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On February 23, 2018, PubMed Central Canada (PMC Canada) will be taken offline permanently. No author manuscripts will be deleted, and the approximately 2,900 manuscripts authored by Canadian Institutes of Health Research (CIHR)-funded researchers currently in the archive will be copied to the National Research Council’s (NRC) Digital Repository over the coming months. These manuscripts along with all other content will also remain publicly searchable on PubMed Central (US) and Europe PubMed Central, meaning such manuscripts will continue to be compliant with the Tri-Agency Open Access Policy on Publications.

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1.  Girdin Is an Intrinsic Regulator of Neuroblast Chain Migration in the Rostral Migratory Stream of the Postnatal Brain 
In postnatally developing and adult brains, interneurons of the olfactory bulb (OB) are continuously generated at the subventricular zone of the forebrain. The newborn neuroblasts migrate tangentially to the OB through a well defined pathway, the rostral migratory stream (RMS), where the neuroblasts undergo collective migration termed “chain migration.” The cell-intrinsic regulatory mechanism of neuroblast chain migration, however, has not been uncovered. Here we show that mice lacking the actin-binding Akt substrate Girdin (a protein that interacts with Disrupted-In-Schizophrenia 1 to regulate neurogenesis in the dentate gyrus) have profound defects in neuroblast chain migration along the RMS. Analysis of two gene knock-in mice harboring Girdin mutants identified unique amino acid residues in Girdin’s C-terminal domain that are responsible for the regulation of neuroblast chain migration but revealed no apparent requirement of Girdin phosphorylation by Akt. Electron microscopic analyses demonstrated the involvement of Girdin in neuroblast cell–cell interactions. These findings suggest that Girdin is an important intrinsic factor that specifically governs neuroblast chain migration along the RMS.
doi:10.1523/JNEUROSCI.1130-11.2011
PMCID: PMC5491307  PMID: 21632933
2.  Suppression of skin tumorigenesis in CD109-deficient mice 
Oncotarget  2016;7(50):82836-82850.
CD109 is a glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed in several types of human cancers, particularly squamous cell carcinomas. We previously reported that CD109-deficient mice exhibit epidermal hyperplasia and chronic skin inflammation. Although we found that CD109 regulates differentiation of keratinocytes in vivo, the function of CD109 in tumorigenesis remains unknown. In this study, we investigated the role of CD109 in skin tumorigenesis using a two-stage carcinogenesis model in CD109-deficient mice with chronic skin inflammation. Immunohistochemical analysis revealed a higher level of TGF-β protein expression in the dermis of CD109-deficient mice than in that of wild-type mice. Additionally, immunofluorescence analysis showed that Smad2 phosphorylation and Nrf2 expression were enhanced in primary keratinocytes from CD109-deficient mice compared with in those from wild-type mice. Although no significant difference was found in conversion rates from papilloma to carcinoma between wild-type and CD109-deficient mice in the carcinogenesis model, we observed fewer and smaller papillomas in CD109-deficient mice than in wild-type mice. Apoptosis and DNA damage marker levels were significantly reduced in CD109-deficient skin compared with in wild-type skin at 24 h after 7, 12-dimethylbenz (α) anthracene treatment. Furthermore, mutation-specific PCR revealed that the mutation frequency of the H-ras gene was less in CD109-deficient skin than in wild-type skin in this model. These results suggest that CD109 deficiency suppresses skin tumorigenesis by enhancing TGF-β/Smad/Nrf2 pathway activity and decreasing the mutation frequency of the H-ras gene.
doi:10.18632/oncotarget.12653
PMCID: PMC5347736  PMID: 27756876
skin carcinogenesis; CD109; TGF-β; p21; Nrf2
3.  Identification of Meflin as a Potential Marker for Mesenchymal Stromal Cells 
Scientific Reports  2016;6:22288.
Bone marrow-derived mesenchymal stromal cells (BM-MSCs) in culture are derived from BM stromal cells or skeletal stem cells. Whereas MSCs have been exploited in clinical medicine, the identification of MSC-specific markers has been limited. Here, we report that a cell surface and secreted protein, Meflin, is expressed in cultured MSCs, fibroblasts and pericytes, but not other types of cells including epithelial, endothelial and smooth muscle cells. In vivo, Meflin is expressed by immature osteoblasts and chondroblasts. In addition, Meflin is found on stromal cells distributed throughout the BM, and on pericytes and perivascular cells in multiple organs. Meflin maintains the undifferentiated state of cultured MSCs and is downregulated upon their differentiation, consistent with the observation that Meflin-deficient mice exhibit increased number of osteoblasts and accelerated bone development. In the bone and BM, Meflin is more highly expressed in primitive stromal cells that express platelet-derived growth factor receptor α and Sca-1 than the Sca-1-negative adipo-osteogenic progenitors, which create a niche for hematopoiesis. Those results are consistent with a decrease in the number of clonogenic colony-forming unit-fibroblasts within the BM of Meflin-deficient mice. These preliminary data suggest that Meflin is a potential marker for cultured MSCs and their source cells in vivo.
doi:10.1038/srep22288
PMCID: PMC4770287  PMID: 26924503
4.  CCDC88A mutations cause PEHO-like syndrome in humans and mouse 
Brain  2016;139(4):1036-1044.
Progressive Encephalopathy with oedema, Hypsarrhythmia and Optic atrophy (PEHO) is a rare, neurodegenerative disorder of unknown aetiology. Nahorski et al. identify the first causative recessive mutation in CCDC88A, which encodes the actin-binding protein Girdin. The phenotype and brain anatomy of the Ccdc88a knockout mouse resemble those of human PEHO syndrome.
