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1.  Cruciferous vegetables intake and the risk of colorectal cancer: a meta-analysis of observational studies 
Annals of Oncology  2012;24(4):1079-1087.
Background
Epidemiological studies have reported inconsistent associations between cruciferous vegetable (CV) intake and colorectal cancer (CRC) risk. To our knowledge, a comprehensive and quantitative assessment of the association between CV intake and CRC has not been reported.
Methods
Relevant articles were identified by searching MEDLINE. We pooled the relative risks (RR) from individual studies using a random-effect model and carried out heterogeneity and publication bias analyses.
Results
Twenty-four case–control and 11 prospective studies were included in our analysis. When all studies were pooled, we yielded a significantly inverse association between CV (RR: 0.82; 95% confidence interval 0.75–0.90) intake and CRC risk. Specific analysis for cabbage and broccoli yielded similar result. When separately analyzed, case–control studies of CV intake yield similar results, and the results from the prospective studies showed borderline statistical significance. Moreover, significant inverse associations were also observed in colon cancer and its distal subsite both among prospective and case–control studies.
Conclusions
Findings from this meta-analysis provide evidence that high intake of CV was inversely associated with the risk of CRC and colon cancer in humans. Further analysis on other specific CV, food preparation methods, stratified results by anatomic cancer site, and subsite of colon cancer should be extended in future study.
doi:10.1093/annonc/mds601
PMCID: PMC3603442  PMID: 23211939
colorectal cancer; cruciferous vegetables; dietary; epidemiology; meta-analysis
2.  Population Pharmacokinetics and Dose Optimization of Mycophenolic Acid in HCT Recipients Receiving Oral Mycophenolate Mofetil 
Journal of clinical pharmacology  2013;53(4):393-402.
We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. 4,496 MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance and volume of the central compartment were 24.2 L/hr and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA clearance by 33.8%. The optimal LSS was immediately before and at 0.25, 1.25, 2, and 4hr after oral MMF administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation.
doi:10.1002/jcph.14
PMCID: PMC3612130  PMID: 23382105
Mycophenolic acid; population pharmacokinetics; limited sampling schedule; hematopoietic cell transplantation; dosing simulation
3.  ROS-dependent activation of JNK converts p53 into an efficient inhibitor of oncogenes leading to robust apoptosis 
Cell Death and Differentiation  2014;21(4):612-623.
Rescue of the p53 tumor suppressor is an attractive cancer therapy approach. However, pharmacologically activated p53 can induce diverse responses ranging from cell death to growth arrest and DNA repair, which limits the efficient application of p53-reactivating drugs in clinic. Elucidation of the molecular mechanisms defining the biological outcome upon p53 activation remains a grand challenge in the p53 field. Here, we report that concurrent pharmacological activation of p53 and inhibition of thioredoxin reductase followed by generation of reactive oxygen species (ROS), result in the synthetic lethality in cancer cells. ROS promote the activation of c-Jun N-terminal kinase (JNK) and DNA damage response, which establishes a positive feedback loop with p53. This converts the p53-induced growth arrest/senescence to apoptosis. We identified several survival oncogenes inhibited by p53 in JNK-dependent manner, including Mcl1, PI3K, eIF4E, as well as p53 inhibitors Wip1 and MdmX. Further, we show that Wip1 is one of the crucial executors downstream of JNK whose ablation confers the enhanced and sustained p53 transcriptional response contributing to cell death. Our study provides novel insights for manipulating p53 response in a controlled way. Further, our results may enable new pharmacological strategy to exploit abnormally high ROS level, often linked with higher aggressiveness in cancer, to selectively kill cancer cells upon pharmacological reactivation of p53.
doi:10.1038/cdd.2013.186
PMCID: PMC3950324  PMID: 24413150
TrxR; ROS; JNK; p53; Wip1; inhibition of oncogenes
5.  Quantitative analysis of contrast-enhanced ultrasonography: differentiating focal nodular hyperplasia from hepatocellular carcinoma 
The British Journal of Radiology  2013;86(1023):20120536.
Objective:
To explore the potential of quantitative analysis of contrast-enhanced ultrasonography (CEUS) in differentiating focal nodular hyperplasia (FNH) from hepatocellular carcinoma (HCC).
Methods:
34 cases of FNH and 66 cases of HCC (all lesions <5 cm) were studied using CEUS to evaluate enhancement patterns and using analytic software Sonoliver® (Image-Arena™ v.4.0, TomTec Imaging Systems, Munich, Germany) to obtain quantitative features of CEUS in the region of interest. The quantitative features of maximum of intensity (IMAX), rise slope (RS), rise time (RT) and time to peak (TTP) were compared between the two groups and applied to further characterise both FNH and HCC with hypoenhancing patterns in the late phase on CEUS.
