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1.  GLP-1 inhibits and adrenaline stimulates glucagon release by differential modulation of N- and L-type Ca2+ channel-dependent exocytosis 
Cell metabolism  2010;11(6):543-553.
SUMMARY
Glucagon secretion is inhibited by glucagon-like peptide-1 (GLP-1) and stimulated by adrenaline. These opposing effects on glucagon secretion are mimicked by low (1-10 nM) and high (10 μM) concentrations of forskolin, respectively. The expression of GLP-1 receptors in α-cells is <0.2% of that in β-cells. The GLP-1-induced suppression of glucagon secretion is PKA-dependent, glucose-independent and does not involve paracrine effects mediated by insulin or somatostatin. GLP-1 is without much effect on α-cell electrical activity but selectively inhibits N-type Ca2+-channels and exocytosis. Adrenaline stimulates α-cell electrical activity, increases [Ca2+]i, enhances L-type Ca2+-channel activity and accelerates exocytosis. The stimulatory effect is partially PKA-independent and reduced in Epac2-deficient islets. We propose that GLP-1 inhibits glucagon secretion by PKA-dependent inhibition of the N-type Ca2+-channels via a small increase in intracellular cAMP ([cAMP]i). Adrenaline stimulates L-type Ca2+-channel-dependent exocytosis by activation of the low-affinity cAMP sensor Epac2 via a large increase in [cAMP]i.
doi:10.1016/j.cmet.2010.04.007
PMCID: PMC4310935  PMID: 20519125
2.  Coupled ferroelectric polarization and magnetization in spinel FeCr2S4 
Scientific Reports  2014;4:6530.
One of the core issues for multiferroicity is the strongly coupled ferroelectric polarization and magnetization, while so far most multiferroics have antiferromagnetic order with nearly zero magnetization. Magnetic spinel compounds with ferrimagnetic order may be alternative candidates offering large magnetization when ferroelectricity can be activated simultaneously. In this work, we investigate the ferroelectricity and magnetism of spinel FeCr2S4 in which the Fe2+ sublattice and Cr3+ sublattice are coupled in antiparallel alignment. Well defined ferroelectric transitions below the Fe2+ orbital ordering termperature Too = 8.5 K are demonstrated. The ferroelectric polarization has two components. One component arises mainly from the noncollinear conical spin order associated with the spin-orbit coupling, which is thus magnetic field sensitive. The other is probably attributed to the Jahn-Teller distortion induced lattice symmetry breaking, occuring below the orbital ordering of Fe2+. Furthermore, the coupled ferroelectric polarization and magnetization in response to magnetic field are observed. The present work suggests that spinel FeCr2S4 is a multiferroic offering both ferroelectricity and ferrimagnetism with large net magnetization.
doi:10.1038/srep06530
PMCID: PMC4185382  PMID: 25284432
4.  An animal experimental study of porous magnesium scaffold degradation and osteogenesis 
Our objective was to observe the biodegradable and osteogenic properties of magnesium scaffolding under in vivo conditions. Twelve 6-month-old male New Zealand white rabbits were randomly divided into two groups. The chosen operation site was the femoral condyle on the right side. The experimental group was implanted with porous magnesium scaffolds, while the control group was implanted with hydroxyapatite scaffolds. X-ray and blood tests, which included serum magnesium, alanine aminotransferase (ALT), creatinine (CREA), and blood urea nitrogen (BUN) were performed serially at 1, 2, and 3 weeks, and 1, 2, and 3 months. All rabbits were killed 3 months postoperatively, and the heart, kidney, spleen, and liver were analyzed with hematoxylin and eosin (HE) staining. The bone samples were subjected to microcomputed tomography scanning (micro-CT) and hard tissue biopsy. SPSS 13.0 (USA) was used for data analysis, and values of P<0.05 were considered to be significant. Bubbles appeared in the X-ray of the experimental group after 2 weeks, whereas there was no gas in the control group. There were no statistical differences for the serum magnesium concentrations, ALT, BUN, and CREA between the two groups (P>0.05). All HE-stained slices were normal, which suggested good biocompatibility of the scaffold. Micro-CT showed that magnesium scaffolds degraded mainly from the outside to inside, and new bone was ingrown following the degradation of magnesium scaffolds. The hydroxyapatite scaffold was not degraded and had fewer osteoblasts scattered on its surface. There was a significant difference in the new bone formation and scaffold bioabsorption between the two groups (9.29±1.27 vs 1.40±0.49 and 7.80±0.50 vs 0.00±0.00 mm3, respectively; P<0.05). The magnesium scaffold performed well in degradation and osteogenesis, and is a promising material for orthopedics.
doi:10.1590/1414-431X20144009
PMCID: PMC4165299  PMID: 25098717
Biodegradable; Osteogenic; Magnesium scaffold
5.  Defects of protein production in erythroid cells revealed in a zebrafish Diamond–Blackfan anemia model for mutation in RPS19 
Cell Death & Disease  2014;5(7):e1352-.
