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1.  The interplay of host genetic factors and Epstein-Barr virus in the development of nasopharyngeal carcinoma 
Chinese Journal of Cancer  2014;33(11):556-568.
The interplay between host cell genetics and Epstein-Barr virus (EBV) infection contributes to the development of nasopharyngeal carcinoma (NPC). Understanding the host genetic and epigenetic alterations and the influence of EBV on cell signaling and host gene regulation will aid in understanding the molecular pathogenesis of NPC and provide useful biomarkers and targets for diagnosis and therapy. In this review, we provide an update of the oncogenes and tumor suppressor genes associated with NPC, as well as genes associated with NPC risk including those involved in carcinogen detoxification and DNA repair. We also describe the importance of host genetics that govern the human leukocyte antigen (HLA) complex and immune responses, and we describe the impact of EBV infection on host cell signaling changes and epigenetic regulation of gene expression. High-power genomic sequencing approaches are needed to elucidate the genetic basis for inherited susceptibility to NPC and to identify the genes and pathways driving its molecular pathogenesis.
PMCID: PMC4244319  PMID: 25367335
NPC genetics; Epstein-Barr virus; human leukocyte antigen; cell signaling; inflammation
2.  Fabrication of uniform 4H-SiC mesopores by pulsed electrochemical etching 
Nanoscale Research Letters  2014;9(1):570.
In this letter, the uniform 4H silicon carbide (SiC) mesopores was fabricated by pulsed electrochemical etching method. The length of the mesopores is about 19 μm with a diameter of about 19 nm. The introduction of pause time (Toff) is crucial to form the uniform 4H-SiC mesopores. The pore diameter will not change if etching goes with Toff. The hole concentration decreasing at the pore tips during the Toff is the main reason for uniformity.
PMCID: PMC4198072  PMID: 25324708
Constant pulsed current; Uniform mesopores; Cycle time; Pause time
3.  Inhibition of γ-secretase induces G2/M arrest and triggers apoptosis in renal cell carcinoma 
Oncology Letters  2014;8(1):55-61.
The present study was performed to explore the effects of Notch pathway inhibition on the proliferation and apoptosis of renal carcinoma cells. The expression levels of Notch1 and Jagged1 were examined by western blot analysis and immunohistochemistry in pathologically identified clear cell renal cell carcinoma (RCC) and normal kidney tissues. Next, γ-secretase inhibitor was used to suppress the Notch pathway in renal carcinoma cell lines. The proliferation was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry analysis was performed to determine the apoptosis, as well as cell cycle alteration. The expression of Notch1 and Jagged1 proteins was detected to be higher in tumor tissues than in non-neoplastic tissues by western blot analysis. The positive staining rates of Notch1 and Jagged1 in clear cell RCC were higher than in normal kidney tissues [95.3 vs. 36.4% (P<0. 05); 93.0 vs. 42.4% (P<0.05), respectively]. The expression levels of Notch1 and Jagged1 were found to statistically correlate with tumor size, grade, TNM stage and disease relapse. The suppression of the Notch pathway was associated with cell proliferation inhibition, as well as induced G2/M phase cell cycle arrest and cell apoptosis. The Notch pathway may be important in oncogenesis of clear cell RCC and the γ-secretase inhibitor may be a potential agent for target therapy of RCC.
PMCID: PMC4063651  PMID: 24959218
Notch; γ-secretase; apoptosis; cell cycle arrest
4.  Physiological β-catenin signaling controls self-renewal networks and generation of stem-like cells from nasopharyngeal carcinoma 
BMC Cell Biology  2013;14:44.
A few reports suggested that low levels of Wnt signaling might drive cell reprogramming, but these studies could not establish a clear relationship between Wnt signaling and self-renewal networks. There are ongoing debates as to whether and how the Wnt/β-catenin signaling is involved in the control of pluripotency gene networks. Additionally, whether physiological β-catenin signaling generates stem-like cells through interactions with other pathways is as yet unclear. The nasopharyngeal carcinoma HONE1 cells have low expression of β-catenin and wild-type expression of p53, which provided a possibility to study regulatory mechanism of stemness networks induced by physiological levels of Wnt signaling in these cells.
