/or acetylated core histones. Previous studies have shown that a single amino acid substitution (K798R) in the Brg1 ATPase domain acts via a dominant-negative (dn) mechanism. Genetic studies have demonstrated that Brg1 is an essential gene for early (that is, prior implantation) mouse embryonic development. Brg1 also controls neural stem cell maintenance, terminal differentiation of multiple cell lineages and organs including the T-cells, glial cells and limbs.
To examine the roles of Brg1 in mouse lens development, a dnBrg1 transgenic construct was expressed using the lens-specific αA-crystallin promoter in postmitotic lens fiber cells. Morphological studies revealed abnormal lens fiber cell differentiation in transgenic lenses resulting in cataract. Electron microscopic studies showed abnormal lens suture formation and incomplete karyolysis (that is, denucleation) of lens fiber cells. To identify genes regulated by Brg1, RNA expression profiling was performed in embryonic day 15.5 (E15.5) wild-type and dnBrg1 transgenic lenses. In addition, comparisons between differentially expressed genes in dnBrg1 transgenic, Pax6 heterozygous and Hsf4 homozygous lenses identified multiple genes coregulated by Brg1, Hsf4 and Pax6. DNase IIβ, a key enzyme required for lens fiber cell denucleation, was found to be downregulated in each of the Pax6, Brg1 and Hsf4 model systems. Lens-specific deletion of Brg1 using conditional gene targeting demonstrated that Brg1 was required for lens fiber cell differentiation, for expression of DNase IIβ, for lens fiber cell denucleation and indirectly for retinal development.
These studies demonstrate a cell-autonomous role for Brg1 in lens fiber cell terminal differentiation and identified DNase IIβ as a potential direct target of SWI/SNF complexes. Brg1 is directly or indirectly involved in processes that degrade lens fiber cell chromatin. The presence of nuclei and other organelles generates scattered light incompatible with the optical requirements for the lens.
PMCID: PMC3003251  PMID: 21118511
5.  Pure red cell aplasia due to parvovirus B19 infection after liver transplantation: A case report and review of the literature 
Pure red cell aplasia (PRCA) due to parvovirus B19 (PVB19) infection after solid organ transplantation has been rarely reported and most of the cases were renal transplant recipients. Few have been described after liver transplantation. Moreover, little information on the management of this easily recurring disease is available at present. We describe the first case of a Chinese liver transplant recipient with PVB19-induced PRCA during immunosuppressive therapy. The patient suffered from progressive anemia with the lowest hemoglobin level of 21 g/L. Bone marrow biopsy showed selectively inhibited erythropoiesis with giant pronormoblasts. Detection of PVB19-DNA in serum with quantitative polymerase chain reaction (PCR) revealed a high level of viral load. After 2 courses of intravenous immunoglobulin (IVIG) therapy, bone marrow erythropoiesis recovered with his hemoglobin level increased to 123 g/L. He had a low-level PVB19 load for a 5-mo follow-up period without recurrence of PRCA, and finally the virus was cleared. Our case indicates that clearance of PVB19 by IVIG in transplant recipients might be delayed after recovery of anemia.
PMCID: PMC4146984  PMID: 17461508
Pure red cell aplasia; Parvovirus B19; Intravenous immunoglobulin; Recurrence; Liver transplantation
6.  Relationship between matrix metalloproteinase-2 mRNA expression and clinicopathological and urokinase-type plasminogen activator system parameters and prognosis in human gastric cancer 
AIM: To investigate the relationship between matrix metalloproteinase-2 (MMP-2) mRNA expression and clinicopathologic and urokinase-type plasminogen activator (uPA) system parameter and prognosis in human gastric cancer.
METHODS: Expression of MMP-2 mRNA, uPA, and uPA-R mRNA in tumor tissues and ≥5 cm adjacent normal tissues from 67 cases of gastric cancer was studied using RT-PCR and Northern blot respectively. Survival analyses were done using the Kaplan-Meier method.