Diamond–Blackfan anemia (DBA) is a rare congenital red cell aplasia that classically presents during early infancy in DBA patients. Approximately, 25% of patients carry a mutation in the ribosomal protein (RP) S19 gene; mutations in RPS24, RPS17, RPL35A, RPL11, and RPL5 have been reported. How ribosome protein deficiency causes defects specifically to red blood cells in DBA has not been well elucidated. To genetically model the predominant ribosome defect in DBA, we generated an rps19 null mutant through the use of TALEN-mediated gene targeting in zebrafish. Molecular characterization of this mutant line demonstrated that rps19 deficiency reproduced the erythroid defects of DBA, including a lack of mature red blood cells and p53 activation. Notably, we found that rps19 mutants' production of globin proteins was significantly inhibited; however, globin transcript level was either increased or unaffected in rps19 mutant embryos. This dissociation of RNA/protein levels of globin genes was confirmed in another zebrafish DBA model with defects in rpl11. Using transgenic zebrafish with specific expression of mCherry in erythroid cells, we showed that protein production in erythroid cells was decreased when either rps19 or rpl11 was mutated. L-Leucine treatment alleviated the defects of protein production in erythroid cells and partially rescued the anemic phenotype in both rps19 and rpl11 mutants. Analysis of this model suggests that the decreased protein production in erythroid cells likely contributes to the blood-specific phenotype of DBA. Furthermore, the newly generated rps19 zebrafish mutant should serve as a useful animal model to study DBA. Our in vivo findings may provide clues for the future therapy strategy for DBA.
doi:10.1038/cddis.2014.318
PMCID: PMC4123107  PMID: 25058426
6.  Prognostic value of PTEN loss in men with conservatively managed localised prostate cancer 
British Journal of Cancer  2013;108(12):2582-2589.
Background:
The natural history of prostate cancer is highly variable and difficult to predict. We report on the prognostic value of phosphatase and tensin homologue (PTEN) loss in a cohort of 675 men with conservatively managed prostate cancer diagnosed by transurethral resection of the prostate.
Methods:
The PTEN status was assayed by immunohistochemistry (PTEN IHC) and fluorescent in situ hybridisation (PTEN FISH). The primary end point was death from prostate cancer.
Results:
The PTEN IHC loss was observed in 18% cases. This was significantly associated with prostate cancer death in univariate analysis (hazard ratio (HR)=3.51; 95% CI 2.60–4.73; P=3.1 × 10−14). It was highly predictive of prostate cancer death in the 50% of patients with a low risk score based on Gleason score, PSA, Ki-67 and extent of disease (HR=7.4; 95% CI 2.2–24.6; P=0.012) ), but had no prognostic value in the higher risk patients. The PTEN FISH loss was only weakly associated with PTEN IHC loss (κ=0.5). Both PTEN FISH loss and amplification were univariately predictive of death from prostate cancer, but this was not maintained in the multivariate analyses.
Conclusion:
In low-risk patients, PTEN IHC loss adds prognostic value to Gleason score, PSA, Ki-67 and extent of disease.
doi:10.1038/bjc.2013.248
PMCID: PMC3694239  PMID: 23695019
PTEN; localised prostate cancer; immunohistochemistry; FISH; prognostic factors
7.  Salt-induced epithelial-to-mesenchymal transition in Dahl salt-sensitive rats is dependent on elevated blood pressure 
Dietary salt intake has been linked to hypertension and cardiovascular disease. Accumulating evidence has indicated that salt-sensitive individuals on high salt intake are more likely to develop renal fibrosis. Epithelial-to-mesenchymal transition (EMT) participates in the development and progression of renal fibrosis in humans and animals. The objective of this study was to investigate the impact of a high-salt diet on EMT in Dahl salt-sensitive (SS) rats. Twenty-four male SS and consomic SS-13BN rats were randomized to a normal diet or a high-salt diet. After 4 weeks, systolic blood pressure (SBP) and albuminuria were analyzed, and renal fibrosis was histopathologically evaluated. Tubular EMT was evaluated using immunohistochemistry and real-time PCR with E-cadherin and alpha smooth muscle actin (α-SMA). After 4 weeks, SBP and albuminuria were significantly increased in the SS high-salt group compared with the normal diet group. Dietary salt intake induced renal fibrosis and tubular EMT as identified by reduced expression of E-cadherin and enhanced expression of α-SMA in SS rats. Both blood pressure and renal interstitial fibrosis were negatively correlated with E-cadherin but positively correlated with α-SMA. Salt intake induced tubular EMT and renal injury in SS rats, and this relationship might depend on the increase in blood pressure.
doi:10.1590/1414-431X20133554
PMCID: PMC3982943  PMID: 24676494
Dahl salt-sensitive rats; High salt intake; EMT; Renal fibrosis
8.  Chicken domestication: an updated perspective based on mitochondrial genomes 
Heredity  2012;110(3):277-282.