Introduction of increased β-catenin signaling, haploid expression of β-catenin under control by its natural regulators in transferred chromosome 3, resulted in activation of Wnt/β-catenin networks and dedifferentiation in HONE1 hybrid cell lines, but not in esophageal carcinoma SLMT1 hybrid cells that had high levels of endogenous β-catenin expression. HONE1 hybrid cells displayed stem cell-like properties, including enhancement of CD24+ and CD44+ populations and generation of spheres that were not observed in parental HONE1 cells. Signaling cascades were detected in HONE1 hybrid cells, including activation of p53- and RB1-mediated tumor suppressor pathways, up-regulation of Nanog-, Oct4-, Sox2-, and Klf4-mediated pluripotency networks, and altered E-cadherin expression in both in vitro and in vivo assays. qPCR array analyses further revealed interactions of physiological Wnt/β-catenin signaling with other pathways such as epithelial-mesenchymal transition, TGF-β, Activin, BMPR, FGFR2, and LIFR- and IL6ST-mediated cell self-renewal networks. Using β-catenin shRNA inhibitory assays, a dominant role for β-catenin in these cellular network activities was observed. The expression of cell surface markers such as CD9, CD24, CD44, CD90, and CD133 in generated spheres was progressively up-regulated compared to HONE1 hybrid cells. Thirty-four up-regulated components of the Wnt pathway were identified in these spheres.
Wnt/β-catenin signaling regulates self-renewal networks and plays a central role in the control of pluripotency genes, tumor suppressive pathways and expression of cancer stem cell markers. This current study provides a novel platform to investigate the interaction of physiological Wnt/β-catenin signaling with stemness transition networks.
PMCID: PMC3819748  PMID: 24073846
Physiological Wnt/β-catenin signaling; Nasopharyngeal carcinoma; Self-renewal network; Chromosome 3 transfer; Stemness transition; Tumor suppressor genes; Cancer stem cell markers
5.  Susceptibility of XPD and hOGG1 genetic variants to prostate cancer 
Biomedical Reports  2013;1(4):679-683.
DNA repair genes are important in maintaining genomic stability and integrity. DNA repair gene polymorphisms, such as those of the human homolog of 8-oxoguanine DNA glycosylase 1 (hOGG1) and excision repair cross-complementing rodent repair deficiency, complementation group 2/Xeroderma pigmentosum complementation group D (ERCC2/XPD), contribute to carcinogenesis. The aim of this study was to investigate the association of prostate cancer (PCa) risk with hOGG1 and ERCC2/XPD genetic variants. A case-control study of 200 cases including 100 PCa patients and 100 healthy subjects was conducted. Two single-nucleotide polymorphisms (SNPs) (ERCC2/XPD Arg156Arg and hOGG1 Ser326Cys) were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results demonstrated a significant association of the XPD156 homozygous (AA, OR=3.80; 95% CI: 1.19–12.18; P=0.017), heterozygous (AC, OR=2.48; 95% CI: 1.02–6.35; P=0.033) and combined (AA+AC, OR=2.76; 95% CI: 1.18–6.84; P=0.011) mutant genotypes with a predisposition to high-risk PCa. In the stratified analysis, predisposition to high-risk PCa was also associated with the mutant genotypes of hOGG1 326 homozygous mutant (GG, OR=2.93; 95% CI: 1–8.74; P=0.033). The results also showed that the A allele of XPD Arg156Arg and the G allele of hOGG1 Ser326Cys were associated with an increased risk of PCa (OR=1.86 and 1.62; 95% CI: 1.13–3.06 and 1–2.67, respectively). In conclusion, the findings of this study demonstrated that the ERCC2/XPD Arg156Arg and hOGG1 Ser326Cys polymorphisms increased the susceptibility to high-risk PCa.
PMCID: PMC3917053  PMID: 24649009
prostate cancer; single-nucleotide polymorphism; excision repair cross-complementing rodent repair deficiency; complementation group 2/Xeroderma pigmentosum complementation group D; human homolog of the 8-oxoguanine DNA glycosylase 1
6.  The Effects of Periconceptional Risk Factor Exposure and Micronutrient Supplementation on Birth Defects in Shaanxi Province in Western China 
PLoS ONE  2012;7(12):e53429.
1) To understand the current prevalence and main types of birth defects, 2) assess the periconceptional exposure of factors associated with birth defects in Shaanxi Province, and 3) provide scientific evidence for local governments to formulate services for the primary prevention of birth defects.
