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1.  The structure of the symptoms of major depression: exploratory and confirmatory factor analysis in depressed Han Chinese women 
Psychological Medicine  2013;44(7):1391-1401.
The symptoms of major depression (MD) are clinically diverse. Do they form coherent factors that might clarify the underlying nature of this important psychiatric syndrome?
Symptoms at 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. Exploratory factor analysis (EFA) and confirmatoryfactor analysis (CFA) were performed in Mplus in random split-half samples.
The preliminary EFA results were consistently supported by the findings from CFA. Analyses of the nine DSM-IV MD symptomatic A criteria revealed two factors loading on: (i) general depressive symptoms; and (ii) guilt/suicidal ideation. Examining 14 disaggregated DSM-IV criteria revealed three factors reflecting: (i) weight/appetite disturbance; (ii) general depressive symptoms; and (iii) sleep disturbance. Using all symptoms (n = 27), we identified five factors that reflected: (i) weight/appetite symptoms; (ii) general retarded depressive symptoms; (iii) atypical vegetative symptoms; (iv) suicidality/hopelessness; and (v) symptoms of agitation and anxiety.
MD is a clinically complex syndrome with several underlying correlated symptom dimensions. In addition to a general depressive symptom factor, a complete picture must include factors reflecting typical/atypical vegetative symptoms, cognitive symptoms (hopelessness/suicidal ideation), and an agitated symptom factor characterized by anxiety, guilt, helplessness and irritability. Prior cross-cultural studies, factor analyses of MD in Western populations and empirical findings in this sample showing risk factor profiles similar to those seen in Western populations suggest that our results are likely to be broadly representative of the human depressive syndrome.
PMCID: PMC3967839  PMID: 23920138
Atypical symptoms; China; cognitive symptoms; depression; factor analysis
2.  Childhood sexual abuse and the risk for recurrent major depression in Chinese women 
Psychological Medicine  2011;42(2):409-417.
Studies in Western countries have repeatedly shown that women with a history of childhood sexual abuse (CSA) are at increased risk for developing major depression (MD). Would this relationship be found in China?
Three levels of CSA (non-genital, genital, and intercourse) were assessed by self-report in two groups of Han Chinese women: 1970 clinically ascertained with recurrent MD and 2597 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression and regression coefficients by linear or Poisson regression.
Any form of CSA was significantly associated with recurrent MD [OR 3.26, 95% confidence interval (CI) 1.95–5.45]. This association strengthened with increasing CSA severity: non-genital (OR 2.47, 95% CI 1.17–5.23), genital (OR 2.77, 95% CI 1.32–5.83) and intercourse (OR 13.35, 95% CI 1.83–97.42). The association between any form of CSA and MD remained significant after accounting for parental history of depression, childhood emotional neglect (CEN), childhood physical abuse (CPA) and parent–child relationship. Among the depressed women, those with CSA had an earlier age of onset, longer depressive episodes and an increased risk for generalized anxiety disorder (GAD; OR 1.92, 95% CI 1.39–2.66) and dysthymia (OR 2.16, 95% CI 1.52–3.09).
In Chinese women CSA is strongly associated with MD and this association increases with greater severity of CSA. Depressed women with CSA have an earlier age of onset, longer depressive episodes and increased co-morbidity with GAD and dysthymia. Although reporting biases cannot be ruled out, our results are consistent with the hypothesis that, as in Western countries, CSA substantially increases the risk for MD in China.
PMCID: PMC3250087  PMID: 21835095
Childhood sexual abuse; co-morbidity; major depression
3.  Cognitive trio: relationship with major depression and clinical predictors in Han Chinese women 
Psychological Medicine  2013;43(11):2265-2275.
Previous studies support Beck's cognitive model of vulnerability to depression. However, the relationship between his cognitive triad and other clinical features and risk factors among those with major depression (MD) has rarely been systematically studied.
The three key cognitive symptoms of worthlessness, hopelessness and helplessness were assessed during their lifetime worst episode in 1970 Han Chinese women with recurrent MD. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression.
Compared to patients who did not endorse the cognitive trio, those who did had a greater number of DSM-IV A criteria, more individual depressive symptoms, an earlier age at onset, a greater number of episodes, and were more likely to meet diagnostic criteria for melancholia, postnatal depression, dysthymia and anxiety disorders. Hopelessness was highly related to all the suicidal symptomatology, with ORs ranging from 5.92 to 6.51. Neuroticism, stressful life events (SLEs) and a protective parental rearing style were associated with these cognitive symptoms.
During the worst episode of MD in Han Chinese women, the endorsement of the cognitive trio was associated with a worse course of depression and an increased risk of suicide. Individuals with high levels of neuroticism, many SLEs and high parental protectiveness were at increased risk for these cognitive depressive symptoms. As in Western populations, symptoms of the cognitive trio appear to play a central role in the psychopathology of MD in Chinese women.
PMCID: PMC3807662  PMID: 23425530
Cognitive trio; Han Chinese women; major depression; suicide; symptoms
4.  Evaluation of dose reduction and image quality in chest CT using adaptive statistical iterative reconstruction with the same group of patients 
The British Journal of Radiology  2012;85(1018):e906-e911.