Domestic chickens (Gallus gallus domesticus) fulfill various roles ranging from food and entertainment to religion and ornamentation. To survey its genetic diversity and trace the history of domestication, we investigated a total of 4938 mitochondrial DNA (mtDNA) fragments including 2843 previously published and 2095 de novo units from 2044 domestic chickens and 51 red junglefowl (Gallus gallus). To obtain the highest possible level of molecular resolution, 50 representative samples were further selected for total mtDNA genome sequencing. A fine-gained mtDNA phylogeny was investigated by defining haplogroups A–I and W–Z. Common haplogroups A–G were shared by domestic chickens and red junglefowl. Rare haplogroups H–I and W–Z were specific to domestic chickens and red junglefowl, respectively. We re-evaluated the global mtDNA profiles of chickens. The geographic distribution for each of major haplogroups was examined. Our results revealed new complexities of history in chicken domestication because in the phylogeny lineages from the red junglefowl were mingled with those of the domestic chickens. Several local domestication events in South Asia, Southwest China and Southeast Asia were identified. The assessment of chicken mtDNA data also facilitated our understanding about the Austronesian settlement in the Pacific.
doi:10.1038/hdy.2012.83
PMCID: PMC3668654  PMID: 23211792
chicken; mtDNA; domestication; phylogeny; Austronesian
9.  MiR-19a/b modulate the metastasis of gastric cancer cells by targeting the tumour suppressor MXD1 
Wu, Q | Yang, Z | An, Y | Hu, H | Yin, J | Zhang, P | Nie, Y | Wu, K | Shi, Y | Fan, D
Cell Death & Disease  2014;5(3):e1144-.
The microRNAs 19a and 19b, hereafter collectively referred to as miR-19a/b, were recognised to be the most important miRNAs in the oncomiRs—miR-17-92 cluster. However, the exact roles of miR-19a/b in cancers have not been elucidated. In the present study, miR-19a/b was found to be over-expressed in gastric cancer tissues and significantly associated with the patients' metastasis of gastric cancer. Using gain or loss-of-function in in vitro and in vivo experiments, a pro-metastatic function of miR-19a/b was observed in gastric cancer. Furthermore, reporter gene assay and western blot showed that MXD1 is a direct target of miR-19a/b. Functional assays showed that not only MXD1 had an opposite effect to miR-19a/b in the regulation of gastric cancer cells, but also overexpression of MXD1 reduced both miR-19a/b and c-Myc levels, indicating a potential positive feedback loop among miR-19a/b, MXD1 and c-Myc. In conclusion, miR-17-92 cluster members miR-19a/b facilitated gastric cancer cell migration, invasion and metastasis through targeting the antagonist of c-Myc -- MXD1, implicating a novel mechanism for the malignant phenotypes of gastric cancer.
doi:10.1038/cddis.2014.110
PMCID: PMC3973221  PMID: 24675462
MiR-19; MXD1; metastasis; gastric cancer
10.  Prognostic value of Ki-67 for prostate cancer death in a conservatively managed cohort 
British Journal of Cancer  2013;108(2):271-277.
Background:
Standard clinical parameters cannot accurately differentiate indolent from aggressive prostate cancer. Our previous work showed that immunohistochemical (IHC) Ki-67 improved prediction of prostate cancer death in a cohort of conservatively treated clinically localised prostate cancers diagnosed by transurethral resection of the prostate (TURP). Here, we present results in a more clinically relevant needle biopsy cohort.
Methods:
Biopsy specimens were microarrayed. The percentage of Ki-67 positively stained malignant cells per core was measured and the maximum score per individual used in analysis of time to death from prostate cancer using a Cox proportional hazards model.
Results:
In univariate analysis (n=293), the hazard ratio (HR) (95% confidence intervals) for dichotomous Ki-67 (⩽10%, >10%) was 3.42 (1.76, 6.62) χ2 (1 df)=9.8, P=0.002. In multivariate analysis, Ki-67 added significant predictive information to that provided by Gleason score and prostate-specific antigen (HR=2.78 (1.42, 5.46), χ2 (1 df)=7.0, P=0.008).
Conclusion:
The IHC Ki-67 scoring on prostate needle biopsies is practicable and yielded significant prognostic information. It was less informative than in the previous TURP cohort where tumour samples were larger and more comprehensive, but in more contemporary cohorts with larger numbers of biopsies per patient, Ki-67 may prove a more powerful biomarker.
doi:10.1038/bjc.2012.598
PMCID: PMC3566811  PMID: 23329234
localised prostate cancer; prognostic factors; Ki-67; needle biopsy
11.  Mir143 expression inversely correlates with nuclear ERK5 immunoreactivity in clinical prostate cancer 
British Journal of Cancer  2013;108(1):149-154.
Background:
Aberrant mitogen/extracellular signal-regulated kinase 5 (MEK5)–extracellular signal-regulated protein kinase 5 (ERK5)-mediated signalling has been implicated in a number of tumour types including prostate cancer (CaP). The mechanism for ERK5 activation in CaP remains to be fully elucidated. Studies have recently implicated the role of microRNA (miRNA) mir143 expression in the regulation of ERK5 expression.
Methods:
We utilised a tissue microarray (TMA) of 530 CaP cores from 168 individual patients and stained for both mir143 and ERK5. These TMAs were scored by a combination of observer and automated methods.