We sampled 16,541 households from 128 townships in 16 counties/districts in Shaanxi province using a multi-stage random sampling method. Among them, 10,544 women who had live born or stillborn infants with gestational age ≥28 weeks between 2008 and 2009 were interviewed using a structured questionnaire designed to collect information about periconceptional risk factor exposure, health care service utilization, and micronutrient supplements. Logistic regression was performed to assess the risk factors associated with birth defects and adjustments were made for imbalanced social-demographic characteristics between case and control groups.
The prevalence of congenital birth defect in Shaanxi province was 14.3/1000 births. The environment risk factors associated with birth defects include unhealthy lifestyle (Alcohol, odds ratio (OR): 3.60, 95% confidence interval (CI) 1.64−7.91; Smoking, OR: 1.32, 95% CI: 0.99−1.75; Drink strong tea, OR: 1.81, 95% CI: 1.27−2.59), exposure to heavy pollution (OR: 1.53, 95% CI: 1.01−2.30), maternal diseases (OR: 1.77, 95% CI: 1.35−2.33), drug use (OR: 2.11, 95% CI: 1.51−2.95), maternal chemical pesticide exposure (OR: 2.30, 95% CI: 1.16−4.57), and adverse pregnancy history (OR: 10.10, 95% CI: 7.55−13.53). Periconceptional folic acid or multiple micronutrients including folic acid supplementation, was associated with a reduced rate of birth defects (OR: 0.54, 95% CI: 0.29−0.998).
Health care service utilization, unhealthy lifestyle factors, and environment risk factors seem to be associated with birth defects in Shaanxi province. Governmental agencies should focus on effective primary preventative methods, such as the delivery of periconceptional health education for minimizing potential risk factor exposures, periconceptional folic acid or micronutrient supplementation, environment monitoring, and assessment of factories with high levels of pollution.
PMCID: PMC3534073  PMID: 23300928
7.  Involvement of reactive oxygen species in 2-methoxyestradiol-induced apoptosis in human neuroblastoma cells 
Cancer letters  2011;313(2):201-210.
Neuroblastoma is the most common extra-cranial solid tumor in children. Despite advances in the treatment of childhood cancer, outcomes for children with advanced-stage neuroblastoma remain poor. Here we reported that 2-methoxyestradiol (2-ME) inhibited the proliferation and induced apoptosis in human neuroblastoma SK-N-SH and SH-SY5Y cells. 2-ME treatment also resulted in the generation of ROS and the loss of mitochondrial membrane potential in SK-N-SH and SH-SY5Y, indicating that 2-ME-induced apoptosis is mediated by ROS. This is supported by the results that have shown that co-treatment with antioxidants, VC, L-GSH and MitoQ10, decreased 2-ME-induced generation of ROS and the loss of the mitochondrial membrane potential, increased the Bcl-2/Bax ratio, decreased 2-ME-induced activation of caspase-9 and caspase-3 and the up-regulation of apoptosis-inducing factor (AIF), and prevented 2-ME-induced apoptosis in SK-N-SH and SH-SY5Y cells. These results suggested that oxidative stress plays an important role in 2-ME-induced apoptotic death of human neuroblastoma cells.
PMCID: PMC3224534  PMID: 21978530
2-Methoxyestradiol; Neuroblastoma; Reactive oxygen species; Apoptosis
8.  Skin lesion classification using relative color features 
Clinically, it is difficult to differentiate the early stage of malignant melanoma and certain benign skin lesions due to similarity in appearance. Our research uses image analysis of clinical skin images and relative color-based pattern recognition techniques to enhance the images and improve differentiation of these lesions.
First, the relative color images were created from digitized photographic images. Then, they were segmented into objects and morphologically filtered. Next, the relative color features were extracted from the objects to form two different feature spaces; a lesion feature space and an object feature space. The two feature spaces serve as two data models to be analyzed to determine the best features. Finally, we used a statistical analysis model of relative color features, which better classifies the various types of skin lesions.
The best features found for differentiation of melanoma and benign skin lesions from this study are area, mean in the red and blue bands, standard deviation in the red and green bands, skewness in the green band, and entropy in the red band. With the relative color feature algorithm developed, the best results were obtained with a multi-layer perceptron neural network model. This showed an overall classification success of 79%, with 70% of the benign lesions successfully classified, and 86% of malignant melanoma successfully classified.
