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1.  Cognitive trio: relationship with major depression and clinical predictors in Han Chinese women 
Psychological Medicine  2013;43(11):2265-2275.
Background
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.
Method
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.
Results
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.
Conclusions
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.
doi:10.1017/S0033291713000160
PMCID: PMC3807662  PMID: 23425530
Cognitive trio; Han Chinese women; major depression; suicide; symptoms
2.  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.
Background
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?
Method
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.
Results
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.
Conclusions
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.
doi:10.1017/S003329171300192X
PMCID: PMC3967839  PMID: 23920138
Atypical symptoms; China; cognitive symptoms; depression; factor analysis
4.  FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium 
Agarwal, D | Pineda, S | Michailidou, K | Herranz, J | Pita, G | Moreno, L T | Alonso, M R | Dennis, J | Wang, Q | Bolla, M K | Meyer, K B | Menéndez-Rodríguez, P | Hardisson, D | Mendiola, M | González-Neira, A | Lindblom, A | Margolin, S | Swerdlow, A | Ashworth, A | Orr, N | Jones, M | Matsuo, K | Ito, H | Iwata, H | Kondo, N | Hartman, M | Hui, M | Lim, W Y | T-C Iau, P | Sawyer, E | Tomlinson, I | Kerin, M | Miller, N | Kang, D | Choi, J-Y | Park, S K | Noh, D-Y | Hopper, J L | Schmidt, D F | Makalic, E | Southey, M C | Teo, S H | Yip, C H | Sivanandan, K | Tay, W-T | Brauch, H | Brüning, T | Hamann, U | Dunning, A M | Shah, M | Andrulis, I L | Knight, J A | Glendon, G | Tchatchou, S | Schmidt, M K | Broeks, A | Rosenberg, E H | van't Veer, L J | Fasching, P A | Renner, S P | Ekici, A B | Beckmann, M W | Shen, C-Y | Hsiung, C-N | Yu, J-C | Hou, M-F | Blot, W | Cai, Q | Wu, A H | Tseng, C-C | Van Den Berg, D | Stram, D O | Cox, A | Brock, I W | Reed, M W R | Muir, K | Lophatananon, A | Stewart-Brown, S | Siriwanarangsan, P | Zheng, W | Deming-Halverson, S | Shrubsole, M J | Long, J | Shu, X-O | Lu, W | Gao, Y-T | Zhang, B | Radice, P | Peterlongo, P | Manoukian, S | Mariette, F | Sangrajrang, S | McKay, J | Couch, F J | Toland, A E | Yannoukakos, D | Fletcher, O | Johnson, N | Silva, I dos Santos | Peto, J | Marme, F | Burwinkel, B | Guénel, P | Truong, T | Sanchez, M | Mulot, C | Bojesen, S E | Nordestgaard, B G | Flyer, H | Brenner, H | Dieffenbach, A K | Arndt, V | Stegmaier, C | Mannermaa, A | Kataja, V | Kosma, V-M | Hartikainen, J M | Lambrechts, D | Yesilyurt, B T | Floris, G | Leunen, K | Chang-Claude, J | Rudolph, A | Seibold, P | Flesch-Janys, D | Wang, X | Olson, J E | Vachon, C | Purrington, K | Giles, G G | Severi, G | Baglietto, L | Haiman, C A | Henderson, B E | Schumacher, F | Le Marchand, L | Simard, J | Dumont, M | Goldberg, M S | Labrèche, F | Winqvist, R | Pylkäs, K | Jukkola-Vuorinen, A | Grip, M | Devilee, P | Tollenaar, R A E M | Seynaeve, C | García-Closas, M | Chanock, S J | Lissowska, J | Figueroa, J D | Czene, K | Eriksson, M | Humphreys, K | Darabi, H | Hooning, M J | Kriege, M | Collée, J M | Tilanus-Linthorst, M | Li, J | Jakubowska, A | Lubinski, J | Jaworska-Bieniek, K | Durda, K | Nevanlinna, H | Muranen, T A | Aittomäki, K | Blomqvist, C | Bogdanova, N | Dörk, T | Hall, P | Chenevix-Trench, G | Easton, D F | Pharoah, P D P | Arias-Perez, J I | Zamora, P | Benítez, J | Milne, R L
British Journal of Cancer  2014;110(4):1088-1100.
Background:
Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium.
Methods:
Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression.
Results:
Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02–1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2.