Results:
We observed a strong inverse relation between ERK5 and mir143, which manifested itself most strongly in the subgroup of 417 cores with non-zero mir143 and ERK5 immunoreactivity, or with only one of mir143 or ERK5 being zero (cc=0.2558 and P<0.0001). Mir143 neither correlate with Gleason scores or prostate-specific antigen levels, nor was it a predictor of disease-specific survival on univariate analysis.
Conclusion:
Although the mechanism for ERK5 activation in CaP remains to be fully elucidated, we have further validated the potential role of mir143 in regulating ERK5 levels in the clinical context. In addition, we demonstrate that the automated counting method for nuclear ERK5 is a clinically useful alterative to observer counting method in patient stratification in the context of ERK5 targeting therapy.
doi:10.1038/bjc.2012.510
PMCID: PMC3553517  PMID: 23321517
mir143; ERK5; prostate cancer
12.  Identification and functional analysis of 9p24 amplified genes in human breast cancer 
Oncogene  2011;31(3):10.1038/onc.2011.227.
Previously, our group identified a novel amplicon at chromosome 9p24 in human esophageal and breast cancers, and cloned the novel gene, GASC1 (gene amplified in squamous cell carcinoma 1, also known as JMJD2C/KDM4C), from this amplicon. GASC1 is a histone demethylase involved in the deregulation of histone methylation in cancer cells. In the current study, we aimed to comprehensively characterize the genes in the 9p24 amplicon in human breast cancer. We performed extensive genomic analyses on a panel of cancer cell lines and narrowed the shortest region of overlap to approximately 2 Mb. Based on statistical analysis of copy number increase and overexpression, the 9p24 amplicon contains six candidate oncogenes. Among these, four genes (GASC1 UHRF2, KIAA1432 and C9orf123) are overexpressed only in the context of gene amplification while two genes (ERMP1 and IL33) are overexpressed independent of the copy number increase. We then focused our studies on the UHRF2 gene, which has a potential involvement in both DNA methylation and histone modification. Knocking down UHRF2 expression inhibited the growth of breast cancer cells specifically with 9p24 amplification. Conversely, ectopic overexpression of UHRF2 in non-tumorigenic MCF10A cells promoted cell proliferation. Furthermore, we demonstrated that UHRF2 has the ability to suppress the expression of key cell-cycle inhibitors, such as p16INK4a, p21Waf1/Cip1 and p27Kip1. Taken together, our studies support the notion that the 9p24 amplicon contains multiple oncogenes that may integrate genetic and epigenetic codes and have important roles in human tumorigenesis.
doi:10.1038/onc.2011.227
PMCID: PMC3886828  PMID: 21666724
chromosome 9p24; GASC1; UHRF2; gene amplification
13.  Non-rigid illusory contours and global shape transformations defined by spatiotemporal boundary formation 
Spatiotemporal boundary formation (SBF) is the perception of form, global motion, and continuous boundaries from relations of discrete changes in local texture elements (Shipley and Kellman, 1994). In two experiments, small, circular elements underwent small displacements whenever an edge of an invisible (virtual) object passed over them. Unlike previous studies that examined only rigidly translating objects, we tested virtual objects whose properties changed continuously. Experiment 1 tested rigid objects that changed in orientation, scale, and velocity. Experiment 2 tested objects that transformed non-rigidly taking on a series of shapes. Robust SBF occurred for all of the rigid transformations tested, as well as for non-rigid virtual objects, producing the perception of continuously bounded, smoothly deforming shapes. These novel illusions involve perhaps the most extreme cases of visual perception of continuous boundaries and shape from minimal information. They show that SBF encompasses a wider range of illusory phenomena than previously understood, and they present substantial challenges for existing models of SBF.
doi:10.3389/fnhum.2014.00978
PMCID: PMC4267208  PMID: 25566018
illusory contours; spatiotemporal interpolation; spatiotemporal boundary formation; perceptual organization
14.  Pin1 modulates p63α protein stability in regulation of cell survival, proliferation and tumor formation 
Li, C | Chang, D L | Yang, Z | Qi, J | Liu, R | He, H | Li, D | Xiao, Z X
Cell Death & Disease  2013;4(12):e943-.
The homolog of p53 gene, p63, encodes multiple p63 protein isoforms. TAp63 proteins contain an N-terminal transactivation domain similar to that of p53 and function as tumor suppressors; whereas ΔNp63 isoforms, which lack the intact N-terminal transactivation domain, are associated with human tumorigenesis. Accumulating evidence demonstrating the important roles of p63 in development and cancer development, the regulation of p63 proteins, however, is not fully understood. In this study, we show that peptidyl-prolyl isomerase Pin1 directly binds to and stabilizes TAp63α and ΔNp63α via inhibiting the proteasomal degradation mediated by E3 ligase WWP1. We further show that Pin1 specifically interacts with T538P which is adjacent to the P550PxY543 motif, and disrupts p63α–WWP1 interaction. In addition, while Pin1 enhances TAp63α-mediated apoptosis, it promotes ΔNp63α-induced cell proliferation. Furthermore, knockdown of Pin1 in FaDu cells inhibits tumor formation in nude mice, which is rescued by simultaneous knockdown of WWP1 or ectopic expression of ΔNp63α. Moreover, overexpression of Pin1 correlates with increased expression of ΔNp63α in human oral squamous cell carcinoma samples. Together, these results suggest that Pin1-mediated modulation of ΔNp63α may have a causative role in tumorigenesis.