Progressive Encephalopathy with oedema, Hypsarrhythmia and Optic atrophy (PEHO) is a rare, neurodegenerative disorder of unknown aetiology. Nahorski et al. identify the first causative recessive mutation in CCDC88A, which encodes the actin-binding protein Girdin. The phenotype and brain anatomy of the Ccdc88a knockout mouse resemble those of human PEHO syndrome.
Progressive encephalopathy with oedema, hypsarrhythmia and optic atrophy (PEHO) syndrome is a rare Mendelian phenotype comprising severe retardation, early onset epileptic seizures, optic nerve/cerebellar atrophy, pedal oedema, and early death. Atypical cases are often known as PEHO-like, and there is an overlap with ‘early infantile epileptic encephalopathy’. PEHO is considered to be recessive, but surprisingly since initial description in 1991, no causative recessive gene(s) have been described. Hence, we report a multiplex consanguineous family with the PEHO phenotype where affected individuals had a homozygous frame-shift deletion in CCDC88A (c.2313delT, p.Leu772*ter). Analysis of cDNA extracted from patient lymphocytes unexpectedly failed to show non-sense mediated decay, and we demonstrate that the mutation produces a truncated protein lacking the crucial C-terminal half of CCDC88A (girdin). To further investigate the possible role of CCDC88A in human neurodevelopment we re-examined the behaviour and neuroanatomy of Ccdc88a knockout pups. These mice had mesial-temporal lobe epilepsy, microcephaly and corpus callosum deficiency, and by postnatal Day 21, microcephaly; the mice died at an early age. As the mouse knockout phenotype mimics the human PEHO phenotype this suggests that loss of CCDC88A is a cause of the PEHO phenotype, and that CCDC88A is essential for multiple aspects of normal human neurodevelopment.
doi:10.1093/brain/aww014
PMCID: PMC4806221  PMID: 26917597
PEHO syndrome; girdin; neurodevelopmental disorder; epilepsy; microcephaly
5.  Role for Daple in non‐canonical Wnt signaling during gastric cancer invasion and metastasis 
Cancer Science  2015;107(2):133-139.
In gastric cancer, the non‐canonical Wnt signaling pathway is activated by Wnt5a, which has a critical role in disease outcome. Previous studies have shown that Wnt5a mediates the expression of the extracellular matrix protein laminin γ2 through Rac and JNK activation to promote gastric cancer progression. However, the mechanism of this regulatory pathway has not been completely addressed. The scaffold protein Dvl is a major component of the Wnt signaling pathway. Here, we show that Dvl‐associating protein with a high frequency of leucine residues (Daple) mediates Wnt5a‐induced laminin γ2 expression. Immunohistochemical analysis showed marked expression of Daple in advanced clinical stages of gastric cancer, where it highly correlated with Wnt5a/b and laminin γ2 expression, the depth of wall invasion, and the frequency of lymph node metastasis. In cultured cancer cells, Daple depletion led to the suppression of Wnt5a‐induced Rac and JNK activation, laminin γ2 expression, and cell migration and invasion. Accordingly, Daple depletion also suppressed liver metastasis in a mouse xenograft model of gastric cancer. These results suggest that the non‐canonical Wnt signaling pathway contributes to gastric cancer progression at least in part via Daple, which provides a new therapeutic opportunity for the treatment of the disease.
doi:10.1111/cas.12848
PMCID: PMC4768387  PMID: 26577606
Daple; gastric cancer; invasion; metastasis; Wnt signaling
6.  Regulation of cargo-selective endocytosis by dynamin 2 GTPase-activating protein girdin 
The EMBO Journal  2014;33(18):2098-2112.
In clathrin-mediated endocytosis (CME), specificity and selectivity for cargoes are thought to be tightly regulated by cargo-specific adaptors for distinct cellular functions. Here, we show that the actin-binding protein girdin is a regulator of cargo-selective CME. Girdin interacts with dynamin 2, a GTPase that excises endocytic vesicles from the plasma membrane, and functions as its GTPase-activating protein. Interestingly, girdin depletion leads to the defect in clathrin-coated pit formation in the center of cells. Also, we find that girdin differentially interacts with some cargoes, which competitively prevents girdin from interacting with dynamin 2 and confers the cargo selectivity for CME. Therefore, girdin regulates transferrin and E-cadherin endocytosis in the center of cells and their subsequent polarized intracellular localization, but has no effect on integrin and epidermal growth factor receptor endocytosis that occurs at the cell periphery. Our results reveal that girdin regulates selective CME via a mechanism involving dynamin 2, but not by operating as a cargo-specific adaptor.
doi:10.15252/embj.201488289
PMCID: PMC4195775  PMID: 25061227
clathrin-mediated endocytosis; dynamin; girdin; GTPase-activating protein; selective endocytosis
7.  Regulation of cargo-selective endocytosis by dynamin 2 GTPase-activating protein girdin 
The EMBO Journal  2014;33(18):2098-2112.
In clathrin-mediated endocytosis (CME), specificity and selectivity for cargoes are thought to be tightly regulated by cargo-specific adaptors for distinct cellular functions. Here, we show that the actin-binding protein girdin is a regulator of cargo-selective CME. Girdin interacts with dynamin 2, a GTPase that excises endocytic vesicles from the plasma membrane, and functions as its GTPase-activating protein. Interestingly, girdin depletion leads to the defect in clathrin-coated pit formation in the center of cells. Also, we find that girdin differentially interacts with some cargoes, which competitively prevents girdin from interacting with dynamin 2 and confers the cargo selectivity for CME. Therefore, girdin regulates transferrin and E-cadherin endocytosis in the center of cells and their subsequent polarized intracellular localization, but has no effect on integrin and epidermal growth factor receptor endocytosis that occurs at the cell periphery. Our results reveal that girdin regulates selective CME via a mechanism involving dynamin 2, but not by operating as a cargo-specific adaptor.
doi:10.15252/embj.201488289
PMCID: PMC4195775  PMID: 25061227
clathrin-mediated endocytosis; dynamin; girdin; GTPase-activating protein; selective endocytosis
8.  Suppression of REV7 enhances cisplatin sensitivity in ovarian clear cell carcinoma cells 
Cancer Science  2014;105(5):545-552.
