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1.  Development of a photographic scale for consistency and guidance in dermatological assessment of forearm sun damage 
Archives of dermatology  2011;147(1):31-36.
Objectives
To develop a photographic sun damage assessment scale in forearm skin and assess its feasibility in assuring consistent identification, description and quantification of sun damage when used as part of an ongoing Dermatologic Assessment Scoring system in clinical studies.
Design
Blinded comparison. Ninetysix standardized 8×10 digital photographs of participant forearms were taken. The photographs were then graded by our expert dermatologist using the existing clinical sun damage assessment scale used in clinical trials until all categories contained photographs representative of each clinical sign. The expert dermatologist's set of grades created the criterion standard. The same photos were put into binders in triplicate in random arrangement and were provided to five blinded community dermatologists who rated them using the clinical sun damage assessment scale.
We took standardized 8×10 digital photographs of participant forearms and graded them into scoring categories by clinical sign using our existing clinical sun damage assessment scale until all categories were saturated for each clinical sign. Initial selection and grading were performed by our designated dermatologist expert to create a criterion standard. Three binders each containing 96 randomly arranged photos were graded by 5 blinded community dermatologists and a second reading by our criterion standard dermatologist.
Setting
Academic skin cancer prevention clinical trials clinic with a high level of experience assessing sundamaged skin.
Participants
Convenience sample consisting of any adult over 18 years of age including participants taking part in screenings, chemoprevention, and/or biomarker studies. Six community and academic dermatologists were recruited to grade the photographs.
Main Outcome Measure(s)
Reproducibility and agreement of grading among dermatologists as assessed by Spearman's correlation coefficient to assess the correlation of scores given for the same photograph, kappa statistics for ordinal data, and variability of scoring among dermatologists using ANOVA models with evaluating physician and photos as main effects and interaction effect variables to account for the difference in scoring among dermatologists.
Results
The correlations (~70% to above 90%) between dermatologists were all statistically significant (p < 0.0001) Scores showed good to substantial agreement but were significantly different (p<0.0001) for each of the four clinical signs and the difference varied significantly (p<0.0001) from photo to photo.
Conclusions
The use of the photographic sun damage assessment scale is highly feasible with an acceptable inter-observer agreement. Our findings also suggest that training will be useful in improving physician agreement on grading of the photographs.
doi:10.1001/archdermatol.2010.392
PMCID: PMC4133014  PMID: 21242389
2.  LOX-1 abrogation reduces cardiac hypertrophy and collagen accumulation following chronic ischemia in the mouse 
Gene therapy  2011;19(5):522-531.
We hypothesized that lectin-like oxidized LDL receptor-1 (LOX-1) deletion may inhibit oxidative stress signals, reduce collagen accumulation and attenuate cardiac remodeling after chronic ischemia. Activation of LOX-1 plays a significant role in the development of inflammation, apoptosis and collagen signals during acute ischemia. Wild-type and LOX-1 knockout (KO) mice were subjected to occlusion of left coronary artery for 3 weeks. Markers of cardiac hypertrophy, fibrosis-related signals (collagen IV, collagen-1 and fibronectin) and oxidant load (nicotinamide adenine dinucleotide phosphate oxidase expression, activity of mitogen-activated protein kinases and left ventricular (LV) tissue thiobarbituric acid reactive substances) were analyzed. In in vitro experiments, HL-1 cardiomyocytes were transfected with angiotensin II (Ang II) type 1 receptor (AT1R) or type 2 receptor (AT2R) genes to determine their role in the cardiomyocyte hypertrophy. LOX-1 KO mice had 25% improvement in survival over the 3-week period of chronic ischemia. LOX-1 deletion reduced collagen deposition and cardiomyocyte hypertrophy (~75%) in association with a decrease in oxidant load and AT1R upregulation (all P<0.05). The LOX-1 KO mice hearts exhibited a disintegrin and metalloproteinase 10 (ADAM10) and a disintegrin and metalloproteinase 17 (ADAM17) expression and matrix metalloproteinase 2 activity, and increased AT2R expression (P<0.05). Attenuation of cardiac remodeling was associated with improved cardiac hemodynamics (LV ±dp/dt and cardiac ejection fraction). In vitro studies showed that it is AT1R, and not AT2R overexpression that induces cardiomyocyte hypertrophy. We demonstrate for the first time that LOX-1 deletion reduces oxidative stress and related intracellular signaling, which leads to attenuation of the positive feedback loop involving AT1R and LOX-1. This results in reduced chronic cardiac remodeling.
doi:10.1038/gt.2011.133
PMCID: PMC4045006  PMID: 21938018
cardiac remodeling; chronic ischemia; LOX-1
3.  Cross-national differences in the prevalence and correlates of burden among older family caregivers in the WHO World Mental Health (WMH) Surveys 
Psychological medicine  2012;43(4):865-879.
Background
Current trends in population aging affect both recipients and providers of informal family caregiving, as the pool of family caregivers is shrinking while demand is increasing. Epidemiologic research has not yet examined the implications of these trends for burdens experienced by aging family caregivers.
Methods
Cross-sectional community surveys in 20 countries asked 13,892 respondents ages 50+ about the objective (time, financial) and subjective (distress, embarrassment) burdens they experience in providing care to first-degree relatives with 12 broadly-defined serious physical and mental conditions. Differential burden was examined by country income category, kinship status, and type of condition.