Results:
The sensitivity and specificity of CEUS for diagnosis of FNH were 67.6% and 93.9%, respectively. For quantitative analysis, IMAX and RS in FNHs were significantly higher than those in HCCs (p<0.05), while RT and TTP in FNHs were significantly shorter (p<0.05). Both the 11 FNHs and 62 HCCs with hypo-enhancing patterns in the late phase were further characterised with their quantitative features, and the sensitivity and specificity of IMAX for diagnosis of FNH were 90.9% and 43.5%, RS 81.8% and 80.6%, RT 90.9% and 71.0%, and TTP 90.9% and 71.0%, respectively.
Conclusion:
The quantitative features of CEUS in FNH and HCC were significantly different, and they could further differentiate FNH from HCC following conventional CEUS.
Advances in knowledge:
Our findings suggest that quantitative analysis of CEUS can improve the accuracy of differentiating FNH from HCC.
doi:10.1259/bjr.20120536
PMCID: PMC3608056  PMID: 23392189
6.  PSGL-1/selectin and ICAM-1/CD18 interactions are involved in macrophage-induced drug resistance in myeloma 
Leukemia  2012;27(3):702-710.
Chemoresistance is the major obstacle in multiple myeloma (MM) management. We previously showed that macrophages protect myeloma cells, on a cell contact basis, from melphalan or dexamethasone-induced apoptosis in vitro. In this study, we found that macrophage-mediated myeloma drug resistance was also seen with purified macrophages from myeloma patients’ bone marrow (BM) in vitro and was confirmed in vivo using the human myeloma-SCID (severe combined immunodeficient) mouse model. By profiling differentially regulated and paired plasma membrane protein genes, we showed that PSGL-1 (P-selectin glycoprotein ligand-1)/selectins and ICAM-1/CD18 played an important role in macrophage-mediated myeloma cell drug resistance, as blocking antibodies against these molecules or genetic knockdown of PSGL-1 or ICAM-1 in myeloma cells repressed macrophages’ ability to protect myeloma cells. Interaction of macrophages and myeloma cells via these molecules activated Src and Erk1/2 kinases and c-myc pathways and suppressed caspase activation induced by chemotherapy drugs. Thus, our study sheds new light on the mechanism of drug resistance in MM and provides novel targets for improving the efficacy of chemotherapy in patients.
doi:10.1038/leu.2012.272
PMCID: PMC3652581  PMID: 22996336
macrophage; multidrug resistance; multiple myeloma; PSGL-1
7.  Depletion of pre-mRNA splicing factor Cdc5L inhibits mitotic progression and triggers mitotic catastrophe 
Mu, R | Wang, Y-B | Wu, M | Yang, Y | Song, W | Li, T | Zhang, W-N | Tan, B | Li, A-L | Wang, N | Xia, Q | Gong, W-L | Wang, C-G | Zhou, T | Guo, N | Sang, Z-H | Li, H-Y
Cell Death & Disease  2014;5(3):e1151-.
Disturbing mitotic progression via targeted anti-mitotic therapy is an attractive strategy for cancer treatment. Therefore, the exploration and elucidation of molecular targets and pathways in mitosis are critical for the development of anti-mitotic drugs. Here, we show that cell division cycle 5-like (Cdc5L), a pre-mRNA splicing factor, is a regulator of mitotic progression. Depletion of Cdc5L causes dramatic mitotic arrest, chromosome misalignments and sustained activation of spindle assembly checkpoint, eventually leading to mitotic catastrophe. Moreover, these defects result from severe impairment of kinetochore-microtubule attachment and serious DNA damage. Genome-wide gene expression analysis reveals that Cdc5L modulates the expression of a set of genes involved in the mitosis and the DNA damage response. We further found that the pre-mRNA splicing efficiency of these genes were impaired when Cdc5L was knocked down. Interestingly, Cdc5L is highly expressed in cervical tumors and osteosarcoma. Finally, we demonstrate that downregulation of Cdc5L decreases the cell viability of related tumor cells. These results suggest that Cdc5L is a key regulator of mitotic progression and highlight the potential of Cdc5L as a target for cancer therapy.
doi:10.1038/cddis.2014.117
PMCID: PMC3973201  PMID: 24675469
mitotic catastrophe; chromosome misalignment; RNA processing
8.  MicroRNA-23a/b and microRNA-27a/b suppress Apaf-1 protein and alleviate hypoxia-induced neuronal apoptosis 
Chen, Q | Xu, J | Li, L | Li, H | Mao, S | Zhang, F | Zen, K | Zhang, C-Y | Zhang, Q
Cell Death & Disease  2014;5(3):e1132-.