Human REV7 (also known as MAD2L2 and MAD2B) is involved in DNA repair, cell cycle regulation, gene transcription, and carcinogenesis. In this study, we evaluated the expression of REV7 in epithelial ovarian cancer (EOC) and analyzed the association between its expression and chemosensitivity in ovarian clear cell carcinoma (CCC) cells. Expression of REV7 in human EOC tissues was assessed by immunohistochemical staining. Expression was detected in the majority of EOCs (92.0%) with especially high levels of expression frequently observed in CCCs (73.5%) compared with that of non-CCCs (53.4%). Enhanced immunoreactivity to REV7 was associated with poor prognosis represented by reduced progression-free survival in advanced stage (stage II–IV) EOC as assessed using Kaplan–Meier curves and log–rank tests. The effects of REV7 knockdown on cell proliferation and chemosensitivity in CCC cells were also analyzed in vitro and in vivo. Knockdown of REV7 in CCC cells decreased cell proliferation without affecting cell cycle distribution. Additionally, the number of apoptotic cells and DNA damaged cells were increased after cisplatin treatment. In a nude mouse tumor xenograft model, inoculated REV7-knockdown tumors showed significantly reduced tumor volumes after cisplatin treatment compared with those of the control group. These findings indicate that depletion of REV7 enhances sensitivity to cisplatin treatment in CCC, suggesting that REV7 is a candidate molecular target in CCC management.
doi:10.1111/cas.12390
PMCID: PMC4317831  PMID: 24597627
Apoptosis; chemosensitivity; cisplatin; DNA damage; ovarian clear cell carcinoma
9.  The REV7 Subunit of DNA Polymerase ζ Is Essential for Primordial Germ Cell Maintenance in the Mouse* 
The Journal of Biological Chemistry  2013;288(15):10459-10471.
Background: Biological significance of REV7 in mouse development has not been elucidated.
Results: REV7-deficient mice show germ cell aplasia at birth in both sexes, and primordial germ cells (PGCs) were lost because of apoptosis during migration at an early embryonic stage.
Conclusion: REV7 is essential for PGC maintenance in the mouse.
Significance: REV7 is a novel regulator of PGC survival.
REV7 (also known as MAD2L2 and MAD2B) is involved in DNA repair, cell cycle regulation, gene expression, and carcinogenesis. In vitro studies show that REV7 interacts with several proteins and regulates their function. It has been reported that human REV7 is highly expressed in the adult testis by Northern blot analysis. However, the significance of REV7 in mammalian development has not been elucidated. Here, we present analyses of REV7-deficient (Rev7−/−) mice to clarify the significance of Rev7 in mouse development. In WT mice (Rev7+/+), Rev7 expression was ubiquitously observed in the embryo and confined to germ cells in the testes after birth. Rev7−/− mice exhibited growth retardation and a partial embryonic lethal phenotype. Mice that survived to adulthood were infertile in both sexes and showed germ cell aplasia in the testes and ovaries. Analyses of Rev7−/− embryos revealed that primordial germ cells (PGCs) were present at embryonic day 8.5 (E8.5). However, progressive loss of PGCs was observed during migration, and PGCs were absent in the genital ridges at E13.5. An increase of apoptotic cells was detected not only among PGCs but also in the forebrain of the Rev7−/− embryo, whereas cell proliferation was unaffected. Moreover, DNA damage accumulation and increased levels of histone methylation were detected in Rev7−/− embryos, and expression of Oct4 and Nanog was deregulated by REV7 deficiency at E8.5. These findings indicate that Rev7 is essential for PGC maintenance by prevention of apoptotic cell death in the mouse.
doi:10.1074/jbc.M112.421966
PMCID: PMC3624428  PMID: 23463509
Apoptosis; DNA Damage; Embryo; Gene Knockout; Histone Methylation; Infertility; Primordial Germ Cell
10.  Expression of RET finger protein predicts chemoresistance in epithelial ovarian cancer 
Cancer Medicine  2012;1(2):218-229.
Resistance to platinum- and taxane-based chemotherapy is a major cause of treatment failure in ovarian cancer. Thus, it is necessary to develop a predictive marker and molecular target for overcoming drug resistance in ovarian cancer treatment. In a previous report, using an in vitro model, we found that the RET finger protein (RFP) (also known as tripartite motif-containing protein 27, TRIM27) confers cancer cell resistance to anticancer drugs. However, the significance of RFP expression in cancer patients remains elusive. In this study, we showed that RFP was expressed in 62% of ovarian cancer patients and its positivity significantly correlated with drug resistance. Consistent with clinical data, depletion of RFP by RNA interference (RNAi) in ovarian cancer cell lines, SKOV3 and HEY, significantly increased carboplatin- or paclitaxel-induced apoptosis and resulted in reduced anticancer drug resistance. In a nude mouse tumor xenograft model, inoculated RFP-knockdown ovarian cancer cells exhibited lower carboplatin resistance than control cells. These findings suggest that RFP could be a predictive marker for chemoresistance in ovarian cancer patients and also a candidate for a molecular-targeted agent.