The objective of this study was to compare the image quality and radiation dose of chest CT images reconstructed with a blend of adaptive statistical iterative reconstruction (ASIR) and filtered back-projection (FBP) with images generated using conventional FBP.
Patients with chest CT re-examinations were alternately assigned to two scanners with different reconstruction techniques. The study groups included noise index (NI) 11 with 30% ASIR (A30), NI 13 with 40% ASIR (A40), NI 15 with 50% ASIR (A50) and NI 17 with 60% ASIR (A60), sequentially changed every 2 months. The control images were obtained using FBP and NI 11. All acquisitions were performed with automatic dose modulation. Paired t-test and non-parameter test were applied to compare the difference.
The radiation doses were significantly lower in the examinations that used ASIR (p<0.001). The mean dose reduction rate was 27.7%, 45.2%, 57.1% and 71.8% for Groups A30, A40, A50 and A60, respectively. The image quality of Groups A30–A50 was not inferior to that of the control examinations. The image noise of Group A60 was greater and subjective image quality was inferior to that of the control.
ASIR enabled the use of a higher NI with automatic dose modulation. With 50% ASIR and a NI of 15, the effective radiation dose was reduced by 57%, without compromising image quality.
PMCID: PMC3474005  PMID: 22595496
5.  Drug-mediated inhibition of Fli-1 for the treatment of leukemia 
Blood Cancer Journal  2012;2(1):e54-.
The Ets transcription factor, Fli-1 is activated in murine erythroleukemia and overexpressed in various human malignancies including Ewing's sarcoma, induced by the oncogenic fusion protein EWS/Fli-1. Recent studies by our group and others have demonstrated that Fli-1 plays a key role in tumorigenesis, and disrupting its oncogenic function may serve as a potential treatment option for malignancies associated with its overexpression. Herein, we describe the discovery of 30 anti-Fli-1 compounds, characterized into six functional groups. Treatment of murine and human leukemic cell lines with select compounds inhibits Fli-1 protein or mRNA expression, resulting in proliferation arrest and apoptosis. This anti-cancer effect was mediated, at least in part through direct inhibition of Fli-1 function, as anti-Fli-1 drug treatment inhibited Fli-1 DNA binding to target genes, such as SHIP-1 and gata-1, governing hematopoietic differentiation and proliferation. Furthermore, treatment with select Fli-1 inhibitors revealed a positive relationship between the loss of DNA-binding activity and Fli-1 phosphorylation. Accordingly, anti-Fli-1 drug treatment significantly inhibited leukemogenesis in a murine erythroleukemia model overexpressing Fli-1. This study demonstrates the ability of this drug-screening strategy to isolate effective anti-Fli-1 inhibitors and highlights their potential use for the treatment of malignancies overexpressing this oncogene.
PMCID: PMC3270256  PMID: 22829238
erythroleukemia; Fli-1; drug inhibition
6.  Common genetic variability in ESR1 and EGF in relation to endometrial cancer risk and survival 
British Journal of Cancer  2009;100(8):1358-1364.
We investigated common genetic variation in the entire ESR1 and EGF genes in relation to endometrial cancer risk, myometrial invasion and endometrial cancer survival. We genotyped a dense set of single-nucleotide polymorphisms (SNPs) in both genes and selected haplotype tagging SNPs (tagSNPs). The tagSNPs were genotyped in 713 Swedish endometrial cancer cases and 1567 population controls and the results incorporated into logistic regression and Cox proportional hazards models. We found five adjacent tagSNPs covering a region of 15 kb at the 5′ end of ESR1 that decreased the endometrial cancer risk. The ESR1 variants did not, however, seem to affect myometrial invasion or endometrial cancer survival. For the EGF gene, no association emerged between common genetic variants and endometrial cancer risk or myometrial invasion, but we found a five-tagSNP region that covered 51 kb at the 5′ end of the gene where all five tagSNPs seemed to decrease the risk of dying from endometrial cancer. One of the five tagSNPs in this region was in strong linkage disequilibrium (LD) with the untranslated A61G (rs4444903) EGF variant, earlier shown to be associated with risk for other forms of cancer.
PMCID: PMC2676544  PMID: 19319135
ESR1; EGF; polymorphism; endometrial cancer; survival
7.  ASCL1 and RET expression defines a clinically relevant subgroup of lung adenocarcinoma characterized by neuroendocrine differentiation 
Oncogene  2013;33(29):3776-3783.
ASCL1 is an important regulatory transcription factor in pulmonary neuroendocrine (NE) cell development, but its value as a biomarker of NE differentiation in lung adenocarcinoma (AD) and as a potential prognostic biomarker remains unclear. We examined ASCL1 expression in lung cancer samples of varied histologic subtype, clinical outcome and smoking status and compared with expression of traditional NE markers. ASCL1 mRNA expression was found almost exclusively in smokers with AD, in contrast to non-smokers and other lung cancer subtypes. ASCL1 protein expression by immunohistochemical (IHC) analysis correlated best with synaptophysin compared with chromogranin and CD56/NCAM. Analysis of a compendium of 367 microarray-based gene expression profiles in stage I lung adenocarcinomas identified significantly higher expression levels of the RET oncogene in ASCL1-positive tumors (ASCL1+) compared with ASCL1− tumors (q-value <10−9). High levels of RET expression in ASCL1+ but not in ASCL1− tumors was associated with significantly shorter overall survival (OS) in stage 1 (P = 0.007) and in all AD (P = 0.037). RET protein expression by IHC had an association with OS in the context of ASCL1 expression. In silico gene set analysis and in vitro experiments by ASCL1 shRNA in AD cells with high endogenous expression of ASCL1 and RET implicated ASCL1 as a potential upstream regulator of the RET oncogene. Also, silencing ASCL1 in AD cells markedly reduced cell growth and motility. These results suggest that ASCL1 and RET expression defines a clinically relevant subgroup of ∼10% of AD characterized by NE differentiation.
