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1.  Higher diet quality reduces risks of neural tube defects and orofacial clefts 
To examine whether better maternal diet quality was associated with reduced risk for selected birth defects.
A multi-center, population-based case-control study, the National Birth Defects Prevention Study.
Ten participating centers in the United States.
Eligible subjects’ estimated due dates were from October, 1997 through December, 2005. Telephone interviews were conducted with 72% of case and 67% of control mothers. Analyses included 936 cases with neural tube defects (NTDs), 2,475 with orofacial clefts, and 6,147 non-malformed controls.
Main exposures
Food-frequency data were used to calculate the Mediterranean Diet Score (MDS) and Diet Quality Index (DQI), modeled after existing indices.
Main outcome measures
Adjusted odds ratios.
After covariate adjustment, increasing diet quality based on either index was associated with reduced risks for the birth defects studied. The strongest association was between anencephaly and DQI; the odds ratio (OR) for highest versus lowest quartile was 0.49 (95% CI 0.31, 0.75). ORs for cleft lip+/−cleft palate and cleft palate and DQI were also notable, with ORs = 0.66 (0.54, 0.81) and 0.74 (0.56, 0.96), respectively.
Healthier maternal dietary patterns, as measured by diet quality scores, were associated with reduced risks of NTDs and clefts. These results suggest that dietary approaches could lead to further reduction in risks of major birth defects and complement existing efforts to fortify foods and encourage periconceptional multivitamin use.
PMCID: PMC3973484  PMID: 21969361
4.  Meat consumption and risk of lung cancer: evidence from observational studies 
Annals of Oncology  2012;23(12):3163-3170.
A number of epidemiological studies have reported inconsistent findings on the association between meat consumption and lung cancer.
We therefore conducted a systematic review and meta-analysis to investigate the relationship between meat consumption and lung cancer risk in epidemiological studies.
Twenty-three case–control and 11 cohort studies were included. All studies adjusted for smoking or conducted in never smokers. The summary relative risks (RRs) of lung cancer for the highest versus lowest intake categories were 1.35 (95% confidence interval (CI) 1.08–1.69) for total meat, 1.34 (95% CI 1.18–1.52) for red meat, and 1.06 (95% CI 0.90–1.25) for processed meat. An inverse association was found between poultry intake and lung cancer (RR = 0.91, 95% CI 0.85–0.97), but not for total white meat (RR = 1.06, 95% CI 0.82–1.37) or fish (RR = 1.01, 95% CI 0.96–1.07).
The relationship between meat intake and lung cancer risk appears to depend on the types of meat consumed. A high intake of red meat may increase the risk of lung cancer by about 35%, while a high intake of poultry decreases the risk by about 10%. More well-designed cohort studies on meat mutagens or heme iron, meat cooking preferences, and doneness level are needed to fully characterize this meat–lung cancer association.
PMCID: PMC3501234  PMID: 22855553
case–control study; cohort study; lung cancer; meat consumption; meta-analysis
5.  Sp1 phosphorylation by cyclin-dependent kinase 1/cyclin B1 represses its DNA-binding activity during mitosis in cancer cells 
Oncogene  2012;31(47):4946-4959.
Sp1 is important for the transcription of many genes. Our previous studies have shown that Sp1 is degraded in normal cell, but it is preserved in cancer cells during mitosis and exists a priori in the daughter cells, ready to engage in gene transcription and thereby contributes to the proliferation and survival of cancer cells. The mechanism by which Sp1 is preserved in cancer cells during mitosis remains unknown. In this study, we observed that Sp1 strongly colocalized with cyclin-dependent kinase 1 (CDK1)/cyclin B1 during mitosis. Moreover, we showed that Sp1 is a novel mitotic substrate of CDK1/cyclin B1 and is phosphorylated by it at Thr 739 before the onset of mitosis. Phospho-Sp1 reduced its DNA-binding ability and facilitated the chromatin condensation process during mitosis. Mutation of Thr739 to alanine resulted in Sp1 remaining in the chromosomes, delayed cell-cycle progression, and eventually led to apoptosis. Screening of Sp1-associated proteins during mitosis by using liquid chromatography/mass spectrometry indicated the tethering of Sp1 to myosin/F-actin. Furthermore, phospho-Sp1 and myosin/F-actin appeared to exist as a congregated ring at the periphery of the chromosome. However, at the end of mitosis and the beginning of interphase, Sp1 was dephosphorylated by PP2A and returned to the chromatin. These results indicate that cancer cells use CDK1 and PP2A to regulate the movement of Sp1 in and out of the chromosomes during cell-cycle progression, which may benefit cancer-cell proliferation.