Conclusion:
Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.
doi:10.1038/bjc.2013.769
PMCID: PMC3929867  PMID: 24548884
breast cancer; SNP; FGF receptors; susceptibility; disease subtypes
6.  Estimation of Ultrasound Strain Indices in Carotid Plaque and Correlation to Cognitive Dysfunction 
Carotid plaque prone to release emboli may be predicted by increased strain variations within plaque due to arterial pulsation over a cardiac cycle. Non-invasive ultrasound strain imaging may therefore be a viable surrogate to determine the risk of embolic stroke and possible cognitive impairment. Ultrasound strain imaging was performed on 24 human subjects with significant plaque, who also underwent standardized cognitive assessment (Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)) prior to a carotid endarterectomy (CEA) procedure. Radiofrequency signals were acquired using a Siemens Antares with a VFX 13-5 linear array transducer. Plaque regions were segmented by a radiologist at end-diastole using the Medical Imaging Interaction Toolkit. A hierarchical block-matching motion tracking algorithm was utilized to estimate the cumulated axial, lateral, and shear strains within the imaging plane. The maximum strain indices of the plaque, defined as mean accumulated strain over a small region of interest in the plaque with large deformations, were obtained. All the strain indices were then correlated with RBANS Total score. Overall cognitive performance was negatively associated with maximum axial and lateral strains respectively. The results demonstrate a direct relationship between the maximum axial and lateral strain indices in carotid plaque and cognitive impairment.
doi:10.1109/EMBC.2014.6944903
PMCID: PMC4288023  PMID: 25571271
7.  Correlation of Cognitive Function with Ultrasound Strain Indices in Carotid Plaque 
Ultrasound in medicine & biology  2013;40(1):10.1016/j.ultrasmedbio.2013.08.001.
Instability in carotid vulnerable plaque can generate cerebral microemboli, that may be related to both stroke and eventual cognitive abnormality. Strain imaging to detect plaque vulnerability based on regions with large strain fluctuations, with arterial pulsation, may be able to determine risk of cognitive impairment. Plaque instability may be characterized by increased strain variations over a cardiac cycle. Radiofrequency signals for ultrasound strain imaging were acquired from the carotid arteries of 24 human subjects using a Siemens Antares with a VFX 13-5 linear array transducer. These patients underwent standardized cognitive assessment (Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)). Plaque regions were segmented by a radiologist at end-diastole using the Medical Imaging Interaction Toolkit. A hierarchical block-matching motion tracking algorithm was utilized to estimate the cumulated axial, lateral, and shear strains within the imaging plane. The maximum, minimum and peak-to-peak strain indices in the plaque computed from the mean cumulated strain over a small region of interest in the plaque with large deformations, were obtained. The maximum and peak-to-peak mean cumulated strain indices over the entire plaque region were also computed. All the strain indices were then correlated with RBANS Total performance. Overall cognitive performance (RBANS Total) was negatively associated with values of the maximum strain and the peak-to-peak for axial and lateral strains respectively. There was no significant correlation between the RBANS Total score and shear strain, and strain indices averaged over the entire identified plaque for this group of patients. However, correlation of the maximum lateral strain was higher for symptomatic patients (r=−0.650, p=0.006) than that for asymptomatic patients (r=−0.115, p=0.803). On the other hand correlation for maximum axial strain averaged over the entire plaque region was significantly higher for asymptomatic patients (r=−0.817, p=0.016) than that for symptomatic patients (r=−0.224, p=0.402). The results reveal a direct relationship between the maximum axial and lateral strain indices in carotid plaque with cognitive impairment.
doi:10.1016/j.ultrasmedbio.2013.08.001
PMCID: PMC3849143  PMID: 24120415
Elastography; elasticity imaging; carotid plaque; motion tracking; multi-level; displacement; strain; vascular cognitive dementia
8.  The role, mechanism and potentially therapeutic application of microRNA-29 family in acute myeloid leukemia 
Cell Death and Differentiation  2013;21(1):100-112.