Results
Among the 26.9-42.5% respondents in high, upper-middle, and low/lower-middle income countries reporting serious relative health conditions, 35.7-42.5% reported burden. Of those, 25.2-29.0% spent time and 13.5-19.4% money, while 24.4-30.6% felt distress and 6.4-21.7% embarrassment. Mean caregiving hours/week given any was 16.6-23.6 (169.9-205.8 hours/week/100 people ages 50+). Burden in low/lower-middle income countries was 2-3-fold higher than in higher income countries, with financial burden given any averaging 14.3% of median family income in high, 17.7% in upper-middle, and 39.8% in low/lower-middle income countries. Higher burden was reported by women than men and for conditions of spouses and children than parents or siblings.
Conclusions
Uncompensated family caregiving is an important societal asset that offsets rising formal healthcare costs. However, the substantial burdens experienced by aging caregivers across multiple family health conditions and geographic regions threaten the continued integrity of their caregiving capacity. Initiatives supporting older family caregivers are consequently needed, especially in low/lower-middle income countries.
doi:10.1017/S0033291712001468
PMCID: PMC4045502  PMID: 22877824
family burden; cross-national; caregivers; epidemiology; mental health
4.  Exposure–Response Modeling of Clinical End Points Using Latent Variable Indirect Response Models 
Exposure–response modeling facilitates effective dosing regimen selection in clinical drug development, where the end points are often disease scores and not physiological variables. Appropriate models need to be consistent with pharmacology and identifiable from the time courses of available data. This article describes a general framework of applying mechanism-based models to various types of clinical end points. Placebo and drug model parameterization, interpretation, and assessment are discussed with a focus on the indirect response models.
doi:10.1038/psp.2014.15
PMCID: PMC4076802  PMID: 24897307
5.  A multinational study of mental disorders, marriage, and divorce 
Acta psychiatrica Scandinavica  2011;124(6):474-486.
Objective
Estimate predictive associations of mental disorders with marriage and divorce in a cross-national sample.
Method
Population surveys of mental disorders included assessment of age at first marriage in 19 countries (n = 46 128) and age at first divorce in a subset of 12 countries (n = 30 729). Associations between mental disorders and subsequent marriage and divorce were estimated in discrete time survival models.
Results
Fourteen of 18 premarital mental disorders are associated with lower likelihood of ever marrying (odds ratios ranging from 0.6 to 0.9), but these associations vary across ages of marriage. Associations between premarital mental disorders and marriage are generally null for early marriage (age 17 or younger), but negative associations come to predominate at later ages. All 18 mental disorders are positively associated with divorce (odds ratios ranging from 1.2 to 1.8). Three disorders, specific phobia, major depression, and alcohol abuse, are associated with the largest population attributable risk proportions for both marriage and divorce.
Conclusion
This evidence adds to research demonstrating adverse effects of mental disorders on life course altering events across a diverse range of socioeconomic and cultural settings. These effects should be included in considerations of public health investments in preventing and treating mental disorders.
doi:10.1111/j.1600-0447.2011.01712.x
PMCID: PMC4011132  PMID: 21534936
mental disorders; marriage; divorce
6.  Comparative analysis of lifestyle factors, screening test use, and clinicopathologic features in association with survival among Asian Americans with colorectal cancer 
Yi, M | Xu, J | Liu, P | Chang, G J | Du, X L | Hu, C-y | Song, Y | He, J | Ren, Y | Wei, Y | Yang, J | Hunt, K K | Li, X
British Journal of Cancer  2013;108(7):1508-1514.
Background:
Colorectal cancer (CRC) diagnoses and disease-specific survival (DSS) vary between ethnic groups in the United States. However, few studies have assessed differences among Asian subgroups.
Methods:
The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients with invasive CRC between 1988 and 2008. Differences in clinicopathologic features, and DSS rates were compared among Asian subgroups. The California Health Interview Survey was used to examine risk factors and screening patterns for CRC.
Results:
The study included 359 374 patients with 8.4% Asian. Patients in all Asian subgroups were younger (median: 68 years) at diagnosis than non-Hispanic white (NHW) patients (median: 72 years). Most Asian subgroups, except Hawaiians, had better DSS than NHW patients although Asian subgroups had more advanced disease than NHW. Indian/Pakistani patients had a higher 5-year DSS than other Asian subgroups. Obesity proportions were lower in Asian subgroups (<50.2%) than in NHW (59.8%). Vietnamese men and Korean women had the lowest proportions of CRC screening. Advance tumour stages were highly associated with worse DSS in each ethnicity group. High tumour grades were associated with worse DSS in NHW, Filipino, and Chinese. Older age at diagnosis was associated with worse DSS in most ethnicity groups except Hawaiian and Vietnamese.
Conclusion:
Disparities exist between Asians and NHW with CRC, and among various Asian subgroups. Differences in cancer clinicopathologic features, patients' behavioural habits, lifestyle, and screening patterns may explain some differences in CRC survival observed among ethnic groups.
doi:10.1038/bjc.2013.97
PMCID: PMC3629437  PMID: 23470470
Asian Americans; colorectal cancer; lifestyle factors; screening test; clinicopathologic; survival
7.  STAT3 and HIF1α cooperatively activate HIF1 target genes in MDA-MB-231 and RCC4 cells 
Oncogene  2013;33(13):1670-1679.