PMCID: PMC4329973  PMID: 24037524
prognostic biomarker; MASH1; lung cancer; neuroendocrine; microarray
8.  STAT signaling in mammary gland differentiation, cell survival and tumorigenesis 
Molecular and cellular endocrinology  2013;382(1):10.1016/j.mce.2013.03.014.
The mammary gland is a unique organ that undergoes extensive and profound changes during puberty, menstruation, pregnancy, lactation and involution. The changes that take place during puberty involve large-scale proliferation and invasion of the fat-pad. During pregnancy and lactation, the mammary cells are exposed to signaling pathways that inhibit apoptosis, induce proliferation and invoke terminal differentiation. Finally, during involution the mammary gland is exposed to milk stasis, programed cell death and stromal reorganization to clear the differentiated milk-producing cells. Not surprisingly, the signaling pathways responsible for bringing about these changes in breast cells are often subverted during the process of tumorigenesis. The STAT family of proteins is involved in every stage of mammary gland development, and is also frequently implicated in breast tumorigenesis. While the roles of STAT3 and STAT5 during mammary gland development and tumorigenesis are well studied, others members, e.g. STAT1 and STAT6, have only recently been observed to play a role in mammary gland biology. Continued investigation into the STAT protein network in the mammary gland will likely yield new biomarkers and risk factors for breast cancer, and may also lead to novel prophylactic or therapeutic strategies against breast cancer.
PMCID: PMC3748257  PMID: 23541951
STATs; mammary gland development; breast cancer; pregnancy; lactation; involution
9.  Gambogic acid synergistically potentiates cisplatin-induced apoptosis in non-small-cell lung cancer through suppressing NF-κB and MAPK/HO-1 signalling 
British Journal of Cancer  2013;110(2):341-352.
Gambogic acid (GA) has been reported to have potent anticancer activity and is authorised to be tested in phase II clinical trials for treatment of non-small-cell lung cancer (NSCLC). The present study aims to investigate whether GA would be synergistic with cisplatin (CDDP) against the NSCLC.
1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), combination index (CI) isobologram, western blot, quantitative PCR, flow cytometry, electrophoretic mobility shift assay, xenograft tumour models and terminal deoxynucleotide transferase-mediated dUTP nick-end labelling analysis were used in this study.
The cell viability results showed that sequential CDDP-GA treatment resulted in a strong synergistic action in A549, NCI-H460, and NCI-H1299 cell lines, whereas the reverse sequence and simultaneous treatments led to a slight synergistic or additive action. Increased sub-G1 phase cells and enhanced PARP cleavage demonstrated that the sequence of CDDP-GA treatment markedly increased apoptosis in comparison with other treatments. Furthermore, the sequential combination could enhance the activation of caspase-3, -8, and 9, increase the expression of Fas and Bax, and decrease the expression of Bcl-2, survivin and X-inhibitor of apoptosis protein (X-IAP) in A549 and NCI-H460 cell lines. In addition, increased apoptosis was correlated with enhanced reactive oxygen species generation. Importantly, it was found that, followed by CDDP treatment, GA could inhibit NF-κB and mitogen-activated protein kinase (MAPK)/heme oxygenase-1 (HO-1) signalling pathways, which have been validated to reduce ROS release and confer CDDP resistance. The roles of NF-κB and MAPK pathways were further confirmed by using specific inhibitors, which significantly increased ROS release and apoptosis induced by the sequential combination of CDDP and GA. Moreover, our results indicated that the combination of CDDP and GA exerted increased antitumour effects on A549 xenograft models through inhibiting NF-κB, HO-1, and subsequently inducing apoptosis.
Gambogic acid sensitises lung cancer cells to CDDP in vitro and in vivo in NSCLC through inactivation of NF-κB and MAPK/HO-1 signalling pathways, providing a rationale for the combined use of CDDP and GA in lung cancer chemotherapy.
PMCID: PMC3899775  PMID: 24300974
gambogic acid; cisplatin; lung cancer; NF-κB; apoptosis; heme oxygenase-1
10.  Morphine stimulates platelet-derived growth factor receptor-β signalling in mesangial cells in vitro and transgenic sickle mouse kidney in vivo 
BJA: British Journal of Anaesthesia  2013;111(6):1004-1012.
Pain and renal dysfunction occur in sickle cell disease. Morphine used to treat pain also co-activates platelet-derived growth factor receptor-β (PDGFR-β), which can adversely affect renal disease. We examined the influence of morphine in mesangial cells in vitro and in mouse kidneys in vivo.
