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1.  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.
PMCID: PMC3982943  PMID: 24676494
Dahl salt-sensitive rats; High salt intake; EMT; Renal fibrosis
2.  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.
PMCID: PMC3668654  PMID: 23211792
chicken; mtDNA; domestication; phylogeny; Austronesian
3.  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.
PMCID: PMC3973221  PMID: 24675462
MiR-19; MXD1; metastasis; gastric cancer
4.  Prognostic value of Ki-67 for prostate cancer death in a conservatively managed cohort 
British Journal of Cancer  2013;108(2):271-277.
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.
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.
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).
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.
PMCID: PMC3566811  PMID: 23329234
localised prostate cancer; prognostic factors; Ki-67; needle biopsy
5.  Mir143 expression inversely correlates with nuclear ERK5 immunoreactivity in clinical prostate cancer 
British Journal of Cancer  2013;108(1):149-154.
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.
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.
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.
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.
PMCID: PMC3553517  PMID: 23321517
mir143; ERK5; prostate cancer
6.  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.
PMCID: PMC3886828  PMID: 21666724
chromosome 9p24; GASC1; UHRF2; gene amplification
7.  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.
PMCID: PMC3877541  PMID: 24309930
p63; Pin1; WWP1; tumorigenesis; xenograft
8.  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.
PMCID: PMC3877551  PMID: 24309937
mesenchymal stem cells; array-based comparative genomic hybridization; copy number variations; mRNA-Seq
9.  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.
PMCID: PMC3824650  PMID: 24136221
CSCs; carcinoma/cancer microenvironments; multilineage differentiation potential; Oct4; microvascular endothelial cells
10.  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.
PMCID: PMC3920930  PMID: 24176853
Transcriptome; γ-irradiation; apoptosis; dynamic response; glioblastoma; radioresistance
11.  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
12.  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.
PMCID: PMC3789189  PMID: 24030155
overexpression; 4EBP1; p70S6K; Akt; coxsackievirus b3; apoptosis
13.  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.
PMCID: PMC3740302  PMID: 23774064
Erbin; STAT3; IL-6; cervical cancer; anoikis; metastasis
14.  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.
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.
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).
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).
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.
PMCID: PMC3364123  PMID: 22538975
SVM; EMT; regional lymph node metastasis; colorectal cancer
15.  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
16.  Partial germline reversions can increase VRC07 potency and breadth 
Retrovirology  2012;9(Suppl 2):P101.
PMCID: PMC3441513
20.  Pleiotropic Effects of GIP on Islet Function Involve Osteopontin 
Diabetes  2011;60(9):2424-2433.
The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic β-cell function by potentiating insulin secretion and β-cell proliferation. Recently, a combined analysis of several genome-wide association studies (Meta-analysis of Glucose and Insulin-Related Traits Consortium [MAGIC]) showed association to postprandial insulin at the GIP receptor (GIPR) locus. Here we explored mechanisms that could explain the protective effects of GIP on islet function.
Associations of GIPR rs10423928 with metabolic and anthropometric phenotypes in both nondiabetic (N = 53,730) and type 2 diabetic individuals (N = 2,731) were explored by combining data from 11 studies. Insulin secretion was measured both in vivo in nondiabetic subjects and in vitro in islets from cadaver donors. Insulin secretion was also measured in response to exogenous GIP. The in vitro measurements included protein and gene expression as well as measurements of β-cell viability and proliferation.
The A allele of GIPR rs10423928 was associated with impaired glucose- and GIP-stimulated insulin secretion and a decrease in BMI, lean body mass, and waist circumference. The decrease in BMI almost completely neutralized the effect of impaired insulin secretion on risk of type 2 diabetes. Expression of GIPR mRNA was decreased in human islets from carriers of the A allele or patients with type 2 diabetes. GIP stimulated osteopontin (OPN) mRNA and protein expression. OPN expression was lower in carriers of the A allele. Both GIP and OPN prevented cytokine-induced reduction in cell viability (apoptosis). In addition, OPN stimulated cell proliferation in insulin-secreting cells.