PMCID: PMC3184884  PMID: 18211602
skin lesion; melanoma; relative color features; image classification; pattern recognition; CVIPtools
9.  Extracellular protease ADAMTS9 suppresses esophageal and nasopharyngeal carcinoma tumor formation by inhibiting angiogenesis 
Cancer research  2010;70(13):5567-5576.
ADAMTS metalloprotease family member ADAMTS9 maps to 3p14.2 and shows significant associations with the aerodigestive tract cancers esophageal squamous cell carcinoma (ESCC) and nasopharyngeal carcinoma (NPC). However, the functional impact of ADAMTS9 on cancer development has not been explored. In this study, we evaluated hypothesized anti-angiogenic and tumor suppressive functions of ADAMTS9 in ESCC and NPC, in stringent tumorigenicity and matrigel plug angiogenesis assays. ADAMTS9 activation suppressed tumor formation in nude mice. Conversely, knockdown of ADAMTS9 resulted in clones reverting to the tumorigenic phenotype of the parental cells. In vivo angiogenesis assays revealed a reduction in microvessel numbers in gel plugs injected with tumor-suppressive cell transfectants. Similarly, conditioned media from cell transfectants dramatically reduced the tube-forming capacity of human umbilical vein endothelial cells (HUVECs). These activities were associated with a reduction in expression levels of the pro-angiogenic factors MMP9 and VEGFA, which were consistently reduced in ADAMTS9 transfectants derived from both cancers. Taken together, our results indicate that ADAMTS9 contributes an important function in the tumor microenvironment that acts to inhibit angiogenesis and tumor growth in both ESCC and NPC.
PMCID: PMC2896444  PMID: 20551050
ADAMTS9; tumor suppression; angiogenesis; esophageal carcinoma; nasopharyngeal carcinoma
10.  Efficient repair of DNA double-strand breaks in malignant cells with structural instability 
Mutation research  2010;683(1-2):115-122.
Aberrant repair of DNA double strand breaks (DSBs) is thought to be important in the generation of gross chromosomal rearrangements (GCRs). To examine how DNA DSBs might lead to GCRs, we investigated the repair of a single DNA DSB in a structurally unstable cell line. An I-SceI recognition site was introduced into OVCAR-8 cells between a constitutive promoter (EF1α) and the Herpes simplex virus thymidine kinase (TK) gene, which confers sensitivity to gancyclovir (GCV). Expression of I-SceI in these cells caused a single DSB. Clones with aberrant repair could acquire resistance to GCV by separation of the EF1α promoter from the TK gene, or deletion of either the EF1α promoter or the TK gene. All mutations that we identified were interstitial deletions. Treatment of cells with etoposide or bleomycin, agents known to produce DNA DSBs following expression of I-SceI also did not generate GCRs. Because we identified solely interstitial deletions using the aforementioned negative selection system, we developed a positive selection system to produce GCR. A construct containing an I-SceI restriction site immediately followed by a hygromycin phosphotransferase cDNA, with no promoter, was stably integrated into OVCAR-8 cells. DNA DSBs were produced by an I-SceI expression vector. None of the hygromycin resistant clones recovered had linked the hygromycin phosphotransferase cDNA to an endogenous promoter, but had instead captured a portion of the I-SceI expression vector. These results indicate that even in a structurally unstable malignant cell line, the majority of DNA DSBs are repaired by religation of the two broken chromosome ends, without the introduction of a GCR.
PMCID: PMC2797445  PMID: 19909760
DNA double strand break (DSB); chromosomal rearrangement; I-SceI; ovarian cancer
11.  Validity of self-reported weight, height and resultant body mass index in Chinese adolescents and factors associated with errors in self-reports 
BMC Public Health  2010;10:190.
Validity of self-reported height and weight has not been adequately evaluated in diverse adolescent populations. In fact there are no reported validity studies conducted in Asian children and adolescents. This study aims to examine the accuracy of self-reported weight, height, and resultant BMI values in Chinese adolescents, and of the adolescents' subsequent classification into overweight categories.
Weight and height were self-reported and measured in 1761 adolescents aged 12-16 years in a cross-sectional survey in Xi'an city, China. BMI was calculated from both reported values and measured values. Bland-Altman plots with 95% limits of agreement, Pearson's correlation and Kappa statistics were calculated to assess the agreement.