Abnormal proliferation, apoptosis repression and differentiation blockage of hematopoietic stem/progenitor cells have been characterized to be the main reasons leading to acute myeloid leukemia (AML). Previous studies showed that miR-29a and miR-29b could function as tumor suppressors in leukemogenesis. However, a comprehensive investigation of the function and mechanism of miR-29 family in AML development and their potentiality in AML therapy still need to be elucidated. Herein, we reported that the family members, miR-29a, -29b and -29c, were commonly downregulated in peripheral blood mononuclear cells and bone marrow (BM) CD34+ cells derived from AML patients as compared with the healthy donors. Overexpression of each miR-29 member in THP1 and NB4 cells markedly inhibited cell proliferation and promoted cell apoptosis. AKT2 and CCND2 mRNAs were demonstrated to be targets of the miR-29 members, and the role of miR-29 family was attributed to the decrease of Akt2 and CCND2, two key signaling molecules. Significantly increased Akt2, CCND2 and c-Myc levels in the AML cases were detected, which were correlated with the decreased miR-29 expression in AML blasts. Furthermore, a feed-back loop comprising of c-Myc, miR-29 family and Akt2 were found in myeloid leukemogenesis. Reintroduction of each miR-29 member partially corrected abnormal cell proliferation and apoptosis repression and myeloid differentiation arrest in AML BM blasts. An intravenous injection of miR-29a, -29b and -29c in the AML model mice relieved leukemic symptoms significantly. Taken together, our finding revealed a pivotal role of miR-29 family in AML development and rescue of miR-29 family expression in AML patients could provide a new therapeutic strategy.
doi:10.1038/cdd.2013.133
PMCID: PMC3857615  PMID: 24076586
acute myeloid leukemia; cell proliferation and apoptosis; miR-29 family; diagnostic markers; therapeutic targets
9.  Surface modification of graphene nanopores for protein translocation 
Nanotechnology  2013;24(49):495102.
Studies of DNA translocation through graphene nanopores have revealed their potential for DNA sequencing. Here we report a study of protein translocation through chemically modified graphene nanopores. A transmission electron microscope (TEM) was used to cut nanopores with diameters between 5-20 nm in multilayer graphene prepared by chemical vapor deposition (CVD). After oxygen plasma treatment, the dependence of the measured ionic current on salt concentration and pH was consistent with a small surface charge induced by the formation of carboxyl groups. While translocation of gold nanoparticles (10 nm) was readily detected through such treated pores of a larger diameter, translocation of protein ferritin was not observed either for oxygen plasma treated pores, or for pores modified with mercaptohexadecanoic acid. Ferritin translocation events were reliably observed after the pores were modified with the phospholipid-PEG (DPPE-PEG750) amphiphile. The ion current signature of translocation events was complex, suggesting that a series of interactions between the protein and pore occur during the process.
doi:10.1088/0957-4484/24/49/495102
PMCID: PMC3925770  PMID: 24231385
Nanopore; Graphene; surface modification; phospholipid-PEG amphiphile; protein translocation
10.  MiR-221 promotes the development of androgen independence in prostate cancer cells via downregulation of HECTD2 and RAB1A 
Oncogene  2013;33(21):2790-2800.
Hormone-sensitive prostate cancer typically progresses to castration resistant prostate cancer (CRPC) after the androgen deprivation therapy. We investigated the impact of microRNAs (miRs) in the transition of prostate cancer to CRPC. MiR-221/-222 was highly expressed in bone metastatic CRPC tumor specimens. We previously demonstrated that transient overexpression of miR-221/-222 in LNCaP promoted the development of the CRPC phenotype. In current study, we show that stably overexpressing miR-221 confers androgen independent (AI) cell growth in LNCaP by rescuing LNCaP cells from growth arrest at G1 phase due to the lack of androgen. Overexpressing of miR-221 in LNCaP reduced the transcription of a subgroup of androgen-responsive genes without affecting the androgen receptor (AR) or AR-androgen integrity. By performing systematic biochemical and bioinformatical analyses, we identified two miR-221 targets, HECTD2 and RAB1A, which could mediate the development of CRPC phenotype in multiple prostate cancer cell lines. Downregulation of HECTD2 significantly affected the androgen-induced and AR-mediated transcription, and downregulation of HECTD2 or RAB1A enhances AI cell growth. As a result of the elevated expression of miR-221, expression of many cell cycle genes was altered and pathways promoting epithelial to mesenchymal transition/tumor metastasis were activated. We hypothesize that a major biological consequence of upregulation of miR-221 is reprogramming of AR signaling, which in turn may mediate the transition to the CRPC phenotype.
doi:10.1038/onc.2013.230
PMCID: PMC3883998  PMID: 23770851
microRNA; miR-221; castration resistant prostate cancer; androgen receptor signaling
11.  IKVAV regulates ERK1/2 and Akt signalling pathways in BMMSC population growth and proliferation 
Li, B | Qiu, T | Zhang, P | Wang, X | Yin, Y | Li, S
Cell Proliferation  2014;47(2):133-145.
