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2.  CD123 targeting oncolytic adenoviruses suppress acute myeloid leukemia cell proliferation in vitro and in vivo 
Li, G | Li, X | Wu, H | Yang, X | Zhang, Y | Chen, L | Wu, X | Cui, L | Wu, L | Luo, J | Liu, X Y
Blood Cancer Journal  2014;4(3):e194-.
We report here a novel strategy to redirect oncolytic adenoviruses to CD123 by carry a soluble coxsackie-adenovirus receptor (sCAR)-IL3 expression cassette in the viral genome to form Ad.IL3, which sustainably infected acute myeloid leukemia (AML) cells through CD123. Ad.IL3 was further engineered to harbor gene encoding manganese superoxide dismutase (MnSOD) or mannose-binding plant lectin Pinellia pedatisecta agglutinin (PPA), forming Ad.IL3-MnSOD and Ad.IL3-PPA. As compared with Ad.IL3 or Ad.sp-E1A control, Ad.IL3-MnSOD and Ad.IL3-PPA significantly suppressed in vitro proliferation of HL60 and KG-1 cells. Elevated apoptosis was detected in HL60 and KG-1 cells treated with either Ad.IL3-MnSOD or Ad.IL3-PPA. The caspase-9–caspase-7 pathway was determined to be activated by Ad.IL3-MnSOD as well as by Ad.IL3-PPA in HL60 cells. In an HL60/Luc xenograft nonobese diabetic/severe-combined immunodeficiency mice model, Ad.IL3-MnSOD and Ad.IL3-PPA suppressed cancer cell growth as compared with Ad.IL3. A significant difference of cancer cell burden was detected between Ad.IL3 and Ad.IL3-PPA groups at day 9 after treatment. Furthermore, Ad.IL3-MnSOD significantly prolonged mouse survival as compared with Ad.sp-E1A. These findings demonstrated that Ad.IL3-gene could serve as a novel agent for AML therapy. Harboring sCAR-ligand expression cassette in the viral genome may provide a universal method to redirect oncolytic adenoviruses to various membrane receptors on cancer cells resisting serotype 5 adenovirus infection.
doi:10.1038/bcj.2014.15
PMCID: PMC3972701  PMID: 24658372
3.  Synergistic action by multi-targeting compounds produces a potent compound combination for human NSCLC both in vitro and in vivo 
Zhang, C | Zhai, S | Li, X | Zhang, Q | Wu, L | Liu, Y | Jiang, C | Zhou, H | Li, F | Zhang, S | Su, G | Zhang, B | Yan, B
Cell Death & Disease  2014;5(3):e1138-.
By screening a collection of one hundred combinations of thiazolidinone compounds, we identified one combination (M4) that synergistically inhibited the growth of H460 and H460/TaxR cells and tumor growth in H460/TaxR xenograft mice. A whole genome microarray assay showed that genes involved in negative regulation of microtubule polymerization or depolymerization, intracellular protein kinase cascade, positive regulation of histone acetylation, cell cycle arrest and apoptosis were upregulated. Further analysis proved that the four compounds act as either microtubule polymerization inhibitors or histone deacetylase inhibitors. They act synergistically targeting multiple proteins and leading to the regulation of cell cycle checkpoint proteins, including p53, p21, cdc25C and cdc2, the activation of caspases, JNK, p38 cascades and the inactivation of Akt. These events resulted in the G2/M cell cycle arrest and cell apoptosis. These data provide a new strategy for discovering anticancer drugs and drug combinations for drug-resistant cancers.
doi:10.1038/cddis.2014.76
PMCID: PMC3973217  PMID: 24651441
thiazolidinone; combination therapy; synergistic effect; histone deacetylase inhibitor; P-glycoprotein; apoptosis
4.  Induction of autophagy and senescence by knockdown of ROC1 E3 ubiquitin ligase to suppress the growth of liver cancer cells 
Yang, D | Li, L | Liu, H | Wu, L | Luo, Z | Li, H | Zheng, S | Gao, H | Chu, Y | Sun, Y | Liu, J | Jia, L
Cell Death and Differentiation  2012;20(2):235-247.