These findings support β-cell proliferative and antiapoptotic roles for GIP in addition to its action as an incretin hormone. Identification of a link between GIP and OPN may shed new light on the role of GIP in preservation of functional β-cell mass in humans.
PMCID: PMC3161325  PMID: 21810601
21.  Efficacy of an unsupervised 8-month rifampicin-containing regimen for the treatment of pulmonary tuberculosis in HIV-infected adults 
National Tuberculosis Treatment Centre, Mulago Hospital, Kampala, Uganda.
To assess the efficacy of a daily, self-administered 8-month rifampicin-containing regimen for the treatment of pulmonary tuberculosis (TB) in human immunodeficiency virus (HIV) infected adults.
Treatment outcomes in patients with pulmonary TB treated with a single 8-month regimen and followed in a prospective epidemiological study.
Two hundred and sixty-five HIV-infected and 26 non-HIV-infected adults with initial episodes of pulmonary tuberculosis were treated with 2 months of daily isoniazid (INH), rifampicin (RMP), ethambutol and pyrazinamide followed by 6 months of daily INH + RMP. Median follow-up was 17.8 months. Ninety-five per cent of the HIV-infected and all of the non-HIV-infected patients who had sputum examined were sputum culture negative after 2 months of treatment. Twenty-two HIV-infected and no non-HIV-infected patients died during treatment. Relapse rates were 8.4% (5.9 per 100 person-years of observation [PYO], 95%CI 3.2–8.6) among HIV-infected patients and 4.5% (2.1/100 PYO, 95%CI 0–7.8) for non-HIV-infected patients. Adverse drug reactions occurred in 37% of the HIV-infected patients; most were minor and self-limiting.
An 8-month RMP-containing regimen was well tolerated and effective in the treatment of HIV-infected adults with initial episodes of pulmonary TB. Relapse rates were similar to those reported with 6-month short-course regimens in HIV-infected individuals. Decisions about the duration of anti-tuberculosis treatment for HIV-infected adults must balance programme resources and the likelihood of poor compliance with longer regimens with the potential for a modest decrease in relapses with longer treatment.
PMCID: PMC3419476  PMID: 11092715
tuberculosis; HIV; AIDS; rifampicin; relapse; RFLP
22.  CM2 antigen, a potential novel molecule participating in glucuronide transport on rat hepatocyte canalicular membrane 
The polarized molecules predominately distributing at hepatocyte canalicular surface play a vital role in disclosing the process of bile formation and etiopathogenisis of cholestatic live diseases. Therefore, it is important to find novel polarized molecules on hepatocyte canalicular membrane. In the present study, canalicular membrane vesicles (CMVs) isolated from rat hepatocyte by density gradient centrifugation were used as immunogens to produce hybridoma and 46 strains of monoclonal antibodies (mAb) against CMVs were obtained. With a series of morphological assay methods, including immunohistochemistry, immunofluorescence and immuno-electron microscope, the antigens recognized by canalicular mAb1 (CM1) and canalicular mAb2 (CM2) were confirmed to predominately distribute at hepatocyte canalicular membrane. Transport activity assay revealed that CM2 could inhibit ATP-dependent E217βG uptake of rat hepatocyte CMVs. Meanwhile, Western blotting analysis showed that the molecular mass of CM2 antigen was approximately 110kDa, which was much less than Mr 180kDa of multidrug resistance-associated protein 2 (MRP2) involved in glucuronide transport. These data indicated that CM2 antigen might be a potential novel molecule participating in glucuronide transport on the hepatocyte canalicular membrane.
PMCID: PMC3493972  PMID: 23027342
hepatocyte canalicular membrane; glucuronide transport; canalicular mAb2 (CM2); hybridoma technique.
