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1.  Adipogenic placenta-derived mesenchymal stem cells are not lineage restricted by withdrawing extrinsic factors: developing a novel visual angle in stem cell biology 
Hu, C | Cao, H | Pan, X | Li, J | He, J | Pan, Q | Xin, J | Yu, X | Li, J | Wang, Y | Zhu, D | Li, L
Cell Death & Disease  2016;7(3):e2141-.
Current evidence implies that differentiated bone marrow mesenchymal stem cells (BMMSCs) can act as progenitor cells and transdifferentiate across lineage boundaries. However, whether this unrestricted lineage has specificities depending on the stem cell type is unknown. Placental-derived mesenchymal stem cells (PDMSCs), an easily accessible and less invasive source, are extremely useful materials in current stem cell therapies. No studies have comprehensively analyzed the transition in morphology, surface antigens, metabolism and multilineage potency of differentiated PDMSCs after their dedifferentiation. In this study, we showed that after withdrawing extrinsic factors, adipogenic PDMSCs reverted to a primitive cell population and retained stem cell characteristics. The mitochondrial network during differentiation and dedifferentiation may serve as a marker of absent or acquired pluripotency in various stem cell models. The new population proliferated faster than unmanipulated PDMSCs and could be differentiated into adipocytes, osteocytes and hepatocytes. The cell adhesion molecules (CAMs) signaling pathway and extracellular matrix (ECM) components modulate cell behavior and enable the cells to proliferate or differentiate during the differentiation, dedifferentiation and redifferentiation processes in our study. These observations indicate that the dedifferentiated PDMSCs are distinguishable from the original PDMSCs and may serve as a novel source in stem cell biology and cell-based therapeutic strategies. Furthermore, whether PDMSCs differentiated into other lineages can be dedifferentiated to a primitive cell population needs to be investigated.
PMCID: PMC4823931  PMID: 26986509
2.  Obscure gastrointestinal bleeding: diagnostic performance of 64-section multiphase CT enterography and CT angiography compared with capsule endoscopy 
He, B | Gong, S | Hu, C | Fan, J | Qian, J | Huang, S | Cui, L | Ji, Y
The British Journal of Radiology  2014;87(1043):20140229.
To compare the diagnostic capabilities between capsule endoscopy (CE) and multislice CT (MSCT) enterography in combination with MSCT angiography for assessment of obscure gastrointestinal bleeding (OGIB).
A total of 127 patients with OGIB were looked at in this study. 82 patients (aged 42.7 ± 19.1 years; 34 males) were assigned to receive MSCT diagnosis and 67 patients to (aged 53.9 ± 16.2 years; 28 males) receive CE diagnosis. Among them, 22 patients (aged 54.1 ± 19.1 years; 12 males) received both examinations. Oral isotonic mannitol and intramuscular injection of anisodamine were performed; non-ionic contrast (iopromide, 370 mg I ml−1) was intravenously administered; and then multiphase scanning was conducted at arterial, small intestinal and portal venous phases in MSCT. The results were compared with findings of reference standards including double balloon enteroscopy, digital subtraction angiography, intraoperative pathological examination and/or clinical diagnosis.
Administration of anisodamine markedly increased the satisfaction rate of bowel filling (94.67% vs 28.57%; p < 0.001) but not the diagnostic yield (p = 0.293) of MSCT. Compared with MSCT, CE showed an improved overall diagnostic yield (68.66% vs 47.56%; p = 0.010), which was also observed in overt bleeding patients (i.e. patients with continued passage of visible blood) (76.19% vs 51.02%; p = 0.013) and in patients aged younger than 40 years of age (85% vs 51.28%; p = 0.024). However, CE had similar positive rates to MSCT (p > 0.05). Among the 22 cases in whom both examinations were conducted, CE showed no significantly different diagnostic capability compared with MSCT (p = 0.4597).
Both CE and MSCT are safe and effective diagnostic methods for OGIB.
Advances in knowledge:
CE is preferred for overt bleeding or patients aged younger than 40 years. The combined use of CE and MSCT is recommended in OGIB diagnosis.
PMCID: PMC4207170  PMID: 25248830
3.  The effects of comorbidity in defining major depression subtypes associated with long-term course and severity 
Psychological medicine  2014;44(15):3289-3302.