Regulator of Cullins-1 (ROC1) or RING box protein-1 (RBX1) is an essential RING component of Cullin-RING ligase (CRL). Our previous studies showed that ROC1 is required for the growth of several cancer cell lines while ROC1 siRNA silencing inactivates CRL, leading to cell cycle arrest, cell senescence and/or apoptosis. However, it is completely unknown whether ROC1 knockdown triggers autophagic response by inactivating CRL. Moreover, the role of ROC1 in liver cancer remains elusive. In this study, we reported that ROC1 knockdown significantly inhibited the growth of liver cancer cells by sequentially and independently inducing autophagy and p21-dependent cell senescence. Mechanism analysis revealed that ROC1 silencing triggered autophagy by inhibition of mammalian target of rapamycin (mTOR) activity due to accumulation of mTOR-inhibitory protein Deptor, a substrate of CRL. Consistently, Deptor knockdown significantly blocked autophagy response upon ROC1 silencing. Biologically, autophagy response upon ROC1 silencing was a survival signal, and blockage of autophagy pathway sensitized cancer cells to apoptosis. Finally, we demonstrated that ROC1 was overexpressed in hepatocellular carcinomas, which is associated with poor prognosis of liver cancer patients. These findings suggest that ROC1 is an appealing drug target for liver cancer and provide a proof-of-concept evidence for a novel drug combination of ROC1 inhibitor and an autophagy inhibitor for effective treatment of liver cancer by enhancing apoptosis.
doi:10.1038/cdd.2012.113
PMCID: PMC3554346  PMID: 22935614
ROC1; Cullin-RING ligase; autophagy; senescence; Deptor
5.  CCN3/NOV gene expression in human prostate cancer is directly suppressed by the androgen receptor 
Wu, L | Runkle, C | Jin, H-J | Yu, J | Li, J | Yang, X | Kuzel, T | Lee, C | Yu, J
Oncogene  2013;33(4):504-513.
Androgen receptor (AR) has essential roles during prostate cancer progression. With genome-wide AR-binding sites mapped to high resolution, studies have recently reported AR as a transcriptional repressor. How AR inhibits gene expression and how this contributes to prostate cancer, however, are incompletely understood. Through meta-analysis of microarray data, here we nominate nephroblastoma overexpressed (NOV) as a top androgen-repressed gene. We show that NOV is directly suppressed by androgen through the AR. AR occupies the NOV enhancer and communicates with the NOV promoter through DNA looping. AR activation recruits the polycomb group protein EZH2, which subsequently catalyzes histone H3 lysine 27 tri-methylation around the NOV promoter, thus leading to repressive chromatin remodeling and epigenetic silencing. Concordantly, AR and EZH2 inhibition synergistically restored NOV expression. NOV is downregulated in human prostate cancer wherein AR and EZH2 are upregulated. Functionally, NOV inhibits prostate cancer cell growth in vitro and in vivo. NOV reconstitution reverses androgen-induced cell growth and NOV knockdown drives androgen-independent cell growth. In addition, NOV expression is restored by hormone-deprivation therapies in mice and prostate cancer patients. Therefore, using NOV as a model gene we gained further understanding of the mechanisms underlying AR-mediated transcriptional repression. Our findings establish a tumor-suppressive role of NOV in prostate cancer and suggest that one important, but previously underestimated, manner by which AR contributes to prostate cancer progression is through inhibition of key tumor-suppressor genes.
doi:10.1038/onc.2012.602
PMCID: PMC3796014  PMID: 23318417
androgen receptor; polycomb EZH2; NOV; CCN3
6.  Towards stable silicon nanoarray hybrid solar cells 
Scientific Reports  2014;4:3715.
Silicon nanoarray hybrid solar cells benefit from the ease of fabrication and the cost-effectiveness of the hybrid structure, and represent a new research focus towards the utilization of solar energy. However, hybrid solar cells composed of both inorganic and organic components suffer from the notorious stability issue, which has to be tackled before the hybrid solar cells could become a viable alternative for harvesting solar energy. Here we show that Si nanoarray/PEDOT:PSS hybrid solar cells with improved stability can be fabricated via eliminating the water inclusion in the initial formation of the heterojunction between Si nanoarray and PEDOT:PSS. The Si nanoarray hybrid solar cells are stable against rapid degradation in the atmosphere environment for several months without encapsulation. This finding paves the way towards the real-world applications of Si nanoarray hybrid solar cells.
doi:10.1038/srep03715
PMCID: PMC3893641  PMID: 24430057
7.  CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications 
Leukemia  2013;28(1):155-165.
The key nuclear export protein CRM1/XPO1 may represent a promising novel therapeutic target in human multiple myeloma (MM). Here we showed that chromosome region maintenance 1 (CRM1) is highly expressed in patients with MM, plasma cell leukemia cells and increased in patient cells resistant to bortezomib treatment. CRM1 expression also correlates with increased lytic bone and shorter survival. Importantly, CRM1 knockdown inhibits MM cell viability. Novel, oral, irreversible selective inhibitors of nuclear export (SINEs) targeting CRM1 (KPT-185, KPT-330) induce cytotoxicity against MM cells (ED50<200 nM), alone and cocultured with bone marrow stromal cells (BMSCs) or osteoclasts (OC). SINEs trigger nuclear accumulation of multiple CRM1 cargo tumor suppressor proteins followed by growth arrest and apoptosis in MM cells. They further block c-myc, Mcl-1, and nuclear factor κB (NF-κB) activity. SINEs induce proteasome-dependent CRM1 protein degradation; concurrently, they upregulate CRM1, p53-targeted, apoptosis-related, anti-inflammatory and stress-related gene transcripts in MM cells. In SCID mice with diffuse human MM bone lesions, SINEs show strong anti-MM activity, inhibit MM-induced bone lysis and prolong survival. Moreover, SINEs directly impair osteoclastogenesis and bone resorption via blockade of RANKL-induced NF-κB and NFATc1, with minimal impact on osteoblasts and BMSCs. These results support clinical development of SINE CRM1 antagonists to improve patient outcome in MM.
