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author:("Zhang, laying")
1.  Effects of Dietary Coconut Oil as a Medium-chain Fatty Acid Source on Performance, Carcass Composition and Serum Lipids in Male Broilers 
This study was conducted to investigate the effects of dietary coconut oil as a medium-chain fatty acid (MCFA) source on performance, carcass composition and serum lipids in male broilers. A total of 540, one-day-old, male Arbor Acres broilers were randomly allotted to 1 of 5 treatments with each treatment being applied to 6 replicates of 18 chicks. The basal diet (i.e., R0) was based on corn and soybean meal and was supplemented with 1.5% soybean oil during the starter phase (d 0 to 21) and 3.0% soybean oil during the grower phase (d 22 to 42). Four experimental diets were formulated by replacing 25%, 50%, 75%, or 100% of the soybean oil with coconut oil (i.e., R25, R50, R75, and R100). Soybean oil and coconut oil were used as sources of long-chain fatty acid and MCFA, respectively. The feeding trial showed that dietary coconut oil had no effect on weight gain, feed intake or feed conversion. On d 42, serum levels of total cholesterol, low-density lipoprotein cholesterol, and low-density lipoprotein/high-density lipoprotein cholesterol were linearly decreased as the coconut oil level increased (p<0.01). Lipoprotein lipase, hepatic lipase, and total lipase activities were linearly increased as the coconut oil level increased (p<0.01). Abdominal fat weight/eviscerated weight (p = 0.05), intermuscular fat width (p<0.01) and subcutaneous fat thickness (p<0.01) showed a significant quadratic relationship, with the lowest value at R75. These results indicated that replacement of 75% of the soybean oil in diets with coconut oil is the optimum level to reduce fat deposition and favorably affect lipid profiles without impairing performance in broilers.
PMCID: PMC4283167  PMID: 25557818
Broiler; Medium-chain Fatty Acid; Growth Performance; Carcass Composition; Serum Lipid
2.  Association between Lipid Ratios and Insulin Resistance in a Chinese Population 
PLoS ONE  2015;10(1):e0116110.
To explore the association of lipid ratios and triglyceride (TG) with insulin resistance (IR) in a Chinese population. We also provide the clinical utility of lipid ratios to identify men and women with IR.
This cross-sectional study included 614 men and 1055 women without diabetes. Insulin resistance was defined by homeostatic model assessment of IR > 2.69. Lipid ratios included the TG/ high density lipoprotein cholesterol (HDL-C), the total cholesterol (TC)/HDL-C and the low density lipoprotein cholesterol (LDL-C)/HDL –C. Logistic regression models and accurate estimates of the area under the receiver operating characteristic (AUROC) curves were obtained.
In normal-weight men, none of lipid ratios nor TG was associated with IR. In overweight/obese men, normal-weight women and overweight/obese women, the TG/HDL-C, the TC/HDL-C and TG were significantly associated with IR, and the associations were independent of waist circumference. All of the AUROCs for the TG/HDL-C and TG were > 0.7. The AUROCs for TC/HDL-C ratio were 0.69–0.77. The optimal cut-offs for TG/HDL-C were 1.51 in men and 0.84 in women. The optimal cut-offs for TG were 1.78 mmol/L in men and 1.49 mmol/L in women, respectively. In men, the optimal cut-off for LDL-C/HDL-C is 3.80. In women, the optimal cut-off for LDL-C/HDL-C is 3.82.
The TG/HDL-C, the TC/HDL-C and TG are associated with IR in overweight/obese men, normal-weight and overweight/obese women. The LDL-C/HDL-C is only associated with IR in normal-weight women. The TG/HDL-C and TG might be used as surrogate markers for assessing IR.
PMCID: PMC4312024  PMID: 25635876
3.  Effects of Wharton’s jelly-derived mesenchymal stem cells on neonatal neutrophils 
Mesenchymal stem cells (MSCs) have been proposed as autologous therapy for inflammatory diseases in neonates. MSCs from umbilical cord Wharton’s jelly (WJ-MSCs) are accessible, with high proliferative capacity. The effects of WJ-MSCs on neutrophil activity in neonates are not known. We compared the effects of WJ-MSCs on apoptosis and the expression of inflammatory, oxidant, and antioxidant mediators in adult and neonatal neutrophils.
WJ-MSCs were isolated, and their purity and function were confirmed by flow cytometry. Neutrophils were isolated from cord and adult blood by density centrifugation. The effects of neutrophil/WJ-MSC co-culture on apoptosis and gene and protein expression were measured.
WJ-MSCs suppressed neutrophil apoptosis in a dose-dependent manner. WJ-MSCs decreased gene expression of NADPH oxidase-1 in both adult and neonatal neutrophils, but decreased heme oxygenase-1 and vascular endothelial growth factor and increased catalase and cyclooxygenase-2 in the presence of lipopolysaccharide only in adult cells. Similarly, generation of interleukin-8 was suppressed in adult but not neonatal neutrophils. Thus, WJ-MSCs dampened oxidative, vascular, and inflammatory activity by adult neutrophils, but neonatal neutrophils were less responsive. Conversely, Toll-like receptor-4, and cyclooxygenase-2 were upregulated in WJ-MSCs only in the presence of adult neutrophils, suggesting an inflammatory MSC phenotype that is not induced by neonatal neutrophils.
Whereas WJ-MSCs altered gene expression in adult neutrophils in ways suggesting anti-inflammatory and antioxidant effects, these responses were attenuated in neonatal cells. In contrast, inflammatory gene expression in WJ-MSCs was increased in the presence of adult but not neonatal neutrophils. These effects should be considered in clinical trial design before WJ-MSC-based therapy is used in infants.