Mouse mesangial cells treated with 1 μM morphine in vitro or kidneys of transgenic homozygous or hemizygous sickle or control mice (n=3 for each), treated with morphine (0.75, 1.4, 2.14, 2.8, 3.6, and 4.3 mg kg−1 day−1 in two divided doses during the first, second, third, fourth, fifth, and sixth weeks, respectively), were used. Western blotting, bromylated deoxy uridine incorporation-based cell proliferation assay, reverse transcriptase-polymerase chain reaction, immunofluorescent microscopy, and blood/urine chemistry were used to analyse signalling, cell proliferation, opioid receptor (OP) expression, and renal function.
Morphine stimulated phosphorylation of PDGFR-β and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) to the same extent as induced by platelet-derived growth factor-BB (PDGF-BB) and promoted a two-fold increase in mesangial cell proliferation. The PDGFR-β inhibitor, AG1296, OP antagonists, and silencing of μ- and κ-OP abrogated morphine-induced MAPK/ERK phosphorylation and proliferation by ∼100%. Morphine treatment of transgenic mice resulted in phosphorylation of PDGFR-β, MAPK/ERK, and signal transducer and activator of transcription 3 (Stat3) in the kidneys. Morphine inhibited micturition and blood urea nitrogen (BUN) clearance and increased BUN and urinary protein in sickle mice.
Morphine stimulates mitogenic signalling leading to mesangial cell proliferation and promotes renal dysfunction in sickle mice.
PMCID: PMC3828056  PMID: 23820675
morphine; nephropathy; pain; platelet-derived growth factor; sickle cell disease
11.  M180 Amelogenin Processed by MMP20 is Sufficient for Decussating Murine Enamel 
Journal of Dental Research  2013;92(12):1118-1122.
Amelogenin (AMELX) and matrix metalloproteinase-20 (MMP20) are essential for proper enamel development. Amelx and Mmp20 mutations cause amelogenesis imperfecta. MMP20, a protease secreted by ameloblasts, is responsible for processing enamel proteins, including AMELX, during the secretory stage of enamel formation. Of at least 16 different amelogenin splice products, the most abundant isoform found in murine ameloblasts and developing enamel is the M180 protein. To understand the role of MMP20 processing of M180 AMELX, we generated AmelxKO/Mmp20KO (DKO) mice with an amelogenin (M180Tg) transgene. We analyzed the enamel phenotype by SEM to determine enamel structure and thickness, µCT, and by nanoindentation to quantify enamel mechanical properties. M180Tg/DKO mouse enamel had 37% of the hardness of M180Tg/AmelxKO teeth and demonstrated a complete lack of normal prismatic architecture. Although molar enamel of M180Tg/AmelxKO mice was thinner than WT, it had similar mechanical properties and decussating enamel prisms, which were abolished by the loss of MMP20 in the M180Tg/DKO mice. Retention of the C-terminus or complete lack of this domain is unable to rescue amelogenin null enamel. We conclude that among amelogenins, M180 alone is sufficient for normal enamel mechanical properties and prism patterns, but that additional amelogenin splice products are required to restore enamel thickness.
PMCID: PMC3834654  PMID: 24072097
matrix metalloproteinase-20; knockout mouse; transgenic mouse; amelogenesis; imperfecta; ameloblasts; tooth calcification
12.  Infected hematopoietic stem cells and with integrated HBV DNA generate defective T cells in chronic HBV infection patients 
Shi, Y | Lan, Y | Cao, F | Teng, Y | Li, L | Wang, F | Li, J | Zhou, J | Li, Y
Journal of Viral Hepatitis  2014;21(7):e39-e47.
A weak T-cell response plays a key role in the persistence of hepatitis B virus (HBV) infection. We aimed to confirm that T-cell defects in patients with chronic HBV infection are associated with HBV DNA infection of bone marrow (BM) hematopoietic stem cells (HSCs). Using reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH), we observed the transcription of HBsAg coding genes and confirmed the integration of HBV DNA in CD34+ BM HSCs from chronic HBV infection patients. T cells were generated by coculturing the HSCs with delta-like ligand 1-expressing OP9 (OP9-DL1) cells. The phenotypes of the T cells were then evaluated by flow cytometric (FACS) analysis on days 14 and 25. The results demonstrated that fewer CD3+TCRaβ+ CD3+CD4+ and CD4+CD8+ T cells were generated from the HSCs of the patients than from the healthy controls, (P < 0.01) but the frequency of CD3+D8+ T cells was not significantly different between the two group (P > 0.05). In contrast, CD4+CD25+ T cells were more in the patient group than in healthy controls (P < 0.01) on both days 14 and 25. There were fewer CD3+CD4+/CD3+CD8+ cells in the patient group than in the healthy control group on day 25 (P < 0.05). Less proliferation and lower levels of IL-2 and IFN- γ were also observed in the patient group compared with the control group (P < 0.05).These data suggest that HBV DNA infected and integrated into the BM HSCs from patients with chronic HBV infection and that these BM HSCs generated defective T cells.
PMCID: PMC4237112  PMID: 24620791
HBV DNA; HSCs; integration; replication; T-cell defects
13.  Mitochondrial dysfunction-associated OPA1 cleavage contributes to muscle degeneration: preventative effect of hydroxytyrosol acetate 
Wang, X | Li, H | Zheng, A | Yang, L | Liu, J | Chen, C | Tang, Y | Zou, X | Li, Y | Long, J | Liu, J | Zhang, Y | Feng, Z
Cell Death & Disease  2014;5(11):e1521-.