The 95% limits of agreement were -11.16 and 6.46 kg for weight, -4.73 and 7.45 cm for height, and -4.93 and 2.47 kg/m2 for BMI. Pearson correlation between measured and self-reported values was 0.912 for weight, 0.935 for height and 0.809 for BMI. Weighted Kappa was 0.859 for weight, 0.906 for height and 0.754 for BMI. Sensitivity for detecting overweight (includes obese) in adolescents was 56.1%, and specificity was 98.6%. Subjects' area of residence, age and BMI were significant factors associated with the errors in self-reporting weight, height and relative BMI.
Reported weight and height does not have an acceptable agreement with measured data. Therefore, we do not recommend the application of self-reported weight and height to screen for overweight adolescents in China. Alternatively, self-reported data could be considered for use, with caution, in surveillance systems and epidemiology studies.
PMCID: PMC2864211  PMID: 20384994
12.  Randomized Trial of Piperaquine with Sulfadoxine-Pyrimethamine or Dihydroartemisinin for Malaria Intermittent Preventive Treatment in Children 
PLoS ONE  2009;4(9):e7164.
The long terminal half life of piperaquine makes it suitable for intermittent preventive treatment for malaria but no studies of its use for prevention have been done in Africa. We did a cluster randomized trial to determine whether piperaquine in combination with either dihydroartemisin (DHA) or sulfadoxine-pyrimethamine (SP) is as effective, and better tolerated, than SP plus amodiaquine (AQ), when used for intermittent preventive treatment in children delivered by community health workers in a rural area of Senegal.
Treatments were delivered to children 3–59 months of age in their homes once per month during the transmission season by community health workers. 33 health workers, each covering about 60 children, were randomized to deliver either SP+AQ, DHA+PQ or SP+PQ. Primary endpoints were the incidence of attacks of clinical malaria, and the incidence of adverse events.
1893 children were enrolled. Coverage of monthly rounds and compliance with daily doses was similar in all groups; 90% of children received at least 2 monthly doses. Piperaquine combinations were better tolerated than SP+AQ with a significantly lower risk of common, mild adverse events. 103 episodes of clinical malaria were recorded during the course of the trial. 68 children had malaria with parasitaemia >3000/µL, 29/671 (4.3%) in the SP+AQ group, compared with 22/604 (3.6%) in the DHA+PQ group (risk difference 0.47%, 95%CI −2.3%,+3.3%), and 17/618 (2.8%) in the SP+PQ group (risk difference 1.2%, 95%CI −1.3%,+3.6%). Prevalences of parasitaemia and the proportion of children carrying Pfdhfr and Pfdhps mutations associated with resistance to SP were very low in all groups at the end of the transmission season.
Seasonal IPT with SP+PQ in children is highly effective and well tolerated; the combination of two long-acting drugs is likely to impede the emergence of resistant parasites.
Trial Registration NCT00529620
PMCID: PMC2747010  PMID: 19784374
13.  Assessment of dietary intake among pregnant women in a rural area of western China 
BMC Public Health  2009;9:222.
Adequate maternal nutrient intake during pregnancy is important to ensure satisfactory birth outcomes. There are no data available on the usual dietary intake among pregnant women in rural China. The present study describes and evaluates the dietary intake in a cohort of pregnant women living in two counties of rural Shaanxi, western China.
1420 pregnant women were recruited from a trial that examined the effects of micronutrient supplementation on birth outcomes. Dietary information was collected at the end of their trimester or after delivery with an interviewed-administrated semi-quantitative food frequency questionnaire (FFQ). Nutrients intake was calculated from the FFQ and compared to the Estimated Average Requirements (EAR). The EAR cut-offs based on the Chinese Nutrition Society Dietary Reference Intakes (DRIs) were used to assess the prevalence of inadequate dietary intakes of energy, protein, calcium, zinc, riboflavin, vitamin C and folate. Mann-Whitney U and Kruskal Wallis tests were used to compare nutrient intakes across subgroups.
The mean nutrient intakes assessed by the FFQ was similar to those reported in the 2002 Chinese National Nutrition and Health Survey from women living in rural areas except for low intakes of protein, fat, iron and zinc. Of the participants, 54% were at risk of inadequate intake of energy. There were high proportions of pregnant women who did not have adequate intakes of folate (97%) and zinc (91%). Using the "probability approach", 64% of subjects had an inadequate consumption of iron.
These results reveal that the majority of pregnant women in these two counties had low intakes of nutrients that are essential for pregnancy such as iron and folate.