RESULTS: The expression rates of MMP-2 mRNA, uPA and uPA-R mRNA in tumor tissues (31%, 41%, and 51%, respectively) were significantly higher than those in ≥5 cm adjacent tissues (19%, 11%, and 9%; χ2 = 4.59, 43.58, and 53.24 respectively, P<0.05, 0.0001, and 0.0001, respectively). Expression of MMP-2 mRNA was significantly correlated with lymph node metastasis (metastasis: 61.9%, no metastasis: 39.1%, χ2 = 7.61, P<0.05), Lauren’s classification of diffuse/mixed types: 54.2%, intestinal type: 26.3%, χ2 = 4.25, P<0.05, expression of uPA and uPA-R mRNA (uPA+: 55.1%, uPA-: 22.2% and uPA-R+: 54.9%, uPA-R-: 18.8%, χ2 = 5.72 and 6.40 respectively, P<0.05). Kaplan-Meier survival analysis of MMP-2 mRNA expression did not show significant difference in all 67 cases, but revealed an association of the expression of MMP-2 mRNA, uPA, and uPA-R mRNA with worse prognosis (P = 0.0083, 0.0160, and 0.0094, respectively).
CONCLUSION: MMP-2 may play an important role in the development of invasion and metastasis of gastric cancer.
PMCID: PMC4316052  PMID: 15929171
Gastric cancer; Matrix metalloproteinase-2; Urokinase-type plasminogen activator
7.  Adenovirus-mediated CTLA4Ig gene inhibits infiltration of immune cells and cell apoptosis in rats after liver transplantation 
AIM: To investigate the role of adenovirus-mediated CTLA4Ig gene therapy in inhibiting the infiltration of macrophages and CD8+T cells and cell apoptosis after liver transplantation.
METHODS: The rat orthotopic liver transplantation model was applied. The rats were divided into three groups: group I: rejection control (SD-to-Wistar); group II: acute rejection treated with intramuscular injection of CsA 3.0 mg/(kg·d) for 12 d (SD-to-Wistar+CsA); groupIII: injection of 1×109 PFU adenovirus-mediated CTLA4Ig gene liquor in dorsal vein of penis 7 d before liver transplantation (SD-to-Wistar+CTLA4Ig). Immunohistochemistry and transferase-mediated dUTP nick-end labeling (TUNEL) were used to analyze the expression of CTLA4Ig gene in liver, infiltration of macrophages and CD8+T cells, cell apoptosis in grafts at different time-points after liver transplantation. Histopathological examination was done.
RESULTS: CTLA4Ig gene expression was positive in liver on d 7 after administering adenovirus-mediated CTLA4Ig gene via vein, and remained positive until day 60 after liver transplantation. Infiltration of macrophages and CD8+T cells in CTLA4Ig-treated group was less than in rejection control group and CsA-treated group. The apoptotic index of rejection group on d 3, 5, and 7 were significantly higher than that of CTLA4Ig-treated group. A good correlation was found between severity of rejection reaction and infiltration of immune activator cells or cell apoptotic index in grafts.
CONCLUSION: CTLA4Ig gene is constantly expressed in liver and plays an important role in inducing immune tolerance.
PMCID: PMC4250774  PMID: 15742417
Liver transplantation; Adenovirus; CTLA4Ig; Apoptosis
8.  Spatiotemporal expression of BMP7 in the development of anorectal malformations in fetal rats 
The aim of this study was to determine the expression patterns of bone morphogenetic protein 7 (BMP7) during anorectal development in normal rat embryos and in embryos with anorectal malformations (ARM), and to investigate the possible role of BMP7 in the pathogenesis of ARM. ARM was induced by treating rat embryos with ethylenethiourea on the 10th gestational day (GD10). Embryos were harvested by Cesarean delivery and the spatiotemporal expression of BMP7 was evaluated in normal (n=168) and ARM embryos (n=171) from GD13 to GD16 using immunohistochemistry staining and western blot analysis. Immunohistochemical staining in normal embryos revealed that BMP7 was abundantly expressed on the epithelium of the urorectal septum (URS) and the hindgut on GD13, and BMP7-immunopositive cells were extensively detected in the URS, hindgut, and cloacal membrane by GD14. Increased positive tissue staining was noted on the fused tissue of the URS and the thin anal membrane on GD15. In ARM embryos, the epithelium of the cloaca, URS, and anorectum were negatively or only faintly immunostained for BMP7. BMP7 protein expression showed time-dependent changes in the developing hindgut according to western blotting, and reached a peak on GD15 during anus formation. BMP7 expression levels from GD14 to GD15 were significantly lower in the ARM group compared with the normal group (P<0.05). Spatiotemporal expression of BMP7 was disrupted in ARM embryos during anorectal morphogenesis from GD13 to GD16. These results suggest that downregulation of BMP7 at the time of cloacal separation into the primitive rectum and UGS might be related to the development of ARM.