PMCID: PMC4317142
inflammation; umbilical cord; apoptosis; neutrophil; mesenchymal stem cells
4.  Decreased functional expression of Grp78 and Grp94 inhibits proliferation and attenuates apoptosis in a human gastric cancer cell line in vitro 
Oncology Letters  2014;9(3):1181-1186.
The aim of the present study was to determine the effect of downregulating the expression of glucose-regulated protein 78 (Grp78) and Grp94 upon the rate of proliferation and apoptosis in the human gastric cancer SGC-7901 cell line. The SGC-7901 cells were divided into three groups as follows: i) An experimental group co-transfected with the small interfering RNA vectors, psiSTRIKE™/Grp78 and psiSTRIKE/Grp94; ii) a negative control group, in which only Lipofectamine 2000™ was used to transfect the cells; and iii) a blank control group, in which cells were left untouched and not transfected with any agent. The transcriptional expression of Grp78 and Grp94 was assayed by reverse transcription polymerase chain reaction, and the protein expression of Grp78 and Grp94 was determined using an immunofluorescence assay at 24, 48 and 72 h post-transfection. The rates of cellular proliferation and apoptosis were assayed using MTT and flow cytometry analyses, respectively. The mRNA and protein expression of Grp78 and Grp94 in the gastric cancer cells was downregulated at 72 h post-transfection. In addition, the results of the MTT assay revealed that the proliferation rate of the gastric cancer cells in the co-transfected group was significantly inhibited at 72 h post-transfection compared with the control groups (P<0.05). The apoptosis ratio was significantly increased in the experimental group compared with the control groups (P<0.05). The co-transfection of the SGC-7901 cells with psiSTRIKE/Grp78 and psiSTRIKE/Grp94 markedly reduced the expression of Grp78 and Grp94, respectively. Furthermore, the reduction in the expression of Grp78 and Grp94 inhibited cellular proliferation and significantly downregulated the rate of apoptosis in the SGC-7901 cells in vitro.
PMCID: PMC4315086  PMID: 25663878
Grp78; Grp94; RNA interference; cell proliferation; apoptosis
5.  RNA-Seq Reveals Leaf Cuticular Wax-Related Genes in Welsh Onion 
PLoS ONE  2014;9(11):e113290.
The waxy cuticle plays a very important role in plant resistance to various biotic and abiotic stresses and is an important characteristic of Welsh onions. Two different types of biangan Welsh onions (BG) were selected for this study: BG, a wild-type covered by wax, which forms a continuous lipid membrane on its epidermal cells, and GLBG, a glossy mutant of BG whose epidermal cells are not covered by wax. To elucidate the waxy cuticle-related gene expression changes, we used RNA-Seq to compare these two Welsh onion varieties with distinct differences in cuticular wax. The de novo assembly yielded 42,881 putative unigenes, 25.41% of which are longer than 1,000 bp. Among the high-quality unique sequences, 22,289 (52.0%) had at least one significant match to an existing gene model. A total of 798 genes, representing 1.86% of the total putative unigenes, were differentially expressed between these two Welsh onion varieties. The expression patterns of four important unigenes that are related to waxy cuticle biosynthesis were confirmed by RT-qPCR and COG class annotation, which demonstrated that these genes play an important role in defense mechanisms and lipid transport and metabolism. To our knowledge, this study is the first exploration of the Welsh onion waxy cuticle. These results may help to reveal the molecular mechanisms underlying the waxy cuticle and will be useful for waxy gene cloning, genetics and breeding as well as phylogenetic and evolutionary studies of the Welsh onion.
PMCID: PMC4240658  PMID: 25415343
6.  Effects of dietary Selenomethionine supplementation on growth performance, antioxidant status, plasma selenium concentration, and immune function in weaning pigs 
This study was designed to evaluate the efficacy of DL-selenomethionine (DL-SeMet) supplementation on growth performance, antioxidant status, plasma selenium (Se) concentration, and immune function of weaning pigs. 216 weaning pigs were randomly allocated to 6 treatments with 6 replicates each according to a complete randomized block design. Each replicate had six pigs. Diet of group one was corn-soybean basal diet without any additional Se supplement. Group 2 was supplemented with 0.3 mg/kg of Se from sodium selenite. Groups 3-6 were supplemented with 0.1, 0.3, 0.5, and 0.7 mg/kg of Se from DL-SeMet, respectively. The trial lasted for 42 days.
Pigs supplemented with 0.3 and 0.7 mg/kg DL-SeMet obtained better feed gain ratio (P < 0.05). The best antioxidant ability (serum, liver, and muscle) was shown in 0.1-0.3 mg/kg DL-SeMet groups (P < 0.05). The plasma Se concentration increased as the dietary DL-SeMet level elevated. The immunity among groups was not affected.
DL-SeMet supplementation in the diet significantly improved the growth performance, antioxidant ability and plasma Se content of weaning pigs. DL-SeMet can replace sodium selenite in the diet of weaning pigs.
PMCID: PMC4198736  PMID: 25324971
Antioxidant status; Growth performance; Plasma selenium concentration; Selenomethionine; Weaning pigs
Identification of Endocrine Disrupting Chemicals is one of the important goals of environmental chemical hazard screening. We report on the development of validated in silico predictors of chemicals likely to cause Estrogen Receptor (ER)-mediated endocrine disruption to facilitate their prioritization for future screening. A database of relative binding affinity of a large number of ERα and/or ERβ ligands was assembled (546 for ERα and 137 for ERβ). Both single-task learning (STL) and multi-task learning (MTL) continuous Quantitative Structure-Activity Relationships (QSAR) models were developed for predicting ligand binding affinity to ERα or ERβ. High predictive accuracy was achieved for ERα binding affinity (MTL R2=0.71, STL R2=0.73). For ERβ binding affinity, MTL models were significantly more predictive (R2=0.53, p<0.05) than STL models. In addition, docking studies were performed on a set of ER agonists/antagonists (67 agonists and 39 antagonists for ERα, 48 agonists and 32 antagonists for ERβ, supplemented by putative decoys/non-binders) using the following ER structures (in complexes with respective ligands) retrieved from the Protein Data Bank: ERα agonist (PDB ID: 1L2I), ERα antagonist (PDB ID: 3DT3), ERβ agonist (PDB ID: 2NV7), ERβ antagonist (PDB ID: 1L2J). We found that all four ER conformations discriminated their corresponding ligands from presumed non-binders. Finally, both QSAR models and ER structures were employed in parallel to virtually screen several large libraries of environmental chemicals to derive a ligand- and structure-based prioritized list of putative estrogenic compounds to be used for in vitro and in vivo experimental validation.