Trial registration
PMCID: PMC2716336  PMID: 19589154
14.  Increased p38-MAPK is responsible for chemotherapy resistance in human gastric cancer cells 
BMC Cancer  2008;8:375.
Chemoresistance is one of the main obstacles to successful cancer therapy and is frequently associated with Multidrug resistance (MDR). Many different mechanisms have been suggested to explain the development of an MDR phenotype in cancer cells. One of the most studied mechanisms is the overexpression of P-glycoprotein (P-gp), which is a product of the MDR1 gene. Tumor cells often acquire the drug-resistance phenotype due to upregulation of the MDR1 gene. Overexpression of MDR1 gene has often been reported in primary gastric adenocarcinoma.
This study investigated the role of p38-MAPK signal pathway in vincristine-resistant SGC7901/VCR cells. P-gp and MDR1 RNA were detected by Western blot analysis and RT-PCR amplification. Mitgen-activated protein kinases and function of P-gp were demonstrated by Western blot and FACS Aria cytometer analysis. Ap-1 activity and cell apoptosis were detected by Dual-Luciferase Reporter Assay and annexin V-PI dual staining.
The vincristine-resistant SGC7901/VCR cells with increased expression of the multidrug-resistance 1 (MDR1) gene were resistant to P-gp-related drug and P-gp-unrelated drugs. Constitutive increases of phosphorylated p38-MAPK and AP-1 activities were also found in the drug-resistant cells. Inhibition of p38-MAPK by SB202190 reduced activator protein-1 (AP-1) activity and MDR1 expression levels and increased the sensitivity of SGC7901/VCR cells to chemotherapy.
Activation of the p38-MAPK pathway might be responsible for the modulation of P-glycoprotein-mediated and P-glycoprotein-unmediated multidrug resistance in the SGC7901/VCR cell line.
PMCID: PMC2628930  PMID: 19091131
15.  Impact of micronutrient supplementation during pregnancy on birth weight, duration of gestation, and perinatal mortality in rural western China: double blind cluster randomised controlled trial 
Objective To examine the impact of antenatal supplementation with multiple micronutrients or iron and folic acid compared with folic acid alone on birth weight, duration of gestation, and maternal haemoglobin concentration in the third trimester.
Design Cluster randomised double blind controlled trial.
Setting Two rural counties in north west China.
Participants 5828 pregnant women and 4697 live births.
Interventions Villages were randomised for all pregnant women to take either daily folic acid (control), iron with folic acid, or multiple micronutrients with a recommended allowance of 15 vitamins and minerals.
Main outcome measures Birth weight, length, and head circumference measured within 72 hours after delivery. Neonatal survival assessed at the six week follow-up visit.
Results Birth weight was 42 g (95% confidence interval 7 to 78 g) higher in the multiple micronutrients group compared with the folic acid group. Duration of gestation was 0.23 weeks (0.10 to 0.36 weeks) longer in the iron-folic acid group and 0.19 weeks (0.06 to 0.32 weeks) longer in the multiple micronutrients group. Iron-folic acid was associated with a significantly reduced risk of early preterm delivery (<34 weeks) (relative risk 0.50, 0.27 to 0.94, P=0.031). There was a significant increase in haemoglobin concentration in both iron-folic acid (5.0 g/l, 2.0 to 8.0 g/l, P=0.001) and multiple micronutrients (6.9 g/l, 4.1 to 9.6 g/l, P<0.001) groups compared with folic acid alone. In post hoc analyses there were no significant differences for perinatal mortality, but iron-folic acid was associated with a significantly reduced early neonatal mortality by 54% (relative risk 0.46, 0.21 to 0.98).
Conclusion In rural populations in China antenatal supplementation with iron-folic acid was associated with longer gestation and a reduction in early neonatal mortality compared with folic acid. Multiple micronutrients were associated with modestly increased birth weight compared with folic acid, but, despite this weight gain, there was no significant reduction in early neonatal mortality. Pregnant women in developing countries need sufficient doses of iron in nutrient supplements to maximise reductions in neonatal mortality.
Trial registration ISRCTN08850194.
PMCID: PMC2577799  PMID: 18996930
16.  Mandatory chromosomal segment balance in aneuploid tumor cells 
BMC Cancer  2007;7:21.
