Acute Upper Gastrointestinal Bleeding Due to Metastatic Lung Cancer: An Unusual Case

There have been several published reports on metastatic lesions in the stomach, but the number of cases have been limited due to the low frequency of the condition. Metastatic lesions in the stomach are usually asymptomatic. A 55-year-old man with known metastatic lung adenocancer exhibited epigastric pain, hematemesis, and melena. A bleeding, ulcerated gastric metastasis was found and treated with endoscopic therapy and omeprazole

Recital Program

Utah State University\u27s Youth Conservatory students perform. Featuring the students of Erin Astill, Dennis Hirst, and Kevin Olson.https://digitalcommons.usu.edu/music_programs/1142/thumbnail.jp

Identification of the P-TEFb complex-interacting domain of Brd4 as an inhibitor of HIV-1 replication by functional cDNA library screening in MT-4 cells

AbstractWe conducted a phenotypic cDNA screening using a T cell line-based assay to identify human genes that render cells resistant to human immunodeficiency virus type 1 (HIV-1). We isolated potential HIV-1 resistance genes, including the carboxy terminal domain (CTD) of bromodomain-containing protein 4 (Brd4). Expression of GFP-Brd4-CTD was tolerated in MT-4 and Jurkat cells in which HIV-1 replication was markedly inhibited. We provide direct experimental data demonstrating that Brd4-CTD serves as a specific inhibitor of HIV-1 replication in T cells. Our method is a powerful tool for the identification of host factors that regulate HIV-1 replication in T cells

Zinc Maintains Embryonic Stem Cell Pluripotency and Multilineage Differentiation Potential via AKT Activation