PMCID: PMC3775906  PMID: 23707773
Endocrine Disrupting Chemicals; Estrogen Receptor; Quantitative Structure-Activity Relationships modeling; Multi-Task Learning; Docking; Virtual Screening
8.  Acquisition of a Quantitative, Stoichiometrically Conserved Ratiometric Marker of Maturation Status in Stem Cell-Derived Cardiac Myocytes 
Stem Cell Reports  2014;3(4):594-605.
There is no consensus in the stem cell field as to what constitutes the mature cardiac myocyte. Thus, helping formalize a molecular signature for cardiac myocyte maturation would advance the field. In the mammalian heart, inactivation of the “fetal” TNNI gene, TNNI1 (ssTnI), together in temporal concert with its stoichiometric replacement by the adult TNNI gene product, TNNI3 (cTnI), represents a quantifiable ratiometric maturation signature. We examined the TNNI isoform transition in human induced pluripotent stem cell (iPSC) cardiac myocytes (hiPSC-CMs) and found the fetal TNNI signature, even during long-term culture. Rodent stem cell-derived and primary myocytes, however, transitioned to the adult TnI profile. Acute genetic engineering of hiPSC-CMs enabled a rapid conversion toward the mature TnI profile. While there is no single marker to denote the mature cardiac myocyte, we propose that tracking the cTnI:ssTnI protein isoform ratio provides a valuable maturation signature to quantify myocyte maturation status across laboratories.
Graphical Abstract
•The TNNI gene switch is a quantitative maturation signal for hiPSC-CMs•TnI isoform ratio is necessary, but not sufficient, to establish the mature state•TNNI protein isoform switching is stalled in hiPSC-CMs•Gene transfer enables acquisition of the mature TNNI signature in hiPSC-CMs
In this article, Metzger and colleagues show that the stoichiometrically conserved TNNI isoform developmental profile in human iPSC cardiac myocytes (hiPSC-CMs) is fetal-like, even during long-term culture. This work shows evidence that tracking the cTnI:ssTnI protein isoform ratio can provide a maturation signature to quantify cardiac myocyte maturation, enabling useful comparisons across laboratories.
PMCID: PMC4223713  PMID: 25358788
9.  Detection and characterization of Wolbachia infection in silkworm 
Genetics and Molecular Biology  2014;37(3):573-580.
Wolbachia naturally infects a wide variety of arthropods, where it plays important roles in host reproduction. It was previously reported that Wolbachia did not infect silkworm. By means of PCR and sequencing we found in this study that Wolbachia is indeed present in silkworm. Phylogenetic analysis indicates that Wolbachia infection in silkworm may have occurred via transfer from parasitic wasps. Furthermore, Southern blotting results suggest a lateral transfer of the wsp gene into the genomes of some wild silkworms. By antibiotic treatments, we found that tetracycline and ciprofloxacin can eliminate Wolbachia in the silkworm and Wolbachia is important to ovary development of silkworm. These results provide clues towards a more comprehensive understanding of the interaction between Wolbachia and silkworm and possibly other lepidopteran insects.
PMCID: PMC4171764  PMID: 25249781
Wolbachia; silkworm; wsp; antibiotics
10.  Disclosure of parental HIV infection to children and psychosocial impact on children in China: a qualitative study 
This qualitative study aims to investigate parental HIV disclosure and psychological impact from the perspectives of their children. In-depth individual interviews with 47 children who had lost one or both parents to AIDS were conducted in China. All transcripts were coded using the software ATLAS.ti 5. Results showed that few of children knew of parental HIV status before the death of their parents. The main disclosers were the children’s current caregivers. Some children knew about their parent’s HIV infection based on their own observations or through overheard conversation, or their interactions with villagers. Both positive and negative psychological outcomes related to parental HIV disclosure were reported. Psychological counseling is needed for both parents and children to dealing with the parental HIV infection.
PMCID: PMC3992264  PMID: 24761258
Parental HIV disclosure; Psychosocial impact; Orphan; China
11.  Serum Lipid Profiles, Lipid Ratios and Chronic Kidney Disease in a Chinese Population 
Aim: To examine the association of serum lipids, lipid ratios with Chronic Kidney Disease (CKD) in a Chinese population. Methods: Data were drawn from a cross-sectional survey in China. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 or albuminuria-to-creatinine ratio (ACR) > 30 mg/g. Multivariable logistic regressions and multivariate regression models were used. Serum lipids and lipid ratios included total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), TG/HDL-C ratio, TC/HDL-C ratio and LDL-C/HDL-C ratio. Results: In men, only logarithm-transformed (log) TG was associated with CKD. The odds ratio (every SD increment) was 1.39 (95% CI 1.03–1.87, P = 0.03). In women, none of the serum lipids and lipid ratios was associated with CKD. Using multivariate regression models, it was shown that log TG and log TG/HDL-C were negatively correlated with eGFR (P < 0.05) in men and LDL-C and log LDL-C/HDL-C ratio were correlated with ACR in men. In female subjects, serum TC, log TG, log TG/HDL-C and log TC/HDL-C were negatively correlated with eGFR (P < 0.05). All of serum lipid profiles and lipid related ratio were not correlated with ACR in women. Conclusion: Serum TG is the only suitable predictor for CKD in men. However, in women, none of serum lipids and lipid ratio can be used as a predictor for CKD. Log TG and log TG/HDL-C are negatively correlated with eGFR in both genders.