Solid tumors often exhibit simultaneously inflammatory and hypoxic microenvironments. The ‘signal transducer and activator of transcription-3’ (STAT3)-mediated inflammatory response and the hypoxia-inducible factor (HIF)-mediated hypoxia response have been independently shown to promote tumorigenesis through the activation of HIF or STAT3 target genes and to be indicative of a poor prognosis in a variety of tumors. We report here for the first time that STAT3 is involved in the HIF1, but not HIF2-mediated hypoxic transcriptional response. We show that inhibiting STAT3 activity in MDA-MB-231 and RCC4 cells by a STAT3 inhibitor or STAT3 small interfering RNA significantly reduces the levels of HIF1, but not HIF2 target genes in spite of normal levels of hypoxia-inducible transcription factor 1α (HIF1α) and HIF2α protein. Mechanistically, STAT3 activates HIF1 target genes by binding to HIF1 target gene promoters, interacting with HIF1α protein and recruiting coactivators CREB binding protein (CBP) and p300, and RNA polymerase II (Pol II) to form enhanceosome complexes that contain HIF1α, STAT3, CBP, p300 and RNA Pol II on HIF1 target gene promoters. Functionally, the effect of STAT3 knockdown on proliferation, motility and clonogenic survival of tumor cells in vitro is phenocopied by HIF1α knockdown in hypoxic cells, whereas STAT3 knockdown in normoxic cells also reduces cell proliferation, motility and clonogenic survival. This indicates that STAT3 works with HIF1 to activate HIF1 target genes and to drive HIF1-depedent tumorigenesis under hypoxic conditions, but also has HIF-independent activity in normoxic and hypoxic cells. Identifying the role of STAT3 in the hypoxia response provides further data supporting the effectiveness of STAT3 inhibitors in solid tumor treatment owing to their usefulness in inhibiting both the STAT3 and HIF1 pro-tumorigenic signaling pathways in some cancer types.
doi:10.1038/onc.2013.115
PMCID: PMC3868635  PMID: 23604114
cotranscriptional activation; HIF; hypoxia; STAT3; transcription
8.  TLR2-dependent selective autophagy regulates NF-κB lysosomal degradation in hepatoma-derived M2 macrophage differentiation 
Cell Death and Differentiation  2012;20(3):515-523.
Autophagy is a lysosomal pathway for cellular homeostasis control. Both non-selective bulk autophagy and selective autophagy of specific proteins or organelles have been found. Selective autophagy prevents cells from pathogen invasion and stress damage, but its role in regulating transcriptional factors is not clear. Using a macrophage cell differentiation model, the role of autophagy in nuclear factor-κB (NF-κB) regulation is investigated. The bone marrow-derived macrophages (BMDMs) will differentiate into a M2-like phenotype in the presence of hepatoma tumor cell condition medium (CM). The TLR2 signaling drives this M2 polarization and causes NF-κB p65 degradation via lysosome-dependent pathway. The CM-induced ubiquitinated- NF-κB p65 forms aggresome-like structures (ALS) in the cytoplasm of cultured and hepatoma-associated M2 macrophages. This NF-κB p65-contained ALS is recognized by p62/SQSTM1 and degraded by selective autophagy. Treatment with the lysosomal inhibitor bafilomycin A1 or the knockdown of Atg5 can prevent CM-induced NK-κB p65 degradation and induce M2 macrophages to produce a high level of pro-inflammatory cytokines. Furthermore, TLR2 signal induces sustained phosphorylation of extracellular signal-regulated kinase 1/2 to facilitate this autophagy-dependent NF-κB regulation. Our finding provides a novel pathway of NF-κB regulation by p62/SQSTM1-mediated selective autophagy.
doi:10.1038/cdd.2012.146
PMCID: PMC3569990  PMID: 23175187
selective autophagy; NF-κB; TLR2; p62/SQSTM1; extracellular signal-regulated kinase 1/2 (ERK1/2)
9.  miR-1207-5p and miR-1266 suppress gastric cancer growth and invasion by targeting telomerase reverse transcriptase 
Cell Death & Disease  2014;5(1):e1034-.
hTERT is the catalytic subunit of the telomerase complex. Elevated expression of hTERT is associated with the expansion and metastasis of gastric tumor. In this study, we aimed to identify novel tumor suppressor miRNAs that restrain hTERT expression. We began our screen for hTERT-targeting miRNAs with a miRNA microarray. miRNA candidates were further filtered by bioinformatic analysis, general expression pattern in different cell lines, gain-of-function effects on hTERT protein and the potential of these effects to suppress hTERT 3′ untranslated region (3′UTR) luciferase activity. The clinical relevance of two miRNAs (miR-1207-5p and miR-1266) was evaluated by real-time RT-PCR. The effects of these miRNAs on cell growth, cell cycle and invasion of gastric cancer cells were measured with CCK-8, flow cytometry and transwell assays. Finally, the ability of these miRNAs to suppress the transplanted tumors was also investigated. Fourteen miRNAs were identified using a combination of bioinformatics and miRNA microarray analysis. Of these fourteen miRNAs, nine were expressed at significantly lower levels in hTERT-positive cell lines compared with hTERT-negative cell lines and five could downregulate hTERT protein expression. Only miR-1207-5p and miR-1266 interacted with the 3′ UTR of hTERT and the expression levels of these two miRNAs were significantly decreased in gastric cancer tissues. These two miRNAs also inhibited gastric tumor growth in vitro and in vivo. Altogether, miR-1207-5p and miR-1266 were determined to be hTERT suppressors in gastric cancer, and the delivery of these two miRNAs represents a novel therapeutic strategy for gastric cancer treatment.
doi:10.1038/cddis.2013.553
PMCID: PMC4040688  PMID: 24481448
tumor-suppressor miRNA; hTERT; gastric cancer
10.  Functional analyses of the mutation nt-128 T→G in the hepatocyte nuclear factor-1α promoter region in Chinese diabetes pedigrees 
Aims
Hepatocyte nuclear factor-1α (HNF-1α) regulates the expression of genes encoding proteins involved in glucose metabolism and insulin secretion. Mutations in the HNF-1α gene cause maturity-onset diabetes of the young Type 3. However, the mechanism leading to this disease has not been completely ascertained. Previously, we found a novel mutation in the regulatory element of the human HNF-1α gene in two Chinese diabetes pedigrees. The nucleotide at position -128 T was substituted by G (nt-128 T→G). In this study, we analysed the functional defect of nt-128 T→G in HNF-1α transcription activity.