[EN] Embryonic stem cells (ESCs) possess remarkable abilities, as they can differentiate into all cell types (pluripotency) and be self-renewing, giving rise to two identical cells. These characteristics make ESCs a powerful research tool in fundamental embryogenesis as well as candidates for use in regenerative medicine. Significant efforts have been devoted to developing protocols to control ESC fate, including soluble and complex cocktails of growth factors and small molecules seeking to activate/inhibit key signaling pathways for the maintenance of pluripotency states or activate differentiation. Here we describe a novel method for the effective maintenance of mouse ESCs, avoiding the supplementation of complex inhibitory cocktails or cytokines, e.g., LIF. We show that the addition of zinc to ESC cultures leads to a stable pluripotent state that shares biochemical, transcriptional and karyotypic features with the classical LIF treatment. We demonstrate for the first time that ESCs maintained in long-term cultures with added zinc, are capable of sustaining a stable ESCs pluripotent phenotype, as well as differentiating efficiently upon external stimulation. We show that zinc promotes long-term ESC self-renewal (>30 days) via activation of ZIP7 and AKT signaling pathways. Furthermore, the combination of zinc with LIF results in a synergistic effect that enhances LIF effects, increases AKT and STAT3 activity, promotes the expression of pluripotency regulators and avoids the expression of differentiation markers.PR acknowledges support from the Spanish Ministry of Science, Innovation and Universities (RTI2018-096794), and Fondo Europeo de Desarrollo Regional (FEDER). CIBER-BBN was an initiative funded by the VI National R&D&I Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. MS-S acknowledges support from the UK Engineering and Physical Sciences Research Council (EPSRC - EP/P001114/1).Mnatsakanyan, H.; Sabater I Serra, R.; Salmerón Sánchez, M.; Rico Tortosa, PM. (2019). Zinc Maintains Embryonic Stem Cell Pluripotency and Multilineage Differentiation Potential via AKT Activation. Frontiers in Cell and Developmental Biology. 7:1-17. https://doi.org/10.3389/fcell.2019.00180S1177Anzellotti, A. I., & Farrell, N. P. (2008). Zinc metalloproteins as medicinal targets. Chemical Society Reviews, 37(8), 1629. doi:10.1039/b617121bArmstrong, L., Hughes, O., Yung, S., Hyslop, L., Stewart, R., Wappler, I., … Lako, M. (2006). The role of PI3K/AKT, MAPK/ERK and NFκβ signalling in the maintenance of human embryonic stem cell pluripotency and viability highlighted by transcriptional profiling and functional analysis. Human Molecular Genetics, 15(11), 1894-1913. doi:10.1093/hmg/ddl112Bechard, M., & Dalton, S. (2009). Subcellular Localization of Glycogen Synthase Kinase 3β Controls Embryonic Stem Cell Self-Renewal. Molecular and Cellular Biology, 29(8), 2092-2104. doi:10.1128/mcb.01405-08Ten Berge, D., Kurek, D., Blauwkamp, T., Koole, W., Maas, A., Eroglu, E., … Nusse, R. (2011). Embryonic stem cells require Wnt proteins to prevent differentiation to epiblast stem cells. Nature Cell Biology, 13(9), 1070-1075. doi:10.1038/ncb2314Cardone, M. H. (1998). Regulation of Cell Death Protease Caspase-9 by Phosphorylation. Science, 282(5392), 1318-1321. doi:10.1126/science.282.5392.1318Chen, S., Do, J. T., Zhang, Q., Yao, S., Yan, F., Peters, E. C., … Ding, S. (2006). Self-renewal of embryonic stem cells by a small molecule. Proceedings of the National Academy of Sciences, 103(46), 17266-17271. doi:10.1073/pnas.0608156103Clevers, H. (2016). Modeling Development and Disease with Organoids. Cell, 165(7), 1586-1597. doi:10.1016/j.cell.2016.05.082Cohen, L., Sekler, I., & Hershfinkel, M. (2014). The zinc sensing receptor, ZnR/GPR39, controls proliferation and differentiation of colonocytes and thereby tight junction formation in the colon. Cell Death & Disease, 5(6), e1307-e1307. doi:10.1038/cddis.2014.262Czechanski, A., Byers, C., Greenstein, I., Schrode, N., Donahue, L. R., Hadjantonakis, A.