doi:10.1002/cam4.32
PMCID: PMC3544444  PMID: 23342271
Carboplatin; chemoresistance; epithelial ovarian cancer; paclitaxel; RET finger protein
11.  Search for lepton flavour violation in the eμ continuum with the ATLAS detector in \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\sqrt{s} = 7~\mbox{TeV}$\end{document}pp collisions at the LHC 
Aad, G. | Abbott, B. | Abdallah, J. | Abdelalim, A. A. | Abdesselam, A. | Abdinov, O. | Abi, B. | Abolins, M. | Abramowicz, H. | Abreu, H. | Acerbi, E. | Acharya, B. S. | Adams, D. L. | Addy, T. N. | Adelman, J. | Adomeit, S. | Adragna, P. | Adye, T. | Aefsky, S. | Aguilar-Saavedra, J. A. | Aharrouche, M. | Ahlen, S. P. | Ahles, F. | Ahmad, A. | Ahsan, M. | Aielli, G. | Akdogan, T. | Åkesson, T. P. A. | Akimoto, G. | Akimov, A. V. | Akiyama, A. | Aktas, A. | Alam, M. S. | Alam, M. A. | Albrand, S. | Aleksa, M. | Aleksandrov, I. N. | Aleppo, M. | Alessandria, F. | Alexa, C. | Alexander, G. | Alexandre, G. | Alexopoulos, T. | Alhroob, M. | Aliev, M. | Alimonti, G. | Alison, J. | Aliyev, M. | Allport, P. P. | Allwood-Spiers, S. E. | Almond, J. | Aloisio, A. | Alon, R. | Alonso, A. | Alviggi, M. G. | Amako, K. | Amelung, C. | Ammosov, V. V. | Amorim, A. | Amorós, G. | Amram, N. | Anastopoulos, C. | Andeen, T. | Anders, C. F. | Anderson, K. J. | Andreazza, A. | Andrei, V. | Anduaga, X. S. | Angerami, A. | Anghinolfi, F. | Anjos, N. | Annovi, A. | Antonaki, A. | Antonelli, M. | Antonelli, S. | Antonov, A. | Antos, J. | Anulli, F. | Aoun, S. | Aperio Bella, L. | Apolle, R. | Arabidze, G. | Aracena, I. | Arai, Y. | Arce, A. T. H. | Archambault, J. P. | Arfaoui, S. | Arguin, J-F. | Arik, E. | Arik, M. | Armbruster, A. J. | Arnaez, O. | Arnault, C. | Artamonov, A. | Artoni, G. | Arutinov, D. | Asai, M. | Asai, S. | Asfandiyarov, R. | Ask, S. | Åsman, B. | Asner, D. | Asquith, L. | Assamagan, K. | Astbury, A. | Astvatsatourov, A. | Atoian, G. | Aubert, B. | Auge, E. | Augsten, K. | Aurousseau, M. | Austin, N. | Avolio, G. | Avramidou, R. | Axen, D. | Azuelos, G. | Azuma, Y. | Baak, M. A. | Baccaglioni, G. | Bacci, C. | Bach, A. M. | Bachacou, H. | Bachas, K. | Bachy, G. | Backes, M. | Backhaus, M. | Badescu, E. | Bagnaia, P. | Bahinipati, S. | Bai, Y. | Bailey, D. C. | Bain, T. | Baines, J. T. | Baker, O. K. | Baker, M. D. | Baker, S. | Baltasar Dos Santos Pedrosa, F. | Banas, E. | Banerjee, P. | Banerjee, Sw. | Banfi, D. | Bangert, A. | Bansal, V. | Bansil, H. S. | Barak, L. | Baranov, S. P. | Barbaro Galtieri, A. | Barber, T. | Barberio, E. L. | Barberis, D. | Barbero, M. | Bardin, D. Y. | Barillari, T. | Barisonzi, M. | Barklow, T. | Barlow, N. | Barnett, B. M. | Barnett, R. M. | Baroncelli, A. | Barr, A. J. | Barreiro, F. | Barreiro Guimarães da Costa, J. | Barrillon, P. | Bartoldus, R. | Barton, A. E. | Bartsch, D. | Bartsch, V. | Bates, R. L. | Batkova, L. | Batley, J. R. | Battaglia, A. | Battistin, M. | Battistoni, G. | Bauer, F. | Bawa, H. S. | Beare, B. | Beau, T. | Beauchemin, P. H. | Beccherle, R. | Bechtle, P. | Beck, G. A. | Beck, H. P. | Beckingham, M. | Becks, K. H. | Beddall, A. J. | Beddall, A. | Bedikian, S. | Bednyakov, V. A. | Bee, C. P. | Begel, M. | Behar Harpaz, S. | Behera, P. K. | Beimforde, M. | Belanger-Champagne, C. | Bell, P. J. | Bell, W. H. | Bella, G. | Bellagamba, L. | Bellina, F. | Bellomo, G. | Bellomo, M. | Belloni, A. | Beloborodova, O. | Belotskiy, K. | Beltramello, O. | Ben Ami, S. | Benary, O. | Benchekroun, D. | Benchouk, C. | Bendel, M. | Benedict, B. H. | Benekos, N. | Benhammou, Y. | Benjamin, D. P. | Benoit, M. | Bensinger, J. R. | Benslama, K. | Bentvelsen, S. | Beretta, M. | Berge, D. | Bergeaas Kuutmann, E. | Berger, N. | Berghaus, F. | Berglund, E. | Beringer, J. | Bernardet, K. | Bernat, P. | Bernhard, R. | Bernius, C. | Berry, T. | Bertin, A. | Bertolucci, F. | Besana, M. I. | Besson, N. | Bethke, S. | Bhimji, W. | Bianchi, R. M. | Bianco, M. | Biebel, O. | Bieniek, S. P. | Biesiada, J. | Biglietti, M. | Bilokon, H. | Bindi, M. | Binet, S. | Bingul, A. | Bini, C. | Biscarat, C. | Bitenc, U. | Black, K. M. | Blair, R. E. | Blanchard, J.-B. | Blanchot, G. | Blocker, C. | Blocki, J. | Blondel, A. | Blum, W. | Blumenschein, U. | Bobbink, G. J. | Bobrovnikov, V. B. | Bocchetta, S. 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This paper presents a search for the t-channel exchange of an R-parity violating scalar top quark (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\tilde{t}$\end{document}) in the e±μ∓ continuum using 2.1 fb−1 of data collected by the ATLAS detector in \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\sqrt{s}=7~\mbox{TeV}$\end{document}pp collisions at the Large Hadron Collider. Data are found to be consistent with the expectation from the Standard Model backgrounds. Limits on R-parity-violating couplings at 95 % C.L. are calculated as a function of the scalar top mass (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$m_{\tilde{t}}$\end{document}). The upper limits on the production cross section for pp→eμX, through the t-channel exchange of a scalar top quark, ranges from 170 fb for \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$m_{\tilde{t}}=95~\mbox{GeV}$\end{document} to 30 fb for \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$m_{\tilde{t}}=1000~\mbox{GeV}$\end{document}.