doi:10.1038/leu.2013.115
PMCID: PMC3883926  PMID: 23588715
multiple myeloma (MM); selective inhibitors of nuclear export (SINEs) against CRM1/XPO1; osteoclasts (OC); nuclear factor-κB (NF-κB) activation; nuclear export protein; tumor suppressors
8.  Application of prospective ECG-triggered dual-source CT coronary angiography for infants and children with coronary artery aneurysms due to Kawasaki disease 
Duan, Y | Wang, X | Cheng, Z | Wu, D | Wu, L
The British Journal of Radiology  2012;85(1020):e1190-e1197.
Objectives
The aim of this study was to prospectively evaluate the initial application and value of prospective electrocardiogram (ECG)-triggered dual-source CT coronary angiography (DSCTCA) in the diagnosis of infants and children with coronary artery aneurysms due to Kawasaki disease.
Methods
19 children [12 males; mean age 13.47 months, range 3 months to 5 years; mean heart rate 112 beats per minute (bpm), range 83–141 bpm] underwent prospective ECG-triggered DSCTCA with free breathing. Subjective image quality was assessed on a five-point scale (1, excellent; 5, non-diagnostic) by two blinded observers. The location, number and size of each aneurysm were observed and compared with those of transthoracic echocardiography (TTE) performed within 1 week. Interobserver agreement concerning the subjective image quality was evaluated with Cohen's κ-test. Bland–Altman analysis was used to evaluate the agreement on measurements (diameter and length of aneurysms) between DSCTCA and TTE. The average effective dose required for DSCTCA was calculated for all children.
Results
All interobserver agreement for subjective image quality assessment was excellent (κ=0.87). The mean±standard deviation (SD) aneurysm diameter with DSCTCA was 0.76±0.36 cm and with TTE was 0.76±0.39 cm. The mean±SD aneurysm length with DSCTCA was 2.06±1.35 cm and with TTE was 2.00±1.22 cm. The Bland–Altman plot for agreement between DSCTCA and TTE measurements showed good agreement. The mean effective dose was 0.36±0.06 mSv.
Conclusion
As an alternative diagnostic modality, prospective ECG-triggered DSCTCA with excellent image quality and low radiation exposure has been proved useful for diagnosing infants and children with coronary artery aneurysms due to Kawasaki disease.
Advances in knowledge
Prospective ECG–triggered DSCTCA for infants and children allows rapid, accurate assessment of coronary aneurysms due to Kawasaki diseases, compared with TTE.
doi:10.1259/bjr/18174517
PMCID: PMC3611723  PMID: 22932064
9.  Predictors of Adherence in the Women’s Health Initiative Calcium and Vitamin D Trial 
The authors analyzed data from the Women’s Health Initiative (WHI) Calcium and Vitamin D Supplementation Trial (CaD) to learn more about factors affecting adherence to clinical trial study pills (both active and placebo). Most participants (36,282 postmenopausal women aged 50–79 years) enrolled in CaD 1 year after joining either a hormone trial or the dietary modification trial of WHI. The WHI researchers measured adherence to study pills by weighing the amount of remaining pills at an annual study visit; adherence was primarily defined as taking ≥ 80% of the pills. The authors in this study examined a number of behavioral, demographic, procedural, and treatment variables for association with study pill adherence. They found that relatively simple procedures (ie, phone contact early in the study [4 weeks post randomization] and direct social contact) later in the trial may improve adherence. Also, at baseline, past pill-use experiences, personal supplement use, and relevant symptoms may be predictive of adherence in a supplement trial.