doi:10.1038/cddis.2013.468
PMCID: PMC3877541  PMID: 24309930
p63; Pin1; WWP1; tumorigenesis; xenograft
15.  Long-term cultured mesenchymal stem cells frequently develop genomic mutations but do not undergo malignant transformation 
Wang, Y | Zhang, Z | Chi, Y | Zhang, Q | Xu, F | Yang, Z | Meng, L | Yang, S | Yan, S | Mao, A | Zhang, J | Yang, Y | Wang, S | Cui, J | Liang, L | Ji, Y | Han, Z-B | Fang, X | Han, Z C
Cell Death & Disease  2013;4(12):e950-.
Cultured human umbilical cord mesenchymal stem cells (hUC-MSCs) are being tested in several clinical trials and encouraging outcomes have been observed. To determine whether in vitro expansion influences the genomic stability of hUC-MSCs, we maintained nine hUC-MSC clones in long-term culture and comparatively analyzed them at early and late passages. All of the clones senesced in culture, exhibiting decreased telomerase activity and shortened telomeres. Two clones showed no DNA copy number variations (CNVs) at passage 30 (P30). Seven clones had ≥1 CNVs at P30 compared with P3, and one of these clones appeared trisomic chromosome 10 at the late passage. No tumor developed in immunodeficient mice injected with hUC-MSCs, regardless of whether the cells had CNVs at the late passage. mRNA-Seq analysis indicated that pathways of cell cycle control and DNA damage response were downregulated during in vitro culture in hUC-MSC clones that showed genomic instability, but the same pathways were upregulated in the clones with good genomic stability. These results demonstrated that hUC-MSCs can be cultured for many passages and attain a large number of cells, but most of the cultured hUC-MSCs develop genomic alterations. Although hUC-MSCs with genomic alterations do not undergo malignant transformation, periodic genomic monitoring and donor management focusing on genomic stability are recommended before these cells are used for clinical applications.
doi:10.1038/cddis.2013.480
PMCID: PMC3877551  PMID: 24309937
mesenchymal stem cells; array-based comparative genomic hybridization; copy number variations; mRNA-Seq
16.  Single-cell clones of liver cancer stem cells have the potential of differentiating into different types of tumor cells 
Liu, H | Zhang, W | Jia, Y | Yu, Q | Grau, G E | Peng, L | Ran, Y | Yang, Z | Deng, H | Lou, J
Cell Death & Disease  2013;4(10):e857-.
Cancer stem cells (CSCs) are believed to be a promising target for cancer therapy because these cells are responsible for tumor development, maintenance and chemotherapy resistance. Finding out the critical factors regulating CSC fate is the key for target therapy of CSCs. Just as normal stem cells are regulated by their microenvironment (niche), CSCs are also regulated by cells in the tumor microenvironment. However, whether various tumor microenvironments can induce CSCs to differentiate into different cancer cells is not clear. Here, we show that single-cell-cloned CSCs, accidentally obtained from a human liver cancer microvascular endothelial cells, express classic stem cell markers, genes associated with self-renewal and pluripotent factors and possess colony-forming ability in vitro and the ability of serial transplantation in vivo. The single-cell-cloned CSCs treated with the different tumor cell/tissue-derived conditioned culture medium, which is a mimic of carcinoma microenvironment, could differentiate into corresponding tumor cells and express specific markers of the respective type of tumor cells at the gene, protein and cell levels, respectively. Interestingly, this multilineage differentiation potential of single-cell-cloned liver CSCs sharply declined after the specific knockdown of octamer-binding transcription factor 4 (Oct4) alone, even though they were under the same induction conditions (carcinoma microenvironments). These data support the hypothesis that single-cell-cloned liver CSCs have the potential of differentiating into different types of tumor cells, and the tumor microenvironment does play a crucial role in deciding differentiation directions. Simultaneously, Oct4 in CSCs is indispensable in this process. These factors are promising targets for liver CSC-specific therapy.
doi:10.1038/cddis.2013.340
PMCID: PMC3824650  PMID: 24136221
CSCs; carcinoma/cancer microenvironments; multilineage differentiation potential; Oct4; microvascular endothelial cells
17.  Transcriptome analysis of glioma cells for the dynamic response to γ-irradiation and dual regulation of apoptosis genes: a new insight into radiotherapy for glioblastomas 
Cell Death & Disease  2013;4(10):e895-.