PMCID: PMC4466941  PMID: 26097554
Anorectal malformation; BMP7; embryogenesis; development; rat
9.  Genistein attenuates glucocorticoid-induced bone deleterious effects through regulation Eph/ephrin expression in aged mice 
Objective: This study was performed to investigate bone deteriorations and the involvement of skeletal Eph/ephrin signaling pathway of GIOP aged mice in response to the treatment of genistein. Methods: The biomarkers in serum and urine were measured, tibias were taken for the measurement on gene and protein expression and histomorphology analysis, and femurs were taken for the measurement on bone Ca and three-dimensional architecture of trabecular bone. Results: Genistein showed a greater increase in bone Ca, BMD and significantly increased FGF-23 and OCN, reduced TRACP-5b, PTH and CTX in GIOP mice. Genistein reversed DXM-induced trabecular deleterious effects and stimulated bone remodeling. The treatment of DXM group with genistein significantly elevated the ratio of OPG/RANKL. Moreover, genistein administration down-regulated the mRNA and protein expression of Eph A2 and ephrin A2 in tibia of the GIOP mice. In contrast, the mRNA and protein expression of Eph B4 and ephrin B2 were increased in mice treated by DXM with genistein as compared to the DXM single treatment. Conclusions: DXM-induced trabecular bone micro-structure deterioration in aged mice was involved in the regulation of the Eph receptors and ephrin ligands. Genistein might represent a therapy with bone-forming as well as an anti-resorptive activity in GIOP mice. The underlying mechanism was mediated, at least partially, through regulation Eph/ephrin signaling.
PMCID: PMC4348890  PMID: 25755727
Eph/ephrin; bone; genistein; dexamethasone
10.  Autoimmune pancreatitis associated with a pancreatic pseudocyst treated by distal pancreatectomy with splenectomy: case report 
Autoimmune pancreatitis is a unique type of chronic pancreatitis, which is rarely associated with pseudocyst. A 48-year-old lady was admitted to our department with a rapidly growing cystic mass in the pancreatic tail with an elevated concentration of serum carbohydrate antigen 19-9 (CA19-9). She had a history of autoimmune pancreatitis and received steroid treatment. Imaging studies demonstrated a cystic mass in the pancreatic tail. The mass kept growing despite restoration of steroid treatment. Eventually, the patient underwent distal pancreatectomy with splenectomy. Histopathological examination revealed the existence of pseudocyst, significant lymphocytic infiltration, and fibrotic change in the pancreatic tail.
PMCID: PMC4258021  PMID: 25429726
Autoimmune pancreatitis; Distal pancreatectomy; Pseudocyst
11.  Tumor Progression in the LPB-Tag Transgenic Model of Prostate Cancer is Altered by Vitamin D Receptor and Serum Testosterone Status 
Previous studies have suggested that 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) induces cell cycle arrest and/or apoptosis in prostate cancer cells in vitro, suggesting that vitamin D may be a useful adjuvant therapy for prostate cancer and a chemopreventive agent. Most epidemiological data however shows a weak link between serum 25(OH)D3 and risk of prostate cancer. To explore dichotomy we have compared tumor progression in the LPB-Tag model of prostate in VDR knock out (VDRKO) and wild type (VDRWT) mice. On the C57BL/6 background LPB-Tag tumors progress significantly more rapidly in the VDRKO mice. VDRKO tumors show significantly higher levels of cell proliferation than VDRWT tumors. In mice supplemented with testosterone to restore the serum levels to the normal range, these difference in tumor progression, and proliferation are abrogated, suggesting that there is considerable cross-talk between the androgen receptor (AR) and the vitamin D axis which is reflected in significant changes in steady state mRNA levels of the AR, PCNA, cdk2 survivin and IGFR1 and 2 genes. These alterations may explain the differences between the in vitro data and the epidemiological studies.