Objectives
The molecular mechanism of bone marrow mesenchymal stem cell (BMMSC) population growth and proliferation, induced by Isoleucyl-lysyl-valyl-alanyl-valine (IKVAV), was explored in this study.
Materials and methods
IKVAV peptides were synthesized by the solid-phase method. Influence of IKVAV on BMMSC population growth and proliferation were investigated by assays of CCK-8, flow cytometry, real-time PCR and western blotting.
Results
IKVAV peptide was found to induce proliferation and proliferating cell nuclear antigen (PCNA) synthesis of BMMSC in a dose- and time-dependent manner. Cell cycle analysis showed that the proportion of IKVAV-treated BMMSC in S phase in was higher than controls. Western blot results suggested that mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signalling pathways were activated by IKVAV by enhancing phosphorylation levels of ERK1/2 and Akt in the BMMSCs. Meanwhile, phosphorylation levels of ERK1/2 and Akt were partially blocked by ERK1/2 inhibitor (PD98059) and Akt inhibitor (wortmannin), respectively.
Conclusions
Our results demonstrated that IKVAV stimulated BMMSC population growth and proliferation by activating MAPK/ERK1/2 and PI3K/Akt signalling pathways. This study is the first to reveal an enhancement effect of IKVAV peptide on BMMSC at the signal transduction level, and the outcome could provide experimental evidence for application of IKVAV-grafted scaffolds in the field of BMMSC-based tissue engineering.
doi:10.1111/cpr.12094
PMCID: PMC4232901  PMID: 24617901
12.  The Specific Role of FAM20C in Amelogenesis 
Journal of Dental Research  2013;92(11):995-999.
Previously, we showed that Sox2-Cre;Fam20Cfl/fl mice in which Fam20C was ubiquitously inactivated had severe defects in dentin, enamel, and bone, along with hypophosphatemia. It remains to be determined if the enamel defects in the mice with universal inactivation of Family with sequence similarity 20-C (FAM20C) were associated with the dentin defects and whether hypophosphatemia in the knockout mice contributed to the enamel defects. In this study, we crossed Fam20Cfl/fl mice with keratin 14-Cre (K14-Cre) transgenic mice to specifically inactivate Fam20C in the epithelial cells, including the dental epithelial cells that are responsible for forming tooth enamel. X-ray, backscattered scanning electron microscopic, and histological analyses showed that the K14-Cre;Fam20Cfl/fl mice had severe enamel and ameloblast defects, while their dentin and alveolar bone were not significantly affected. Accordingly, serum biochemistry of the K14-Cre;Fam20Cfl/fl mice showed normal phosphate and FGF23 levels in the circulation. Analysis of these data indicates that, while FAM20C is a molecule essential to amelogenesis, its inactivation in the dental epithelium does not significantly affect dentinogenesis. Hypophosphatemia makes no significant contribution to the enamel defects in the mice with the ubiquitous deletion of Fam20C.
doi:10.1177/0022034513504588
PMCID: PMC3797537  PMID: 24026952
FGF23; biomineralization; hypophosphatemia; FAM20C; amelogenesis; kinase
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.
doi:10.1038/cddis.2014.473
PMCID: PMC4260731  PMID: 25393477
14.  Activation of volume-sensitive outwardly rectifying chloride channel by ROS contributes to ER stress and cardiac contractile dysfunction: involvement of CHOP through Wnt 
Shen, M | Wang, L | Wang, B | Wang, T | Yang, G | Shen, L | Wang, T | Guo, X | Liu, Y | Xia, Y | Jia, L | Wang, X
Cell Death & Disease  2014;5(11):e1528-.