doi:10.1140/epjc/s10052-012-2040-z
PMCID: PMC4370899  PMID: 25814838
12.  First in man demonstration of direct endothelin-mediated natriuresis & diuresis 
Endothelin (ET) receptor antagonists are potentially novel therapeutic agents in chronic kidney disease and resistant hypertension but their use is complicated by sodium and water retention. In animal studies, this side effect arises from ETB receptor blockade in the renal tubule. Previous attempts to determine whether this mechanism operates in humans have been confounded by the hemodynamic consequences of ET receptor stimulation / blockade.
We aimed to determine the effects of ET signalling on salt transport in the human nephron by administering sub-pressor doses of the ET-1 precursor, big ET-1. We conducted a 2-phase randomized, double-blind, placebo-controlled crossover study in 10 healthy volunteers. Following sodium restriction, subjects received either intravenous placebo or big ET-1, in escalating dose (up to 300pmol/min). This increased plasma concentration and urinary excretion of ET-1. Big ET-1 reduced heart rate (~8 beats/min) but did not otherwise affect systemic hemodynamics or glomerular filtration rate. Big ET-1 increased the fractional excretion of sodium (from 0.5 to 1.0%). It also increased free water clearance and tended to increase the abundance of the sodium-potassium-chloride co-transporter (NKCC2) in urinary extracellular vesicles.
Our protocol induced modest increases in circulating and urinary ET-1. Sodium and water excretion increased in the absence of significant hemodynamic perturbation, supporting a direct action of ET-1 on the renal tubule. Our data also suggest that sodium reabsorption is stimulated by ET-1 in the thick ascending limb and suppressed in the distal renal tubule. Fluid retention associated with ET receptor antagonist therapy may be circumvented by co-prescribing potassium-sparing diuretics.
doi:10.1161/HYPERTENSIONAHA.116.08832
PMCID: PMC5739104  PMID: 28507171
endothelin; natriuresis; diuresis; NKCC2; ENaC
13.  Enzymes of the one-carbon folate metabolism as anticancer targets predicted by survival rate analysis 
Scientific Reports  2018;8:303.
The significance of mitochondrial metabolism in cancer cells has recently been gaining attention. Among other findings, One-carbon folate metabolism has been reported to be closely associated with cellular characteristics in cancer. To study molecular targets for efficient cancer therapy, we investigated the association between the expressions of genes that code enzymes involved in one-carbon metabolism and survival rate of patients with adenocarcinomas of the colorectum and lung. Patients with high expression of genes that control the metabolic cycle of tetrahydrofolate (THF) in mitochondria, SHMT2, MTHFD2, and ALDH1L2, have a shorter overall survival rate compared with patients with low expression of these genes. Our results revealed that these genes could be novel and more promising anticancer targets than dihydrofolate reductase (DHFR), the current target of drug therapy linked with folate metabolism, suggesting the rationale of drug discovery in cancer medicine.
doi:10.1038/s41598-017-18456-x
PMCID: PMC5762868  PMID: 29321536
14.  Radiation therapy for stage IVA uterine cervical cancer: treatment outcomes including prognostic factors and risk of vesicovaginal and rectovaginal fistulas 
Oncotarget  2017;8(68):112855-112866.
Purpose
To evaluate the safety and efficacy of radiation therapy for stage IVA uterine cervical cancer and to identify an optimal radiation regimen.
Results
Seventeen of the 28 patients developed recurrence after radiation therapy (local recurrence in 10 and distant metastasis in 12). The local control and distant metastasis-free rates at 3 years in all patients were 61% and 49%, respectively. Fourteen patients died after radiation therapy, and all but 2 died of tumor progression. The disease-free, cause-specific, and overall survival rates at 3 years in all patients were 32%, 49%, and 45%, respectively, and the estimated median survival time was 32 months. Tumor size (P = 0.007) and involvement in the lower third of vagina (P = 0.006) were significant prognostic factors for local control. Older age (P = 0.018) and performance status (P = 0.020) were significant prognostic factors for distant metastasis. The presence of hydronephrosis was the sole significant prognostic factor for survival (P = 0.026). Only 2 patients developed grade 3 late toxicities (vesicovaginal fistula and radiation proctitis, respectively).
