Genetic variations in CD14 promoter and acute lymphoblastic leukemia susceptibility in a Chinese population

Recent findings suggest that CD14 may play a role in tumor development. Previous case-control studies have revealed that CD14 -260C/T and -651?C/T polymorphisms contribute to the risk of human diseases. However, the relationship between these two functional polymorphisms and susceptibility to acute lymphoblastic leukemia (ALL) has not been explored. In this study, we performed a case-control study in a Chinese population. We found that an increased risk of ALL was associated with the -260?TT (odds ratio [OR]=1.85, 95% confidence interval [CI]=1.26-2.63) genotype compared with the CT or CC genotype. No significant association was found between -651?CC genotype and ALL (OR=1.13, 95% CI=0.77-1.69). Moreover, the increased risk was only associated with the -260?TT genotype in B-ALL (OR=1.99, 95% CI=1.34-3.01) but not in T-ALL (OR=1.48, 95% CI=0.79-2.84). The findings suggest that CD14-260C/T polymorphism can contribute to B-ALL risk in a Chinese population.     

Niclosamide suppresses cancer cell growth by inducing Wnt co-receptor LRP6 degradation and inhibiting the Wnt/β-catenin pathway

The Wnt/β-catenin signaling pathway is important for tumor initiation and progression. The low density lipoprotein receptor-related protein-6 (LRP6) is an essential Wnt co-receptor for Wnt/β-catenin signaling and represents a promising anticancer target. Recently, the antihelminthic drug, niclosamide was found to inhibit Wnt/β-catenin signaling, although the mechanism was not well defined. We found that niclosamide was able to suppress LRP6 expression and phosphorylation, block Wnt3A-induced β-catenin accumulation, and inhibit Wnt/β-catenin signaling in HEK293 cells. Furthermore, the inhibitory effects of niclosamide on LRP6 expression/phosphorylation and Wnt/β-catenin signaling were conformed in human prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. Moreover, we showed that the mechanism by which niclosamide suppressed LRP6 resulted from increased degradation as evident by a shorter half-life. Finally, we demonstrated that niclosamide was able to induce cancer cell apoptosis, and displayed excellent anticancer activity with IC(50) values less than 1 μM for prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. The IC(50) values are comparable to those shown to suppress the activities of Wnt/β-catenin signaling in prostate and breast cancer cells. Our data indicate that niclosamide is a unique small molecule Wnt/β-catenin signaling inhibitor targeting the Wnt co-receptor LRP6 on the cell surface, and that niclosamide has a potential to be developed a novel chemopreventive or therapeutic agent for human prostate and breast cancer.     

Molecular determinants of enterovirus 71 viral entry: cleft around GLN-172 on VP1 protein interacts with variable region on scavenge receptor B 2

Enterovirus 71 (EV71) is one of the major pathogens that cause hand, foot, and mouth disease outbreaks in young children in the Asia-Pacific region in recent years. Human scavenger receptor class B 2 (SCARB2) is the main cellular receptor for EV71 on target cells. The requirements of the EV71-SCARB2 interaction have not been fully characterized, and it has not been determined whether SCARB2 serves as an uncoating receptor for EV71. Here we compared the efficiency of the receptor from different species including human, horseshoe bat, mouse, and hamster and demonstrated that the residues between 144 and 151 are critical for SCARB2 binding to viral capsid protein VP1 of EV71 and seven residues from the human receptor could convert murine SCARB2, an otherwise inefficient receptor, to an efficient receptor for EV71 viral infection. We also identified that EV71 binds to SCARB2 via a canyon of VP1 around residue Gln-172. Soluble SCARB2 could convert the EV71 virions from 160 S to 135 S particles, indicating that SCARB2 is an uncoating receptor of the virus. The uncoating efficiency of SCARB2 significantly increased in an acidic environment (pH 5.6). These studies elucidated the viral capsid and receptor determinants of enterovirus 71 infection and revealed a possible target for antiviral interventions.     

Association between the p73 exon 2 G4C14-to-A4T14 polymorphism and cancer risk: a meta-analysis

The TP53 homolog p73 is structurally and functionally similar to TP53 and plays an important role in modulating cell-cycle control, apoptosis, and cell growth. G4C14-to-A4T14 is the most commonly studied polymorphism of this gene for its association with risk of cancers, but the results are confusing rather than conclusive. We performed a meta-analysis using 21 eligible studies with a total of 7581 patients and 10,413 controls to summarize the data for an association between the p73 G4C14-to-A4T14 polymorphism and cancer risk. Compared with the common GC/GC genotype, the AT carriers (AT/GC, AT/AT) had a 1.18-fold elevated risk of cancer (95% confidence interval [CI]=1.11-1.25, p<0.00001) in a dominant genetic model as estimated in a fixed effect model. The effect of the G4C14-to-A4T14 polymorphism was further evaluated through stratification analysis. In four lung cancer studies, the variant genotypes had a significantly increased risk of lung cancer (odds ratio [OR]=1.16, 95% CI=1.04-1.28, p=0.005). Similar phenomena were also found in two squamous cell carcinoma of the head and neck studies (OR=1.32, 95% CI=1.12-1.56, p=0.0010), two oral cancer studies (OR=1.57, 95% CI=1.26-1.95, p<0.0001), and three colorectal cancer studies (OR=1.23, 95% CI=1.01-1.50, p=0.04). Increased risk of cancer associated with G4C14-to-A4T14 variant genotypes was pronounced in Caucasians (OR=1.21, 95% CI=1.11-1.31, p<0.00001), the Japanese population (OR=1.24, 95% CI=1.01-1.52, p=0.04), and the Korean population (OR=1.27, 95% CI=1.07-1.52, p=0.007). Our meta-analysis suggests that the p73 G4C14-to-A4T14 polymorphism genotypes (GC/AT+AT/AT) may be associated with an increased risk of cancer in most cancer types and ethnicities.     