Endoplasmic reticulum (ER) stress occurring in stringent conditions is critically involved in cardiomyocytes apoptosis and cardiac contractile dysfunction (CCD). However, the molecular machinery that mediates cardiac ER stress and subsequent cell death remains to be fully deciphered, which will hopefully provide novel therapeutic targets for these disorders. Here, we establish tunicamycin-induced model of cardiomyocyte ER stress, which effectively mimicks pathological stimuli to trigger CCD. Tunicamycin activates volume-sensitive outward rectifying Cl− currents. Blockade of the volume-sensitive outwardly rectifying (VSOR) Cl− channel by 4,4'-diisothiocya-natostilbene-2,2'-disulfonic acid (DIDS), a non-selective Cl− channel blocker, and 4-(2-butyl-6,7-dichlor-2-cyclopentyl-indan-1-on-5-yl) oxybutyric acid (DCPIB), a selective VSOR Cl− channel blocker, improves cardiac contractility, which correlates with suppressed ER stress through inhibiting the canonical GRP78/eIF2α/ATF4 and XBP1 pathways, and promotes survival of cardiomyocytes by inverting tunicamycin-induced decrease of Wnt through the CHOP pathway. VSOR activation of tunicamycin-treated cardiomyocytes is attributed to increased intracellular levels of reactive oxygen species (ROS). Our study demonstrates a pivotal role of ROS/VSOR in mediating ER stress and functional impairment of cardiomyocytes via the CHOP-Wnt pathway, and suggests the therapeutic values of VSOR Cl− channel blockers against ER stress-associated cardiac anomalies.
doi:10.1038/cddis.2014.479
PMCID: PMC4260737  PMID: 25412307
15.  Superconductivity in Strong Spin Orbital Coupling Compound Sb2Se3 
Scientific Reports  2014;4:6679.
Recently, A2B3 type strong spin orbital coupling compounds such as Bi2Te3, Bi2Se3 and Sb2Te3 were theoretically predicated to be topological insulators and demonstrated through experimental efforts. The counterpart compound Sb2Se3 on the other hand was found to be topological trivial, but further theoretical studies indicated that the pressure might induce Sb2Se3 into a topological nontrivial state. Here, we report on the discovery of superconductivity in Sb2Se3 single crystal induced via pressure. Our experiments indicated that Sb2Se3 became superconductive at high pressures above 10 GPa proceeded by a pressure induced insulator to metal like transition at ~3 GPa which should be related to the topological quantum transition. The superconducting transition temperature (TC) increased to around 8.0 K with pressure up to 40 GPa while it keeps ambient structure. High pressure Raman revealed that new modes appeared around 10 GPa and 20 GPa, respectively, which correspond to occurrence of superconductivity and to the change of TC slop as the function of high pressure in conjunction with the evolutions of structural parameters at high pressures.
doi:10.1038/srep06679
PMCID: PMC4202213  PMID: 25327696
16.  Therapeutic Hypothermia as a Neuroprotective Strategy in Neonatal Hypoxic-Ischemic Brain Injury and Traumatic Brain Injury 
Current molecular medicine  2012;12(10):1282-1296.
Evidence shows that artificially lowering body and brain temperature can significantly reduce the deleterious effects of brain injury in both newborns and adults. Although the benefits of therapeutic hypothermia have long been known and applied clinically, the underlying molecular mechanisms have yet to be elucidated. Hypoxic-ischemic brain injury and traumatic brain injury both trigger a series of biochemical and molecular events that cause additional brain insult. Induction of therapeutic hypothermia seems to ameliorate the molecular cascade that culminates in neuronal damage. Hypothermia attenuates the toxicity produced by the initial injury that would normally produce reactive oxygen species, neurotransmitters, inflammatory mediators, and apoptosis. Experiments have been performed on various depths and levels of hypothermia to explore neuroprotection. This review summarizes what is currently known about the beneficial effects of therapeutic hypothermia in experimental models of neonatal hypoxic-ischemic brain injury and traumatic brain injury, and explores the molecular mechanisms that could become the targets of novel therapies. In addition, this review summarizes the clinical implications of therapeutic hypothermia in newborn hypoxic-ischemic encephalopathy and adult traumatic brain injury.
PMCID: PMC4173077  PMID: 22834830
Apoptosis; hypothermia; hypoxic-ischemic encephalopathy; neonatal hypoxic-ischemic brain injury; neuroprotection; traumatic brain injury
17.  Epigenomic alterations define lethal CIMP-positive ependymomas of infancy 
Nature  2014;506(7489):445-450.
Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.
doi:10.1038/nature13108
PMCID: PMC4174313  PMID: 24553142
18.  Pharmaco-proteomic Opportunities for Individualizing Neurovascular Treatment 
Neurological research  2013;35(5):448-456.