Materials and Methods
Twenty-eight patients with stage IVA uterine cervical cancer received radiation therapy. All patients initially received external pelvic irradiation at a median dose of 50.4 Gy in 28 fractions. Twenty patients also received high-dose-rate intracavitary brachytherapy at a median dose of 22 Gy in 4 fractions. These fraction sizes were lower than conventional sizes. The total median dose for all 28 patients was 68.7 Gy.
Conclusions
Radiation therapy is safe and effective for treatment of stage IVA uterine cervical cancer. The reduced radiation dose per fraction may contribute to the prevention of vesicovaginal fistula formation.
doi:10.18632/oncotarget.22836
PMCID: PMC5762556
cervical cancer; radiation therapy; stage IVA; uterine cervix; vesicovaginal fistula
15.  First-in-Man Demonstration of Direct Endothelin-Mediated Natriuresis and Diuresis 
Supplemental Digital Content is available in the text.
Endothelin (ET) receptor antagonists are potentially novel therapeutic agents in chronic kidney disease and resistant hypertension, but their use is complicated by sodium and water retention. In animal studies, this side effect arises from ETB receptor blockade in the renal tubule. Previous attempts to determine whether this mechanism operates in humans have been confounded by the hemodynamic consequences of ET receptor stimulation/blockade. We aimed to determine the effects of ET signaling on salt transport in the human nephron by administering subpressor doses of the ET-1 precursor, big ET-1. We conducted a 2-phase randomized, double-blind, placebo-controlled crossover study in 10 healthy volunteers. After sodium restriction, subjects received either intravenous placebo or big ET-1, in escalating dose (≤300 pmol/min). This increased plasma concentration and urinary excretion of ET-1. Big ET-1 reduced heart rate (≈8 beats/min) but did not otherwise affect systemic hemodynamics or glomerular filtration rate. Big ET-1 increased the fractional excretion of sodium (from 0.5 to 1.0%). It also increased free water clearance and tended to increase the abundance of the sodium–potassium–chloride cotransporter (NKCC2) in urinary extracellular vesicles. Our protocol induced modest increases in circulating and urinary ET-1. Sodium and water excretion increased in the absence of significant hemodynamic perturbation, supporting a direct action of ET-1 on the renal tubule. Our data also suggest that sodium reabsorption is stimulated by ET-1 in the thick ascending limb and suppressed in the distal renal tubule. Fluid retention associated with ET receptor antagonist therapy may be circumvented by coprescribing potassium-sparing diuretics.
doi:10.1161/HYPERTENSIONAHA.116.08832
PMCID: PMC5739104  PMID: 28507171
diuresis; endothelin; hypertension; kidney; natriuresis
16.  An inclusive Research Education Community (iREC): Impact of the SEA-PHAGES program on research outcomes and student learning 
Significance
The Science Education Alliance–Phage Hunters Advancing Genomics and Evolutionary Science program is an inclusive Research Education Community with centralized programmatic and scientific support, in which broad student engagement in authentic science is linked to increased accessibility to research experiences for students; increased persistence of these students in science, technology, engineering, and mathematics; and increased scientific productivity for students and faculty alike.
Engaging undergraduate students in scientific research promises substantial benefits, but it is not accessible to all students and is rarely implemented early in college education, when it will have the greatest impact. An inclusive Research Education Community (iREC) provides a centralized scientific and administrative infrastructure enabling engagement of large numbers of students at different types of institutions. The Science Education Alliance–Phage Hunters Advancing Genomics and Evolutionary Science (SEA-PHAGES) is an iREC that promotes engagement and continued involvement in science among beginning undergraduate students. The SEA-PHAGES students show strong gains correlated with persistence relative to those in traditional laboratory courses regardless of academic, ethnic, gender, and socioeconomic profiles. This persistent involvement in science is reflected in key measures, including project ownership, scientific community values, science identity, and scientific networking.
doi:10.1073/pnas.1718188115
PMCID: PMC5754813  PMID: 29208718
bacteriophage; genomics; science education; evolution; assessment
17.  Liver Abscess and Portal Vein Thrombosis Due to Ileal Diverticulitis Mediated by Barium Fluoroscopy 
Internal Medicine  2017;56(23):3255-3259.
We report a case of liver abscess and portal vein thrombosis, which occurred due to diverticulitis at the terminal ileum in a 59-year-old man. The patient underwent a barium fluoroscopic examination 1 month before presenting to our hospital. He also showed liver dysfunction due to thrombosis at the superior mesenteric and portal veins. His inflammation gradually subsided after the initiation of treatment, but the recovery was not sufficient. Thus, surgery was performed. The patient condition improved after surgery and he was discharged. Barium examinations are relatively safe, but can sometimes cause severe adverse effects in patients with certain risk factors, and an appropriate diagnosis and treatment are necessary when symptoms appear.
doi:10.2169/internalmedicine.9223-17
PMCID: PMC5742403  PMID: 29021445
barium; liver abscess; diverticulitis; superior mesenteric vein thrombosis; portal vein thrombosis
18.  Evaluation of myocardial glucose metabolism in hypertrophic cardiomyopathy using 18F-fluorodeoxyglucose positron emission tomography 
PLoS ONE  2017;12(11):e0188479.
Background
The purposes of this study were to assess the usefulness of myocardial 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) for evaluating myocardial metabolic status in hypertrophic cardiomyopathy (HCM) and the therapeutic efficacy of alcohol septal ablation (ASA) in hypertrophic obstructive cardiomyopathy (HOCM).