Methods
Luciferase reporter gene assays were carried out to examine the functional characteristics of this mutant. Electrophoretic mobility shift assays and chromatin immunoprecipitation were performed to confirm the binding of nuclear proteins to oligonucleotides.
Results
The variant construct (nt-128 T→G) had a 1.65-fold increase in promoter activity compared with that of the wild-type construct in HepG2 cells and a 1.33-fold increase in MIN6 cells, respectively. The variant resided at a FOXA/ HNF-3 binding site identified by a series of competitive electrophoretic mobility shift assays and antibody supershift analyses. The assays showed a differential binding affinity in the wild-type and the nt-128 T→G mutant fragments by FOXA/ HNF-3. Chromatin immunoprecipitation indicated that FOXA/ HNF-3 bound to this region in vivo. One nucleotide substitution in the FOXA/ HNF-3 site in the human HNF-1α regulatory element caused an increase of HNF-1α transcriptional activity.
Conclusions
Our data suggested that this substitution in the promoter region affects DNA–protein interaction and HNF-1α gene transcription. The mutant may contribute to the development of diabetes in these two nt-128 T→G pedigrees of Chinese.
doi:10.1111/j.1464-5491.2012.03626.x
PMCID: PMC3570122  PMID: 22413961
11.  IBP-mediated suppression of autophagy promotes growth and metastasis of breast cancer cells via activating mTORC2/Akt/FOXO3a signaling pathway 
Chen, S | Han, Q | Wang, X | Yang, M | Zhang, Z | Li, P | Chen, A | Hu, C | Li, S
Cell Death & Disease  2013;4(10):e842-.
Interferon regulatory factor-4 binding protein (IBP) is a novel upstream activator of Rho GTPases. Our previous studies have shown that ectopic expression of IBP was correlated with malignant behaviors of human breast cancer cells, and invasive human breast cancer had high expression of IBP that promoted the proliferation of these cells. However, it remains unknown whether autophagy inhibition contributes to IBP-mediated tumorigenesis. In this study, we for the first time, reported that upregulation of IBP expression significantly suppressed the autophagy of breast cancer cells, and downregulation of IBP expression markedly induced autophagy of these cells. Further investigation revealed that IBP effectively counteracted autophagy by directly activating mammalian target of rapamycin complex 2 (mTORC2) and upregulating phosphorylation of Akt on ser473 and FOXO3a on Thr32. Moreover, IBP-mediated suppression of autophagy was dependent on mTORC2/Akt/FOXO3a signaling pathway. Finally, our results demonstrated that IBP-mediated breast cancer cell growth in vitro and in vivo was strongly correlated with suppression of mTORC2-dependent autophagy. These findings suggest that the anti-autophagic property of IBP has an important role in IBP-mediated tumorigenesis, and IBP may serve as an attractive target for treatment of breast cancer.
doi:10.1038/cddis.2013.380
PMCID: PMC3824689  PMID: 24113176
autophagy; interferon regulatory factor-4 binding protein; breast cancer; small interfering RNA; tumorigenesis; mammalian target of rapamycin complex 2
12.  High-resolution human cervical spinal cord imaging at 7 T 
NMR in biomedicine  2011;25(7):891-899.
We present high-resolution anatomical imaging of the cervical spinal cord in healthy volunteers at the ultrahigh field of 7 T with a prototype four-channel radiofrequency coil array, in comparison with 3-T imaging of the same subjects. Signal-to-noise ratios at both field strengths were estimated using the rigorous Kellman method. Spinal cord cross-sectional area measurements were performed, including whole-cord measurements at both fields and gray matter segmentation at 7 T. The 7-T array coil showed reduced sagittal coverage, comparable axial coverage and the expected significantly higher signal-to-noise ratio compared with equivalent 3-T protocols. In the cervical spinal cord, the signal-to-noise ratio was found by the Kellman method to be higher by a factor of 3.5 with the 7-T coil than with standard 3-T coils. Cervical spine imaging in healthy volunteers at 7 T revealed not only detailed white/gray matter differentiation, but also structures not visualized at lower fields, such as denticulate ligaments, nerve roots and rostral–caudal blood vessels. Whole-cord cross-sectional area measurements showed good agreement at both field strengths. The measurable gray/white matter cross-sectional areas at 7 T were found to be comparable with reports from histology. These pilot data demonstrate the use of higher signal-to-noise ratios at the ultrahigh field of 7 T for significant improvement in anatomical resolution of the cervical spinal cord, allowing the visualization of structures not seen at lower field strength, particularly for axial imaging.
doi:10.1002/nbm.1809
PMCID: PMC3377161  PMID: 22183956
cervical spine; 7 T; gradient echo imaging; high field; gray/white matter
13.  Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4 
Diabetologia  2013;56(6):1291-1305.
Aims/hypothesis
Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians.
Methods
We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations.
Results
We identified CDKN2A/B and four novel type 2 diabetes association signals with p < 1 × 10−5 from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (pmeta = 2.6 × 10−8; OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (pmeta = 2.3 × 10−10) and a population of European descent (p = 8.6 × 10−3). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians.
Conclusions/interpretation
Our study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-013-2874-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-013-2874-4
PMCID: PMC3648687  PMID: 23532257
Chinese; Diabetes; East Asians; Genetics; Genome-wide association study
14.  TCF3, a novel positive regulator of osteogenesis, plays a crucial role in miR-17 modulating the diverse effect of canonical Wnt signaling in different microenvironments 
Liu, W | Liu, Y | Guo, T | Hu, C | Luo, H | Zhang, L | Shi, S | Cai, T | Ding, Y | Jin, Y
Cell Death & Disease  2013;4(3):e539-.