Neurovascular disease often involves multi-organ system injury. For example, patent foramen ovale (PFO) related ischemic strokes involve not just the brain, but also the heart, the lung, and the peripheral vascular circulation. For higher-risk but high-reward systemic therapy (e.g., thrombolytics, therapeutic hypothermia, PFO closure) to be implemented safely, very careful patient selection and close monitoring of disease progression and therapeutic efficacy are imperative. For example, more than a decade after the approval of therapeutic hypothermic and intravenous thrombolysis treatments, they both remain extremely underutilized, in part due to lack of clinical tools for patient selection or to follow therapeutic efficacy. Therefore, in order to understand the complexity of the global effects of clinical neurovascular diseases and their therapies, a systemic approach may offer a unique perspective and provide tools with clinical utility. Clinical proteomic approaches may be promising to monitor systemic changes in complex multi-organ diseases – especially where the disease process can be “sampled” in clinically accessible fluid such as blood, urine and CSF. Here, we describe a “pharmaco-proteomic” approach to three major challenges in translational neurovascular research directly at bedside – in order to better stratify risk, widen therapeutic windows, explore novel targets to be validated at the bench – 1) thrombolytic treatment for ischemic stroke, 2) therapeutic hypothermia for post cardiac arrest syndrome, and 3) treatment for patent foramen ovale (PFO) related paradoxical embolic stroke. In the future, this clinical proteomics approach may help to improve patient selection, ensure more precise clinical phenotyping for clinical trials, and individualize patient treatment.
doi:10.1179/1743132813Y.0000000213
PMCID: PMC4153693  PMID: 23711324
patent foramen ovale (PFO) related stroke; proteomics; cardiac arrest; therapeutic hypothermia; thrombolysis
19.  Accelerated partial-breast irradiation using intensity-modulated proton radiotherapy: do uncertainties outweigh potential benefits? 
The British Journal of Radiology  2013;86(1029):20130176.
Objective:
Passive scattering proton beam (PSPB) radiotherapy for accelerated partial-breast irradiation (APBI) provides superior dosimetry for APBI three-dimensional conformal photon radiotherapy (3DCRT). Here we examine the potential incremental benefit of intensity-modulated proton radiotherapy (IMPT) for APBI and compare its dosimetry with PSPB and 3DCRT.
Methods:
Two theoretical IMPT plans, TANGENT_PAIR and TANGENT_ENFACE, were created for 11 patients previously treated with 3DCRT APBI and were compared with PSPB and 3DCRT plans for the same CT data sets. The impact of range, motion and set-up uncertainties as well as scanned spot mismatching between fields of IMPT plans was evaluated.
Results:
IMPT plans for APBI were significantly better regarding breast skin sparing (p<0.005) and other normal tissue sparing than 3DCRT plans (p<0.01) with comparable target coverage (p=ns). IMPT plans were statistically better than PSPB plans regarding breast skin (p<0.002) and non-target breast (p<0.007) in higher dose regions but worse or comparable in lower dose regions. IMPT plans using TANGENT_ENFACE were superior to that using TANGENT_PAIR in terms of target coverage (p<0.003) and normal tissue sparing (p<0.05) in low-dose regions. IMPT uncertainties were demonstrated for multiple causes. Qualitative comparison of dose–volume histogram confidence intervals for IMPT suggests that numeric gains may be offset by IMPT uncertainties.
Conclusion:
Using current clinical dosimetry, PSPB provides excellent dosimetry compared with 3DCRT with fewer uncertainties compared with IMPT.
Advances in knowledge:
As currently delivered in the clinic, PSPB planning for APBI provides as good or better dosimetry than IMPT with less uncertainty.
doi:10.1259/bjr.20130176
PMCID: PMC3755395  PMID: 23728947
20.  A retrospective study of ampullary adenocarcinomas: overall survival and responsiveness to fluoropyrimidine-based chemotherapy† 
Annals of Oncology  2013;24(9):2349-2353.
Background
Whether carcinomas of the ampulla of Vater should be classified with biliary tract tumors and treated in a similar manner remains unknown. We sought to compare the outcomes of similarly staged periampullary adenocarcinomas (AAs) and analyze the chemotherapy responsiveness of AAs.
Patients and methods
A total of 905 patients with resected periampullary adenocarcinomas were identified from a prospective surgical registry from 1988 to 2010. A second cohort of 64 metastatic AA patients from 1992 to 2009 who received either front-line fluoropyrimidine-based or gemcitabine-based chemotherapy was also identified.