doi:10.3200/BMED.34.4.145-155
PMCID: PMC3770154  PMID: 19064373
adherence; calcium supplementation; clinical trial; women
10.  Involvement of Src tyrosine kinase and protein kinase C in the expression of macrophage migration inhibitory factor induced by H2O2 in HL-1 mouse cardiac muscle cells 
Macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, plays an important role in the pathogenesis of atrial fibrillation; however, the upstream regulation of MIF in atrial myocytes remains unclear. In the present study, we investigated whether and how MIF is regulated in response to the renin-angiotensin system and oxidative stress in atrium myocytes (HL-1 cells). MIF protein and mRNA levels in HL-1 cells were assayed using immunofluorescence, real-time PCR, and Western blot. The result indicated that MIF was expressed in the cytoplasm of HL-1 cells. Hydrogen peroxide (H2O2), but not angiotensin II, stimulated MIF expression in HL-1 cells. H2O2-induced MIF protein and gene levels increased in a dose-dependent manner and were completely abolished in the presence of catalase. H2O2-induced MIF production was completely inhibited by tyrosine kinase inhibitors genistein and PP1, as well as by protein kinase C (PKC) inhibitor GF109203X, suggesting that redox-sensitive MIF production is mediated through tyrosine kinase and PKC-dependent mechanisms in HL-1 cells. These results suggest that MIF is upregulated by HL-1 cells in response to redox stress, probably by the activation of Src and PKC.
doi:10.1590/1414-431X20132936
PMCID: PMC3854426  PMID: 24036910
Macrophage migration inhibitory factor; HL-1 cells; Hydrogen peroxide; Atrial fibrillation; Protein kinases
11.  The JAK2/STAT3 and mitochondrial pathways are essential for quercetin nanoliposome-induced C6 glioma cell death 
Cell Death & Disease  2013;4(8):e746-.
The formulation of quercetin nanoliposomes (QUE-NLs) has been shown to enhance QUE antitumor activity in C6 glioma cells. At high concentrations, QUE-NLs induce necrotic cell death. In this study, we probed the molecular mechanisms of QUE-NL-induced C6 glioma cell death and examined whether QUE-NL-induced programmed cell death involved Bcl-2 family and mitochondrial pathway through STAT3 signal transduction pathway. Downregulation of Bcl-2 and the overexpression of Bax by QUE-NL supported the involvement of Bcl-2 family proteins upstream of C6 glioma cell death. In addition, the activation of JAK2 and STAT3 were altered following exposure to QUE-NLs in C6 glioma cells, suggesting that QUE-NLs downregulated Bcl-2 mRNAs expression and enhanced the expression of mitochondrial mRNAs through STAT3-mediated signaling pathways either via direct or indirect mechanisms. There are several components such as ROS, mitochondrial, and Bcl-2 family shared by the necrotic and apoptotic pathways. Our studies indicate that the signaling cross point of the mitochondrial pathway and the JAK2/STAT3 signaling pathway in C6 glioma cell death is modulated by QUE-NLs. In conclusion, regulation of JAK2/STAT3 and ROS-mediated mitochondrial pathway agonists alone or in combination with treatment by QUE-NLs could be a more effective method of treating chemical-resistant glioma.
doi:10.1038/cddis.2013.242
PMCID: PMC3763427  PMID: 23907460
quercetin nanoliposomes; programmed cell death; JAK2/STAT3; mitochondrial pathway
12.  Loss of cell adhesion molecule CHL1 improves homeostatic adaptation and survival in hypoxic stress 
Cell Death & Disease  2013;4(8):e768-.
Close homologue of L1 (CHL1) is a transmembrane cell adhesion molecule that is critical for brain development and for the maintenance of neural circuits in adults. Recent studies revealed that CHL1 has diverse roles and is involved in the regulation of recovery after spinal cord injury. CHL1 expression was downregulated in the cerebral cortex, hypothalamus, and brain stem after the induction of acute hypoxia (AH). In the current study, we sought to address the role of CHL1 in regulating homeostasis responses to hypoxia using CHL1-knockout (CHL1−/−) mice. We found that, compared with wild-type littermates, CHL1−/− mice showed a dramatically lower mortality rate and an augmented ventilatory response after they were subjected to AH. Immunofluorescence staining revealed that CHL1 was expressed in the carotid body (CB), the key oxygen sensor in rodents, and CHL1 expression level in the CB as assayed by western blot was decreased after hypoxic exposure. The number of glomus cells and the expression of tyrosine hydroxylase (a marker for glomus cells) in the CB of CHL1−/− mice appeared to be increased compared with CHL1+/+ mice. In addition, in the ex vivo CB preparation, hypoxia induced a significantly greater afferent nerve discharge in CHL1−/− mice compared with CHL1+/+ mice. Furthermore, the arterial blood pressure and plasma catecholamine levels of CHL1−/− mice were also significantly higher than those of CHL1+/+ mice. Our findings first demonstrate that CHL1 is a novel intrinsic factor that is involved in CB function and in the ventilatory response to AH.
doi:10.1038/cddis.2013.284
PMCID: PMC3763446  PMID: 23949217
CHL1; acute hypoxia; homeostatic adaptation; survival
13.  Dynamic equilibrium between cancer stem cells and non-stem cancer cells in human SW620 and MCF-7 cancer cell populations 
Yang, G | Quan, Y | Wang, W | Fu, Q | Wu, J | Mei, T | Li, J | Tang, Y | Luo, C | Ouyang, Q | Chen, S | Wu, L | Hei, T K | Wang, Y
British Journal of Cancer  2012;106(9):1512-1519.