Wnt signaling pathways are a highly conserved pathway, which plays an important role from the embryonic development to bone formation. The effect of Wnt pathway on osteogenesis relies on their cellular environment and the expression of target genes. However, the molecular mechanism of that remains unclear. On the basis of the preliminary results, we observed the contrary effect of canonical Wnt signaling on osteogenic differentiation of periodontal ligament stem cells (PDLSCs) in the different culture environment. Furthermore, we found that the expression level of miR-17 was also varied with the change in the culture environment. Therefore, we hypothesized that miR-17 and canonical Wnt signaling may have potential interactions, particularly the inner regulation relationship in different microenvironments. In this paper, we observed that canonical Wnt signaling promoted osteogenesis of PDLSCs in the fully culture medium, while inhibited it in the osteogenic differentiation medium. Interestingly, alteration in the expression level of endogenous miR-17 could partially reverse the different effect of canonical Wnt signaling. Furthermore, the role of miR-17 was because of its target gene TCF3 (transcription factor 3), a key transcription factor of canonical Wnt pathway. Overexpression of TCF3 attenuated the effect of miR-17 on modulating canonical Wnt signaling. Finally, we elucidated that TCF3 enhanced osteogenesis both in vitro and in vivo. In brief, the different level of miR-17 was the main cause of the different effect of canonical Wnt signaling, and TCF3 was the crucial node of miR-17–canonial Wnt signaling regulation loop. This understanding of microRNAs regulating signaling pathways in different microenvironments may pave the way for fine-tuning the process of osteogenesis in bone-related disorders.
doi:10.1038/cddis.2013.65
PMCID: PMC3613843  PMID: 23492770
transcription factor 3; miR-17; canonical Wnt signaling; osteogenesis; microenvironment
15.  Nuclear factor-κB modulates osteogenesis of periodontal ligament stem cells through competition with β-catenin signaling in inflammatory microenvironments 
Chen, X | Hu, C | Wang, G | Li, L | Kong, X | Ding, Y | Jin, Y
Cell Death & Disease  2013;4(2):e510-.
Inflammation can influence multipotency and self-renewal of mesenchymal stem cells (MSCs), resulting in their awakened bone-regeneration ability. Human periodontal ligament tissue-derived MSCs (PDLSCs) have been isolated, and their differentiation potential was found to be defective due to β-catenin signaling indirectly regulated by inflammatory microenvironments. Nuclear factor-κB (NF-κB) is well studied in inflammation by many different groups. The role of NF-κB needs to be studied in PDLSCs, although genetic evidences have recently shown that NF-κB inhibits osteoblastic bone formation in mice. However, the mechanism as to how inflammation leads to the modulation of β-catenin and NF-κB signaling remains unclear. In this study, we investigated β-catenin and NF-κB signaling through regulation of glycogen synthase kinase 3β activity (GSK-3β, which modulates β-catenin and NF-κB signaling) using a specific inhibitor LiCl and a phosphatidylinositol 3-kinase (PI3K) inhibitor LY 294002. We identified that NF-κB signaling might be more important for the regulation of osteogenesis in PDLSCs from periodontitis compared with β-catenin. BAY 11-7082 (an inhibitor of NF-κB) could inhibit phosphorylation of p65 and partly rescue the differentiation potential of PDLSCs in inflammation. Our data indicate that NF-κB has a central role in regulating osteogenic differentiation of PDLSCs in inflammatory microenvironments. Given the molecular mechanisms of NF-κB in osteogenic differentiation governed by inflammation, it can be said that NF-κB helps in improving stem cell-mediated inflammatory bone disease therapy.
doi:10.1038/cddis.2013.14
PMCID: PMC3734811  PMID: 23449446
periodontal ligament stem cell; NF-κB; GSK-3β; osteogenic differentiation; inflammation
16.  Effect of pregnancy on emtricitabine pharmacokinetics* 
HIV Medicine  2011;13(4):226-235.
Objectives
The aim of the study was to describe emtricitabine pharmacokinetics during pregnancy and postpartum.
Methods
The International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT), formerly Pediatric AIDS Clinical Trials Group (PACTG), study P1026s is a prospective pharmacokinetic study of HIV-infected pregnant women taking antiretrovirals for clinical indications, including a cohort taking emtricitabine 200 mg once daily. Intensive steady-state 24-hour emtricitabine pharmacokinetic profiles were performed during the third trimester and 6–12 weeks postpartum, and on maternal and umbilical cord blood samples collected at delivery. Emtricitabine was measured by liquid chromatography–mass spectrometry with a quantification limit of 0.0118 mg/L. The target emtricitabine area under the concentration versus time curve, from time 0 to 24 hours post dose (AUC0-24), was ≥7 mg h/L (≤30% reduction from the typical AUC of 10 mg h/L in nonpregnant historical controls). Third-trimester and postpartum pharmacokinetics were compared within subjects.
Results
Twenty-six women had pharmacokinetics assessed during the third trimester (median 35 weeks of gestation) and 22 postpartum (median 8 weeks postpartum). Mean [90% confidence interval (CI)] emtricitabine pharmacokinetic parameters during the third trimester vs. postpartum were, respectively: AUC: 8.0 (7.1–8.9) vs. 9.7 (8.6–10.9) mg h/L (P = 0.072); apparent clearance (CL/F): 25.0 (22.6–28.3) vs. 20.6 (18.4–23.2) L/h (P = 0.025); 24 hour post dose concentration (C24): 0.058 (0.037–0.063) vs. 0.085 (0.070–0.010) mg/L (P = 0.006). The mean cord:maternal ratio was 1.2 (90% CI 1.0–1.5). The viral load was <400 HIV-1 RNA copies/mL in 24 of 26 women in the third trimester, in 24 of 26 at delivery, and in 15 of 19 postpartum. Within-subject comparisons demonstrated significantly higher CL/F and significantly lower C24 during pregnancy; however, the C24 was well above the inhibitory concentration 50%, or drug concentration that suppresses viral replication by half (IC50) in all subjects.