Cardiac Hypertrophy Involves Both Myocyte Hypertrophy and Hyperplasia in Anemic Zebrafish

Background

An adult zebrafish heart possesses a high capacity of regeneration. However, it has been unclear whether and how myocyte hyperplasia contributes to cardiac remodeling in response to biomechanical stress and whether myocyte hypertrophy exists in the zebrafish. To address these questions, we characterized the zebrafish mutant tr265/tr265, whose Band 3 mutation disrupts erythrocyte formation and results in anemia. Although Band 3 does not express and function in the heart, the chronic anemia imposes a sequential biomechanical stress towards the heart.

Methodology/Principal Findings

Hearts of the tr265/tr265 Danio rerio mutant become larger than those of the sibling by week 4 post fertilization and gradually exhibit characteristics of human cardiomyopathy, such as muscular disarray, re-activated fetal gene expression, and severe arrhythmia. At the cellular level, we found both increased individual cardiomyocyte size and increased myocyte proliferation can be detected in week 4 to week 12 tr265/tr265 fish. Interestingly, all tr265/tr265 fish that survive after week-12 have many more cardiomyocytes of smaller size than those in the sibling, suggesting that myocyte hyperplasia allows the long-term survival of these fish. We also show the cardiac hypertrophy process can be recapitulated in wild-type fish using the anemia-inducing drug phenylhydrazine (PHZ).

Conclusions/Significance

The anemia-induced cardiac hypertrophy models reported here are the first adult zebrafish cardiac hypertrophy models characterized. Unlike mammalian models, both cardiomyocyte hypertrophy and hyperplasia contribute to the cardiac remodeling process in these models, thus allowing the effects of cardiomyocyte hyperplasia on cardiac remodeling to be studied. However, since anemia can induce effects on the heart other than biomechanical, non-anemic zebrafish cardiac hypertrophy models shall be generated and characterized.     

Degradation of the LDL receptor class 2 mutants is mediated by a proteasome-dependent pathway

Familial hypercholesterolemia is a genetic disorder that results from various gene mutations, primarily within the LDL receptor (LDLR). Approximately 50% of the LDLR mutations are defined as class 2 mutations, with the mutant proteins partially or entirely retained in the endoplasmic reticulum. To determine the degradation pathway of the LDLR class 2 mutants, we examined the effects of inhibition of several potential pathways on the levels of the wild-type LDLR and its four representative class 2 mutants (S156L, C176Y, E207K, and C646Y) stably expressed in Chinese hamster ovary (CHO) cells. We found that proteasome inhibitors MG132 and lactacystin blocked the degradation of the LDLR mutants, but not that of the wild-type LDLR. Treatment of CHO cells with these proteasome inhibitors led to a significant accumulation of the mutants at steady state. Furthermore, cell surface levels of the LDLR mutants were significantly increased upon inhibition of the proteasome degradation pathway. In contrast to the proteasome inhibitors, inhibitors of trypsin-like proteases, chymotrypsin-like proteases, and lysosomal pathway inhibitors did not affect the levels of the LDLR mutants. Taken together, these data demonstrate that the proteasome is the principal degradation pathway for LDLR class 2 mutants.     

Determination of genetic relationships among shape Phaseolus vulgaris populations in a conical cross from RAPD marker analyses

Random-amplified polymorphic DNA (RAPD) markers were used to determine genetic relationships among Phaseolus vulgaris breeding populations. Genetic distances were calculated from the distribution of 317 RAPD markers among 8 parents, 10 individuals from 8 cycle-one populations, 10 individuals from 6 cycle-two populations and 10 individuals from 2 cycle-three populations of a conical cross. Genetic distances between populations and parents were consistent with their degree of relationship in the crossing scheme indicating that a RAPD analysis is a sensitive and useful method for categorizing breeding materials according to their genetic similarities. Genetic variation among individuals within populations increased from cycle one to cycle three and variation among populations within the cycles decreased from cycle one to cycle three in the conical cross. The results showed that this crossing scheme can be used to collect the genetic diversity in eight parents into a single plant breeding population. Abbreviations: CBB, common bacterial blight; GD, genetic distance; RAPD, random-amplified polymorphic DNA     

耐砷促生菌对超富集植物蜈蚣草砷吸收及根际微生物群落的调控作用

【目的】分析添加外源促植物生长微生物(plant growth-promoting bacteria,PGPB)对植物生长、砷富集和根际微生物的影响,为植物-微生物联合修复砷污染土壤提供参考。【方法】通过添加外源PGPB,研究蜈蚣草生物量和砷富集量与外源微生物促植物生长特性的关系,采用高通量测序技术分析蜈蚣草根际微生物群落在外源PGPB干预下的变化规律。【结果】2株根际菌(假单胞菌PG12、芽孢杆菌R19)和1株内生菌(恶臭假单胞菌S6)具备典型的促植物生长特性,对蜈蚣草的促生作用顺序为：PG12>S6>R19,与对照组相比,生物量分别提高了234%(P<0.01)、136%(P<0.01)和67%;添加外源PGPB后,蜈蚣草砷含量从对照的18.50 mg提高到了31.25-46.95 mg,增幅高达153%(PG12)和139%(S6),对应的蜈蚣草砷浓度从2616.34mg/kg降至1348.04-2 156.23 mg/kg,呈现出典型的砷“稀释效应”;α多样性指数Sobs、Chao和Ace显示,仅R19处理显著提高了根际微生物的群落多样性,而β多样性指数...