Expression of apoptotic protease activating factor-1 (Apaf-1) gradually decreases during brain development, and this decrease is likely responsible for the decreased sensitivity of brain tissue to apoptosis. However, the mechanism by which Apaf-1 expression is decreased remains elusive. In the present study, we found that four microRNAs (miR-23a/b and miR-27a/b) of miR-23a-27a-24 and miR-23b-27b-24 clusters play key roles in modulating the expression of Apaf-1. First, we found that miR-23a/b and miR-27a/b suppressed the expression of Apaf-1 in vitro. Interestingly, the expression of the miR-23-27-24 clusters in the mouse cortex gradually increased in a manner that was inversely correlated with the pattern of Apaf-1 expression. Second, hypoxic injuries during fetal distress caused reduced expression of the miR-23b and miR-27b that was inversely correlated with an elevation of Apaf-1 expression during neuronal apoptosis. Third, we made neuronal-specific transgenic mice and found that overexpressing the miR-23b and miR-27b in mouse neurons inhibited the neuronal apoptosis induced by intrauterine hypoxia. In conclusion, our results demonstrate, in central neural system, that miR-23a/b and miR-27a/b are endogenous inhibitory factors of Apaf-1 expression and regulate the sensitivity of neurons to apoptosis. Our findings may also have implications for the potential target role of microRNAs in the treatment of neuronal apoptosis-related diseases.
doi:10.1038/cddis.2014.92
PMCID: PMC3973202  PMID: 24651435
brain development; neuron; apoptosis; microRNA; fetal distress
9.  Loss of TACSTD2 contributed to squamous cell carcinoma progression through attenuating TAp63-dependent apoptosis 
Wang, F | Liu, X | Yang, P | Guo, L | Liu, C | Li, H | Long, S | Shen, Y | Wan, H
Cell Death & Disease  2014;5(3):e1133-.
Tumor-associated calcium signal transducer 2 (TACSTD2), a calcium signal transducer, is universally expressed in stratified squamous epithelia of many organs, including skin, esophagus and cervix. Although TACSTD2, was reported to be overexpressed in many epithelial tumors, which has increased interest in using it as a molecular target for cancer therapy, the role of TACSTD2 in carcinogenesis of squamous cell carcinoma (SCC) is largely unclear and controversial. To explore the role of TACSTD2, temporal-spatial expression of TACSTD2 was analyzed in both normal and SCC tissues. Our data demonstrate that Tacstd2 expression and membrane localization are tightly associated with stratified epithelial homeostasis, while loss of TACSTD2 was identified in poorly differentiated SCC tissues collected from cervix, esophagus, head and neck. Gradual loss of TACSTD2 was correlated with stepwise progression of SCC. Consistent with these in vivo observations, our data show that inhibition of Tacstd2 expression significantly inhibited chemotherapeutic reagent-induced apoptosis, and TACSTD2 regulated apoptotic gene expression through P63 containing the transactivation domain (TAp63). These findings indicated that loss of TACSTD2 could promote SCC progression and treatment resistance through attenuating chemotherapeutic reagent-induced apoptosis through TAp63, and TACSTD2 could be used as a marker for pathological grading of SCC.
doi:10.1038/cddis.2014.96
PMCID: PMC3973208  PMID: 24651436
TACSTD2; squamous cell carcinoma; apoptosis; TAp63; tumor progression
10.  An automated approach to analyze microstructural remodeling from confocal microscopies of ventricular myocytes from diseased hearts 
Biomedizinische Technik. Biomedical engineering  2012;10.1515/bmt-2012-4438 /j/bmte.2012.57.issue-s1-B/bmt-2012-4438/bmt-2012-4438.xml.
Various types of heart disease are associated with structural remodeling of cardiac cells. In this work, we present a software framework for automated analyses of structures and protein distributions involved in excitation-contraction coupling in cardiac muscle cells (myocytes). The software framework was designed for processing sets of three-dimensional image stacks, which were created by fluorescent labeling and scanning confocal microscopy of ventricular myocytes from a rabbit infarction model. Design of the software framework reflected the large data volume of image stacks and their large number by selection of efficient and automated methods of digital image processing. Specifically, we selected methods with small user interaction and automated parameter identification by analysis of image stacks. We applied the software framework to exemplary data yielding quantitative information on the arrangement of cell membrane (sarcolemma), the density of ryanodine receptor clusters and their distance to the sarcolemma. We suggest that the presented software framework can be used to automatically quantify various aspects of cellular remodeling, which will provide insights in basic mechanisms of heart diseases and their modeling using computational approaches. Further applications of the developed approaches include clinical cardiological diagnosis and therapy planning.
doi:10.1515/bmt-2012-4438
PMCID: PMC3594376  PMID: 22944798
11.  IKK-β mediates hydrogen peroxide induced cell death through p85 S6K1 
Cell Death and Differentiation  2012;20(2):248-258.