Background:
Cancer stem cells (CSCs) paradigm suggests that CSCs might have important clinical implications in cancer therapy. Previously, we reported that accumulation efficiency of CSCs is different post low- and high-LET irradiation in 48 h.
Methods:
Cancer stem cells and non-stem cancer cells (NSCCs) were sorted and functionally identified through a variety of assays such as antigen profiles and sphere formation. Inter-conversion between CSCs and NSCCs were in situ visualised. Cancer stem cells proportions were assayed over multiple generations under normal and irradiation surroundings. Supplement and inhibition of TGF-β1, as well as immunofluorescence assay of E-cadherin and Vimentin, were performed.
Results:
Surface antigen markers of CSCs and NSCCs exist in an intrinsic homoeostasis state with spontaneous and in situ visualisable inter-conversions, irrespective of prior radiations. Supplement with TGF-β1 accelerates the equilibrium, whereas inhibition of TGF-β signalling disturbs the equilibrium and significantly decreases CSC proportion. Epithelial mesenchymal transition (EMT) might be activated during the process.
Conclusion:
Our results indicate that the intrinsic inter-conversion and dynamic equilibrium between CSCs and NSCCs exist under normal and irradiation surroundings, and TGF-β might have important roles in the equilibrium through activating EMT.
doi:10.1038/bjc.2012.126
PMCID: PMC3341854  PMID: 22472879
cancer stem cells; inter-conversion; dynamic equilibrium; radiation; epithelial mesenchymal transition
14.  Unique FISH Patterns Associated with Cancer Progression of Oral Dysplasia 
Journal of Dental Research  2012;91(1):52-57.
Subgroups of patients with oral pre-malignant lesions (OPLs) are at extremely high risk for developing invasive cancer in spite of surgical excision. The objective of this study was to evaluate the utility of specific genes and their associated centromeres as markers to stratify OPLs for their cancer risk. Samples used in this study included 35 oral dysplasia with known outcome and 20 normal oral mucosa. Of the dysplasias, 20 were from an ongoing longitudinal study showing progression. The remaining 15 cases (2 of which progressed) were chosen from the population-based, provincial BC Oral Biopsy Service (OBS). Copy number alterations at EGFR, CEP7, CCND1, and CEP11 were evaluated by fluorescent in situ hybridization (FISH). There was no significant difference in demographics between progressors and non-progressors. Specific FISH profiles at these genes and their corresponding centromeres were associated with progression. High gene gain of CCND1 was associated with an 8-fold elevated risk of progression compared with those with no gain in time-to-progression analysis. Numerical alterations of EGFR and CCND1 and their centromeres might be an effective means for identifying OPLs at risk. Future studies will expand on this analysis and set the stage for application of this approach in routine clinical practice.
doi:10.1177/0022034511425676
PMCID: PMC3232118  PMID: 21990607
oral dysplasia; progression; EGFR; CCND1; fluorescent in situ hybridization; chromosomal instability
15.  Structural properties of the tubular appendage spinae from marine bacterium Roseobacter sp. strain YSCB 
Scientific Reports  2012;2:950.
Spinae are tubular surface appendages broadly found in Gram-negative bacteria. Little is known about their architecture, function or origin. Here, we report structural characterization of the spinae from marine bacteria Roseobacter sp. YSCB. Electron cryo-tomography revealed that a single filament winds into a hollow flared base with progressive change to a cylinder. Proteinase K unwound the spinae into proteolysis-resistant filaments. Thermal treatment ripped the spinae into ribbons that were melted with prolonged heating. Circular dichroism spectroscopy revealed a dominant beta-structure of the spinae. Differential scanning calorimetry analyses showed three endothermic transformations at 50–85°C, 98°C and 123°C, respectively. The heating almost completely disintegrated the spinae, abolished the 98°C transition and destroyed the beta-structure. Infrared spectroscopy identified the amide I spectrum maximum at a position similar to that of amyloid fibrils. Therefore, the spinae distinguish from other bacterial appendages, e.g. flagella and stalks, in both the structure and mechanism of assembly.
doi:10.1038/srep00950
PMCID: PMC3517982  PMID: 23230515
17.  Abuse and dependence on prescription opioids in adults: a mixture categorical and dimensional approach to diagnostic classification 
Psychological medicine  2010;41(3):653-664.
Background
For the emerging DSM-V, it has been recommended that dimensional and categorical methods be used simultaneously in diagnostic classification; however, little is known about this combined approach for abuse and dependence.
Method
Using data (n=37 708) from the 2007 National Survey on Drug Use and Health (NSDUH), DSM-IV criteria for prescription opioid abuse and dependence among non-prescribed opioid users (n=3037) were examined using factor analysis (FA), latent class analysis (LCA, categorical), item response theory (IRT, dimensional), and factor mixture (hybrid) approaches.