Conclusions
While we found higher emtricitabine CL/F and lower C24 and AUC during pregnancy compared with postpartum, these changes were not sufficiently large to warrant dose adjustment during pregnancy. Umbilical cord blood concentrations were similar to maternal concentrations.
doi:10.1111/j.1468-1293.2011.00965.x
PMCID: PMC3342997  PMID: 22129166
emtricitabine; HIV; pregnancy; pharmacokinetics
17.  Association of genetic variation in FTO with risk of obesity and type 2 diabetes with data from 96,551 East and South Asians 
Diabetologia  2011;55(4):981-995.
Aims/hypothesis
FTO harbours the strongest known obesity-susceptibility locus in Europeans. While there is growing evidence for a role for FTO in obesity risk in Asians, its association with type 2 diabetes, independently of BMI, remains inconsistent. To test whether there is an association of the FTO locus with obesity and type 2 diabetes, we conducted a meta-analysis of 32 populations including 96,551 East and South Asians.
Methods
All studies published on the association between FTO-rs9939609 (or proxy [r2 > 0.98]) and BMI, obesity or type 2 diabetes in East or South Asians were invited. Each study group analysed their data according to a standardised analysis plan. Association with type 2 diabetes was also adjusted for BMI. Random-effects meta-analyses were performed to pool all effect sizes.
Results
The FTO-rs9939609 minor allele increased risk of obesity by 1.25-fold/allele (p = 9.0 × 10−19), overweight by 1.13-fold/allele (p = 1.0 × 10−11) and type 2 diabetes by 1.15-fold/allele (p = 5.5 × 10−8). The association with type 2 diabetes was attenuated after adjustment for BMI (OR 1.10-fold/allele, p = 6.6 × 10−5). The FTO-rs9939609 minor allele increased BMI by 0.26 kg/m2 per allele (p = 2.8 × 10−17), WHR by 0.003/allele (p = 1.2 × 10−6), and body fat percentage by 0.31%/allele (p = 0.0005). Associations were similar using dominant models. While the minor allele is less common in East Asians (12–20%) than South Asians (30–33%), the effect of FTO variation on obesity-related traits and type 2 diabetes was similar in the two populations.
Conclusions/interpretation
FTO is associated with increased risk of obesity and type 2 diabetes, with effect sizes similar in East and South Asians and similar to those observed in Europeans. Furthermore, FTO is also associated with type 2 diabetes independently of BMI.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-011-2370-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-011-2370-7
PMCID: PMC3296006  PMID: 22109280
Asians; FTO; Meta-analysis; Obesity; Type 2 diabetes
18.  Integration of CNS survival and differentiation by HIF2α 
Cell Death and Differentiation  2011;18(11):1757-1770.
Hypoxia-inducible factor (HIF) 1α and HIF2α and the inhibitor of apoptosis survivin represent prominent markers of many human cancers. They are also widely expressed in various embryonic tissues, including the central nervous system; however, little is known about their functions in embryos. Here, we show that zebrafish HIF2α protects neural progenitor cells and neural differentiation processes by upregulating the survivin orthologues birc5a and birc5b during embryogenesis. Morpholino-mediated knockdown of hif2α reduced the transcription of birc5a and birc5b, induced p53-independent apoptosis and abrogated neural cell differentiation. Depletion of birc5a and birc5b recaptured the neural development defects that were observed in the hif2α morphants. The phenotypes induced by HIF2α depletion were largely rescued by ectopic birc5a and birc5b mRNAs, indicating that Birc5a and Birc5b act downstream of HIF2α. Chromatin immunoprecipitation assay revealed that HIF2α binds to birc5a and birc5b promoters directly to modulate their transcriptions. Knockdown of hif2α, birc5a or birc5b reduced the expression of the cdk inhibitors p27/cdkn1b and p57/cdkn1c and increased ccnd1/cyclin D1 transcription in the surviving neural progenitor cells. The reduction in elavl3/HuC expression and enhanced pcna, nestin, ascl1b and sox3 expression indicate that the surviving neural progenitor cells in hif2α morphants maintain a high proliferation rate without terminally differentiating. We propose that a subset of developmental defects attributed to HIF2α depletion is due in part to the loss of survivin activity.
doi:10.1038/cdd.2011.44
PMCID: PMC3190110  PMID: 21546908
HIF2α; surviving; neural progenitor cells; apoptosis
19.  A common variant of NOS1AP is associated with QT interval duration in a Chinese population with Type 2 diabetes 
Aims
Electrocardiographic ventricular repolarization QT parameters are independent risk factors for cardiovascular events and sudden cardiac death in diabetic patients. The aim of the study was to investigate the association of polymorphisms of the nitric oxide synthase 1 adaptor protein (NOS1AP) gene with QT interval in Chinese subjects with or without Type 2 diabetes.
Methods
Three single nucleotide polymorphisms (SNPs) (rs10494366, rs12143842 and rs12029454) were genotyped in 1240 Type 2 diabetic patients (631 men and 609 women) and 1196 normal controls (433 men and 763 women). Individuals with overt diseases other than diabetes were excluded. Heart-rate corrected QT interval (QTc) was determined by standard 12-lead ECG and Bazett formula. Sex-pooled analysis and sex-specific analysis for genotype–phenotype association were both conducted.