23.  Pituicytoma: case report and literature review 
The British Journal of Radiology  2011;84(999):e055-e057.
Pituicytoma is a rare primary tumour of the neurohypophysis or infundibulum, which masquerades as a pituitary adenoma. We present a pituicytoma case in a 45-year-old female presenting as a focal lesion of the neurohypophysis. This case report reviews the clinical, neuroimaging and histopathological features of this rare tumour in order to understand it better.
PMCID: PMC3473875  PMID: 21325358
24.  Association of genetic variation in FTO with risk of obesity and type 2 diabetes with data from 96,551 East and South Asians 
Diabetologia  2011;55(4):981-995.
FTO harbours the strongest known obesity-susceptibility locus in Europeans. While there is growing evidence for a role for FTO in obesity risk in Asians, its association with type 2 diabetes, independently of BMI, remains inconsistent. To test whether there is an association of the FTO locus with obesity and type 2 diabetes, we conducted a meta-analysis of 32 populations including 96,551 East and South Asians.
All studies published on the association between FTO-rs9939609 (or proxy [r2 > 0.98]) and BMI, obesity or type 2 diabetes in East or South Asians were invited. Each study group analysed their data according to a standardised analysis plan. Association with type 2 diabetes was also adjusted for BMI. Random-effects meta-analyses were performed to pool all effect sizes.
The FTO-rs9939609 minor allele increased risk of obesity by 1.25-fold/allele (p = 9.0 × 10−19), overweight by 1.13-fold/allele (p = 1.0 × 10−11) and type 2 diabetes by 1.15-fold/allele (p = 5.5 × 10−8). The association with type 2 diabetes was attenuated after adjustment for BMI (OR 1.10-fold/allele, p = 6.6 × 10−5). The FTO-rs9939609 minor allele increased BMI by 0.26 kg/m2 per allele (p = 2.8 × 10−17), WHR by 0.003/allele (p = 1.2 × 10−6), and body fat percentage by 0.31%/allele (p = 0.0005). Associations were similar using dominant models. While the minor allele is less common in East Asians (12–20%) than South Asians (30–33%), the effect of FTO variation on obesity-related traits and type 2 diabetes was similar in the two populations.
FTO is associated with increased risk of obesity and type 2 diabetes, with effect sizes similar in East and South Asians and similar to those observed in Europeans. Furthermore, FTO is also associated with type 2 diabetes independently of BMI.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-011-2370-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC3296006  PMID: 22109280
Asians; FTO; Meta-analysis; Obesity; Type 2 diabetes
25.  First-pass perfusion imaging of solitary pulmonary nodules with 64-detector row CT: comparison of perfusion parameters of malignant and benign lesions 
The British Journal of Radiology  2010;83(993):785-790.
The purpose of this study was to determine the usefulness of first-pass whole nodule perfusion imaging in the differentiation of benign and malignant solitary pulmonary nodules (SPNs). 77 patients with non-calcified SPNs (46 malignant, 22 benign and 9 active inflammatory) underwent first-pass perfusion imaging with a 64-detector row CT scanner. Perfusion, peak enhancement intensity (PEI), time to peak (TTP) and blood volume (BV) were measured and statistically compared among different groups. Mean perfusion, PEI and BV for benign SPNs were significantly lower than those for malignant nodules (p<0.05) and active infections (p<0.05), but the differences were not statistically significant between malignant tumours and active infections (p>0.05). Receiver operating characteristic (ROC) curve analysis showed that SPNs with perfusion greater than 30.6 ml min–1 ml–1, PEI higher than 23.3 HU or BV larger than 12.2 ml per 100 g were more likely to be malignant. In conclusion, first-pass perfusion imaging with 64-detector row CT is a feasible way of assessing whole nodule perfusion and helpful in differentiating benign from malignant SPNs.
PMCID: PMC3473400  PMID: 20647512

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