PMCID: PMC3707305  PMID: 22266860
Sp1; CDK1; PP2A; myosin; mitosis
7.  ER stress-mediated apoptosis induced by celastrol in cancer cells and important role of glycogen synthase kinase-3β in the signal network 
Feng, L | Zhang, D | Fan, C | Ma, C | Yang, W | Meng, Y | Wu, W | Guan, S | Jiang, B | Yang, M | Liu, X | Guo, D
Cell Death & Disease  2013;4(7):e715-.
HeLa cells treated with celastrol, a natural compound with inhibitive effect on proteasome, exhibited increase in apoptotic rate and characteristics of apoptosis. To clarify the signal network activated by celastrol to induce apoptosis, both the direct target proteins and undirect target proteins of celastrol were searched in the present study. Proteasome catalytic subunit β1 was predicted by computational analysis to be a possible direct target of celastrol and confirmed by checking direct effect of celastrol on the activity of recombinant human proteasome subunit β1 in vitro. Undirect target-related proteins of celastrol were searched using proteomic studies including two-dimensional electrophoresis (2-DE) analysis and iTRAQ-based LC-MS analysis. Possible target-related proteins of celastrol such as endoplasmic reticulum protein 29 (ERP29) and mitochondrial import receptor Tom22 (TOM22) were found by 2-DE analysis of total cellular protein expression profiles. Further study showed that celastrol induced ER stress and ER stress inhibitor could ameliorate cell death induced by celastrol. Celastrol induced translocation of Bax into the mitochondria, which might be related to the upregulation of BH-3-only proteins such as BIM and the increase in the expression level of TOM22. To further search possible target-related proteins of celastrol in ER and ER-related fractions, iTRAQ-based LC-MS method was use to analyze protein expression profiles of ER/microsomal vesicles-riched fraction of cells with or without celastrol treatment. Based on possible target-related proteins found in both 2-DE analysis and iTRAQ-based LC-MS analysis, protein–protein interaction (PPI) network was established using bioinformatic analysis. The important role of glycogen synthase kinase-3β (GSK3β) in the signal cascades of celastrol was suggested. Pretreatment of LiCL, an inhibitor of GSK3β, could significantly ameliorate apoptosis induced by celastrol. On the basis of the results of the present study, possible signal network of celastrol activated by celastrol leading to apoptosis was predicted.
PMCID: PMC3730400  PMID: 23846217
celastrol; apoptosis; endothelium reticulum; proteomics; bioinformatics
8.  Superconductivity in Topological Insulator Sb2Te3 Induced by Pressure 
Scientific Reports  2013;3:2016.
Topological superconductivity is one of most fascinating properties of topological quantum matters that was theoretically proposed and can support Majorana Fermions at the edge state. Superconductivity was previously realized in a Cu-intercalated Bi2Se3 topological compound or a Bi2Te3 topological compound at high pressure. Here we report the discovery of superconductivity in the topological compound Sb2Te3 when pressure was applied. The crystal structure analysis results reveal that superconductivity at a low-pressure range occurs at the ambient phase. The Hall coefficient measurements indicate the change of p-type carriers at a low-pressure range within the ambient phase, into n-type at higher pressures, showing intimate relation to superconducting transition temperature. The first principle calculations based on experimental measurements of the crystal lattice show that Sb2Te3 retains its Dirac surface states within the low-pressure ambient phase where superconductivity was observed, which indicates a strong relationship between superconductivity and topology nature.