Methods
Thirty HCM patients (64.4±10.5 years, 14 male, 12 hypertrophic non-obstructive cardiomyopathy [HNCM], 16 HOCM, and 2 dilated phase of HCM) underwent 18F-FDG-PET/CT. 18F-FDG uptake was semi-quantitatively evaluated using an uptake score in each 17 segment and the entire LV or regional standardized uptake value (SUV).
Results
18F-FDG uptake was observed mostly in a hypertrophied myocardium in HNCM patients, whereas 18F-FDG was extensively accumulated beyond the hypertrophied myocardium in HOCM patients. There was a positive correlation between the summed uptake score of 18F-FDG and high-sensitive troponin T level in HNCM patients (r = 0.603, p = 0.049), whereas the score was positively correlated with brain natriuretic peptide level (r = 0.614, p = 0.011) in HOCM patients. In 10 patients who received ASA, the maximum SUV of the entire LV was significantly reduced from 5.6±2.6 to 3.2±2.1 (p = 0.040) after ASA. Reduction of that maximum SUV was particularly significant in the lateral region (from 5.5±2.6 to 2.9 ±2.2, p = 0.024) but not significant in the anteroseptal region (from 4.5±2.6 to 2.9±1.6, p = 0.12).
Conclusion
Extensive 18F-FDG uptake beyond the hypertrophied myocardium was observed in HOCM. ASA attenuates 18F-FDG uptake in a remote lateral myocardium.
doi:10.1371/journal.pone.0188479
PMCID: PMC5703458  PMID: 29176885
19.  Scintillating Organic–Inorganic Layered Perovskite-type Compounds and the Gamma-ray Detection Capabilities 
Scientific Reports  2017;7:14754.
We investigated scintillation properties of organic–inorganic layered perovskite-type compounds under gamma-ray and X-ray irradiation. A crystal of the hybrid compounds with phenethyl amine (17 × 23 × 4 mm) was successfully fabricated by the poor-solvent diffusion method. The bulk sample showed superior scintillation properties with notably high light yield (14,000 photons per MeV) under gamma-rays and very fast decay time (11 ns). The light yield was about 1.4 time higher than that of common inorganic material (GSO:Ce) confirmed under 137Cs and 57Co gamma-rays. In fact, the scintillation light yield was the highest among the organic–inorganic hybrid scintillators. Moreover, it is suggested that the light yield of the crystal was proportional with the gamma-ray energy across 122–662 keV. In addition, the scintillation from the crystal had a lifetime of 11 ns which was much faster than that of GSO:Ce (48 ns) under X-ray irradiation. These results suggest that organic–inorganic layered perovskite-type compounds are promising scintillator for gamma-ray detection.
doi:10.1038/s41598-017-15268-x
PMCID: PMC5676720  PMID: 29116171
20.  Loss of p300 Accelerates MDS-associated Leukemogenesis 
Leukemia  2016;31(6):1382-1390.
The role that changes in DNA methylation and histone modifications play in human malignancies is poorly understood. p300 and CBP, two distinct but highly homologous lysine acetyltransferases (KATs), are mutated in several cancers, suggesting their role as tumor suppressors. In the current study, we found that deletion of p300, but not CBP, markedly accelerated the leukemogenesis of Nup98-HoxD13 (NHD13) transgenic mice, an animal model that phenotypically copies human myelodysplastic syndrome (MDS). p300 deletion restored the ability of NHD13 expressing hematopoietic stem and progenitor cells (HSPCs) to self-renew in vitro, and to expand in vivo, with an increase in stem cell symmetric self-renewal divisions and a decrease in apoptosis. Furthermore, loss of p300, but not CBP, promoted cytokine signaling, including enhanced activation of the MAPK and JAK/STAT pathways in the HSPC compartment. Altogether, our data indicate that p300 plays a pivotal role in blocking the transformation of MDS to acute myeloid leukemia (AML), a role distinct from that of CBP.
doi:10.1038/leu.2016.347
PMCID: PMC5667352  PMID: 27881875
21.  Anteroposterior perception of the trunk position while seated without the feet touching the floor 
Journal of Physical Therapy Science  2017;29(11):2026-2030.
[Purpose] The purpose of this study was to investigate the trunk position perception in the anteroposterior direction in young participants sitting without their feet touching the floor to avoid the influence of the hamstrings tension and the feet pressure on the perception. [Subjects and Methods] Fourteen healthy volunteers were seated on a chair fitted with an original manual goniometer. There were 7 reference positions set at 5° increments, from −15° to 15°, and reproductions of each position were conducted 5 times. Trunk position perception was evaluated by the absolute error between the reproduced trunk angle and the reference position angle. [Results] The results revealed a significant effect of reference position on the absolute error. The absolute error at the −5° reference position was significantly larger than at the −15° and 15° positions, and the absolute error at the 0° position was significantly larger than at the −15°, 10°, and 15° positions. [Conclusion] These results suggest that the perception of extreme forward- and backward-leaning trunk positions while sitting without the feet touching the floor would be higher than in a neutral sitting position. The relationship between the stability of the posture and the perception may be involved in the sitting position.