Ionizing radiation (IR) is of clinical importance for glioblastoma therapy; however, the recurrence of glioma characterized by radiation resistance remains a therapeutic challenge. Research on irradiation-induced transcription in glioblastomas can contribute to the understanding of radioresistance mechanisms. In this study, by using the total mRNA sequencing (RNA-seq) analysis, we assayed the global gene expression in a human glioma cell line U251 MG at various time points after exposure to a growth arrest dose of γ-rays. We identified 1656 genes with obvious changes at the transcriptional level in response to irradiation, and these genes were dynamically enriched in various biological processes or pathways, including cell cycle arrest, DNA replication, DNA repair and apoptosis. Interestingly, the results showed that cell death was not induced even many proapoptotic molecules, including death receptor 5 (DR5) and caspases were activated after radiation. The RNA-seq data analysis further revealed that both proapoptosis and antiapoptosis genes were affected by irradiation. Namely, most proapoptosis genes were early continually responsive, whereas antiapoptosis genes were responsive at later stages. Moreover, HMGB1, HMGB2 and TOP2A involved in the positive regulation of DNA fragmentation during apoptosis showed early continual downregulation due to irradiation. Furthermore, targeting of the TRAIL/DR5 pathway after irradiation led to significant apoptotic cell death, accompanied by the recovered gene expression of HMGB1, HMGB2 and TOP2A. Taken together, these results revealed that inactivation of proapoptotic signaling molecules in the nucleus and late activation of antiapoptotic genes may contribute to the radioresistance of gliomas. Overall, this study provided novel insights into not only the underlying mechanisms of radioresistance in glioblastomas but also the screening of multiple targets for radiotherapy.
doi:10.1038/cddis.2013.412
PMCID: PMC3920930  PMID: 24176853
Transcriptome; γ-irradiation; apoptosis; dynamic response; glioblastoma; radioresistance
18.  Gadd45 Proteins as Critical Signal Transducers Linking NF-κB to MAPK Cascades 
Current cancer drug targets  2009;9(8):915-930.
The growth arrest and DNA damage-inducible 45 (Gadd45) proteins are a group of critical signal transducers that are involved in regulations of many cellular functions. Accumulated data indicate that all three Gadd45 proteins (i.e., Gadd45α, Gadd45β, and Gadd45γ) play essential roles in connecting an upstream sensor module, the transcription Nuclear Factor-κB (NF-κB), to a transcriptional regulating module, mitogen-activated protein kinase (MAPK). This NF-κB-Gadd45(s)-MAPK pathway responds to various kinds of extracellular stimuli and regulates such cell activities as growth arrest, differentiation, cell survival, and apoptosis. Defects in this pathway can also be related to oncogenesis. In the first part of this review, the functions of Gadd45 proteins, and briefly NF-κB and MAPK, are summarized. In the second part, the mechanisms by which Gadd45 proteins are regulated by NF-κB, and how they affect MAPK activation, are reviewed.
PMCID: PMC3762688  PMID: 20025601
GADD45α; Gadd45β; Gadd45γ; NF-κB; JNK; P38; Cell survival and apoptosis
19.  Overexpression of 4EBP1, p70S6K, Akt1 or Akt2 differentially promotes Coxsackievirus B3-induced apoptosis in HeLa cells 
Li, X | Li, Z | Zhou, W | Xing, X | Huang, L | Tian, L | Chen, J | Chen, C | Ma, X | Yang, Z
Cell Death & Disease  2013;4(9):e803-9.
Our previous studies have shown that the inhibition of phosphatidylinositol 3-kinase (PI3K) or mTOR complex 1 can obviously promote the Coxsackievirus B3 (CVB3)-induced apoptosis of HeLa cells by regulating the expression of proapoptotic factors. To further illustrate it, Homo sapiens eIF4E-binding protein 1 (4EBP1), p70S6 kinase (p70S6K), Akt1 and Akt2 were transfected to HeLa cells, respectively. And then, we established the stable transfected cell lines. Next, after CVB3 infection, apoptosis in different groups was determined by flow cytometry; the expressions of Bim, Bax, caspase-9 and caspase-3 were examined by real-time fluorescence quantitative PCR and western blot analysis; the expression of CVB3 mRNA and viral capsid protein VP1 were also analyzed by real-time fluorescence quantitative PCR, western blot analysis and immunofluorescence, respectively. At the meantime, CVB3 replication was observed by transmission electron microscope. We found that CVB3-induced cytopathic effect and apoptosis in transfected groups were more obvious than that in controls. Unexpectedly, apoptosis rate in Akt1 group was higher than others at the early stage after viral infection and decreased with the viral-infected time increasing, which was opposite to other groups. Compared with controls, the expression of CVB3 mRNA was increased at 3, 6, 12 and 24 h postinfection (p. i.) in all groups. At the meantime, VP1 expression in 4EBP1 group was higher than control during the process of infection, while the expressions in the other groups were change dynamically. Moreover, overexpression of 4EBP1 did not affect the mRNA expressions of Bim, Bax, caspase-9 and caspase-3; while protein expressions of Bim and Bax were decreased, the self-cleavages of caspase-9 and caspase-3 were stimulated. Meanwhile, overexpression of p70S6K blocked the CVB3-induced Bim, Bax and caspase-9 expressions but promoted the self-cleavage of caspase-9. In the Akt1 group, it is noteworthy that the expressions of Bim protein were higher than controls at 3 and 6 h p. i. but lower at 24 h p. i., and the expression of Bax protein were higher at 6 and 24 h p. i., while their mRNA expressions were all decreased. Furthermore, overexpression of Akt1 stimulated the procaspase-9 and procaspase-3 expression but blocked their self-cleavages. Overexpression of Akt2, however, had little effect on Bim, Bax and caspase-3, while prevented caspase-9 from self-cleavage at the late stage of CVB3 infection. As stated above, our results demonstrated that overexpression of 4EBP1, p70S6K, Akt1 or Akt2 could promote the CVB3-induced apoptosis in diverse degree via different mediating ways in viral replication and proapoptotic factors in BcL-2 and caspase families. As 4EBP1, p70S6K and Akt are the important substrates of PI3K and mammalian target of rapamycin (mTOR), we further illustrated the role of PI3K/Akt/mTOR signaling pathway in the process of CVB3-induced apoptosis.