Results
A two-class factor mixture model (FMM) combining features of categorical latent classes and dimensional IRT estimates empirically fitted more parsimoniously to abuse and dependence criteria data than models from FA, LCA and IRT procedures respectively. This mixture model included a severely affected group (7%) with a comparatively moderate to high probability (0.32–0.88) of endorsing all abuse and dependence criteria items, and a less severely affected group (93%) with a low probability (0.003–0.16) of endorsing all criteria. The two empirically defined groups differed significantly in the pattern of non-prescribed opioid use, co-morbid major depression, and substance abuse treatment use.
Conclusions
A factor mixture model integrating categorical and dimensional features of classification fits better to DSM-IV criteria for prescription opioid abuse and dependence in adults than a categorical or dimensional approach. Research is needed to examine the utility of this mixture classification for substance use disorders and treatment response.
doi:10.1017/S0033291710000954
PMCID: PMC3086580  PMID: 20459887
DSM-IV; factor mixture model; item response theory; latent class analyses; nosology; prescription opioid use disorders
18.  GHB–Induced Cognitive Deficits During Adolescence and the Role of NMDA Receptor 
Current Neuropharmacology  2011;9(1):240-243.
We have earlier reported that γ-hydroxybutyric acid (GHB) disrupts the acquisition of spatial learning and memory in adolescent rats. GHB is known to interact with several neurotransmitter systems that have been implicated in cognitive functioning. The N-methyl-D-aspartate receptor (NR) -type of glutamate receptor is considered to be an important target for spatial learning and memory. Molecular mechanisms governing the neuroadptations following repeated GHB treatment in adolecent rats remain unknown. We examined the role of NMDA receptor in adolescent GHB-induced cognitive deficit. Adolescent rats were administered with GHB on 6 consecutive days, and surface-expressed NMDA receptor subunits levels were measured. GHB significantly decreased NR1 levels in the frontal cortex. Adolescent GHB also significantly reduced cortical NR2A subunit levels. Our findings support the hypothesis that adolescent GHB-induced cogntive deficits are associated with neuroadaptations in glutamatergic transmission, particulaly NR functioning in the frontal cortex.
doi:10.2174/157015911795017038
PMCID: PMC3137190  PMID: 21886597
Addiction; juvenile; cognitive function; glutamatergic; radioligand binding; western blot; NR subunit; GHB.
19.  Aberrant Processing of Deviant Stimuli in Schizophrenia Revealed by Fusion of FMRI and EEG Data 
Background
Aberrant electrophysiological and hemodynamic processing of auditory oddball stimuli is among the most robustly documented findings in patients with schizophrenia. However, no study to date has directly examined linked patterns of electrical and hemodynamic differences in patients and controls.
Methods
In a recent paper we demonstrated a data-driven approach, joint independent component analysis (jICA) to fuse together functional magnetic resonance imaging (fMRI) and event-related potential (ERP) data and elucidated the chronometry of auditory oddball target detection in healthy control subjects. In this paper we extend our fusion method to identify specific differences in the neuronal chronometry of target detection for chronic schizophrenia patients compared to healthy controls.
Results
We found one linked source, consistent with the N2 response, known to be related to cognitive processing of deviant stimuli, spatially localized to bilateral fronto-temporal regions. This source showed significant between-group differences both in amplitude response and in the fMRI/ERP distribution pattern. These findings are consistent with previous work showing N2 amplitude and latency abnormalities in schizophrenia, and provide new information about the linkage between the two.
Conclusions
In summary, we use a novel approach to isolate and identify a linked fMRI/ERP component which shows marked differences in chronic schizophrenia patients. We also demonstrate that jointly using both fMRI and ERP measures provides a fully picture of the underlying hemodynamic and electrical changes which are present in patients. Our approach also has broad applicability to other diseases such as autism, Alzheimer’s disease, or bipolar disorder.
doi:10.1111/j.1601-5215.2010.00467.x
PMCID: PMC3038634  PMID: 21331320
schizophrenia; fMRI; ERP; data fusion; independent component analysis; N2
20.  p53 mutation, deprivation and poor prognosis in primary breast cancer 
British Journal of Cancer  2010;102(4):719-726.
Background:
The deprivation gap for breast cancer survival remains unexplained by stage at presentation, treatment, or co-morbidities. We hypothesised that p53 mutation might contribute to the impaired outcome observed in patients from deprived communities.
Methods:
p53 mutation status was determined using the Roche Amplichip research test in 246 women with primary breast cancer attending a single cancer centre and related to deprivation, pathology, overall, and disease-free survival.