Mitochondrial dysfunction contributes to the development of muscle disorders, including muscle wasting, muscle atrophy and degeneration. Despite the knowledge that oxidative stress closely interacts with mitochondrial dysfunction, the detailed mechanisms remain obscure. In this study, tert-butylhydroperoxide (t-BHP) was used to induce oxidative stress on differentiated C2C12 myotubes. t-BHP induced significant mitochondrial dysfunction in a time-dependent manner, accompanied by decreased myosin heavy chain (MyHC) expression at both the mRNA and protein levels. Consistently, endogenous reactive oxygen species (ROS) overproduction triggered by carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP), a mitochondrial oxidative phosphorylation inhibitor, was accompanied by decreased membrane potential and decreased MyHC protein content. However, the free radical scavenger N-acetyl-L-cysteine (NAC) efficiently reduced the ROS level and restored MyHC content, suggesting a close association between ROS and MyHC expression. Meanwhile, we found that both t-BHP and FCCP promoted the cleavage of optic atrophy 1 (OPA1) from the long form into short form during the early stages. In addition, the ATPase family gene 3-like 2, a mitochondrial inner membrane protease, was also markedly increased. Moreover, OPA1 knockdown in myotubes was accompanied by decreased MyHC content, whereas NAC failed to prevent FCCP-induced MyHC decrease with OPA1 knockdown, suggesting that ROS might affect MyHC content by modulating OPA1 cleavage. In addition, hydroxytyrosol acetate (HT-AC), an important compound in virgin olive oil, could significantly prevent t-BHP-induced mitochondrial membrane potential and cell viability loss in myotubes. Specifically, HT-AC inhibited t-BHP-induced OPA1 cleavage and mitochondrial morphology changes, accompanied by improvement on mitochondrial oxygen consumption capacity, ATP productive potential and activities of mitochondrial complex I, II and V. Moreover, both t-BHP- and FCCP-induced MyHC decrease was sufficiently inhibited by HT-AC. Taken together, our data provide evidence indicating that mitochondrial dysfunction-associated OPA1 cleavage may contribute to muscle degeneration, and olive oil compounds could be effective nutrients for preventing the development of muscle disorders.
PMCID: PMC4260731  PMID: 25393477
14.  Shear bond strength of dentin and deproteinized enamel of AI mouse incisors 
Pediatric dentistry  2014;36(5):130-136.
To investigate the adhesion through shear bond strength (SBS) testing of a resin composite bonded with a self-etching bonding system (SEB) to amelogenesis imperfecta (AI)-affected deproteinized mouse enamel or dentin; and to compare wild-type (WT), amelogenin null (AmelxKO) and matrix metalloproteinase-20 null (Mmp20KO) enamel and dentin phenotypes using microCT and nanoindentation.
Enamel incisor surfaces of WT, AmelxKO and Mmp20KO mice were treated with SEB with and without NaOCl and tested for SBS. Incisor dentin was also treated with SEB and tested for SBS. These surfaces were further examined by SEM. MicroCT and nanoindentation analyses were performed on mouse dentin and enamel. Data were analyzed for significance by ANOVA.
Deproteinization did not improve SBS of SEB to these AI-affected enamel surfaces. SBS of AmelxKO teeth was similar in dentin and enamel; however, it was higher in Mmp20KO dentin. The nanohardness of knockout enamel was significantly lower than WT, while knockout dentin nanohardness was not different from WT.
Using animal AI models, it was demonstrated that enamel NaOCl deproteinization of hypoplastic and hypoplastic-hypomaturation enamel did not increase shear bond strength while removal of the defective enamel allowed optimal dentin bonding.
PMCID: PMC4196710  PMID: 25303500
Amelogenesis imperfecta; dentin bonding; enamel
15.  Predicting response and survival in chemotherapy-treated triple-negative breast cancer 
British Journal of Cancer  2014;111(8):1532-1541.
In this study, we evaluated the ability of gene expression profiles to predict chemotherapy response and survival in triple-negative breast cancer (TNBC).
Gene expression and clinical–pathological data were evaluated in five independent cohorts, including three randomised clinical trials for a total of 1055 patients with TNBC, basal-like disease (BLBC) or both. Previously defined intrinsic molecular subtype and a proliferation signature were determined and tested. Each signature was tested using multivariable logistic regression models (for pCR (pathological complete response)) and Cox models (for survival). Within TNBC, interactions between each signature and the basal-like subtype (vs other subtypes) for predicting either pCR or survival were investigated.
Within TNBC, all intrinsic subtypes were identified but BLBC predominated (55–81%). Significant associations between genomic signatures and response and survival after chemotherapy were only identified within BLBC and not within TNBC as a whole. In particular, high expression of a previously identified proliferation signature, or low expression of the luminal A signature, was found independently associated with pCR and improved survival following chemotherapy across different cohorts. Significant interaction tests were only obtained between each signature and the BLBC subtype for prediction of chemotherapy response or survival.
The proliferation signature predicts response and improved survival after chemotherapy, but only within BLBC. This highlights the clinical implications of TNBC heterogeneity, and suggests that future clinical trials focused on this phenotypic subtype should consider stratifying patients as having BLBC or not.