PMCID: PMC4211603  PMID: 20347977
12.  F-18 FDG hypermetabolism in mass-forming focal pancreatitis and old hepatic schistosomiasis with granulomatous inflammation misdiagnosed by PET/CT imaging 
Purpose: We report the case of a 59-year-old male patient who presented with space-occupying lesions in the pancreas and liver suggestive of metastatic pancreatic cancer. Materials and methods: Whole-body F-18 fluorodeoxyglucose (FDG) PET/CT imaging and enhanced CT imaging of the lesions were performed in addition to abdominal ultrasound, ERCP, and MRCP. Tumor markers, including CA199 and AFP, were also evaluated. Results: PET/CT imaging showed a soft tissue mass with indistinct boundaries in the head of the pancreas with a maximum SUV of 4.39. A less dense shadow was also found in the left lobe of the liver with an indistinct boundary and a maximum SUV of 4.13. Enhanced CT revealed an enhancing mass in the head of the pancreas on arterial phase imaging as well as a mildly enhancing focus in the left lobe of the liver. The patient was diagnosed with a space-occupying lesion of the uncinate process of the pancreas suggestive of pancreatic cancer with metastasis to the liver. However, serum tumor markers were normal. Postoperative pathology was consistent with chronic pancreatitis and old hepatic schistosomiasis associated with granulomatous inflammation of the liver. Conclusion: This case of mass-forming pancreatitis and granulomatous inflammation in old hepatic schistosomiasis mimicked metastatic pancreatic cancer on PET/CT. Such false positive lesions have not been reported before, and further exploration and investigation are needed.
PMCID: PMC4203259  PMID: 25337288
Pancreatic carcinoma; mass-forming pancreatitis; PET/CT; granulomatous; liver metastasis; schistosome
13.  Vitamin D, intermediary metabolism and prostate cancer tumor progression 
Epidemiological data have demonstrated an inverse association between serum vitamin D3 levels, cancer incidence and related mortality. However, the effects of vitamin D on prostate cancer biology and its utility for prevention of prostate cancer progression are not as well-defined. The data are often conflicting: some reports suggest that vitamin D3 induces apoptosis in androgen dependent prostate cancer cell lines, while others suggest that vitamin D3 only induces cell cycle arrest. Recent molecular studies have identified an extensive synergistic crosstalk between the vitamin D- and androgen-mediated mRNA and miRNA expression, adding an additional layer of post-transcriptional regulation to the known VDR- and AR-regulated gene activation. The Warburg effect, the inefficient metabolic pathway that converts glucose to lactate for rapid energy generation, is a phenomenon common to many different types of cancer. This process supports cell proliferation and promotes cancer progression via alteration of glucose, glutamine and lipid metabolism. Prostate cancer is a notable exception to this general process since the metabolic switch that occurs early during malignancy is the reverse of the Warburg effect. This “anti-Warburg effect” is due to the unique biology of normal prostate cells that harbor a truncated TCA cycle that is required to produce and secret citrate. In prostate cancer cells, the TCA cycle activity is restored and citrate oxidation is used to produce energy for cancer cell proliferation. 1,25(OH)2D3 and androgen together modulates the TCA cycle via transcriptional regulation of zinc transporters, suggesting that 1,25(OH)2D3 and androgen maintain normal prostate metabolism by blocking citrate oxidation. These data demonstrate the importance of androgens in the anti-proliferative effect of vitamin D in prostate cancer and highlight the importance of understanding the crosstalk between these two signaling pathways.