PMCID: PMC3687246  PMID: 23783511
11.  Dialysis Modality for Patients with Turner Syndrome and Renal Failure 
PMCID: PMC3525405  PMID: 22383732
Turner syndrome; renal failure; dialysis modality
12.  Bmp2 Is Required for Odontoblast Differentiation and Pulp Vasculogenesis 
Journal of Dental Research  2012;91(1):58-64.
Using the Bmp2 floxed/3.6Col1a1-Cre (Bmp2-cKOod) mouse model, we have observed severe defects in odontogenesis and dentin formation with the removal of the Bmp2 gene in early-polarizing odontoblasts. The odontoblasts in the Bmp2-cKOod do not mature properly and fail to form proper dentin with normal dentinal tubules and activate terminal differentiation, as reflected by decreased Osterix, Col1a1, and Dspp expression. There is less dentin, and the dentin is hypomineralized and patchy. We also describe an indirect effect of the Bmp2 gene in odontoblasts on formation of the vascular bed and associated pericytes in the pulp. This vascular niche and numbers of CD146+ pericytes are likely controlled by odontogenic and Bmp2-dependent VegfA production in odontoblasts. The complex roles of Bmp2, postulated to be both direct and indirect, lead to permanent defects in the teeth throughout life, and result in teeth with low quantities of dentin and dentin of poor quality.
PMCID: PMC3232115  PMID: 21984706
bone morphogenetic protein 2; blood vessels; dentinogenesis; dental pulp stem cells; odontogenesis; pericytes
13.  Concordance of DMET Plus genotypes with orthogonal genotyping methods 
One approach to circumvent barriers to clinical implementation of pharmacogenetics is to employ pre-prescription genotyping that requires interrogation of multiple pharmacogenetic variants using a high-throughput platform. We compared the performance of the DMET Plus array (1,931 variants in 225 genes) with orthogonal genotyping methods in 220 pediatric patients. A total of 1,692 variants had call rates above 98% and were in Hardy Weinberg equilibrium. Of these, 259 were genotyped by at least one independent method and a total of 19,942 SNP-patient sample pairs were evaluated. The concordance was 99.9% with only 28 genotype discordances observed. For those genes deemed most likely to be clinically relevant (TPMT, CYP2D6, CYP2C19, CYP2C9, VKORC1, DPYD, UGT1A1, and SLCO1B1), a total of 3,799 SNP-patient sample pairs were evaluable and had a concordance of 99.96%. We conclude that the DMET Plus array performs well with primary patient samples when compared to multiple other lower-throughput genotyping methods.
PMCID: PMC3516299  PMID: 22871999
14.  Oxidative Damage Targets Complexes Containing DNA Methyltransferases, SIRT1 and Polycomb Members to Promoter CpG Islands 
Cancer cell  2011;20(5):606-619.
Cancer cells simultaneously harbor global losses and gains in DNA methylation. We demonstrate that inducing cellular oxidative stress by treatment with hydrogen peroxide, recruits DNA methyltransferase 1 (DNMT1) to damaged chromatin. DNMT1 becomes part of a complex(es) containing DNMT3B and members of Polycomb Repressive Complex 4. Hydrogen peroxide treatment causes translocalization of these proteins from non-GC-rich to GC-rich areas. Key components are similarly enriched at gene promoters in an in vivo colitis model. While high expression genes enriched for members of the complex have histone mark and nascent transcription changes, CpG island-containing low expression genes gain promoter DNA methylation. Thus, oxidative damage induces formation and localization of a silencing complex that may explain cancer-specific aberrant DNA methylation and transcriptional silencing.
PMCID: PMC3220885  PMID: 22094255
16.  Control of AIF-mediated cell death by antagonistic functions of CHIP ubiquitin E3 ligase and USP2 deubiquitinating enzyme 
Cell Death and Differentiation  2011;18(8):1326-1336.