PMCID: PMC4143822  PMID: 25075881
serum lipids; lipid ratios; chronic kidney disease
12.  Expression of Androgen Receptor and its Phosphorylated Forms in Breast Cancer Progression 
Cancer  2013;119(14):10.1002/cncr.28092.
Androgen receptor (AR) expression in breast cancers may serve as a prognostic and predictive marker. We examined the expression pattern of AR and its phosphorylated forms, Ser-213 (AR-Ser(P)-213) and Ser-650 (AR-Ser(P)-650), in breast cancer and evaluated their association with clinicopathological parameters.
Immunohistochemistry was performed on primary and distant metastatic breast cancers and benign breast tissue using antibodies against AR, AR-Ser(P)-213, and AR-Ser(P)-650. The levels of cytoplasmic and nuclear expression were scored semiquantitatively using a histoscore.
Nuclear staining of AR was observed in all benign breast tissue and 67% of cancer cases. Nuclear and cytoplasmic AR-Ser(P)-213 was increased in breast cancers 2-fold (p=0.0014 ) and 1.7-fold ( p= 0.05), respectively, compared to benign controls, whereas nuclear and cytoplasmic AR-Ser(P)-650 expression was decreased in tumors by 1.9-fold and 1.7-fold (both p<0.0001), respectively. Increased expression of nuclear or cytoplasmic AR-Ser(P)-213 was observed in metastatic breast cancers (1.3-fold, p=0.05), ER-negative (2.6-fold, p=0.001) and invasive ductal carcinoma (6.8-fold, p=0.04). AR-Ser(P)-650 expression is downregulated in lymph node-positive (1.4-fold, p=0.02) breast cancers, but is upregulated in invasive ductal carcinomas (3.2-fold, p<0.0001) and metastases (1.5-fold, p=0.003). Moreover, in ER-negative breast cancers nuclear AR-Ser(P)-650 was decreased (1.4-fold, p=0.005) and cytoplasmic ARSer(P)-650 was increased (1.4-fold, p=0.003).
AR and its phosphorylation at serines 213 and 650 are differentially expressed in breast cancer tumorigenesis and progression. Phosphorylation of AR at serines 213 and 650 is increased in ER-negative, ductal carcinomas, and metastases and may have predictive value in breast cancer prognosis.
PMCID: PMC3874891  PMID: 23605249
breast; breast neoplasms; androgen; androgen receptor; phosphorylation
13.  Domestic chores workload and depressive symptoms among children affected by HIV/AIDS in China 
AIDS care  2012;25(5):632-639.
Limited data are available regarding the effects of domestic chores workload on psychological problems among children affected by HIV/AIDS in China. The current study aims to examine association between children’s depressive symptoms and the domestic chores workload (i.e., the frequency and the amount of time doing domestic chores). Data were derived from the baseline survey of a longitudinal study which investigated the impact of parental HIV/AIDS on psychological problems of children. A total of 1,449 children in family-based care were included in the analysis: 579 orphaned children who lost one or both parents due to AIDS, 466 vulnerable children living with one or both parents being infected with HIV, and 404 comparison children who did not have HIV/AIDS infected family members in their families. Results showed differences on domestic chores workload between children affected by HIV/AIDS (orphans and vulnerable children) and the comparison children. Children affected by HIV/AIDS worked more frequently and worked longer time on domestic chores than the comparison children. Multivariate linear regression analysis showed that domestic chores workload was positively associated with depressive symptoms. The data suggest that children affected by HIV/AIDS may face increasing burden of domestic chores and it is necessary to reduce the excessive workload of domestic chores among children affected by HIV/AIDS through increasing community-based social support for children in the families affected by HIV/AIDS.
PMCID: PMC3622201  PMID: 22970996
Domestic chores workload; Depressive symptoms; Orphan; HIV/AIDS; China
14.  Functional Consequences of Human Induced Pluripotent Stem Cell Therapy 
Circulation  2013;127(9):997-1008.
The use of cells derived from human induced pluripotent stem cells as cellular therapy for myocardial injury has yet to be examined in a large-animal model.
Methods and Results
Immunosuppressed Yorkshire pigs were assigned to 1 of 3 groups: A myocardial infarction group (MI group; distal left anterior descending coronary artery ligation and reperfusion; n=13); a cell-treatment group (MI with 4×106 vascular cells derived from human induced pluripotent stem cells administered via a fibrin patch; n=14); and a normal group (n=15). At 4 weeks, left ventricular structural and functional abnormalities were less pronounced in hearts in the cell-treated group than in MI hearts (P<0.05), and these improvements were accompanied by declines in scar size (10.4±1.6% versus 8.3±1.1%, MI versus cell-treatment group, P<0.05). The cell-treated group displayed a significant increase in vascular density and blood flow (0.83±0.11 and 1.05±0.13 mL·min−1·g−1, MI versus cell-treatment group, P<0.05) in the periscar border zone (BZ), which was accompanied by improvements in systolic thickening fractions (infarct zone, −10±7% versus 5±5%; BZ, 7±4% versus 23±6%; P<0.05). Transplantation of vascular cells derived from human induced pluripotent stem cells stimulated c-kit+ cell recruitment to BZ and the rate of bromodeoxyuridine incorporation in both c-kit+ cells and cardiomyocytes (P<0.05). Using a magnetic resonance spectroscopic saturation transfer technique, we found that the rate of ATP hydrolysis in BZ of MI hearts was severely reduced, and the severity of this reduction was linearly related to the severity of the elevations of wall stresses (r=0.82, P<0.05). This decline in BZ ATP utilization was markedly attenuated in the cell-treatment group.