PMCID: PMC4030193  PMID: 24860512
vitamin D; androgen; prostate; warburg; miRNA; mRNA
14.  Reduced beta2-glycoprotein I protects macrophages from ox-LDL-induced foam cell formation and cell apoptosis 
Reduced beta2-glycoprotein I (beta2-GPI) is a free thiol-containing form of beta2-GPI that displays a powerful effect in protecting endothelial cells from oxidative stress-induced cell death. The present study aims to investigate the effect of beta2-GPI or reduced beta2-GPI on ox-LDL-induced foam cell formation and on cell apoptosis and to determine the possible mechanisms.
The RAW264.7 macrophage cell line was selected as the experimental material. Oil red O staining and cholesterol measurement were used to detect cholesterol accumulation qualitatively and quantitatively, respectively. Flow cytometry was used to detect cell apoptosis. Real-time quantitative PCR was used to detect the mRNA expression of the main proteins that are associated with the transport of cholesterol, such as CD36, SRB1, ABCA1 and ABCG1. Western blot analysis was used to detect the protein expression of certain apoptosis-related proteins, such as caspase-9, caspase-3, p38 MAPK/p-p38 MAPK and JNK/p-JNK.
Beta2-GPI or reduced beta2-GPI decreased ox-LDL-induced cholesterol accumulation (96.45 ± 8.51 μg/mg protein vs. 114.35 ± 10.38 μg/mg protein, p < 0.05;74.44 ± 5.27 μg/mg protein vs. 114.35 ± 10.38 μg/mg protein, p < 0.01) and cell apoptosis (30.00 ± 5.10% vs. 38.70 ± 7.76%, p < 0.05; 20.66 ± 2.50% vs. 38.70 ± 7.76%, p < 0.01), and there are significant differences between beta2-GPI and reduced beta2-GPI (p < 0.05). Reduced beta2-GPI decreased the ox-LDL-induced expression of CD36 mRNA and ABCA1 mRNA (p < 0.05), as well as CD36, cleaved caspase-9, cleaved caspase-3, p-p38 MAPK and p-JNK proteins (p < 0.05 or p < 0.01). Beta2-GPI did not significantly decrease the expression of ABCA1 mRNA and the p-p38 MAPK protein.
Both beta2-GPI and reduced beta2-GPI inhibit ox-LDL-induced foam cell formation and cell apoptosis, and the latter exhibits a stronger inhibition effect. Both of these glycoproteins reduce the lipid intake of macrophages by downregulating CD36 as well as protein expression. Reduced beta2-GPI inhibits cell apoptosis by reducing the ox-LDL-induced phosphorylation of p38 MAPK and JNK, and the amount of cleaved caspase-3 and caspase-9. Beta2-GPI does not inhibit the ox-LDL-induced phosphorylation of p38 MAPK.
PMCID: PMC3842777  PMID: 24238298
Reduced beta2-glycoprotein I; Beta2-glycoprotein I; Ox-LDL; Foam cell; Apoptosis
15.  Histone deacetylase inhibitors modulate miRNA and mRNA expression, block metaphase, and induce apoptosis in inflammatory breast cancer cells 
Cancer Biology & Therapy  2013;14(7):658-671.
To develop new therapies for inflammatory breast cancer (IBC) we have compared the effects of two hydroxamic acid-based histone deacetylase (HDAC) inhibitors, CG-1521 and Trichostatin A (TSA) on the biology of two IBC cell lines: SUM149PT and SUM190PT. CG-1521 and TSA induce dose (0−10 µM) and time-dependent (0−96 h) increases in the proportion of cells undergoing cell cycle arrest and apoptosis in the presence or absence of 17β-estradiol. In SUM 149PT cells, both CG-1521 and TSA increase the levels of acetylated α-tubulin; however the morphological effects are different: CG-1521 blocks mitotic spindle formation and prevents abscission during cytokinesis while TSA results in an increase in cell size. In SUM190PT cells CG-1521 does not cause an increase in acetylated-α-tubulin and even though TSA significantly increases the levels of acetylated tubulin, neither inhibitor alters the morphology of the cells. Microarray analysis demonstrates that CG-1521 modulates the expression of 876 mRNAs and 63 miRNAs in SUM149PT cells, and 1227 mRNAs and 35 miRNAs in SUM190PT cells. Only 9% of the genes are commonly modulated in both cell lines, suggesting that CG-1521 and TSA target different biological processes in the two cell lines most likely though the inhibition of different HDACs in these cell lines. Gene ontology (GO) analysis reveals that CG-1521 affects the expression of mRNAs that encode proteins associated with the spindle assembly checkpoint, chromosome segregation, and microtubule-based processes in both cell lines and has cell-type specific effects on lipid biosynthesis, response to DNA damage, and cell death.