Results
In the diabetic group, the rs12143842 T allele was associated with a 3.87-ms (P = 0.014, empirical P = 0.039) increase in QTc duration for each additional allele copy, while rs10494366 and rs12029454 exhibited no significant association with QTc. We found no evidence of association for the three SNPs in subjects with normal glucose regulation. No significant SNP-gender and -diabetes affection interaction was observed.
Conclusions
The genetic variant rs12143842 in NOS1AP is associated with QT interval duration in a Chinese population with Type 2 diabetes. Future studies in different populations are needed to validate this finding and to evaluate the impact of NOS1AP variants on cardiovascular events and sudden cardiac death in diabetic patients.
doi:10.1111/j.1464-5491.2010.03072.x
PMCID: PMC2925320  PMID: 20722683
NOS1AP; QT interval; single nucleotide polymorphism
20.  NOVEL LEAD ZIRCONATE TITANATE COMPOSITE VIA FREEZING TECHNOLOGY FOR HIGH FREQUENCY TRANSDUCER APPLICATIONS 
Novel PZT-5A ceramic-polymer composite was prepared via freezing technology. This composite exhibited good dielectric and ferroelectric behaviors. At 1 kHz, the dielectric constant and the dielectric loss were 546 and 0.046, respectively, while the remnant polarization was 13.0 μC/cm2 at room temperature. The electromechanical coupling coefficient (kt) of PZT-5A composite was measured to be 0.54, which is similar to that of PZT piezoelectric ceramic. The piezoelectric coefficient (d33) of PZT-5A composite was determined to be ~250 pC/N. Using this composite, a 58MHz single element transducer with the bandwidth of 70% at −6dB was built, and the insertion loss was tested to be −29dB around the central frequency.
doi:10.1142/S2010135X11000112
PMCID: PMC3141348  PMID: 21785672
Piezoelectric composite; PZT; transducer
21.  ASSOCIATION BETWEEN POLYMORPHIC VARIATION IN VDR AND RXRA AND CIRCULATING LEVELS OF VITAMIN D METABOLITES 
The vitamin D metabolite 1,25(OH)2D is the bioactive ligand of the vitamin D receptor (VDR). VDR forms a heterodimer with the retinoid X receptors (RXRs) that when bound to ligand influences the transcriptional control of genes that regulate circulating levels of vitamin D metabolites. Whether genetic variation in VDR or RXRA affects circulating levels of 1,25(OH)2D or 25(OH)D has not been established. We used a single nucleotide polymorphism (SNP) tagging approach to evaluate the association between SNPs in VDR and RXRA and serum levels of 1,25(OH)2D and 25(OH)D. A total of 42 tagSNPs in VDR and 32 in RXRA were analyzed in a sample of 415 participants. Principal components analyses revealed a gene-level association between RXRA and serum 1,25(OH)2D concentrations (P = 0.01), but not 25(OH)D. No gene-level association was found for VDR with either serum biomarker. At the single SNP level, a significant positive trend was observed for increasing 1,25(OH)2D levels with each additional copy of the A allele for RXRA SNP rs9409929 (Ptrend = 0.003). After a multiple comparisons adjustment, no individual SNP in VDR or RXRA was significantly associated with either outcome. These results demonstrate an association between genetic variation in RXRA and 1,25(OH)2D serum concentrations.
doi:10.1016/j.jsbmb.2010.03.052
PMCID: PMC2906637  PMID: 20307661
VDR; RXR; polymorphism; 25(OH)D; 1,25(OH)2D; vitamin D
22.  Lopinavir protein binding in HIV-1-infected pregnant women 
HIV medicine  2009;11(4):10.1111/j.1468-1293.2009.00767.x.
Background
Pregnancy may alter protein binding (PB) of highly bound protease inhibitors due to changes in plasma concentrations of albumin and α-1 acid glycoprotein (AAG). Small changes in PB can greatly impact the fraction of drug unbound (FU) exerting pharmacological effect. We report lopinavir (LPV) PB during third trimester (antepartum, AP) compared to ≥1.7 weeks postpartum (PP) to determine if FU changes compensate for reduced total concentrations reported previously.
Methods
P1026s enrolled women receiving LPV/ritonavir, soft gel capsules 400/100 mg or 533/133 mg twice daily. LPV FU, albumin and AAG were determined AP and PP.
Results
AP/PP samples were available from 29/25 women respectively with all but one woman receiving the same dose AP/PP. LPV FU was increased 18% AP vs. PP (mean 0.96 ± 0.16% AP vs. 0.82 ± 0.21% PP, P = 0.001). Mean protein concentrations were reduced AP (AAG = 477 mg/L; albumin = 3.28 mg/dL) vs. PP (AAG = 1007 mg/L; albumin = 3.85 mg/dL) (P<0.0001 for each comparison). AAG concentration correlated with LPV binding. Total LPV concentration did not correlate with LPV FU AP or PP. However, higher LPV concentration PP was associated with reduced PB and higher FU after adjustment for AAG.
Conclusions
LPV FU was higher and AAG lower AP vs. PP. The 18% increase in LPV FU AP is smaller than the reduction in total LPV concentration reported previously and is not of sufficient magnitude to eliminate the need for an increased dose during pregnancy.
doi:10.1111/j.1468-1293.2009.00767.x
PMCID: PMC2874627  PMID: 20002783
lopinavir; pharmacokinetics; plasma proteins; pregnancy; protein binding
23.  Troponin T measurement can predict persistent left ventricular dysfunction in peripartum cardiomyopathy 
Heart  2006;93(4):488-490.