doi:10.1589/jpts.29.2026
PMCID: PMC5702840
Trunk; Perception; Sitting
22.  The preventive effect of the impaired liver function for antiemetic therapy against chemotherapy-induced nausea and vomiting in hepatocellular carcinoma patients 
Transarterial chemoembolization and hepatic arterial infusion chemotherapy are recommended for the treatment in patients with intermediate stage of hepatocellular carcinoma. Impaired liver function was sometime observed in patients with hepatocellular carcinoma after transarterial chemoembolization or hepatic arterial infusion chemotherapy. However, what kinds of factors deeply influence in impaired liver function are not clear. A retrospective study was performed to evaluate the risk factors of impaired liver function in cisplatin-naïve patients treated with these therapies using cisplatin. Prior to and 2 months after these therapies, we analyzed the liver function by Child-Pugh score in these patients. For assessing the severity of chemotherapy-induced nausea and vomiting, we utilized the Common Terminology Criteria for Adverse Events ver. 4.0. In hepatocellular carcinoma patients received these therapies using cisplatin, the cancer stage and treatment without neurokinin-1 (NK1) antagonist were found to be independent risk factors of the impaired liver function. The treatment with NK1 antagonist was effective in reducing chemotherapy-induced nausea and vomiting and patients treated with NK1 antagonist kept their liver functions after cisplatin-used these therapies. The treatment with NK1 antagonist was effective in chemotherapy-induced nausea and vomiting and prevented the impaired liver function associated with cisplatin-used these therapies in hepatocellular carcinoma patients.
doi:10.3164/jcbn.17-57
PMCID: PMC5703785
HCC; TACE; HAIC; CINV; NK1 antagonist
23.  Clinical Usefulness of the Platelet-to Lymphocyte Ratio in Patients with Angiosarcoma of the Face and Scalp 
Angiosarcoma of the face and scalp (ASFS) is an extremely aggressive tumor that frequently metastasizes, often leading to death. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) are inflammatory markers that predict outcome of various cancers. We aimed to examine the relationship between pretreatment inflammatory markers and ASFS outcome. We included 17 patients with ASFS and a control group of 56 age- and gender-matched healthy individuals. Total white blood counts, neutrophil, lymphocyte, monocyte, and platelet counts were recorded; NLR, PLR, and LMR were calculated. Kaplan–Meier curves were used to calculate overall survival (OS) and distant metastasis-free survival (DMFS). Optimal cut-off values for each inflammatory marker were calculated using receiver operating curve analysis. Median follow-up was 22 months (range, 6–75). There was a statistically significant difference in absolute neutrophil counts and NLR between patient and control groups. Two-year OS and DMFS rates were 41% and 35%, respectively. In patients with tumors < 10 cm, PLR was highly correlated with DMFS, with the 2-year DMFS for those with a high PLR being 50% compared with 100% for those with a low PLR (p = 0.06). This study suggests that PLR is superior to NLR and LMR, and is a clinically useful marker in patients with ASFS with small tumors.
doi:10.3390/ijms18112402
PMCID: PMC5713370  PMID: 29137187
angiosarcoma; prognosis; distant metastasis; neutrophil-to-lymphocyte ratio; platelet-to-lymphocyte ratio; lymphocyte-to-monocyte ratio
24.  Aerodynamic effects of dimples on soccer ball surfaces 
Heliyon  2017;3(10):e00432.
Recently, the shape and design of the panel on the official ball used in the FIFA World Cup was considerably different from that of a conventional soccer ball (having 32 pentagonal and hexagonal panels). Depending on the number of different panels and their orientation, the aerodynamic force experienced by a ball is believed to change, which in turn changes the ball trajectory. However, not much is known about the impact of the surface forms of a ball on its aerodynamics. Therefore, in the present study, 10 different types of soccer balls were produced and their aerodynamic properties were studied by wind tunnel experiments. The results confirmed that the aerodynamic force acting on the ball varied considerably depending on the existence of dimples on the ball surface. In addition, the 4 types of soccer balls, which had different kinds of roughness, revealed that even balls having the same number and shapes of panels experienced greatly varying aerodynamic forces depending on the surface form of the balls.
doi:10.1016/j.heliyon.2017.e00432
PMCID: PMC5714554
Engineering; Mechanics
25.  Necdin modulates leukemia-initiating cell quiescence and chemotherapy response 
Oncotarget  2017;8(50):87607-87622.
Acute myeloid leukemia (AML) is a devastating illness which carries a very poor prognosis, with most patients living less than 18 months. Leukemia relapse may occur because current therapies eliminate proliferating leukemia cells but fail to eradicate quiescent leukemia-initiating cells (LICs) that can reinitiate the disease after a period of latency. While we demonstrated that p53 target gene Necdin maintains hematopoietic stem cell (HSC) quiescence, its roles in LIC quiescence and response to chemotherapy are unclear. In this study, we utilized two well-established murine models of human AML induced by MLL-AF9 or AML1-ETO9a to determine the role of Necdin in leukemogenesis. We found that loss of Necdin decreased the number of functional LICs and enhanced myeloid differentiation in vivo, leading to delayed development of leukemia induced by MLL-AF9. Importantly, Necdin null LICs expressing MLL-AF9 were less quiescent than wild-type LICs. Further, loss of Necdin enhanced the response of MLL-AF9+ leukemia cells to chemotherapy treatment, manifested by decreased viability and enhanced apoptosis. We observed decreased expression of Bcl2 and increased expression of p53 and its target gene Bax in Necdin null leukemia cells following chemotherapy treatment, indicating that p53-dependent apoptotic pathways may be activated in the absence of Necdin. In addition, we found that loss of Necdin decreased the engraftment of AML1-ETO9a+ hematopoietic stem and progenitor cells in transplantation assays. However, Necdin-deficiency did not affect the response of AML1-ETO9a+ hematopoietic cells to chemotherapy treatment. Thus, Necdin regulates leukemia-initiating cell quiescence and chemotherapy response in a context-dependent manner. Our findings suggest that pharmacological inhibition of Necdin may hold potential as a novel therapy for leukemia patients with MLL translocations.
doi:10.18632/oncotarget.20999
PMCID: PMC5675657
Necdin; leukemia-initiating cells; quiescence; MLL-AF9; chemotherapy

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