doi:10.1038/cddis.2013.331
PMCID: PMC3789189  PMID: 24030155
overexpression; 4EBP1; p70S6K; Akt; coxsackievirus b3; apoptosis
20.  Evaluation of Coarsely Ground Wheat as a Replacement for Ground Corn in the Diets of Lactating Dairy Cows 
Eight multiparous Holstein cows (569±47 kg of BW; 84±17 DIM) were used to evaluate the effects of different levels of coarsely ground wheat (CGW) as replacements for ground corn (GC) in diets on feed intake and digestion, ruminal fermentation, lactation performance, and plasma metabolites profiles in dairy cows. The cows were settled in a replicated 4×4 Latin square design with 3-wk treatment periods; four cows in one of the replicates were fitted with rumen cannulas. The four diets contained 0, 9.6, 19.2, and 28.8% CGW and 27.9, 19.2, 9.6, and 0% GC on dry matter (DM) basis, respectively. Increasing dietary levels of CGW, daily DM intake tended to increase quadratically (p = 0.07); however, apparent digestibility of neutral detergent fiber (NDF) and acid detergent fiber (ADF) were significantly decreased (p<0.01) in cows fed the 28.8% CGW diets. Ruminal pH remained in the normal physiological range for all dietary treatments at all times, except for the 28.8% CGW diets at 6 h after feeding; moreover, increasing dietary levels of CGW, the daily mean ruminal pH decreased linearly (p = 0.01). Increasing the dietary levels of CGW resulted in a linear increase in ruminal propionate (p<0.01) and ammonia nitrogen (NH3-N) (p = 0.06) concentration, while ruminal acetate: propionate decreased linearly (p = 0.03) in cows fed the 28.8% CGW diets. Milk production was not affected by diets; however, percentage and yield of milk fat decreased linearly (p = 0.02) when the level of CGW was increased. With increasing levels of dietary CGW, concentrations of plasma beta-hydroxybutyric acid (BHBA) (p = 0.07) and cholesterol (p<0.01) decreased linearly, whereas plasma glucose (p = 0.08), insulin (p = 0.02) and urea nitrogen (p = 0.02) increased linearly at 6 h after the morning feeding. Our results indicate that CGW is a suitable substitute for GC in the diets of dairy cows and that it may be included up to a level of 19.2% of DM without adverse effects on feed intake and digestion, ruminal fermentation, lactation performance, and plasma metabolites if the cows are fed fiber-sufficient diets.
doi:10.5713/ajas.2013.13059
PMCID: PMC4093492  PMID: 25049874
Dairy Cows; Digestion; Lactation; Plasma Metabolites; Rumen Fermentation; Wheat
21.  Deficiency of Erbin induces resistance of cervical cancer cells to anoikis in a STAT3-dependent manner 
Hu, Y | Chen, H | Duan, C | Liu, D | Qian, L | Yang, Z | Guo, L | Song, L | Yu, M | Hu, M | Shi, M | Guo, N
Oncogenesis  2013;2(6):e52-.
Epithelial cell polarization and integration are essential to their function and loss of epithelial polarity and tissue architecture correlates with the development of aggressive tumors. Erbin is a basolateral membrane-associated protein. The roles of Erbin in establishing cell polarization and regulating cell adhesion have been suggested. Erbin is also a negative regulator in Ras-Raf-ERK (extracellular signal-regulated kinase) signaling pathway. However, the potential functions of Erbin in human cancer are basically unknown. In the present study, we show, for the first time, that loss of Erbin endows cervical cancer cells with resistance to anoikis both in vitro and in vivo and promotes the growth and metastasis of human cervical cancer xenografts in nude mice. We found that knockdown of Erbin induced the phosphorylation, nuclear translocation and transcriptional activities of signal transducer and activator of transcription factor 3 (STAT3) in cervical cancer cells. Overexpression of STAT3C or induction of endogenous STAT3 activation by interleukin (IL)-6 evidently inhibited anoikis of cervical cancer cells, whereas WP1066, a potent inhibitor of Janus-activated kinase 2 (Jak2)/STAT3, effectively blocked the effect of Erbin knockdown on cell survival under anchorage-independent conditions, indicating that loss of Erbin confers resistance of cervical cancer cells to anoikis in a STAT3-dependent manner. Interestingly, IL-6 induced STAT3 activation and Erbin expression simultaneously. Overexpression of STAT3C also significantly upregulated the level of Erbin, whereas the Jak2 inhibitor AG490 remarkably blocked not only STAT3 phosphorylation but also IL-6-induced Erbin expression. Knockdown of Erbin augmented the effects of IL-6 on STAT3 activation and anoikis resistance. In addition, by immunohistochemical analysis of Erbin expression, we demonstrate that the expression of Erbin is significantly decreased or even lost in cervical cancer tissues. These data reveal that Erbin is a novel negative regulator of STAT3, and the IL-6/STAT3/Erbin loop has a crucial role in cervical cancer progression and metastasis.