PMCID: PMC3742495  PMID: 23792638
acetylation; midzone; abscission; chromosome misalignment; cell death; cell cycle
18.  Mutations and Down-Regulation of CDX1 in Children with Anorectal Malformations 
Background: Anorectal malformations (ARMs) represent a variety of congenital disorders that involve abnormal termination of the anorectum. This study was to reveal relation between CDX1 and human ARMs phenotypes.
Methods: 108 Chinese patients and 120 Chinese controls were included in this study. We analyzed the relation between two by PCR, qRT-PCR, western blot and immunofluorescence.
Results: Four heterozygous mutations in CDX1 gene were identified in ARMs patients (3.7%, 4/108), no found in controls. CDX1 protein expression was significantly decreased in the ARMs compared with the control anorectum. All samples analyzed in ARMs group exhibited down-regulated CDX1 mRNA expression in comparison to matched normal group, demonstrated significant differences statistically.
Conclusion: The findings represented the relation between CDX1 mutations and CDX1 genotype. Furthermore, it was suggested that the downregulation of CDX1 might be related to the development of ARMs.
PMCID: PMC3547218  PMID: 23329892
Anorectal malformations; CDX1; mutation; children
19.  Engineered measles virus Edmonston strain used as a novel oncolytic viral system against human hepatoblastoma 
BMC Cancer  2012;12:427.
Hepatoblastoma (HB) is the most common primary, malignant pediatric liver tumor in children. The treatment results for affected children have markedly improved in recent decades. However, the prognosis for high-risk patients who have extrahepatic extensions, invasion of the large hepatic veins, distant metastases and very high alpha-fetoprotein (AFP) serum levels remains poor. There is an urgent need for the development of novel therapeutic approaches.
An attenuated strain of measles virus, derived from the Edmonston vaccine lineage, was genetically engineered to produce carcinoembryonic antigen (CEA). We investigated the antitumor potential of this novel viral agent against human HB both in vitro and in vivo.
Infection of the Hep2G and HUH6 HB cell lines, at multiplicities of infection (MOIs) ranging from 0.01 to 1, resulted in a significant cytopathic effect consisting of extensive syncytia formation and massive cell death at 72–96 h after infection. Both of the HB lines overexpressed the measles virus receptor CD46 and supported robust viral replication, which correlated with CEA production. The efficacy of this approach in vivo was examined in murine Hep2G xenograft models. Flow cytometry assays indicated an apoptotic mechanism of cell death. Intratumoral administration of MV-CEA resulted in statistically significant delay of tumor growth and prolongation of survival.
The engineered measles virus Edmonston strain MV-CEA has potent therapeutic efficacy against HB cell lines and xenografts. Trackable measles virus derivatives merit further exploration in HB treatment.
PMCID: PMC3488522  PMID: 23009685
Hepatoblastoma; Oncolytic; Measles virus Edmonston strain; CD46
20.  Study of InN epitaxial films and nanorods grown on GaN template by RF-MOMBE 
Nanoscale Research Letters  2012;7(1):468.
This paper reports on high-quality InN materials prepared on a GaN template using radio-frequency metalorganic molecular beam epitaxy. We also discuss the structural and electro-optical properties of InN nanorods/films. The X-ray diffraction peaks of InN(0002) and InN(0004) were identified from their spectra, indicating that the (0001)-oriented hexagonal InN was epitaxially grown on the GaN template. Scanning electron microscopic images of the surface morphology revealed a two-dimensional growth at a rate of approximately 0.85 μm/h. Cross-sectional transmission electron microscopy images identified a sharp InN/GaN interface and a clear epitaxial orientation relationship of [0001]InN // [0001]GaN and ( 2¯110)InN // ( 2¯110)GaN. The optical properties of wurtzite InN nanorods were determined according to the photoluminescence, revealing a band gap of 0.77 eV.