Apoptosis inducing factor (AIF) is a mitochondrial oxidoreductase that scavenges reactive oxygen species under normal conditions. Under certain stresses, such as exposure to N-methyl-N′-nitro-N′-nitrosoguanidine (MNNG), AIF is truncated and released from the mitochondria and translocated into the nucleus, where the truncated AIF (tAIF) induces caspase-independent cell death. However, it is unknown how cells decide to kill themselves or operate ways to survive when they encounter stresses that induce the release of tAIF. Here, we demonstrated that USP2 and CHIP contribute to the control of tAIF stability. USP2 deubiquitinated and stabilized tAIF, thus promoting AIF-mediated cell death. In contrast, CHIP ubiquitinated and destabilized tAIF, thus preventing the cell death. Consistently, CHIP-deficient cells showed an increased sensitivity to MNNG. On the other hand, knockdown of USP2 attenuated MNNG-induced cell death. Moreover, exposure to MNNG caused a dramatic decrease in CHIP level, but not that of USP2, concurrent with cell shrinkage and chromatin condensation. These findings indicate that CHIP and USP2 show antagonistic functions in the control of AIF-mediated cell death, and implicate the role of the enzymes as a switch for cells to live or die under stresses that cause tAIF release.
PMCID: PMC3172096  PMID: 21293491
apoptosis inducing factor; caspase-independent cell death; CHIP; USP2; ubiquitin
18.  Cucurbitacin IIa: a novel class of anti-cancer drug inducing non-reversible actin aggregation and inhibiting survivin independent of JAK2/STAT3 phosphorylation 
British Journal of Cancer  2011;104(5):781-789.
Cucurbitacin (Cuc) and triterpene-derived natural products exhibit anti-cancer potential in addition to their conspicuous anti-bacterial and anti-inflammatory activity. Recently, inhibition of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling was shown to underlie the effects of Cuc family on inducing cell death in cancer.
We purified Cuc IIa, the active component from the medicinal plant Hemsleya amalils Diels, which shows different structural modifications from other Cuc derivatives. We investigated the mechanisms of its inhibitory effects on cancer cells in vitro and tumour growth in vivo.
Cuc IIa induced the irreversible clustering of filamentous actin and arrested cell cycle by the increases in G2/M populations. Cuc IIa resulted in the reduced phospho-Histone H3 and markedly increased cleavage of poly-(ADP-ribose) polymerase or PARP, immediate upstream of DNA breakdown as the result of caspase activation, consistent with mitotic blockage-induced cell death. However, unlike other Cuc members, Cuc IIa did not suppress JAK2/STAT3 phosphorylation or alter phosphorylation of mitogen-activated protein kinases. Instead, the expression of the cell cycle-regulated Inhibitor of Apoptosis Protein (IAP) survivin was reduced. Introducing oncoprotein δ-catenin, which increased survivin expression and suppressed small GTPase RhoA, reduced efficacy of Cuc IIa to induce cell death. Supporting the effects of Cuc IIa on actin cytoskeletal signaling, RhoA phosphorylation was reduced suggesting its increased activity.
Cuc IIa is a novel class of anti-cancer drug in suppression of cancer cell expansion by disrupting the actin cytoskeleton and directing the cell to undergo PARP-mediated apoptosis through the inhibition of survivin downstream of JAK2/STAT3.
PMCID: PMC3048206  PMID: 21304528
cucurbitacin IIa; RhoA; survivin; JAK2/STAT3; actin cytoskeleton; apoptosis
19.  International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment 
Annals of Oncology  2010;22(3):515-523.
Background: Inflammatory breast cancer (IBC) represents the most aggressive presentation of breast cancer. Women diagnosed with IBC typically have a poorer prognosis compared with those diagnosed with non-IBC tumors. Recommendations and guidelines published to date on the diagnosis, management, and follow-up of women with breast cancer have focused primarily on non-IBC tumors. Establishing a minimum standard for clinical diagnosis and treatment of IBC is needed.