The IκB kinase (IKK)/NF-κB pathway has been shown to be a major regulator in cell survival. However, the mechanisms through which IKK mediates cell death are not clear. In this study, we showed that IKK-β contributed to hydrogen peroxide (H2O2)-induced cell death independent of the NF-κB pathway. Our results demonstrated that the pro-death function of IKK-β under oxidative stress was mediated by p85 S6K1 (S6 kinase 1), but not p70 S6K1 through a rapamycin-insensitive and mammalian target of rapamycin complex 1 kinase-independent mechanism. We found that IKK-β associated with p85, but not p70 S6K1, which was required for H2O2-induced activation of p85 S6K1. IKK-β and p85 S6K1 contributed to H2O2-induced phosphorylation of Mdm2 (S166) and p53 accumulation. p85 S6K1 is critical for IKK-β-mediated cell death. Thus, these findings established a novel oxidative stress-responsive pathway that involves IKK-β, p85 S6K1 and Mdm2, which is response for H2O2-induced cell death. Our results have important implications for IKK-β and p85 S6K1 as potential targets for the prevention of diseases involved in oxidative stress-induced aberrant cell death.
doi:10.1038/cdd.2012.115
PMCID: PMC3554328  PMID: 22955948
IKK-β; hydrogen peroxide; S6K1; mammalian target of rapamycin
12.  Induction of autophagy and senescence by knockdown of ROC1 E3 ubiquitin ligase to suppress the growth of liver cancer cells 
Yang, D | Li, L | Liu, H | Wu, L | Luo, Z | Li, H | Zheng, S | Gao, H | Chu, Y | Sun, Y | Liu, J | Jia, L
Cell Death and Differentiation  2012;20(2):235-247.
Regulator of Cullins-1 (ROC1) or RING box protein-1 (RBX1) is an essential RING component of Cullin-RING ligase (CRL). Our previous studies showed that ROC1 is required for the growth of several cancer cell lines while ROC1 siRNA silencing inactivates CRL, leading to cell cycle arrest, cell senescence and/or apoptosis. However, it is completely unknown whether ROC1 knockdown triggers autophagic response by inactivating CRL. Moreover, the role of ROC1 in liver cancer remains elusive. In this study, we reported that ROC1 knockdown significantly inhibited the growth of liver cancer cells by sequentially and independently inducing autophagy and p21-dependent cell senescence. Mechanism analysis revealed that ROC1 silencing triggered autophagy by inhibition of mammalian target of rapamycin (mTOR) activity due to accumulation of mTOR-inhibitory protein Deptor, a substrate of CRL. Consistently, Deptor knockdown significantly blocked autophagy response upon ROC1 silencing. Biologically, autophagy response upon ROC1 silencing was a survival signal, and blockage of autophagy pathway sensitized cancer cells to apoptosis. Finally, we demonstrated that ROC1 was overexpressed in hepatocellular carcinomas, which is associated with poor prognosis of liver cancer patients. These findings suggest that ROC1 is an appealing drug target for liver cancer and provide a proof-of-concept evidence for a novel drug combination of ROC1 inhibitor and an autophagy inhibitor for effective treatment of liver cancer by enhancing apoptosis.
doi:10.1038/cdd.2012.113
PMCID: PMC3554346  PMID: 22935614
ROC1; Cullin-RING ligase; autophagy; senescence; Deptor
13.  Involvement of miR-30c in resistance to doxorubicin by regulating YWHAZ in breast cancer cells 
MicroRNAs (miRNAs) are small RNA molecules that modulate gene expression implicated in cancer, which play crucial roles in diverse biological processes, such as development, differentiation, apoptosis, and proliferation. The aim of this study was to investigate whether miR-30c mediated the resistance of breast cancer cells to the chemotherapeutic agent doxorubicin (ADR) by targeting tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ). miR-30c was downregulated in the doxorubicin-resistant human breast cancer cell lines MCF-7/ADR and MDA-MB-231/ADR compared with their parental MCF-7 and MDA-MB-231 cell lines, respectively. Furthermore, we observed that transfection of an miR-30c mimic significantly suppressed the ability of MCF-7/ADR to resist doxorubicin. Moreover, the anti-apoptotic gene YWHAZ was confirmed as a target of miR-30c by luciferase reporter assay, and further studies indicated that the mechanism for miR-30c on the sensitivity of breast cancer cells involved YWHAZ and its downstream p38 mitogen-activated protein kinase (p38MAPK) pathway. Together, our findings provided evidence that miR-30c was one of the important miRNAs in doxorubicin resistance by regulating YWHAZ in the breast cancer cell line MCF-7/ADR.
doi:10.1590/1414-431X20133324
PMCID: PMC3932974  PMID: 24519092
Breast cancer cells; miR-30c; YWHAZ; Doxorubicin resistance
14.  Corrigendum 
Li, J | Sima, W | Ouyang, B | Wang, T | Ziaf, K | Luo, Z | Liu, L | Li, H | Chen, M | Huang, Y | Feng, Y | Hao, Y | Ye, Z
doi:10.1093/jxb/ert001
PMCID: PMC3873127
15.  Long-term survival among Hodgkin's lymphoma patients with gastrointestinal cancer: a population-based study 
Annals of Oncology  2012;24(1):202-208.