Objective
To determine whether measurement of cardiac troponin T (cTnT) concentration in newly diagnosed peripartum cardiomyopathy (PPCM) can be used to predict persistent left ventricular dysfunction after a 6‐month follow‐up.
Patients and methods
This was a prospective, multiple‐centre clinical trial that studied 106 patients with newly diagnosed PPCM surviving over 6 months. cTnT concentration was measured within 2 weeks of the onset of PPCM.
Results
Serum cTnT concentration was negatively correlated with left ventricular ejection fraction (LVEF) at follow‐up (LVEF, r = −0.518, p = 0.0001). Analysis by receiver operator characteristic curve yielded an area under the curve of 0.764 (95% CI 0.669 to 0.860, p = 0.0001, vs null hypothesis value 0.5) for cTnT, and a cTnT concentration cut off of >0.04 ng/ml, predicting persistent left ventricular dysfunction with a sensitivity of 54.9% and a specificity of 90.9%. Among 106 recruited patients, there were 33 patients with cTnT concentrations >0.04 ng/ml and 73 patients with cTnT concentrations ⩽0.04 ng/ml. After a 6‐month follow‐up, there was significantly smaller LVEF (35.42% (13.04% vs 50.16% (10.48%, p = 0.0001) and more persistent left ventricular dysfunction (84.8% vs 31.5%, OR = 12.17 (95% CI 4.17 to 35.57), p = 0.001) in patients with cTnT >0.04 ng/ml than in patients with cTnT ⩽0.04 ng/ml.
Conclusion
Serum cTnT concentration measured within 2 weeks of the onset of PPCM was correlated negatively with LVEF at follow‐up. This marker offers a simple, quick, inexpensive, non‐invasive method for predicting a persistent LVEF of ⩽50%. A cTnT concentration of >0.04 ng/ml predicted persistent left ventricular dysfunction with a sensitivity of 54.9% and a specificity of 90.9%.
doi:10.1136/hrt.2006.087387
PMCID: PMC1861492  PMID: 17065185
24.  Chronic administration of nevirapine during pregnancy: impact of pregnancy on pharmacokinetics 
HIV Medicine  2008;9(4):214-220.
Objectives
To determine the impact of pregnancy on the pharmacokinetics (PK) of nevirapine (NVP) during chronic dosing in HIV-infected women and appropriate NVP dosing in this population.
Methods
Twenty-six pregnant women participating in two open-label Pediatric AIDS Clinical Trials Group studies (P1022 and P1026S) were evaluated. Each patient received 200 mg NVP every 12 h and had PK evaluations during the second or third trimester; these evaluations were repeated postpartum. Paired maternal and cord blood NVP concentrations were collected at delivery in nine patients. Ante- and postpartum comparisons were made using paired t-tests and using a ‘bioequivalence’ approach to determine confidence interval (CI).
Results
The average NVP Area Under the Curve (AUC) was 56 ± 13 mcg*h/mL antepartum and 61 ± 15 mcg*h/mL postpartum. The typical parameters ± standard error were apparent clearance (CL/F)=3.51 ± 0.18 L/h and apparent volume of distribution (Vd/F)=121 ± 19.8 L. There were no significant differences between antepartum and postpartum AUC or pre-dose concentrations. The AUC ratio was 0.90 with a 90% CI of the mean equal to 0.80-1.02. The median ( ± standard deviation) cord blood to maternal NVP concentration ratio was 0.91 ± 0.90.
Conclusions
Pregnancy does not alter NVP PK and the standard dose (200 mg every 12 h) is appropriate during pregnancy.
doi:10.1111/j.1468-1293.2008.00553.x
PMCID: PMC2755564  PMID: 18366444
HIV; nevirapine; non-nucleoside reverse transcriptase; pharmacokinetics; pregnancy
25.  Pharmacokinetics of new 625 mg nelfinavir formulation during pregnancy and postpartum 
HIV Medicine  2008;9(10):875-882.
Objectives
Our objective was to evaluate the pharmacokinetics of nelfinavir (NFV) (625 mg tablets) 1250 mg twice daily during pregnancy and postpartum.
Methods
The participants were HIV-1-infected pregnant women enrolled in P1026s and receiving NFV (625 mg tablets) 1250 mg twice daily as part of routine clinical care. Intensive steady-state 12-h NFV pharmacokinetic profiles were performed during pregnancy and postpartum. The target NFV area under the plasma concentration–time curve (AUC0–12) was ≥ 10th percentile NFV AUC0–12 in non-pregnant historical controls (18.5 μg h/mL).
Results
Of 27 patients receiving NFV, pharmacokinetic data were available for four (second trimester), 27 (third trimester) and 22 (postpartum) patients. The NFV maximum concentration (Cmax), 12-h post-dose concentration (C12) and AUC0–12 were significantly lower during the third trimester compared to postpartum (P ≤ 0.03). The metabolite hydroxyl-tert-butylamide (M8) AUC0–12 and the M8/NFV AUC ratio were lower during the third trimester compared to postpartum (P<0.01). The NFV AUC0–12 exceeded the AUC0–12 target for 15/27 (56%) and 21/22 (95%) of third trimester and postpartum patients, respectively. The minimum concentration (Cmin) was above the suggested minimum trough concentration (0.8 μg/mL) in 15% (third trimester) and 18% (postpartum). The plasma viral load was <400 HIV-1 RNA copies/mL in 81% of patients at delivery.
Conclusions
These results suggest that higher doses of NFV should be considered during pregnancy.
doi:10.1111/j.1468-1293.2008.00640.x
PMCID: PMC2732353  PMID: 18795962
HIV; nelfinavir; pharmacokinetics; pregnancy

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