PMCID: PMC4200088  PMID: 25101563
breast cancer; genomics; subtypes; intrinsic; basal like; chemotherapy; neoadjuvant
16.  Antiviral RNA Interference in Mammalian Cells 
Science (New York, N.Y.)  2013;342(6155):10.1126/science.1241930.
In antiviral RNA interference (RNAi), the DICER enzyme processes virus-derived double-stranded RNA (dsRNA) into small interfering RNAs (siRNAs) that guide ARGONAUTE proteins to silence complementary viral RNA. As a counterdefense, viruses deploy viral suppressors of RNAi (VSRs). Well-established in plants and invertebrates, the existence of antiviral RNAi remains unknown in mammals. Here, we show that undifferentiated mouse cells infected with encephalomyocarditis virus (EMCV) or Nodamura virus (NoV) accumulate ~22-nucleotide RNAs with all the signature features of siRNAs. These derive from viral dsRNA replication intermediates, incorporate into AGO2, are eliminated in Dicer knockout cells, and decrease in abundance upon cell differentiation. Furthermore, genetically ablating a NoV-encoded VSR that antagonizes DICER during authentic infections reduces NoV accumulation, which is rescued in RNAi-deficient mouse cells. We conclude that antiviral RNAi operates in mammalian cells.
PMCID: PMC3853215  PMID: 24115438
17.  Shame, guilt, and communication in lung cancer patients and their partners 
Current Oncology  2014;21(5):e718-e722.
Lung cancer patients report the highest distress levels of all cancer groups. In addition to poor prognosis, the self-blame and stigma associated with smoking might partially account for that distress and prevent patients from requesting help and communicating with their partners. The present study used innovative methods to investigate potential links of shame and guilt in lung cancer recovery with distress and marital adjustment. A specific emphasis was an examination of the impact of shame on partner communication. Lung cancer patients (n = 8) and their partners (n = 8) completed questionnaires and interviews that were videotaped. We report descriptive statistics and Spearman correlations between shame and guilt, relationship talk, marital satisfaction, distress, and smoking status. We coded the interviews for nonverbal expressions of shame.
Greater self-reported shame was associated with decreased relationship-talk frequency and marital satisfaction, and with increased depression and smoking behaviour. Nonverbal shame behaviour also correlated with higher depression and increased smoking behaviour. Guilt results were more mixed. More recent smoking behaviour also correlated with higher depression. At a time when lung cancer patients often do not request help for distress, possibly because of shame, our preliminary study suggests that shame can also disrupt important partner relationships and might prevent patients from disclosing to physicians their need for psychosocial intervention and might increase their social isolation. Even if patients cannot verbally disclose their distress, nonverbal cues could potentially give clinicians an opportunity to intervene.
PMCID: PMC4189577  PMID: 25302043
Lung cancer; shame; guilt; communication; relationships; smoking
18.  PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways 
Cell Death & Disease  2014;5(10):e1437-.
The PI3K/Akt/mTOR pathway has a central role in cancer metastasis and radiotherapy. To develop effective therapeutics to improve radiosensitivity, understanding the possible pathways of radioresistance involved and the effects of a combination of the PI3K/Akt/mTOR inhibitors with radiotherapy on prostate cancer (CaP) radioresistant cells is needed. We found that compared with parent CaP cells, CaP-radioresistant cells demonstrated G0/G1 and S phase arrest, activation of cell cycle check point, autophagy and DNA repair pathway proteins, and inactivation of apoptotic proteins. We also demonstrated that compared with combination of single PI3K or mTOR inhibitors (BKM120 or Rapamycin) and radiation, low-dose of dual PI3K/mTOR inhibitors (BEZ235 or PI103) combined with radiation greatly improved treatment efficacy by repressing colony formation, inducing more apoptosis, leading to the arrest of the G2/M phase, increased double-strand break levels and less inactivation of cell cycle check point, autophagy and non-homologous end joining (NHEJ)/homologous recombination (HR) repair pathway proteins in CaP-radioresistant cells. This study describes the possible pathways associated with CaP radioresistance and demonstrates the putative mechanisms of the radiosensitization effect in CaP-resistant cells in the combination treatment. The findings from this study suggest that the combination of dual PI3K/Akt/mTOR inhibitors (BEZ235 or PI103) with radiotherapy is a promising modality for the treatment of CaP to overcome radioresistance.
PMCID: PMC4237243  PMID: 25275598
19.  Mediterranean Diet and Magnetic Resonance Imaging-Assessed Brain Atrophy in Cognitively Normal Individuals at Risk for Alzheimer's Disease 
Epidemiological evidence linking diet, one of the most important modifiable environmental factors, and risk of Alzheimer's disease (AD) is rapidly increasing. Several studies have shown that higher adherence to a Mediterranean diet (MeDi) is associated with reduced risk of AD. This study examines the associations between high vs. lower adherence to a MeDi and structural MRI-based brain atrophy in key regions for AD in cognitively normal (NL) individuals with and without risk factors for AD.
Cross-sectional study.
Manhattan (broader area).
Fifty-two NL individuals (age 54+12 y, 70% women) with complete dietary information and cross-sectional, 3D T1-weighted MRI scans were examined.