Transplantation of vascular cells derived from human induced pluripotent stem cells mobilized endogenous progenitor cells into the BZ, attenuated regional wall stress, stimulated neovascularization, and improved BZ perfusion, which in turn resulted in marked increases in BZ contractile function and ATP turnover rate.
PMCID: PMC3980462  PMID: 23371930
heart; adenosine triphosphate; stem cells; myocardium; hypertrophy
15.  DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers 
Osorio, Ana | Milne, Roger L. | Kuchenbaecker, Karoline | Vaclová, Tereza | Pita, Guillermo | Alonso, Rosario | Peterlongo, Paolo | Blanco, Ignacio | de la Hoya, Miguel | Duran, Mercedes | Díez, Orland | Ramón y Cajal, Teresa | Konstantopoulou, Irene | Martínez-Bouzas, Cristina | Andrés Conejero, Raquel | Soucy, Penny | McGuffog, Lesley | Barrowdale, Daniel | Lee, Andrew | SWE-BRCA,  | Arver, Brita | Rantala, Johanna | Loman, Niklas | Ehrencrona, Hans | Olopade, Olufunmilayo I. | Beattie, Mary S. | Domchek, Susan M. | Nathanson, Katherine | Rebbeck, Timothy R. | Arun, Banu K. | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | John, Esther M. | Whittemore, Alice S. | Daly, Mary B. | Southey, Melissa | Hopper, John | Terry, Mary B. | Buys, Saundra S. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elizabeth J. | Steele, Linda | Neuhausen, Susan L. | Ding, Yuan Chun | Hansen, Thomas v. O. | Jønson, Lars | Ejlertsen, Bent | Gerdes, Anne-Marie | Infante, Mar | Herráez, Belén | Moreno, Leticia Thais | Weitzel, Jeffrey N. | Herzog, Josef | Weeman, Kisa | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Scuvera, Giulietta | Bonanni, Bernardo | Mariette, Frederique | Volorio, Sara | Viel, Alessandra | Varesco, Liliana | Papi, Laura | Ottini, Laura | Tibiletti, Maria Grazia | Radice, Paolo | Yannoukakos, Drakoulis | Garber, Judy | Ellis, Steve | Frost, Debra | Platte, Radka | Fineberg, Elena | Evans, Gareth | Lalloo, Fiona | Izatt, Louise | Eeles, Ros | Adlard, Julian | Davidson, Rosemarie | Cole, Trevor | Eccles, Diana | Cook, Jackie | Hodgson, Shirley | Brewer, Carole | Tischkowitz, Marc | Douglas, Fiona | Porteous, Mary | Side, Lucy | Walker, Lisa | Morrison, Patrick | Donaldson, Alan | Kennedy, John | Foo, Claire | Godwin, Andrew K. | Schmutzler, Rita Katharina | Wappenschmidt, Barbara | Rhiem, Kerstin | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Plendl, Hans Jörg | Niederacher, Dieter | Sutter, Christian | Wang-Gohrke, Shan | Steinemann, Doris | Preisler-Adams, Sabine | Kast, Karin | Varon-Mateeva, Raymonda | Gehrig, Andrea | Stoppa-Lyonnet, Dominique | Sinilnikova, Olga M. | Mazoyer, Sylvie | Damiola, Francesca | Poppe, Bruce | Claes, Kathleen | Piedmonte, Marion | Tucker, Kathy | Backes, Floor | Rodríguez, Gustavo | Brewster, Wendy | Wakeley, Katie | Rutherford, Thomas | Caldés, Trinidad | Nevanlinna, Heli | Aittomäki, Kristiina | Rookus, Matti A. | van Os, Theo A. M. | van der Kolk, Lizet | de Lange, J. L. | Meijers-Heijboer, Hanne E. J. | van der Hout, A. H. | van Asperen, Christi J. | Gómez Garcia, Encarna B. | Hoogerbrugge, Nicoline | Collée, J. Margriet | van Deurzen, Carolien H. M. | van der Luijt, Rob B. | Devilee, Peter | HEBON,  | Olah, Edith | Lázaro, Conxi | Teulé, Alex | Menéndez, Mireia | Jakubowska, Anna | Cybulski, Cezary | Gronwald, Jacek | Lubinski, Jan | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Johannsson, Oskar Th. | Maugard, Christine | Montagna, Marco | Tognazzo, Silvia | Teixeira, Manuel R. | Healey, Sue | Investigators, kConFab | Olswold, Curtis | Guidugli, Lucia | Lindor, Noralane | Slager, Susan | Szabo, Csilla I. | Vijai, Joseph | Robson, Mark | Kauff, Noah | Zhang, Liying | Rau-Murthy, Rohini | Fink-Retter, Anneliese | Singer, Christian F. | Rappaport, Christine | Geschwantler Kaulich, Daphne | Pfeiler, Georg | Tea, Muy-Kheng | Berger, Andreas | Phelan, Catherine M. | Greene, Mark H. | Mai, Phuong L. | Lejbkowicz, Flavio | Andrulis, Irene | Mulligan, Anna Marie | Glendon, Gord | Toland, Amanda Ewart | Bojesen, Anders | Pedersen, Inge Sokilde | Sunde, Lone | Thomassen, Mads | Kruse, Torben A. | Jensen, Uffe Birk | Friedman, Eitan | Laitman, Yael | Shimon, Shani Paluch | Simard, Jacques | Easton, Douglas F. | Offit, Kenneth | Couch, Fergus J. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Benitez, Javier
PLoS Genetics  2014;10(4):e1004256.
Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03–1.16), p = 2.7×10−3) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03–1.21, p = 4.8×10−3). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
Author Summary
Women harboring a germ-line mutation in the BRCA1 or BRCA2 genes have a high lifetime risk to develop breast and/or ovarian cancer. However, not all carriers develop cancer and high variability exists regarding age of onset of the disease and type of tumor. One of the causes of this variability lies in other genetic factors that modulate the phenotype, the so-called modifier genes. Identification of these genes might have important implications for risk assessment and decision making regarding prevention of the disease. Given that BRCA1 and BRCA2 participate in the repair of DNA double strand breaks, here we have investigated whether variations, Single Nucleotide Polymorphisms (SNPs), in genes participating in other DNA repair pathway may be associated with cancer risk in BRCA carriers. We have selected the Base Excision Repair pathway because BRCA defective cells are extremely sensitive to the inhibition of one of its components, PARP1. Thanks to a large international collaborative effort, we have been able to identify at least two SNPs that are associated with increased cancer risk in BRCA1 and BRCA2 mutation carriers respectively. These findings could have implications not only for risk assessment, but also for treatment of BRCA1/2 mutation carriers with PARP inhibitors.
PMCID: PMC3974638  PMID: 24698998
16.  Primary Burkitt’s lymphoma of the thyroid without Epstein-Barr virus infection: A case report and literature review 
Oncology Letters  2014;7(5):1519-1524.
Primary thyroid lymphomas are rare, and the majority are B-cell lymphoma. Primary Burkitt’s lymphoma (BL) of the thyroid is much less common than the other types of lymphoma. The current study presents the case of an eight-year-old male with a mass in the right lobe of the thyroid, which was detected by B-ultrasound. The patient was diagnosed with BL by immunohistochemistry, fluorescence in situ hybridization analysis of MYC (8q24) and immunoglobulin rearrangement assays. Furthermore, subsequent positron emission tomography-computed tomography scans revealed no abnormal metabolites in the left lobe of the thyroid or in other parts of the body following surgery. The patient underwent alternate R-B-NHL-BFM-90-A and R-B-NHL-BFM-90-B treatment for four cycles each following the thyroidectomy. The patient is well and remains free of disease recurrence following almost four years follow-up. The present study discusses this rare case of primary BL of the thyroid and presents a review of the literature. This case report provides evidence that the immediate diagnosis and treatment of primary Burkitt’s lymphoma of the thyroid is likely to improve patient outcome.
PMCID: PMC3997736  PMID: 24765169
Epstein-Barr virus; fluorescence in situ hybridization; immunoglobulin rearrangement assay; Burkitt’s lymphoma; thyroid
17.  The Discovery of Novel Antimalarial Compounds Enabled by QSAR-based Virtual Screening 
Quantitative structure–activity relationship (QSAR) models have been developed for a dataset of 3133 compounds defined as either active or inactive against P. falciparum. Since the dataset was strongly biased towards inactive compounds, different sampling approaches were employed to balance the ratio of actives vs. inactives, and models were rigorously validated using both internal and external validation approaches. The balanced accuracy for assessing the antimalarial activities of 70 external compounds was between 87% and 100% depending on the approach used to balance the dataset. Virtual screening of the ChemBridge database using QSAR models identified 176 putative antimalarial compounds that were submitted for experimental validation, along with 42 putative inactives as negative controls. Twenty five (14.2%) computational hits were found to have antimalarial activities with minimal cytotoxicity to mammalian cells, while all 42 putative inactives were confirmed experimentally. Structural inspection of confirmed active hits revealed novel chemical scaffolds, which could be employed as starting points to discover novel antimalarial agents.
PMCID: PMC3644566  PMID: 23252936
Antimalarial activity; quantitative structure–activity relationships; virtual screening; experimental confirmation
18.  Secondary mutation in a coding mononucleotide tract in MSH6 causes loss of immunoexpression of MSH6 in colorectal carcinomas with MLH1/PMS2 deficiency 
Immunohistochemical staining for DNA mismatch repair proteins may be affected by various biological and technical factors. Staining variations that could potentially lead to erroneous interpretations have been recognized. A recently recognized staining variation is the significant reduction of staining for MSH6 in some colorectal carcinomas. The frequency and specific characteristics of this aberrant MSH6 staining pattern, however, have not been well analyzed. In this study of 420 colorectal carcinoma samples obtained from patients fulfilling the Revised Bethesda Guidelines, we detected 9 tumors (2%) showing extremely limited staining for MSH6 with positive staining present in <5% of the tumor cells. Our analyses showed that these tumors belonged to two distinct categories: (1) MLH1 and/or PMS2 protein-deficient carcinomas (n=5, including 1 with a pathogenic mutation in PMS2); and (2) MLH1, PMS2 and MSH2 normal but with chemotherapy or chemoradiation therapy before surgery (n=4). To test our hypothesis that somatic mutation in the coding region microsatellite of the MSH6 gene might be a potential underlying mechanism for such limited MSH6 staining, we evaluated frameshift mutation in a (C)8 tract in exon 5 of the MSH6 gene in seven tumors that had sufficient DNA for analysis, and detected mutation in four; all four tumors belonged to the MLH1/PMS2-deficient group. In conclusion, our data outline the main scenarios where significant reduction of MSH6 staining is more likely to occur in colorectal carcinoma, and suggest that somatic mutations of the coding region microsatellites of the MSH6 gene is an underlying mechanism for this staining phenomenon in MLH1/PMS2-deficient carcinomas.
PMCID: PMC3793326  PMID: 22918162
DNA mismatch repair; hereditary non-polyposis colorectal carcinoma; immunohistochemistry; Lynch syndrome; microsatellite instability
19.  CCR2-dependent Recruitment of Macrophages by Tumor Educated Mesenchymal Stromal Cells Promotes Tumor Development and is Mimicked by TNF-alpha 
Cell stem cell  2012;11(6):812-824.