PMCID: PMC3492109  PMID: 22908859
RF-MOMBE; InN; nanorods
21.  Castleman disease mimicked pancreatic carcinoma: report of two cases 
Castleman disease (CD) is an uncommon benign lymphoproliferative disorder, which usually presents as solitary or multiple masses in the mediastinum. Peripancreatic CD was rarely reported. Herein, we report two cases of unicentric peripancreatic CD from our center. A 43-year-old man and a 58-year-old woman were detected to have a pancreatic mass in the routine medical examinations. Both of them were asymptomatic. The computed tomography and ultrasonographic examination revealed a mild enhancing solitary mass at the pancreatic head/neck. No definite preoperative diagnosis was established and Whipple operations were originally planned. The intraoperative frozen section diagnosis of both patients revealed lymphoproliferation. Then the local excisions of mass were performed. Histological examination revealed features of CD of hyaline-vascular type. No recurrence was found during the follow-up period. CD should be included in the differential diagnosis of pancreatic tumors. Local excision is a suitable surgical choice.
PMCID: PMC3447677  PMID: 22824621
Castleman disease; Peripancreatic tumor; Hyaline-vascular type
22.  Long-term survival after chemoembolization of metastatic right atrial tumor thrombus as a presenting feature of hepatocellular carcinoma: A case study 
Oncology Letters  2012;3(5):975-977.
Advanced hepatocellular carcinoma (HCC) with invasion into the heart through the hepatic vein is a recognized rare occurrence with an extremely poor prognosis. Patients who present with right heart tumor thrombus have generally been considered inoperable. Although aggressive resection and liver transplantation treatment have previously been performed, the results remain unsatisfactory. However, HCC with extension into the heart usually indicates a contraindication for transcatheter arterial chemoembolization (TACE). In this study, a rare case of HCC with metastatic inferior vena cava (IVC) and right atrial (RA) tumor thrombus was reported. The young patient was admitted to our department due to Budd-Chiari syndrome. Following diagnosis according to CT image findings and laboratory data, the patient underwent TACE therapy. This treatment resulted in a marked reduction in the liver tumor and the right atrial tumor thrombus. Following TACE therapy, the patient survived for 3 years and 10 months and remains alive without any signs of recurrence. This case indicates that TACE therapy can be used successfully for the treatment of advanced HCC with heart tumor thrombus and may result in long-term survival.
PMCID: PMC3389639  PMID: 22783375
chemoembolization; hepatocellular carcinoma; metastasis; tumor thrombus
23.  Effects of 1α,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells 
Molecular Cancer  2011;10:58.
There is evidence from epidemiological and in vitro studies that the biological effects of testosterone (T) on cell cycle and survival are modulated by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in prostate cancer. To investigate the cross talk between androgen- and vitamin D-mediated intracellular signaling pathways, the individual and combined effects of T and 1,25(OH)2D3 on global gene expression in LNCaP prostate cancer cells were assessed.
Stringent statistical analysis identifies a cohort of genes that lack one or both androgen response elements (AREs) or vitamin D response elements (VDREs) in their promoters, which are nevertheless differentially regulated by both steroids (either additively or synergistically). This suggests that mechanisms in addition to VDR- and AR-mediated transcription are responsible for the modulation of gene expression. Microarray analysis shows that fifteen miRNAs are also differentially regulated by 1,25(OH)2D3 and T. Among these miR-22, miR-29ab, miR-134, miR-1207-5p and miR-371-5p are up regulated, while miR-17 and miR-20a, members of the miR-17/92 cluster are down regulated. A number of genes implicated in cell cycle progression, lipid synthesis and accumulation and calcium homeostasis are among the mRNA targets of these miRNAs. Thus, in addition to their well characterized effects on transcription, mediated by either or both cognate nuclear receptors, 1,25(OH)2D3 and T regulate the steady state mRNA levels by modulating miRNA-mediated mRNA degradation, generating attenuation feedback loops that result in global changes in mRNA and protein levels. Changes in genes involved in calcium homeostasis may have specific clinical importance since the second messenger Ca2+ is known to modulate various cellular processes, including cell proliferation, cell death and cell motility, which affects prostate cancer tumor progression and responsiveness to therapy.