Results:
p53 mutation, identified in 64/246 (26%) of cancers, was most common in 10 out of 17 (58.8%) of the lowest (10th) deprivation decile. Those patients with p53 mutation in the 10th decile had a significantly worse disease-free survival of only 20% at 5 years (Kaplan–Meier logrank χ2=6.050, P=0.014) and worse overall survival of 24% at 5 years (Kaplan–Meier logrank χ2=6.791, P=0.009) than women of deciles 1–9 with p53 mutation (c.f. 56% and 72%, respectively) or patients in the 10th decile with wild-type p53 (no disease relapse or deaths).
Conclusion:
p53 mutation in breast cancer is associated with socio-economic deprivation and may provide a molecular basis, with therapeutic implications, for the poorer outcome in women from deprived communities.
doi:10.1038/sj.bjc.6605540
PMCID: PMC2837559  PMID: 20104224
p53; primary breast cancer; socio-economic deprivation; overall survival; disease-free survival
21.  Molecular and Enzymatic Profiles of Mammalian DNA Methyltransferases: Structures and Targets for Drugs 
Current medicinal chemistry  2010;17(33):4052-4071.
DNA methylation is an epigenetic event involved in a variety array of processes that may be the foundation of genetic phenomena and diseases. DNA methyltransferase is a key enzyme for cytosine methylation in DNA, and can be divided into two functional families (Dnmt1 and Dnmt3) in mammals. All mammalian DNA methyltransferases are encoded by their own single gene, and consisted of catalytic and regulatory regions (except Dnmt2). Via interactions between functional domains in the regulatory or catalytic regions and other adaptors or cofactors, DNA methyltransferases can be localized at selective areas (specific DNA/nucleotide sequence) and linked to specific chromosome status (euchromatin/heterochromatin, various histone modification status). With assistance from UHRF1 and Dnmt3L or other factors in Dnmt1 and Dnmt3a/Dnmt3b, mammalian DNA methyltransferases can be recruited, and then specifically bind to hemimethylated and unmethylated double-stranded DNA sequence to maintain and de novo setup patterns for DNA methylation. Complicated enzymatic steps catalyzed by DNA methyltransferases include methyl group transferred from cofactor Ado-Met to C5 position of the flipped-out cytosine in targeted DNA duplex. In the light of the fact that different DNA methyltransferases are divergent in both structures and functions, and use unique reprogrammed or distorted routines in development of diseases, design of new drugs targeting specific mammalian DNA methyltransferases or their adaptors in the control of key steps in either maintenance or de novo DNA methylation processes will contribute to individually treating diseases related to DNA methyltransferases.
PMCID: PMC3003592  PMID: 20939822
DNA methyltransferase; epigenetics; enzyme catalysis; protein-DNA interactions
22.  Association between Nutritional Status and Positive Childhood Disability Screening Using the Ten Questions Plus Tool in Sarlahi, Nepal 
The study was conducted to examine the association between the indicators of malnutrition and disability of children as reported by caregivers. The Ten Questions Plus questionnaire was administered to caregivers of 1,902 children aged 1–9 years, during August 2007–March 2008, in rural Nepal. Height and weight of children were also measured. The main outcome was a positive response to one or more questions. In total, 514 (27%) children had a positive response to at least one question. Moderate stunting [odds ratio (OR)=1.47, 95% confidence interval (CI) 1.02–2.12) and severe (OR=2.39, 95% CI 1.60–3.57) stunting were independently associated with reported delay in sitting, standing, or walking. Severe stunting was also associated with report of delayed learning compared to other children of similar age (OR=2.01, 95% CI 1.27–3.20). Parental report of disability was quite prevalent in this setting, with over a quarter of the sample screening positive. Chronic malnutrition may be associated with delayed motor and mental development.
PMCID: PMC2995027  PMID: 21261204
Child; Child development; Child nutrition; Cognitive development; Disability; Stunting; Nepal
23.  Mechanism of genotoxicity induced by targeted cytoplasmic irradiation 
British Journal of Cancer  2010;103(8):1263-1268.
Background:
Direct damage to DNA is generally accepted as the main initiator of mutation and cancer induced by environmental carcinogens or ionising radiation. However, there is accumulating evidence suggesting that extracellular/extranuclear targets may also have a key role in mediating the genotoxic effects of ionising radiation. As the possibility of a particle traversal through the cytoplasm is much higher than through the nuclei in environmental radiation exposure, the contribution to genotoxic damage from cytoplasmic irradiation should not be ignored in radiation risk estimation. Although targeted cytoplasmic irradiation has been shown to induce mutations in mammalian cells, the precise mechanism(s) underlying the mutagenic process is largely unknown.
Methods:
A microbeam that can target the cytoplasm of cells with high precision was used to study mechanisms involved in mediating the genotoxic effects in irradiated human–hamster hybrid (AL) cells.