Mesenchymal stromal cells (MSCs) tend to infiltrate into tumors and form a major component of the tumor microenvironment. These tumor-resident MSCs are known to affect tumor growth, but the mechanisms are largely unknown. We found that MSCs isolated from spontaneous lymphomas in mouse (L-MSCs) strikingly enhanced tumor growth in comparison to bone marrow MSCs (BM-MSCs). L-MSCs contributed to greater recruitment of CD11b+Ly6C+ monocytes, F4/80+ macrophages, and CD11b+Ly6G+ neutrophils to the tumor. Depletion of monocytes/macrophages, but not neutrophils, completely abolished tumor promotion of L-MSCs. Furthermore, L-MSCs expressed high levels of CCR2 ligands, and monocyte/macrophage accumulation and L-MSC-mediated tumor promotion were largely abolished in CCR2−/− mice. Intriguingly, TNFα-pretreated BM-MSCs mimicked L-MSCs in their chemokine production profile and ability to promote tumorigenesis of lymphoma, melanoma, and breast carcinoma. Therefore, our findings demonstrate that, in an inflammatory environment, tumor-resident MSCs promote tumor growth by recruiting monocytes/macrophages.
PMCID: PMC3518598  PMID: 23168163
Tumor growth; mesenchymal stem/stromal cells; chemokines; monocytes/macrophages; myeloid derived suppressor cells; immune modulation
20.  Resveratrol Attenuates Diabetic Nephropathy via Modulating Angiogenesis 
PLoS ONE  2013;8(12):e82336.
Angiogenesis plays an important role in the pathogenesis of diabetic nephropathy (DN). In the present study, we investigated the therapeutic potential of resveratrol, a polyphenol with antiangiogenic activity in DN. In a type 1 diabetic rat model, resveratrol treatment blunted the increases of urine albumin excretion, kidney weight and creatinine clearance rate. The increases of glomerular diameter, mesangium accumulation, glomerular basement membrane thickness and renal fibrosis in diabetic rats were also reduced by resveratrol treatment. In the diabetic kidney, increased expression of vascular endothelial growth factor (VEGF), Flk-1 and angiopoietin 2, and reduced expression of Tie-2 were observed. These changes in angiogenic hormones and associated receptors were attenuated by resveratrol treatment. No changes in angiopoietin 1 expression were detected among each group of rats. Resveratrol also significantly downregulated high glucose-induced VEGF and Flk-1 expressions in cultured mouse glomerular podocytes and endothelial cells, respectively. These effects were attenuated by knocking-down silent information regulator 1 (Sirt1) expression. In contrast, upregulation of Sirt1 in cultured endothelial cells reduced Flk-1 expression. Increased permeability and cellular junction disruption of cultured endothelial cells caused by VEGF were also inhibited by resveratrol pretreatment. Taken together, the present study demonstrated that resveratrol may attenuate DN via modulating angiogenesis.
PMCID: PMC3849393  PMID: 24312656
21.  New Insights into the Genomic Organization and Splicing of the Doublesex Gene, a Terminal Regulator of Sexual Differentiation in the Silkworm Bombyx mori 
PLoS ONE  2013;8(11):e79703.
Sex-determination mechanisms differ among organisms. The primary mechanism is diverse, whereas the terminal regulator is relatively-conserved. We analyzed the transcripts of the Bombyx mori doublesex gene (Bmdsx), and reported novel results concerning the genomic organization and expression of Bmdsx. Bmdsx consists of nine exons and eight introns, of which two exons are novel and have not been reported previously. Bmdsx transcripts are spliced to generate seventeen alternatively-spliced forms and eleven putative trans-spliced variants. Thirteen of the alternatively-spliced forms and five of the putative trans-spliced forms are reported here for the first time. Sequence analysis predicts that ten female-specific, six male-specific splice forms and one splice form found in males and females will result in four female-specific, two male-specific Dsx proteins and one Dsx protein common to males and females. The Dsx proteins are expected to be functional and regulate downstream target genes. Some of the predicted Dsx proteins are described here for the first time. Therefore the expression of the dsx gene in B. mori results in a variety of cis- and trans-spliced transcripts and multiple Dsx proteins. These findings show that in B. mori there is a complicated pattern of dsx splicing, and that the regulation of splicing and sex-specific functions of lepidopteran dsx have evolved complexity.
PMCID: PMC3820697  PMID: 24244545
22.  Utility of 5-alpha-reductase inhibitors in active surveillance for favourable risk prostate cancer 
This retrospective review compares prostate-specific antigen (PSA) doubling time (DT) prior to the initiation of a 5-alpha-reductase inhibitor (pre-5-ARI) to after the PSA nadir (post-nadir) has been reached for patients on active surveillance for favourable-risk prostate cancer.
Between 1996 and 2010, a total of 100 men with a history of 5-ARI use were captured from our active surveillance database. Twenty-nine patients had a sufficient number of PSA values to determine both pre-5-ARI and post-nadir DTs. PSADT was calculated using the general linear mixed-model method.
The median follow-up was 69.5 months. The median pre-5-ARI PSADT was 55.8 (range: 6–556.8) months, while the post-nadir value was 25.2 (range: 6–231) months (p = 0.0081). Six patients were reclassified after an average of 67.7 (range: 59–95) months, due to progression in PSADT (n = 2) or Gleason score (n = 4). The median pre-5-ARI and post-nadir DTs for this group were 42.3 (range: 32.4–91.1) and 21.1 (range: 6–44.3) months, respectively.
5-ARIs significantly decreased PSADT compared to prior to their initiation. This effect may be due to preferential suppression of benign tissue following PSA nadir. The resulting PSADT would then represent a more accurate depiction of the true cancer-related DT. If validated with a larger cohort, 5-ARIs may enhance the utility of PSADT as a biomarker of disease progression in active surveillance.