Although variation in long-term course of major depressive disorder (MDD) is not strongly predicted by existing symptom subtype distinctions, recent research suggests that prediction can be improved by using machine learning methods. However, it is not known whether these distinctions can be refined by added information about comorbid conditions. The current report presents results on this question.
Data come from 8,261 respondents with lifetime DSM-IV MDD in the WHO World Mental Health (WMH) Surveys. Outcomes include four retrospectively-reported measures of persistence-severity of course (years in episode; years in chronic episodes, hospitalization for MDD; disability due to MDD). Machine learning methods (regression tree analysis; lasso, ridge, and elastic net penalized regression) followed by k-means cluster analysis were used to augment previously-detected subtypes with information about prior comorbidity to predict these outcomes.
Predicted values were strongly correlated across outcomes. Cluster analysis of predicted values found 3 clusters with consistently high, intermediate, or low values. The high-risk cluster (32.4% of cases) accounted for 56.6–72.9% of high persistence, high chronicity, hospitalization, and disability. This high-risk cluster had both higher sensitivity and likelihood-ratio positive (relative proportions of cases in the high-risk cluster versus other clusters having the adverse outcomes) than in a parallel analysis that excluded measures of comorbidity as predictors.
Although results using the retrospective data reported here suggest that useful MDD subtyping distinctions can be made with machine learning and clustering across multiple indicators of illness persistence-severity, replication is need with prospective data to confirm this preliminary conclusion.
PMCID: PMC4180779  PMID: 25066141
Comorbidity; data mining; depression subtypes; depression symptom profiles; elastic net; machine learning; predictive modeling; risk assessment
4.  Subtypes of major depression: latent class analysis in depressed Han Chinese women 
Psychological medicine  2014;44(15):3275-3288.
Despite substantial research, uncertainty remains about the clinical and etiological heterogeneity of major depression (MD). Can meaningful and valid subtypes be identified and would they be stable cross-culturally?
Symptoms at their lifetime worst depressive episode were assessed at structured psychiatric interview in 6008 women of Han Chinese descent, age ≥30 years, with recurrent DSM-IV MD. Latent class analysis (LCA) was performed in Mplus.
Using the nine DSM-IV MD symptomatic A criteria, the 14 disaggregated DSM-IV criteria and all independently assessed depressive symptoms (n=27), the best LCA model identified respectively three, four and six classes. A severe and non-suicidal class was seen in all solutions, as was a mild/moderate subtype. An atypical class emerged once bidirectional neurovegetative symptoms were included. The non-suicidal class demonstrated low levels of worthlessness/guilt and hopelessness. Patterns of co-morbidity, family history, personality, environmental precipitants, recurrence and body mass index (BMI) differed meaningfully across subtypes, with the atypical class standing out as particularly distinct.
MD is a clinically complex syndrome with several detectable subtypes with distinct clinical and demographic correlates. Three subtypes were most consistently identified in our analyses: severe, atypical and non-suicidal. Severe and atypical MD have been identified in multiple prior studies in samples of European ethnicity. Our non-suicidal subtype, with low levels of guilt and hopelessness, may represent a pathoplastic variant reflecting Chinese cultural influences.
PMCID: PMC4180813  PMID: 25065911
Atypical depression; China; depression; latent class analysis; melancholia; suicidal ideation
5.  Barriers to Mental Health Treatment: Results from the WHO World Mental Health (WMH) Surveys 
Psychological medicine  2013;44(6):1303-1317.
To examine barriers to initiation and continuation of mental health treatment among individuals with common mental disorders.
Data are from the WHO World Mental Health (WMH) Surveys. Representative household samples were interviewed face-to-face in 24 countries. Reasons to initiate and continue treatment were examined in a subsample (n= 63,678) and analyzed at different levels of clinical severity.
Among those with a DSM-IV disorder in the past twelve months, low perceived need was the most common reason for not initiating treatment and more common among moderate and mild than severe cases. Women and younger people with disorders were more likely to recognize a need for treatment. Desire to handle the problem on one’s own was the most common barrier among respondents with a disorder who perceived a need for treatment (63.8%). Attitudinal barriers were much more important than structural barriers both to initiating and continuing treatment. However, attitudinal barriers dominated for mild-moderate cases and structural barriers for severe cases. Perceived ineffectiveness of treatment was the most commonly reported reason for treatment dropout (39.3%) followed by negative experiences with treatment providers (26.9% of respondents with severe disorders).