Results
Overall survival (OS) for AAs was similar to survival with duodenal adenocarcinomas, but was significantly different from both extrahepatic biliary and pancreatic adenocarcinomas (P < 0.001 for each comparison). In multivariate analysis, AAs had a significantly improved OS in comparison with extrahepatic biliary adenocarcinomas (HR = 1.97, P = 0.006). Fluoropyrimidine-based as opposed to gemcitabine-based chemotherapy for metastatic AAs resulted in a significant improvement in time to progression (P = 0.001) but only a trend toward benefit for OS (P = 0.07) in multivariate analysis.
Conclusions
Differences in the natural history of ampullary and extrahepatic biliary adenocarcinomas exist. Analyses of metastatic ampullary adenocarcinomas suggest that fluoropyrimidine-based chemotherapy may represent a more appropriate front-line chemotherapy approach.
doi:10.1093/annonc/mdt191
PMCID: PMC3841462  PMID: 23704197
ampullary adenocarcinomas; chemotherapy; fluoropyrimidine; gemcitabine; periampullary
21.  Model-Based Exposure–Response Analysis of Apixaban to Quantify Bleeding Risk in Special Populations of Subjects Undergoing Orthopedic Surgery 
Population pharmacokinetic (PK) and exposure–response analyses of apixaban were performed using data from phase I–III studies to predict bleeding risks for patients receiving apixaban 2.5 mg b.i.d. after total knee or hip replacement (TKR, THR) surgery (N = 5,510). Renal function, age, gender, and body weight impacted apixaban exposure. Bleeding risk increased as a function of exposure. Predicted bleeding frequencies for TKR and THR populations at risk for high apixaban exposure (female, age > 75 years, calculated creatinine clearance (cCrCL) < 30 ml/min, body weight < 50 kg) (6.85 and 10.3%, respectively) were comparable to the reference population (male/female, age 65−75 years, cCrCL ≥ 80 ml/min, body weight 65−85 kg) (6.18 and 9.32%, respectively). A 100% increase in apixaban exposure is expected to raise bleeding frequencies to 7.25% (TKR) and 10.9% (THR), whereas a 200% increase would raise them to 8.49 and 12.7%. Coexistence of combined patient risk factors or doubling of exposure is not likely to result in a substantial, clinically relevant increase in bleeding risk with 2.5 mg b.i.d. apixaban.
doi:10.1038/psp.2014.34
PMCID: PMC4211262  PMID: 25229619
22.  Downregulation of miR-486-5p contributes to tumor progression and metastasis by targeting protumorigenic ARHGAP5 in lung cancer 
Oncogene  2013;33(9):1181-1189.
We have previously shown that miR-486-5p is one of the most downregulated micro RNAs in lung cancer. The objective of the study was to investigate the role of miR-486-5p in the progression and metastasis of non-small-cell lung cancer (NSCLC). We evaluated miR-486-5p expression status on 76 frozen and 33 formalin-fixed paraffin-embedded tissues of NSCLC by quantitative reverse transcriptase PCR to determine its clinicopathologic significance. We then performed function analysis of miR-486-5p to determine its potential roles on cancer cell migration and invasion in vitro and metastasis in vivo. We also investigated the target genes of miR-486-5p in lung tumorigenesis. miR-486-5p expression level was significantly lower in lung tumors compared with their corresponding normal tissues (P<0.0001), and associated with stage (P =0.0001) and lymph node metastasis of NSCLC (P = 0.0019). Forced expression of miR-486-5p inhibited NSCLC cell migration and invasion in vitro and metastasis in mice by inhibiting cell proliferation. Furthermore, ectopic expression of miR-486-5p in cancer cells reduced ARHGAP5 expression level, whereas miR-486-5p silencing increased its expression. Luciferase assay demonstrated that miR-486-5p could directly bind to the 3′-untranslated region of ARHGAP5. The expression level of miR-486-5p was inversely correlated with that of ARHGAP5 in lung tumor tissues (P =0.0156). Reduced expression of ARHGAP5 considerably inhibited lung cancer cell migration and invasion, resembling that of miR-486-5p overexpression. miR-486-5p may act as a tumor-suppressor contributing to the progression and metastasis of NSCLC by targeting ARHGAP5. miR-486-5p would provide potential diagnostic and therapeutic targets for the disease.
doi:10.1038/onc.2013.42
PMCID: PMC3883922  PMID: 23474761
miR-486-5p; tumor-suppressor gene; lung cancer; ARHGAP5; therapy
23.  Downregulation of miR-302c and miR-520c by 1,25(OH)2D3 treatment enhances the susceptibility of tumour cells to natural killer cell-mediated cytotoxicity 
Min, D | Lv, X-b | Wang, X | Zhang, B | Meng, W | Yu, F | Hu, H
British Journal of Cancer  2013;109(3):723-730.