Subjects were dichotomized into those showing higher vs. lower adherences to the MeDi using published protocols. Estimates of cortical thickness for entorhinal cortex (EC), inferior parietal lobe, middle temporal gyrus, orbitofrontal cortex (OFC) and posterior cingulate cortex (PCC) were obtained by use of automated segmentation tools (FreeSurfer). Multivariate general linear models and linear regressions assessed the associations of MeDi with MRI measures.
Of the 52 participants, 20 (39%) showed higher MeDi adherence (MeDi+) and 32 (61%) showed lower adherence (MeDi-). Groups were comparable for clinical, neuropsychological measures, presence of a family history of AD (FH), and frequency of Apolipoprotein E (APOE) ε4 genotype. With and without controlling for age and total intracranial volume, MeDi+ subjects showed greater thickness of AD-vulnerable ROIs as compared to MeDi- subjects (Wilk's Lambda p=0.026). Group differences were most pronounced in OFC (p=0.001), EC (p=0.03) and PCC (p=0.04) of the left hemisphere. Adjusting for gender, education, FH, APOE status, BMI, insulin resistance scores and presence of hypertension did not attenuate the relationship.
NL individuals showing lower adherence to the MeDi had cortical thinning in the same brain regions as clinical AD patients compared to those showing higher adherence. These data indicate that the MeDi may have a protective effect against tissue loss, and suggest that dietary interventions may play a role in the prevention of AD.
PMCID: PMC4165397  PMID: 25237654
Alzheimer's disease; diet; Mediterranean diet; magnetic resonance imaging (MRI); early detection; brain imaging
20.  Predicting Treatment Effects Using Biomarker Data in a Meta-Analysis of Clinical Trials 
Statistics in medicine  2010;29(18):1875-1889.
A biomarker (S) measured after randomization in a clinical trial can often provide information about the true endpoint (T) and hence the effect of treatment (Z). It can usually be measured earlier and more easily than T and as such may be useful to shorten the trial length. A potential use of S is to completely replace T as a surrogate endpoint to evaluate whether the treatment is effective. Another potential use of S is to serve as an auxiliary variable to help provide information and improve the inference on the treatment effect prediction when T is not completely observed. The objective of this report is to focus on its role as an auxiliary variable and to identify situations when S can be useful to increase efficiency in predicting the treatment effect in a new trial in a multiple-trial setting. Both S and T are continuous. We find that higher efficiency gain is associated with higher trial-level correlation but not individual-level correlation when only S, but not T is measured in a new trial; but, the amount of information recovery from S is usually negligible. However, when T is partially observed in the new trial and the individual-level correlation is relatively high, there is substantial efficiency gain by using S. For design purposes, our results suggest that it is often important to collect markers that have high adjusted individual-level correlation with T and at least a small amount of data on T. The results are illustrated using simulations and an example from a glaucoma clinical trial.
PMCID: PMC4153610  PMID: 20680981
auxiliary variables; biomarker; clinical trials; meta analysis; mixed model; surrogate
21.  Iodine quantification with dual-energy CT: phantom study and preliminary experience with VX2 residual tumour in rabbits after radiofrequency ablation 
Li, Y | Shi, G | Wang, S | Wang, S | Wu, R
The British Journal of Radiology  2013;86(1029):20130143.
The purpose of our study was to validate iodine quantification in a phantom study with dual-source dual-energy CT (DECT) and to apply this technique to differentiate benign periablational reactive tissue from residual tumour in VX2 carcinoma in rabbits after radiofrequency ablation (RFA).
We applied iodine quantification with DECT in a phantom and in VX2 carcinoma in rabbits after incomplete RFA to differentiate benign periablational reactive tissue from residual tumour and evaluated its efficacy in demonstrating response to therapeutic RFA. A series of tubes containing solutions of varying iodine concentration were scanned with DECT. The iodine concentration was calculated and compared with known true iodine concentration. Triple-phase contrast-enhanced DECT data on 24 rabbits with VX2 carcinoma were then assessed at Day 3 (n=6), 1 week (n=6), 2 weeks (n=6) and 3 weeks (n=6) after incomplete RFA independently by 2 readers. Dual-energy postprocessing was used to produce iodine-only images. Regions of interest were positioned on the iodine image over the lesion and, as a reference, over the aorta, to record iodine concentration in the lesion and in the aorta. The pathological specimens were sectioned in the same plane as DECT imaging, and the lesion iodine concentration and lesion-to-aorta iodine ratio of residual tumour and benign periablational reactive tissue were assessed.
There was excellent correlation between calculated and true iodine concentration (r=0.999, p<0.0001) in the phantom study. The lesion iodine concentration and lesion-to-aorta iodine ratio in residual tumour were significantly higher than in benign periablational reactive tissue in the 2-week group during the arterial phase (AP) (p<0.01) and in the 3-week group during both the AP (p<0.05) and the portal venous phase (p<0.05). There was no significant difference between them with respect to the lesion iodine concentration or lesion-to-aorta iodine ratio in the 3-day and 1-week groups.
Iodine quantification with DECT is accurate in a phantom study and can be used to differentiate benign periablational reactive tissue from residual tumour in VX2 carcinoma in rabbits after RFA.
Advances in knowledge:
Iodine quantification with DECT may help in differentiating benign periablational reactive tissue from residual tumour in VX2 carcinoma in rabbits after RFA.