These data indicate that these two hormones combine to drive a differentiated phenotype, and reinforce the idea that the age dependent decline in both hormones results in the de-differentiation of prostate tumor cells, which results in increased proliferation, motility and invasion common to aggressive tumors. These studies also reinforce the potential importance of miRNAs in prostate cancer progression and therapeutic outcomes.
PMCID: PMC3112430  PMID: 21592394
24.  Lens Fiber Cell Differentiation and Denucleation Are Disrupted through Expression of the N-Terminal Nuclear Receptor Box of Ncoa6 and Result in p53-dependent and p53-independent Apoptosis 
Molecular Biology of the Cell  2010;21(14):2453-2468.
Lens fiber cell differentiation, denucleation, and abnormal apoptosis were examined through lens-specific expression of the N-terminal nuclear receptor box of NCOA6 in combination with lens-specific deletion of Ncoa6 in mice. The present data show that early apoptosis in lens fiber cells inhibits their subsequent denucleation.
Nuclear receptor coactivator 6 (NCOA6) is a multifunctional protein implicated in embryonic development, cell survival, and homeostasis. An 81-amino acid fragment, dnNCOA6, containing the N-terminal nuclear receptor box (LXXLL motif) of NCOA6, acts as a dominant-negative (dn) inhibitor of NCOA6. Here, we expressed dnNCOA6 in postmitotic transgenic mouse lens fiber cells. The transgenic lenses showed reduced growth; a wide spectrum of lens fiber cell differentiation defects, including reduced expression of γ-crystallins; and cataract formation. Those lens fiber cells entered an alternate proapoptotic pathway, and the denucleation (karyolysis) process was stalled. Activation of caspase-3 at embryonic day (E)13.5 was followed by double-strand breaks (DSBs) formation monitored via a biomarker, γ-H2AX. Intense terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) signals were found at E16.5. Thus, a window of ∼72 h between these events suggested prolonged though incomplete apoptosis in the lens fiber cell compartment that preserved nuclei in its cells. Genetic experiments showed that the apoptotic-like processes in the transgenic lens were both p53-dependent and p53-independent. Lens-specific deletion of Ncoa6 also resulted in disrupted lens fiber cell differentiation. Our data demonstrate a cell-autonomous role of Ncoa6 in lens fiber cell differentiation and suggest novel insights into the process of lens fiber cell denucleation and apoptosis.
PMCID: PMC2903674  PMID: 20484573
25.  Retinoic acid signaling in mammalian eye development 
Experimental eye research  2009;89(3):280-291.
Retinoic acid (RA) is a biologically active metabolite of vitamin A (retinol) that serves as a signaling molecule during a number of developmental and physiological processes. RA signaling plays multiple roles during embryonic eye development. RA signaling is initially required for reciprocal interactions between the optic vesicle and invaginating lens placode. RA signaling promotes normal development of the ventral retina and optic nerve through its activities in the neural crest cell-derived periocular mesenchyme. RA coordinates these processes by regulating biological activities of a family of non-steroid hormone receptors, RARα/β/γ, and RXRα/β/γ. These DNA-binding transcription factors recognize DNA as RAR/RXR heterodimers and recruit multiprotein transcriptional co-repressor complexes. RA-binding to RAR receptors induces a conformational change in the receptor, followed by the replacement of co-repressor with co-activator complexes. Inactivation of RARα/β/γ receptors in the periocular mesenchyme abrogates anterior eye segment formation. This review summarizes recent genetic studies of RA signaling and progress in understanding the molecular mechanism of transcriptional co-activators that function with RAR/RXR.
PMCID: PMC2756743  PMID: 19427305
anterior segment; lens; nuclear receptors; periocular mesenchyme; optic cup; retina; retinoic acid; vitamin A

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