Background
The increased risk of gastrointestinal (GI) cancers after Hodgkin's lymphoma (HL) is well established. However, no large population-based study has described the actuarial survival after subsequent GI cancers in HL survivors (HL-GI).
Patients and methods
For 209 patients with HL-GI cancers (105 colon, 35 stomach, 30 pancreas, 21 rectum, and 18 esophagus) and 484 165 patients with first primary GI cancers (GI-1), actuarial survival was compared, accounting for age, gender, race, GI cancer stage, radiation for HL, and other variables.
Results
Though survival of HL patients who developed localized stage colon cancer was similar to that of the GI-1 group, overall survival (OS) of HL patients with regional or distant stage colon cancer was reduced [hazard ratio, (HR) = 1.46, P = 0.01]. The HL survivors with regional or distant stage colon cancer in the transverse segment had an especially high risk of mortality (HR: 2.7, P = 0.001 for OS). For localized stomach cancer, OS was inferior among HL survivors (HR = 3.46, P = 0.006).
Conclusions
The HL patients who develop GI cancer experience significantly reduced survival compared with patients with a first primary GI cancer. Further research is needed to explain the inferior survival of HL patients and to define selection criteria for cancer screening in HL survivors.
doi:10.1093/annonc/mds218
PMCID: PMC3525132  PMID: 22855552
cancer survivorship; gastrointestinal cancers; Hodgkin lymphoma; second cancers; SEER
16.  Dietary glycemic load, glycemic index, and carbohydrates on the risk of primary liver cancer among Chinese women and men 
Annals of Oncology  2012;24(1):238-244.
Background
Dietary glycemic index (GI) and glycemic load (GL) typically have a positive relationship with obesity and diabetes, which are risk factors for liver cancer. However, studies on their association with liver cancer have yielded inconsistent results. Therefore, we assessed the association of GI, GL, and carbohydrates with liver cancer risk.
Patients and methods
A total of 72 966 women and 60 207 men from the Shanghai Women's Health Study (SWHS) and the Shanghai Men's Health Study (SMHS) were included for analysis. Food frequency questionnaire (FFQ) data were used to calculate daily dietary GI, GL, and carbohydrate intake. These values were energy adjusted and categorized into quintiles. The hazard ratios (HRs) and 95% confidence intervals (CI) were calculated with adjustment for potential confounders.
Results
After a median follow-up time of 11.2 years for the SWHS and 5.3 years for the SMHS, 139 and 208 incident liver cancer cases were identified in the SWHS and SMHS, respectively. In multivariable Cox regression models, no statistically significant trends by quintile of GI, GL, or carbohydrate intake were observed. Stratification by chronic liver disease/hepatitis, diabetes, or body mass index (BMI) did not alter the findings.
Conclusions
There is little evidence that dietary GI, GL, or carbohydrates affect the incidence of liver cancer in this Asian population.
doi:10.1093/annonc/mds287
PMCID: PMC3525137  PMID: 22898034
Chinese men and women; cohort study; diet; glycemic index; glycemic load; primary liver cancer
17.  Retinal nerve fiber layer and optic disc measurements by spectral domain OCT: normative values and associations in young adults 
Eye  2012;26(12):1563-1570.
Purpose
To determine normative values and associations of retinal nerve fiber layer (RNFL) and optic disc parameters in normal eyes measured by spectral domain optical coherence tomography (OCT).
Methods
In a population-based setting, 1521 young adults were examined as part of the Sydney Adolescent Vascular and Eye Study (SAVES). Their mean age was 17.3±0.6 years. RNFL and optic disc parameter measurements were made using Cirrus HD-OCT 4000.
Results
The average RNFL was found to be 99.4±9.6 μm. RNFL thickness was least for the temporal quadrant (69.9±11.2 μm), followed by the nasal (74.3±12.8 μm), superior (124.7±15.7 μm) and inferior (128.8±17.1 μm) quadrants. The mean disc area in this population was 1.98±0.38 mm2 with a mean rim area of 1.50±0.30 mm2 and a mean cup/disc ratio of 0.44±0.18. Multivariate-adjusted RNFL thickness was marginally greater in East Asian than in white participants (100.1 μm vs 99.5 μm; P=0.0005). The RNFL was thinner with greater axial length (P<0.0001), less positive spherical equivalent refractions (P<0.0001), smaller disc area and rim area (P<0.0001).