PMCID: PMC3755393  PMID: 23884759
22.  Daily physical activity and physical function in adult maintenance hemodialysis patients 
Maintenance hemodialysis (MHD) patients reportedly display reduced daily physical activity (DPA) and physical performance. Low daily physical activity and decreased physical performance are each associated with worse outcomes in chronic kidney disease patients. Although daily physical activity and physical performance might be expected to be related, few studies have examined such relationships in MHD patients, and methods for examining daily physical activity often utilized questionnaires rather than activity monitors. We hypothesized that daily physical activity and physical performance are reduced and correlated with each other even in relatively healthier MHD patients.
Daily physical activity, 6-min walk distance (6-MWT), sit-to-stand, and stair-climbing tests were measured in 72 MHD patients (32 % diabetics) with limited comorbidities and 39 normal adults of similar age and gender mix. Daily physical activity was examined by a physical activity monitor. The human activity profile was also employed.
Daily physical activity with the activity monitor, time-averaged over 7 days, and all three physical performance tests were impaired in MHD patients, to about 60–70 % of normal values (p < 0.0001 for each measurement). Human activity profile scores were also impaired (p < 0.0001). MHD patients spent more time sleeping or in marked physical inactivity (p < 0.0001) and less time in ≥ moderate activity (p < 0.0001). These findings persisted when comparisons to normals were restricted to men or women separately. After adjustment, daily physical activity correlated with 6-MWT but not the two other physical performance tests. Human activity profile scores correlated more closely with all three performance tests than did DPA.
Even in relatively healthy MHD patients, daily physical activity and physical performance are substantially impaired and correlated. Whether training that increases daily physical activity or physical performance will improve clinical outcome in MHD patients needs to be examined.
PMCID: PMC4159490  PMID: 24777474
Chronic kidney disease; Kidney failure; Physical performance; Exercise; Exercise capacity
23.  MiR-630 inhibits proliferation by targeting CDC7 kinase, but maintains the apoptotic balance by targeting multiple modulators in human lung cancer A549 cells 
Cell Death & Disease  2014;5(9):e1426-.
MicroRNAome analyses have shown microRNA-630 (miR-630) to be involved in the regulation of apoptosis. However, its apoptotic role is still debated and its participation in DNA replication is unknown. Here, we demonstrate that miR-630 inhibits cell proliferation by targeting cell-cycle kinase 7 (CDC7) kinase, but maintains the apoptotic balance by targeting multiple activators of apoptosis under genotoxic stress. We identified a novel regulatory mechanism of CDC7 gene expression, in which miR-630 downregulated CDC7 expression by recognizing and binding to four binding sites in CDC7 3'-UTR. We found that miR-630 was highly expressed in A549 and NIH3T3 cells where CDC7 was downregulated, but lower in H1299, MCF7, MDA-MB-231, HeLa and 2BS cells where CDC7 was upregulated. Furthermore, the induction of miR-630 occurred commonly in a variety of human cancer and immortalized cells in response to genotoxic agents. Importantly, downregulation of CDC7 by miR-630 was associated with cisplatin (CIS)-induced inhibitory proliferation in A549 cells. Mechanistically, miR-630 exerted its inhibitory proliferation by blocking CDC7-mediated initiation of DNA synthesis and by inducing G1 arrest, but maintains apoptotic balance under CIS exposure. On the one hand, miR-630 promoted apoptosis by downregulation of CDC7; on the other hand, it reduced apoptosis by downregulating several apoptotic modulators such as PARP3, DDIT4, EP300 and EP300 downstream effector p53, thereby maintaining the apoptotic balance. Our data indicate that miR-630 has a bimodal role in the regulation of apoptosis in response to DNA damage. Our data also support the notion that a certain mRNA can be targeted by several miRNAs, and in particular an miRNA may target a set of mRNAs. These data afford a comprehensive view of microRNA-dependent control of gene expression in the regulation of apoptosis under genotoxic stress.
PMCID: PMC4225225  PMID: 25255219
24.  Anomalous magnetism in strained La1-xSrxCoO3 epitaxial films (0 ≤ x ≤ 0.5) 
Scientific Reports  2014;4:6206.
Spin state controlling has always been a focus of intensive studies due to its importance for novel effect exploration and information technology. Complex oxides with competitive mechanisms are suitable objects of study for this purpose due to their susceptibility to external stimuli. Perovskite cobaltate La1-xSrxCoO3 is one of such oxides. Combined effects of lattice strains and hole-doping have been studied for the LSCO films with 0 ≤ x ≤ 0.5. It is found that the lattice strain, either tensile or compressive, destabilizes the ferromagnetic (FM) state of the epitaxial films, leading to a nonmagnetic state that extensively exists in a doping window embedding deep into the range of the FM phase in bulk counterparts. Density functional theory calculations reveal a distinct spin state transition due to the combined effects of lattice distortion and hole-doping, explaining the unique magnetic behaviors of LSCO.
PMCID: PMC4145284  PMID: 25158695
25.  Relevant mouse model for human monocytic leukemia through Cre/lox-controlled myeloid-specific deletion of PTEN 
Leukemia  2010;24(5):1077-1080.
PMCID: PMC4134872  PMID: 20220776

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