Methods: Recognizing IBC to be a distinct entity, a group of international experts met in December 2008 at the First International Conference on Inflammatory Breast Cancer to develop guidelines for the management of IBC.
Results: The panel of leading IBC experts formed a consensus on the minimum requirements to accurately diagnose IBC, supported by pathological confirmation. In addition, the panel emphasized a multimodality approach of systemic chemotherapy, surgery, and radiation therapy.
Conclusions: The goal of these guidelines, based on an expert consensus after careful review of published data, is to help the clinical diagnosis of this rare disease and to standardize management of IBC among treating physicians in both the academic and community settings.
PMCID: PMC3105293  PMID: 20603440
guidelines; inflammatory breast cancer; management
20.  Promoter polymorphisms in the beta-2 adrenergic receptor are associated with drug-induced gene expression changes and response in acute lymphoblastic leukemia 
We investigated whether genetic polymorphisms in the promoter region of the pro-apoptotic beta-2 adrenergic receptor gene (ADRB2) influence treatment-induced changes in ADRB2 expression in leukemia cells and response to chemotherapy. The ADRB2 promoter region was genotyped in germline DNA from 369 children with acute lymphoblastic leukemia (ALL). For 95 patients, sufficient RNA was available before and after in vivo treatment to assess treatment-induced gene expression changes in ALL cells. After treatment, the median ADRB2 mRNA expression was 9-fold lower in leukemia cells of patients who ultimately relapsed compared to patients who remained in continuous complete remission. Polymorphisms in the ADRB2 promoter were significantly linked to methotrexate induced up-regulation in ADRB2 gene expression in ALL cells. Moreover, the ADRB2 promoter haplotype was significantly related to early treatment response in 245 uniformly treated children with ALL. We conclude that germline polymorphisms in ADRB2 are linked to the antileukemic effects of ALL chemotherapy.
PMCID: PMC3105596  PMID: 20981007
pharmacogenetics; promoter gene polymorphism; treatment-induced gene expression changes
21.  Conserved Catalytic and C-Terminal Regulatory Domains of the C-Terminal Binding Protein Corepressor Fine-Tune the Transcriptional Response in Development ▿  
Molecular and Cellular Biology  2010;31(2):375-384.
Transcriptional corepressors play complex roles in developmental gene regulation. These proteins control transcription by recruiting diverse chromatin-modifying enzymes, but it is not known whether corepressor activities are finely regulated in different developmental settings or whether their basic activities are identical in most contexts. The evolutionarily conserved C-terminal binding protein (CtBP) is recruited by a variety of transcription factors that play crucial roles in development and disease. CtBP contains a central NAD(H) binding core domain that is homologous to D2 hydroxy acid dehydrogenase enzymes, as well as an unstructured C-terminal domain. NAD(H) binding is important for CtBP function, but the significance of its intrinsic dehydrogenase activity, as well as that of the unstructured C terminus, is poorly understood. To clarify the biological relevance of these features, we established genetic rescue assays to determine how different forms of CtBP function in the context of Drosophila melanogaster development. The mutant phenotypes and specific gene regulatory effects indicate that both the catalytic site of CtBP and the C-terminal extension play important, if nonessential roles in development. Our results indicate that the structural and enzymatic features of CtBP, previously thought to be dispensable for overall transcriptional control, are critical for modulating this protein's activity in diverse developmental settings.
PMCID: PMC3019976  PMID: 21078873
22.  New Roles and Mechanism of Action of BMP4 in Postnatal Tooth Cytodifferentiation 
Bone  2010;46(6):1533-1545.