doi:10.1038/oncsis.2013.18
PMCID: PMC3740302  PMID: 23774064
Erbin; STAT3; IL-6; cervical cancer; anoikis; metastasis
22.  Epithelial–mesenchymal transition biomarkers and support vector machine guided model in preoperatively predicting regional lymph node metastasis for rectal cancer 
British Journal of Cancer  2012;106(11):1735-1741.
Background:
Current imaging modalities are inadequate in preoperatively predicting regional lymph node metastasis (RLNM) status in rectal cancer (RC). Here, we designed support vector machine (SVM) model to address this issue by integrating epithelial–mesenchymal-transition (EMT)-related biomarkers along with clinicopathological variables.
Methods:
Using tissue microarrays and immunohistochemistry, the EMT-related biomarkers expression was measured in 193 RC patients. Of which, 74 patients were assigned to the training set to select the robust variables for designing SVM model. The SVM model predictive value was validated in the testing set (119 patients).
Results:
In training set, eight variables, including six EMT-related biomarkers and two clinicopathological variables, were selected to devise SVM model. In testing set, we identified 63 patients with high risk to RLNM and 56 patients with low risk. The sensitivity, specificity and overall accuracy of SVM in predicting RLNM were 68.3%, 81.1% and 72.3%, respectively. Importantly, multivariate logistic regression analysis showed that SVM model was indeed an independent predictor of RLNM status (odds ratio, 11.536; 95% confidence interval, 4.113–32.361; P<0.0001).
Conclusion:
Our SVM-based model displayed moderately strong predictive power in defining the RLNM status in RC patients, providing an important approach to select RLNM high-risk subgroup for neoadjuvant chemoradiotherapy.
doi:10.1038/bjc.2012.82
PMCID: PMC3364123  PMID: 22538975
SVM; EMT; regional lymph node metastasis; colorectal cancer
23.  On-Site Array CGH Applications in Clinical In Vitro Fertilization: Reproductive Outcomes and Impact on Cryopreservation of Non-transferred Human Embryos 
Background: IVF pregnancy rates have trended upward although gains have been accompanied by unwelcome increases in pre-term delivery and multiple gestation. These adverse outcomes happen because multiple embryos are typically transferred during IVF. Integrating newer molecular cytogenetic techniques with IVF can optimize selection of a single embryo for transfer. Methods: The SurePlex DNA amplification system (BlueGnome Ltd; Cambridge, UK) was used on-site for whole genome amplification of human blastocyst trophectoderm (TE) cells obtained by biopsy. IVF patients (initial cycle, age <35, no prior miscarriage, normal karyotype) were prospectively randomized into two groups: In Group 1, embryos were selected on the basis of morphology and comprehensive chromosomal screening via array comparative genomic hybridization (aCGH) from d5 TE biopsy, while Group 2 embryos were assessed by morphology only. All patients underwent a single fresh blastocyst transfer on d6. For embryos in the aCGH group, only one euploid blastocyst was selected for transfer and surplus euploid blastocysts were vitrified. In the non-aCGH (control) group, a single blastocyst was selected for fresh transfer based on appearance only, with vitrification of any surplus blastocysts with satisfactory morphology. Results: Aneuploidy was identified in 191/425 of Group 1 balstocysts (44.9%). Control embryos (n=389) were assessed by microscopy only. A higher clinical pregnancy rate was observed in Group 1 patients compared to the control group (70.9 vs. 45.8%; p = 0.017). Only 64 (28.3%) surplus euploid embryos were frozen in Group 1 while 157 (40.4%) blastocysts were cryopreserved for Group 2 (p=0.017). Conclusion: These data underscore the intrinsic imprecision of IVF when conventional morphology is used alone to select embryos for transfer. Embryos evaluated with aCGH implant with greater efficiency and achieve clinical pregnancy more often than those selected without aCGH. Patients should be advised that aCGH screening may reduce the number of surplus embryos for cryopreservation.
PMCID: PMC3635430
24.  Partial germline reversions can increase VRC07 potency and breadth 
Retrovirology  2012;9(Suppl 2):P101.
doi:10.1186/1742-4690-9-S2-P101
PMCID: PMC3441513

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