Low perceived need and attitudinal barriers are the major barriers to seeking and staying in treatment among individuals with common mental disorders worldwide. Apart from targeting structural barriers, mainly in countries with poor resources, increasing population mental health literacy is an important endeavor worldwide.
PMCID: PMC4100460  PMID: 23931656
mental healthcare; treatment seeking; continuity
7.  Development of a photographic scale for consistency and guidance in dermatological assessment of forearm sun damage 
Archives of dermatology  2011;147(1):31-36.
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.
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.
Academic skin cancer prevention clinical trials clinic with a high level of experience assessing sundamaged skin.
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.
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.
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.
PMCID: PMC4133014  PMID: 21242389
8.  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.
PMCID: PMC4045006  PMID: 21938018
cardiac remodeling; chronic ischemia; LOX-1
9.  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.
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.
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.
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.
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.
PMCID: PMC4045502  PMID: 22877824
family burden; cross-national; caregivers; epidemiology; mental health
10.  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.
PMCID: PMC4076802  PMID: 24897307
11.  A multinational study of mental disorders, marriage, and divorce 
Acta psychiatrica Scandinavica  2011;124(6):474-486.
Estimate predictive associations of mental disorders with marriage and divorce in a cross-national sample.
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.
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.
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.
PMCID: PMC4011132  PMID: 21534936
mental disorders; marriage; divorce
12.  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.
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.
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.
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.
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.
PMCID: PMC3629437  PMID: 23470470
Asian Americans; colorectal cancer; lifestyle factors; screening test; clinicopathologic; survival
13.  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.
PMCID: PMC3868635  PMID: 23604114
cotranscriptional activation; HIF; hypoxia; STAT3; transcription
14.  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.
PMCID: PMC3569990  PMID: 23175187
selective autophagy; NF-κB; TLR2; p62/SQSTM1; extracellular signal-regulated kinase 1/2 (ERK1/2)
15.  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.
PMCID: PMC4040688  PMID: 24481448
tumor-suppressor miRNA; hTERT; gastric cancer
16.  Functional analyses of the mutation nt-128 T→G in the hepatocyte nuclear factor-1α promoter region in Chinese diabetes pedigrees 
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.
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.
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.
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.
PMCID: PMC3570122  PMID: 22413961
17.  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.
PMCID: PMC3824689  PMID: 24113176
autophagy; interferon regulatory factor-4 binding protein; breast cancer; small interfering RNA; tumorigenesis; mammalian target of rapamycin complex 2
18.  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.
PMCID: PMC3377161  PMID: 22183956
cervical spine; 7 T; gradient echo imaging; high field; gray/white matter
19.  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.
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.
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.
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.
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.
PMCID: PMC3648687  PMID: 23532257
Chinese; Diabetes; East Asians; Genetics; Genome-wide association study
20.  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.
PMCID: PMC3613843  PMID: 23492770
transcription factor 3; miR-17; canonical Wnt signaling; osteogenesis; microenvironment
21.  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.
PMCID: PMC3734811  PMID: 23449446
periodontal ligament stem cell; NF-κB; GSK-3β; osteogenic differentiation; inflammation
22.  Effect of pregnancy on emtricitabine pharmacokinetics* 
HIV Medicine  2011;13(4):226-235.
The aim of the study was to describe emtricitabine pharmacokinetics during pregnancy and postpartum.
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.
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.
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.
PMCID: PMC3342997  PMID: 22129166
emtricitabine; HIV; pregnancy; pharmacokinetics
23.  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.
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.
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.
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.
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.
PMCID: PMC3296006  PMID: 22109280
Asians; FTO; Meta-analysis; Obesity; Type 2 diabetes
24.  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.
PMCID: PMC3190110  PMID: 21546908
HIF2α; surviving; neural progenitor cells; apoptosis
25.  A common variant of NOS1AP is associated with QT interval duration in a Chinese population with Type 2 diabetes 
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.
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.
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.
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.
PMCID: PMC2925320  PMID: 20722683
NOS1AP; QT interval; single nucleotide polymorphism

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