Conclusion
This study documents normative values for the RNFL and optic disc measured using Cirrus HD-OCT in young adults. The values and associations reported in this study can inform clinicians on the normal variation in RNFL and optic disc parameters.
doi:10.1038/eye.2012.216
PMCID: PMC3522848  PMID: 23079750
retinal nerve fiber layer; optic disc; optical coherence tomography; Sydney Childhood Eye Study
18.  Notch signaling differentially regulates the cell fate of early endocrine precursor cells and their maturing descendants in the mouse pancreas and intestine 
Developmental biology  2012;371(2):156-169.
Notch signaling inhibits differentiation of endocrine cells in the pancreas and intestine. In a number of cases, the observed inhibition occurred with Notch activation in multipotential cells, prior to the initiation of endocrine differentiation. It has not been established how direct activation of Notch in endocrine precursor cells affects their subsequent cell fate. Using conditional activation of Notch in cells expressing Neurogenin3 or NeuroD1, we examined the effects of Notch in both organs, on cell fate of early endocrine precursors and maturing endocrine-restricted cells respectively. Notch did not preclude the differentiation of a limited number of endocrine cells in either organ when activated in Ngn3+ precursor cells. In addition, in the pancreas most Ngn3+ cells adopted a duct but not acinar cell fate; whereas in intestinal Ngn3+ cells, Notch favored enterocyte and goblet cell fates, while selecting against endocrine and Paneth cell differentiation. A small fraction of NeuroD1+ cells in the pancreas retain plasticity to respond to Notch, giving rise to intraislet ductules as well as cells with no detectable pancreatic lineage markers that appear to have limited ultrastructural features of both endocrine and duct cells. These results suggest that Notch directly regulates cell fate decisions in multipotential early endocrine precursor cells. Some maturing endocrine-restricted NeuroD1+ cells in the pancreas switch to the duct lineage in response to Notch, indicating previously unappreciated plasticity at such a late stage of endocrine differentiation.
doi:10.1016/j.ydbio.2012.08.023
PMCID: PMC3475208  PMID: 22964416
19.  The Association of Concurrent Vitamin D and Sex Hormone Deficiency with Bone Loss and Fracture Risk in Older Men: The MrOS Study 
Low 25-hydroxyvitamin D (VitD), low sex hormones (SH), and high sex hormone binding globulin (SHBG) levels are common in older men. We tested the hypothesis that combinations of low VitD, low SH, and high SHBG would have a synergistic effect on bone mineral density (BMD), bone loss, and fracture risk in older men. Participants were a random subsample of 1468 men (mean age 74) from the Osteoporotic Fractures in Men Study (MrOS) plus 278 MrOS men with incident non-spine fractures studied in a case-cohort design. “Abnormal” was defined as lowest quartile for VitD (<20 ng/ml), bioavailable testosterone (BioT, <163 ng/dl), and bioavailable estradiol (BioE, <11 pg/ml); and highest quartile for SHBG (>59 nM).
Overall, 10% had isolated VitD deficiency; 40% had only low SH or high SHBG; 15% had both SH/SHBG and VitD abnormality, and 35% had no abnormality. Compared to men with all normal levels, those with both SH/SHBG and VitD abnormality tended to be older, more obese, and to report less physical activity. Isolated VitD deficiency, and low BioT with or without low VitD, was not significantly related to skeletal measures. The combination of VitD deficiency with low BioE and/or high SHBG was associated with significantly lower baseline BMD and higher annualized rates of hip bone loss than SH abnormalities alone or no abnormality. Compared to men with all normal levels, the multivariate-adjusted hazard ratio (95% CI) for incident non-spine fracture during 4.6 yr median follow-up was 1.2 (0.8–1.8) for low VitD alone; 1.3 (0.9–1.9) for low BioE and/or high SHBG alone; and 1.6 (1.1–2.5) for low BioE/high SHBG plus low VitD.
In summary, adverse skeletal effects of low sex steroid levels were most pronounced in older men with low VitD levels. The presence of low VitD in the presence of low BioE/high SHBG may contribute substantially to poor skeletal health.
doi:10.1002/jbmr.1697
PMCID: PMC3474871  PMID: 22777902
bone loss; fracture; older men; sex hormones; vitamin
20.  A meta-analysis of lymph node metastasis rate for patients with thoracic oesophageal cancer and its implication in delineation of clinical target volume for radiation therapy 
Ding, X | Zhang, J | Li, B | Wang, Z | Huang, W | Zhou, T | Wei, Y | Li, H
The British Journal of Radiology  2012;85(1019):e1110-e1119.
Objectives
The objective of this study was to pool the lymph node metastasis rate (LNMR) in patients with thoracic oesophageal cancer (TOC) and to determine which node level should be included when undergoing radiation therapy.
Methods
Qualified studies were identified on Medline, Embase, CBM and the Cochrane Library through to the end of April 2011. Pooled estimates of LNMR were obtained through a random-effect model. Possible effect modifiers which might lead to the statistical heterogeneity were identified through meta-regression, and further subgroup analyses of factors influencing LNMR were performed.