Background:
NKG2D recognises several ligands, including polymorphic major histocompatibility complex class I chain-related chain-related proteins A and B (MICA/B) and unique long 16-binding proteins (ULBPs). These ligands are present on cancer cells and are recognised by NKG2D in a cell-structure-sensing manner, triggering natural killer (NK) cell cytotoxicity. However, the mechanisms that control the expression of NKG2D ligands in malignant cells are poorly understood. 1-α,25-Dihydroxyvitamin D3 (1,25(OH)2D3) was recently shown to enhance the susceptibility of melanoma cells to the cytotoxicity of NK cells. However, the function of 1,25(OH)2D3 in other cancers and its potential mechanisms of action remain unknown.
Methods:
The expression levels of miR-302c and miR-520c in Kasumi-1, K562, MCF7 and MDA-MB-231 cells were evaluated using quantitative real-time PCR. The targets of miR-302c and miR-520c were confirmed by luciferase reporter assay. The killing effects of NK92 cells against Kasumi-1, K562, MCF7 and MDA-MB-231 cells were examined using the CytoTox 96 Non-Radioactive Cytotoxicity Assay. The levels of cytokines IFN-γ and granzyme B, which indicate the activation of NK cells, were also measured by enzyme-linked immunosorbent assay.
Results:
Treatment with 1,25(OH)2D3 enhanced the susceptibility of both the haematological tumour cell line Kasumi-1 and solid tumour cell line MDA-MB-231 to NK92 cells. miR-302c and miR-520c expression was induced, and their levels inversely correlated with the levels of NKG2D ligands MICA/B and ULBP2 upon 1,25(OH)2D3 treatment. A luciferase reporter assay revealed that miR-302c and miR-520c directly targeted the 3′-UTRs of MICA/B and ULBP2 and negatively regulated the expression of MIA/B and ULBP2. Moreover, upregulation of miR-302c or miR-520c by transfection of their mimics remarkably reduced the viability of Kasumi-1 cells upon NK cell co-incubation. By contrast, the suppression of the activity of miR-302c or miR-520c by their respective antisense oligonucleotides improved the resistance of Kasumi-1 cells to NK cells.
Conclusion:
1,25(OH)2D3 facilitates the immuno-attack of NK cells against malignant cells partly through downregulation of miR-302c and miR-520c and hence upregulation of the NKG2D ligands MICA/B and ULBP2.
doi:10.1038/bjc.2013.337
PMCID: PMC3738147  PMID: 23820258
NKG2D ligands; miR-302c; miR-520c; 1,25(OH)2D3
24.  Tunneling nanotube (TNT) formation is independent of p53 expression 
doi:10.1038/cdd.2013.61
PMCID: PMC3705610  PMID: 23764777
25.  Effect of periodontal therapy on the subgingival microbiota over a 2-year monitoring period. I. Overall effect and kinetics of change 
Objective
To examine the 2 year post-therapy kinetics of change in the composition of subgingival biofilms.
Material and Methods
178 chronic periodontitis subjects were recruited and clinically monitored at baseline, 3, 6, 12, 18 and 24 months after therapy. All subjects received SRP and 156 one or more of periodontal surgery, systemically administered amoxicillin + metronidazole or local tetracycline at pockets ≥5 mm. Subgingival biofilm samples taken from each subject at each time point were analyzed for their content of 40 bacterial species using checkerboard DNA-DNA hybridization. The significance of changes in median species counts over time was sought using the Wilcoxon or Friedman tests and adjusted for multiple comparisons.
Results
Mean counts were significantly reduced from baseline to 2 years for 30 of the 40 taxa. Marked reductions were observed for periodontal pathogens including Tannerella forsythia, Treponema denticola and Eubacterium nodatum. The kinetics of change differed from species to species. When data were subset according to baseline PD, patterns of change in the microbial profiles were generally similar.
Conclusion
Periodontal therapy leads to a rapid reduction in periodontal pathogens, followed by a slower reduction in other taxa that can be sustained for at least 2 years.
doi:10.1111/jcpe.12117
PMCID: PMC3757950  PMID: 23710672
Chronic periodontitis; Therapy; Microbiology; Kinetics

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