During the phase of overt tooth cytodifferentiation that occurs after birth in the mouse and using the 3.6Collagen1a-Cre, the BMP4 floxed and BMP4 knock-out mice, the BMP4 gene was deleted in early collagen producing odontoblasts around postnatal day 1. BMP4 expression was reduced over 90% in alveolar osteoblasts and odontoblasts. There was decreased rate of predentin to dentin formation and decreased mature odontoblast differentiation reflected in reduced DMP1 expression and proper dentinal tubule formation, as well as reduced Collagen type I and Osteocalcin expression. We observed mutant dysmorphogenic odontoblasts that failed to properly elongate and differentiate. The consequence of this failed differentiation process lead to permanent loss of dentin thickness, apparent enlarged pulp chambers in the molars and reduced bone supporting the tooth structures in mice as old as 10–12 months. Deletion of the BMP4 gene in odontoblasts also indirectly disrupted the process of enamel formation that persisted throughout life. The mechanism for this altered differentiation program in the absence of the BMP4 gene in odontoblasts is from decreased BMP signaling, and decreased expression of three key transcription factors, Dlx3, Dlx5, and Osterix. BMP signaling, as well as Dlx3 and Amelogenin expression, are also indirectly reduced in the ameloblasts of the odontoblast BMP4 cKO mice. This supports a key paracrine or endocrine role of odontoblasts derived BMP4 postnatally on the proper amelogenesis and formation of the enamel.
PMCID: PMC2875306  PMID: 20206312
24.  CHARMM: The Biomolecular Simulation Program 
Journal of computational chemistry  2009;30(10):1545-1614.
CHARMM (Chemistry at HARvard Molecular Mechanics) is a highly versatile and widely used molecular simulation program. It has been developed over the last three decades with a primary focus on molecules of biological interest, including proteins, peptides, lipids, nucleic acids, carbohydrates and small molecule ligands, as they occur in solution, crystals, and membrane environments. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estimators, molecular minimization, dynamics, and analysis techniques, and model-building capabilities. In addition, the CHARMM program is applicable to problems involving a much broader class of many-particle systems. Calculations with CHARMM can be performed using a number of different energy functions and models, from mixed quantum mechanical-molecular mechanical force fields, to all-atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numerous platforms in both serial and parallel architectures. This paper provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM paper in 1983.
PMCID: PMC2810661  PMID: 19444816
biomolecular simulation; CHARMM program; molecular mechanics; molecular dynamics; molecular modeling; biophysical computation; energy function
25.  Survival among women with triple receptor-negative breast cancer and brain metastases 
Annals of Oncology  2009;20(4):621-627.
Background: The purpose of this study was to determine the incidence of and survival following brain metastases among women with triple receptor-negative breast cancer.
Patients and methods: In all, 679 patients with nonmetastatic triple receptor-negative breast cancer diagnosed from 1980 to 2006 were identified. Cumulative incidence of brain metastases was computed. Cox proportional hazards models were fitted to explore factors that predict for development of brain metastases. Survival was computed using the Kaplan–Meier product limit method.
Results: Median follow-up was 26.9 months. In all, 42 (6.2%) patients developed brain metastases with a cumulative incidence at 2 and 5 years of 5.6% [95% confidence interval (CI) 3.8% to 7.9%] and 9.6% (95% CI 6.8% to 13%), respectively. A total of 24 (3.5%) patients developed brain metastases as the first site of recurrence with cumulative incidence at 2 and 5 years of 2.0% (95% CI 2.6% to 6.0%) and 4.9% (95% CI 3.2% to 7.0%), respectively. In the multivariable model, no specific factor was observed to be significantly associated with time to brain metastases. Median survival for all patients who developed brain metastases and those who developed brain metastases as the first site of recurrence was 2.9 months (95% CI 2.0–7.6 months) and 5.8 months (95% CI 1.7–11.0 months), respectively.
Conclusion: In this single-institutional study, patients with nonmetastatic triple receptor-negative breast tumors have a high early incidence of brain metastases associated with poor survival and maybe an ideal cohort to target brain metastases preventive strategies.
PMCID: PMC2722369  PMID: 19150943
brain metastases; breast cancer; triple negative

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