PMCID: PMC3876449  PMID: 24381668
23.  A Recessive Founder Mutation in Regulator of Telomere Elongation Helicase 1, RTEL1, Underlies Severe Immunodeficiency and Features of Hoyeraal Hreidarsson Syndrome 
PLoS Genetics  2013;9(8):e1003695.
Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure and cancer predisposition syndrome in which germline mutations in telomere biology genes account for approximately one-half of known families. Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of DC in which patients also have cerebellar hypoplasia and may present with severe immunodeficiency and enteropathy. We discovered a germline autosomal recessive mutation in RTEL1, a helicase with critical telomeric functions, in two unrelated families of Ashkenazi Jewish (AJ) ancestry. The affected individuals in these families are homozygous for the same mutation, R1264H, which affects three isoforms of RTEL1. Each parent was a heterozygous carrier of one mutant allele. Patient-derived cell lines revealed evidence of telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C. The molecular data and the patterns of inheritance are consistent with a hypomorphic mutation in RTEL1 as the underlying basis of the clinical and cellular phenotypes. This study further implicates RTEL1 in the etiology of DC/HH and immunodeficiency, and identifies the first known homozygous autosomal recessive disease-associated mutation in RTEL1.
Author Summary
Patients with dyskeratosis congenita (DC), a rare inherited disease, are at very high risk of developing cancer and bone marrow failure. The clinical features of DC include nail abnormalities, skin discoloration, and white spots in the mouth. Patients with Hoyeraal-Hreidarsson syndrome (HH) have symptoms of DC plus cerebellar hypoplasia, immunodeficiency, and poor prenatal growth. DC and HH are caused by defects in telomere biology; improperly maintained telomeres are thought to be a major contributor to carcinogenesis. In half the cases of DC, the causative mutation is unknown. By studying families affected by DC for whom a causative mutation has not yet been identified, we have discovered a homozygous germline mutation in RTEL1, a telomere maintenance gene that, if mutated, can result in HH. The mutations result in the inability of the RTEL1 protein to function properly at the telomere, and underscore its important role in telomere biology.
PMCID: PMC3757051  PMID: 24009516
24.  Brain Response to Primary Blast Wave Using Validated Finite Element Models of Human Head and Advanced Combat Helmet 
Blast-induced traumatic brain injury has emerged as a “signature injury” in combat casualty care. Present combat helmets are designed primarily to protect against ballistic and blunt impacts, but the current issue with helmets is protection concerning blasts. In order to delineate the blast wave attenuating capability of the Advanced Combat Helmet (ACH), a finite element (FE) study was undertaken to evaluate the head response against blast loadings with and without helmet using a partially validated FE model of the human head and ACH. Four levels of overpressures (0.27–0.66 MPa) from the Bowen’s lung iso-damage threshold curves were used to simulate blast insults. Effectiveness of the helmet with respect to head orientation was also investigated. The resulting biomechanical responses of the brain to blast threats were compared for human head with and without the helmet. For all Bowen’s cases, the peak intracranial pressures (ICP) in the head ranged from 0.68 to 1.8 MPa in the coup cortical region. ACH was found to mitigate ICP in the head by 10–35%. Helmeted head resulted in 30% lower average peak brain strains and product of strain and strain rate. Among three blast loading directions with ACH, highest reduction in peak ICP (44%) was due to backward blasts whereas the lowest reduction in peak ICP and brain strains was due to forward blast (27%). The biomechanical responses of a human head to primary blast insult exhibited directional sensitivity owing to the different geometry contours and coverage of the helmet construction and asymmetric anatomy of the head. Thus, direction-specific tolerances are needed in helmet design in order to offer omni-directional protection for the human head. The blasts of varying peak overpressures and durations that are believed to produce the same level of lung injury produce different levels of mechanical responses in the brain, and hence “iso-damage” curves for brain injury are likely different than the Bowen curves for lung injury.
PMCID: PMC3731672  PMID: 23935591
traumatic brain injury; primary blast; finite element model; advanced combat helmet model; human head model; intracranial pressure; brain strain and strain rate; head protection
25.  Improved wait time intervals for prostate cancer patients in a multidisciplinary rapid diagnostic unit compared to a community-based referral pattern 
Wait times in cancer diagnosis and treatment may significantly affect a patient’s treatment outcome, prognosis and quality of life. The purpose of this study was to capture wait time intervals for patients with prostate cancer treated with radiotherapy (RT) at the Odette Cancer Centre, Toronto, Ontario, Canada and to compare patients diagnosed in a rapid diagnostic unit (RDU) versus the usual community referral process.
Patients agreed to participate in the study during their RT planning sessions. A semi-structured interview and chart abstraction was conducted to record key wait time milestones.
A total of 87 patients participated in the study: 44 RDU patients and 43 community patients. The median overall wait time intervals from suspicion of prostate cancer to RT was 138 and 183 days, respectively (p = 0.046). There were statistically significant differences observed for other key wait time intervals favouring the RDU cohort: suspicion to decision-to-treat (DTT; p = 0.012), urologist visit to diagnosis (p = 0.0094), diagnosis to DTT (p = 0.018), and diagnosis to treatment (p = 0.016). Risk category and Gleason sum was independently predictive of longer intervals from diagnosis to DTT.
Wait time intervals from suspicion to treatment are significantly shorter for prostate cancer patients in 2011 to 2012 than in 2003 when patients were diagnosed and referred in the community setting. A prostate-specific RDU further reduced a number of key wait time intervals supporting more multidisciplinary RDUs for common diseases. Further work needs to be done to identify why delays are occurring and to develop new processes to minimize delays.
PMCID: PMC3758939  PMID: 24032058

Results 1-25 (60)