Euploid chromosome balance is vitally important for normal development, but is profoundly changed in many tumors. Is each tumor dependent on its own structurally and numerically changed chromosome complement that has evolved during its development and progression?
We have previously shown that normal chromosome 3 transfer into the KH39 renal cell carcinoma line and into the Hone1 nasopharyngeal carcinoma line inhibited their tumorigenicity. The aim of the present study was to distinguish between a qualitative and a quantitative model of this suppression. According to the former, a damaged or deleted tumor suppressor gene would be restored by the transfer of a normal chromosome. If so, suppression would be released only when the corresponding sequences of the exogenous normal chromosome are lost or inactivated. According to the alternative quantitative model, the tumor cell would not tolerate an increased dosage of the relevant gene or segment. If so, either a normal cell derived, or, a tumor derived endogenous segment could be lost.
Fluorescence in Situ Hybridization based methods, as well as analysis of polymorphic microsatellite markers were used to follow chromosome 3 constitution changes in monochromosomal hybrids.
In both tumor lines with introduced supernumerary chromosomes 3, the copy number of 3p21 or the entire 3p tended to fall back to the original level during both in vitro and in vivo growth. An exogenous, normal cell derived, or an endogenous, tumor derived, chromosome segment was lost with similar probability. Identification of the lost versus retained segments showed that the intolerance for increased copy number was particularly strong for 3p14-p21, and weaker for other 3p regions. Gains in copy number were, on the other hand, well tolerated in the long arm and particularly the 3q26-q27 region.
The inability of the cell to tolerate an experimentally imposed gain in 3p14-p21 in contrast to the well tolerated gain in 3q26-q27 is consistent with the fact that the former is often deleted in human tumors, whereas the latter is frequently amplified. The findings emphasize the importance of even minor changes in copy number in seemingly unbalanced aneuploid tumors.
PMCID: PMC1794251  PMID: 17257397
17.  Probing stereoselective inhibition of the acyl binding site of cholesterol esterase with four diastereomers of 2'-N-α-methylbenzylcarbamyl-1, 1'-bi-2-naphthol 
BMC Biochemistry  2005;6:17.
Recently there has been increased interest in pancreatic cholesterol esterase due to correlation between enzymatic activity in vivo and absorption of dietary cholesterol. Cholesterol esterase plays a role in digestive lipid absorption in the upper intestinal tract, though its role in cholesterol absorption in particular is controversial. Serine lipases, acetylcholinesterase, butyrylcholinesterase, and cholesterol esterase belong to a large family of proteins called the α/β-hydrolase fold, and they share the same catalytic machinery as serine proteases in that they have an active site serine residue which, with a histidine and an aspartic or glutamic acid, forms a catalytic triad. The aim of this work is to study the stereoselectivity of the acyl chain binding site of the enzyme for four diastereomers of an inhibitor.
Four diastereomers of 2'-N-α-methylbenzylcarbamyl-1, 1'-bi-2-naphthol (1) are synthesized from the condensation of R-(+)- or S-(-)-1, 1'-bi-2-naphthanol with R-(+)- or S-(-)-α-methylbenzyl isocyanate in the presence of a catalytic amount of pyridine in CH2Cl2. The [α]25D values for (1R, αR)-1, (1R, αS)-1, (1S, αR)-1, and (1S, αS)-1 are +40, +21, -21, and -41°, respectively. All four diastereomers of inhibitors are characterized as pseudo substrate inhibitors of pancreatic cholesterol esterase. Values of the inhibition constant (Ki), the carbamylation constant (k2), and the bimolecular rate constant (ki) for these four diastereomeric inhibitors are investigated. The inhibitory potencies for these four diastereomers are in the descending order of (1R, αR)-1, (1R, αS)-1, (1S, αR)-1, and (1S, αS)-1. The k2 values for these four diastereomers are about the same. The enzyme stereoselectivity for the 1, 1'-bi-2-naphthyl moiety of the inhibitors (R > S, ca. 10 times) is the same as that for 2'-N-butylcarbamyl-1, 1'-bi-2-naphthol (2). The enzyme stereoselectivity for the α-methylbenzylcarbamyl moiety of the inhibitors is also R > S (2–3 times) due to the constraints in the acyl binding site.
We are the first to report that the acyl chain binding site of cholesterol esterase shows stereoselectivity for the four diastereomers of 1.
PMCID: PMC1262691  PMID: 16176589

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