Results
45 observational studies with a total of 18 415 patients were included in the meta-analysis. The pooled estimates of LNMR in upper, middle and lower TOC were 30.7%, 16.8% and 11.0% cervical, 42.0%, 21.1% and 10.5% upper mediastinal, 12.9%, 28.1% and 19.6% middle mediastinal, 2.6%, 7.8% and 23.0% lower mediastinal, and 9%, 21.4% and 39.9% abdominal, respectively. Lymph node metastasis most frequently happened to paratracheal, paraoesophageal, perigastric 106recR and station 7. The most obvious difference (≥15%) of LNMR between two-field and three-field lymphatic dissection occurred in cervical, paratracheal, 106recR and 108.
Conclusions
Through the meta-analysis, more useful information was obtained about clinical target volume (CTV) delineation of TOC patients treated with radiotherapy. However, our study is predominantly a description of squamous carcinoma and the results may not be valid for adenocarcinoma.
doi:10.1259/bjr/12500248
PMCID: PMC3500810  PMID: 22700258
21.  Erythrocyte trans-fatty acids, type 2 diabetes and cardiovascular risk factors in middle-aged and older Chinese individuals 
Diabetologia  2012;55(11):2954-2962.
Aims/hypothesis
Few data are available about intakes and food sources of trans-fatty acids (TFAs) or their associations with cardiometabolic outcomes in Asian people who consume a prudent diet but are experiencing rapid nutritional transitions. We aimed to investigate the relationships between TFA biomarkers and type 2 diabetes and cardiovascular risk factors in Chinese individuals.
Methods
Erythrocyte fatty acids were measured by gas chromatography among 3,107 men and women (50–70 years) recruited from urban and rural areas in Beijing and Shanghai, China.
Results
Total trans-18:1 and two trans-18:2 isomers were detected and accounted for 0.37% of the total fatty acids in the erythrocytes. Concentrations of TFAs were higher in women than men, and in urban than rural residents. Of the TFAs, trans-18:1, but not trans-18:2, showed a modest association with dairy consumption (β=0.27), but not with other foods. After adjustment for BMI, social-demographic, lifestyle and dietary factors and other TFAs, erythrocyte trans-18:1 was shown to be associated with a lower risk of type 2 diabetes (OR comparing extreme quartiles=0.68, 95% CI=0.48, 0.97, ptrend=0.02), as well as 20–50% lower odds of central obesity, dyslipidaemia, hyperglycemia, insulin resistance and chronic inflammation. In contrast, trans-18:2 fatty acids were positively associated with high triacylglycerol (ptrend<0.001) and LDL-cholesterol (ptrend=0.03) levels, but not with diabetes and other cardiometabolic risk factors.
Conclusions/interpretation
Among middle-aged and older Chinese individuals with overall low erythrocyte TFAs levels, trans-18:1 might serve as a marker of dairy intake. Higher trans-18:1 levels were associated with a lower risk of type 2 diabetes, whereas higher trans-18:2 levels were associated with dyslipidaemia.
doi:10.1007/s00125-012-2674-2
PMCID: PMC3681519  PMID: 22886370
Biomarkers; Diet; Dyslipidaemia; trans-Fatty acids; Type 2 diabetes
22.  A set of microRNAs mediate direct conversion of human umbilical cord lining-derived mesenchymal stem cells into hepatocytes 
Cui, L | Shi, Y | Zhou, X | Wang, X | Wang, J | Lan, Y | Wang, M | Zheng, L | Li, H | Wu, Q | Zhang, J | Fan, D | Han, Y
Cell Death & Disease  2013;4(11):e918-.
In a previous study, we elucidated the specific microRNA (miRNA) profile of hepatic differentiation. In this study, we aimed to clarify the instructive role of six overexpressed miRNAs (miR-1246, miR-1290, miR-148a, miR-30a, miR-424 and miR-542-5p) during hepatic differentiation of human umbilical cord lining-derived mesenchymal stem cells (hMSCs) and to test whether overexpression of any of these miRNAs is sufficient to induce differentiation of the hMSCs into hepatocyte-like cells. Before hepatic differentiation, hMSCs were infected with a lentivirus containing a miRNA inhibitor sequence. We found that downregulation of any one of the six hepatic differentiation-specific miRNAs can inhibit HGF-induced hepatic differentiation including albumin expression and LDL uptake. Although overexpression of any one of the six miRNAs alone or liver-enriched miR-122 cannot initiate hepatic differentiation, ectopic overexpression of seven miRNAs (miR-1246, miR-1290, miR-148a, miR-30a, miR-424, miR-542-5p and miR-122) together can stimulate hMSC conversion into functionally mature induced hepatocytes (iHep). Additionally, after transplantation of the iHep cells into mice with CCL4-induced liver injury, we found that iHep not only can improve liver function but it also can restore injured livers. The findings from this study indicate that miRNAs have the capability of directly converting hMSCs to a hepatocyte phenotype in vitro.