Results:
Targeted cytoplasmic irradiation induces oxidative DNA damages and reactive nitrogen species (RNS) in AL cells. Lipid peroxidation, as determined by the induction of 4-hydroxynonenal was enhanced in irradiated cells, which could be suppressed by butylated hydroxyl toluene treatment. Moreover, cytoplasmic irradiation of AL cells increased expression of cyclooxygenase-2 (COX-2) and activation of extracellular signal-related kinase (ERK) pathway.
Conclusion:
We herein proposed a possible signalling pathway involving reactive oxygen/nitrogen species and COX-2 in the cytoplasmic irradiation-induced genotoxicity effect.
doi:10.1038/sj.bjc.6605888
PMCID: PMC2967061  PMID: 20842121
cytoplasmic irradiation; genotoxicity; reactive oxygen/nitrogen species; 4-hydroxynonenal; cyclooxygenase-2
24.  Characterization of ErbB2 Phosphorylation and their Dynamic Changes upon EGF Stimulation in Human Breast Cancer Cells 
RP-123
To understand the fundamental mechanisms underlying ErbB signaling pathway, we present here an approach to fully characterize phosphorylation on those unique sites in ErbB2 and their dynamic changes upon EGF treatment. To gain an efficient immunoprecipitation (IP) of ErbB2, several anti-ErbB2 antibodies were screened by the GeLC-MS analysis. The analytical procedure was used for determine the phosphorylation profiles in ErbB2 upon EGF stimulation in human cancer cell line (SKBR3).To validate identified phosphosites, selected reaction monitoring (SRM) and multiple staged MSn were implemented with a liner ion trap hybrid a high resolution FTMS.The ErbB2 phosphorylation profiles upon EGF treatment at varied 5 time points were determined by the targeted LC-MS method and label-free quantitative analysis. As a result, an optimized IP procedure by using highly selective anti-ErbB2 monoclonal antibodies allowed the effective method to dissociate the heterodimer of EGFR-ErbB2 and thus to explore the phosphorylation events in ErbB2 only.All of tryptic peptides from cytoplasmic region were identified, which allow us to map phosphosites in ErbB2 completely.21 phosphosites (16 new sites and 5 known sites) from 11 peptide fragments were assigned and further confirmed manually by MS spectra. Trace amount of phosphorylated peptides (estimated stoichiomertry, %ES<1%), including di- and tri- phosphopeptides, could be detected and quantified using above label-free quantitative strategy.We observed the remarkable changes of %ES of phosphosites in ErbB2, especially the sites on tyrosine that are closed to the autocatalysis domain (pY1139-pY1248). Our study introduced a highly sensitive and selective approach to monitor the phosphorylation changes in ErbB2 upon ligand binding to EGFR-ErbB2 dimerized RTK. The analytical workflow enabled dynamic quantitation of phosphorylation changes in ErbB2 upon EGF treatments and constituted, to the best of our knowledge, the most comprehensive data set of phosphosites in ErbB2 acquired to date from human cancer cells.
PMCID: PMC2918094
25.  Association of MDMA/ecstasy and other substance use with self-reported sexually transmitted diseases among college-aged adults: a national study 
Public health  2009;123(8):557-564.
SUMMARY
Objectives
MDMA/ecstasy use among college students has increased and reportedly leads to risky sexual behaviours. However, little is known about its association with sexually transmitted diseases (STDs). To evaluate this public health concern, this study examined the association between substance use (particularly MDMA) and self-reported STDs (chlamydia, gonorrhoea, herpes and syphilis) among college students and non-students aged 18–22 years (n=20,858).
Study design
A cross-sectional data analysis of a national survey.
Methods
Data were drawn from the 2005–2006 National Surveys on Drug Use and Health; a nationally representative survey of non-institutionalized Americans. Self-reported STDs and substance use were assessed by the audio computer-assisted self-interviewing method. The association between MDMA use and STDs was determined while taking into account young adults’ use of other substances, healthcare utilization and sociodemographic characteristics.
Results
Overall, 2.1% of college students and 2.5% of non-students reported contracting an STD in the past year. MDMA use in the past year was not associated with STDs. Among non-students, onset of MDMA use before 18 years of age increased the odds of past-year STDs. In both groups, alcohol use, marijuana use, female gender and African American race increased the odds of both past-year and lifetime STDs. Additional analyses indicated that, regardless of college-attending status, greater odds of past-year STDs were noted among users of alcohol and drugs, and users of alcohol alone, but not among users of drugs alone.
Conclusions
Alcohol use is a robust correlate of STDs. Irrespective of college-attending status, young women and African Americans have a higher rate of STDs than young men and Whites.
doi:10.1016/j.puhe.2009.06.012
PMCID: PMC2757289  PMID: 19656538
Alcohol use; College students; Epidemiology; MDMA; Sexually transmitted diseases

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