doi:10.1038/cddis.2013.429
PMCID: PMC3847311  PMID: 24232094
miRNA; mesenchymal stem cells; hepatic differentiation; hepatocytes
23.  The HECTD3 E3 ubiquitin ligase facilitates cancer cell survival by promoting K63-linked polyubiquitination of caspase-8 
Li, Y | Kong, Y | Zhou, Z | Chen, H | Wang, Z | Hsieh, Y-C | Zhao, D | Zhi, X | Huang, J | Zhang, J | Li, H | Chen, C
Cell Death & Disease  2013;4(11):e935-.
Apoptosis resistance is a hurdle for cancer treatment. HECTD3, a new E3 ubiquitin ligase, interacts with caspase-8 death effector domains and ubiquitinates caspase-8 with K63-linked polyubiquitin chains that do not target caspase-8 for degradation but decrease the caspase-8 activation. HECTD3 depletion can sensitize cancer cells to extrinsic apoptotic stimuli. In addition, HECTD3 inhibits TNF-related apoptosis-inducing ligand (TRAIL)-induced caspase-8 cleavage in an E3 ligase activity-dependent manner. Mutation of the caspase-8 ubiquitination site at K215 abolishes the HECTD3 protection from TRAIL-induced cleavage. Finally, HECTD3 is frequently overexpressed in breast carcinomas. These findings suggest that caspase-8 ubiquitination by HECTD3 confers cancer cell survival.
doi:10.1038/cddis.2013.464
PMCID: PMC3847339  PMID: 24287696
ubiquitination; apoptosis; breast cancer; HECTD3; caspase-8
24.  Effect of tanshinone IIA on cardiomyocyte hypertrophy and apoptosis in spontaneously hypertensive rats 
In the present study, the effects of tanshinone IIA (TSN) on the prevention of left ventricular hypertrophy (LVH) and apoptotic processes were observed in spontaneously hypertensive rats (SHRs). A total of 18 SHRs (age, 8 weeks) were randomly divided into three groups. The SHRs in the control group (group S8) were sacrificed at week 8 of the experiment. The SHRs in the treatment group (group D18) and the placebo group (group S18) were injected with TSN and distilled water (1 ml/kg body weight/day), respectively, for 10 weeks, commencing at week 8, and were subsequently sacrificed at week 18. The systolic blood pressure (SBP) and left ventricular mass index (LVMI) were determined. Using hematoxylin and eosin and van Gieson staining, together with immunohistological methods, cardiomyocyte size and diameter, collagen volume fraction (CVF) and perivascular circumferential area (PVCA) were measured. Evaluation of Bcl-2, Bax and p53 expression levels for apoptosis analysis was performed using western blotting. It was observed that the SBP, LVMI, cardiomyocyte size and diameter, CVF, PCVA and cardiomyocyte apoptosis index (Bax and p53 expression) were increased significantly in group S18 compared with group S8. However, Bcl-2 expression levels were decreased in group S18 compared with group S8. The administration of TSN in group D18 resulted in higher Bcl-2 expression levels and significantly decreased LVMI, cardiomyocyte size and diameter, CVF, PCVA, Bax and p53 expression levels compared with group S18. LVH and apoptosis of the cardiac tissues increased with the increasing age of the SHRs. TSN may inhibit the development of LVH and decrease the level of apoptosis in SHRs, possibly via the upregulation of Bcl-2 and the downregulation of Bax and p53 expression.
doi:10.3892/etm.2013.1339
PMCID: PMC3829736  PMID: 24255684
left ventricular hypertrophy; apoptosis; tanshinone IIA; p53; Bcl-2; Bax
25.  Effects of voice on emotional arousal 
Music is a powerful medium capable of eliciting a broad range of emotions. Although the relationship between language and music is well documented, relatively little is known about the effects of lyrics and the voice on the emotional processing of music and on listeners' preferences. In the present study, we investigated the effects of vocals in music on participants' perceived valence and arousal in songs. Participants (N = 50) made valence and arousal ratings for familiar songs that were presented with and without the voice. We observed robust effects of vocal content on perceived arousal. Furthermore, we found that the effect of the voice on enhancing arousal ratings is independent of familiarity of the song and differs across genders and age: females were more influenced by vocals than males; furthermore these gender effects were enhanced among older adults. Results highlight the effects of gender and aging in emotion perception and are discussed in terms of the social roles of music.
doi:10.3389/fpsyg.2013.00675
PMCID: PMC3787249  PMID: 24101908
emotion; music; arousal; perception; gender; aging

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