-K., & Reinholdt, L. G. (2014). Derivation and characterization of mouse embryonic stem cells from permissive and nonpermissive strains. Nature Protocols, 9(3), 559-574. doi:10.1038/nprot.2014.030Doble, B. W. (2003). GSK-3: tricks of the trade for a multi-tasking kinase. Journal of Cell Science, 116(7), 1175-1186. doi:10.1242/jcs.00384Eiselleova, L., Matulka, K., Kriz, V., Kunova, M., Schmidtova, Z., Neradil, J., … Dvorak, P. (2009). A Complex Role for FGF-2 in Self-Renewal, Survival, and Adhesion of Human Embryonic Stem Cells. Stem Cells, 27(8), 1847-1857. doi:10.1002/stem.128Evans, M. (2011). Discovering pluripotency: 30 years of mouse embryonic stem cells. Nature Reviews Molecular Cell Biology, 12(10), 680-686. doi:10.1038/nrm3190Evseenko, D., Zhu, Y., Schenke-Layland, K., Kuo, J., Latour, B., Ge, S., … Crooks, G. M. (2010). Mapping the first stages of mesoderm commitment during differentiation of human embryonic stem cells. Proceedings of the National Academy of Sciences, 107(31), 13742-13747. doi:10.1073/pnas.1002077107Fang, X., Yu, S. X., Lu, Y., Bast, R. C., Woodgett, J. R., & Mills, G. B. (2000). Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proceedings of the National Academy of Sciences, 97(22), 11960-11965. doi:10.1073/pnas.220413597Fischer, A. H., Jacobson, K. A., Rose, J., & Zeller, R. (2008). Hematoxylin and Eosin Staining of Tissue and Cell Sections. Cold Spring Harbor Protocols, 2008(6), pdb.prot4986-pdb.prot4986. doi:10.1101/pdb.prot4986Franke, T. F. (2008). PI3K/Akt: getting it right matters. Oncogene, 27(50), 6473-6488. doi:10.1038/onc.2008.313Hamatake, M., Iguchi, K., Hirano, K., & Ishida, R. (2000). Zinc Induces Mixed Types of Cell Death, Necrosis, and Apoptosis, in Molt-4 Cells. Journal of Biochemistry, 128(6), 933-939. doi:10.1093/oxfordjournals.jbchem.a022844Hamilton, W. B., & Brickman, J. M. (2014). Erk Signaling Suppresses Embryonic Stem Cell Self-Renewal to Specify Endoderm. Cell Reports, 9(6), 2056-2070. doi:10.1016/j.celrep.2014.11.032Heo, J., Lee, J.-S., Chu, I.-S., Takahama, Y., & Thorgeirsson, S. S. (2005). Spontaneous differentiation of mouse embryonic stem cells in vitro: Characterization by global gene expression profiles. Biochemical and Biophysical Research Communications, 332(4), 1061-1069. doi:10.1016/j.bbrc.2005.04.173Hogstrand, C., Kille, P., Nicholson, R. I., & Taylor, K. M. (2009). Zinc transporters and cancer: a potential role for ZIP7 as a hub for tyrosine kinase activation. Trends in Molecular Medicine, 15(3), 101-111. doi:10.1016/j.molmed.2009.01.004Hu, J., Yang, Z., Wang, J., Yu, J., Guo, J., Liu, S., … Cheng, J. (2016). Zinc Chloride Transiently Maintains Mouse Embryonic Stem Cell Pluripotency by Activating Stat3 Signaling. PLOS ONE, 11(2), e0148994. doi:10.1371/journal.pone.0148994Huang, L., Kirschke, C. P., Zhang, Y., & Yu, Y. Y. (2005). The ZIP7 Gene (Slc39a7) Encodes a Zinc Transporter Involved in Zinc Homeostasis of the Golgi Apparatus. Journal of Biological Chemistry, 280(15), 15456-15463. doi:10.1074/jbc.m412188200Jaenisch, R., & Young, R. (2008). Stem Cells, the Molecular Circuitry of Pluripotency and Nuclear Reprogramming. Cell, 132(4), 567-582. doi:10.1016/j.cell.2008.01.015Jeong, C.-H., Cho, Y.-Y., Kim, M.-O., Kim, S.-H., Cho, E.-J., Lee, S.-Y., … Dong, Z. (2010). Phosphorylation of Sox2 Cooperates in Reprogramming to Pluripotent Stem Cells. STEM CELLS, 28(12), 2141-2150. doi:10.1002/stem.540Jo, H., Mondal, S., Tan, D., Nagata, E., Takizawa, S., Sharma, A. K., … Luo, H. R. (2012). Small molecule-induced cytosolic activation of protein kinase Akt rescues ischemia-elicited neuronal death. Proceedings of the National Academy of Sciences, 109(26), 10581-10586. doi:10.1073/pnas.1202810109Johnson-Farley, N. N., Patel, K., Kim, D., & Cowen, D. S. (2007). Interaction of FGF-2 with IGF-1 and BDNF in stimulating Akt, ERK, and neuronal survival in hippocampal cultures. Brain Research, 1154, 40-49. doi:10.1016/j.brainres.2007.04.026Kattman, S. J., Witty, A. D., Gagliardi, M., Dubois, N. C., Niapour, M., Hotta, A., … Keller, G. (2011). Stage-Specific Optimization of Activin/Nodal and BMP Signaling Promotes Cardiac Differentiation of Mouse and Human Pluripotent Stem Cell Lines. Cell Stem Cell, 8(2), 228-240. doi:10.1016/j.stem.2010.12.008Kennedy, S. G., Wagner, A. J., Conzen, S. D., Jordan, J., Bellacosa, A., Tsichlis, P. N., & Hay, N. (1997). The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes & Development, 11(6), 701-713. doi:10.1101/gad.11.6.701Kim, E., Kim, M., Woo, D.-H., Shin, Y., Shin, J., Chang, N., … Lee, J. (2013). Phosphorylation of EZH2 Activates STAT3 Signaling via STAT3 Methylation and Promotes Tumorigenicity of Glioblastoma Stem-like Cells. Cancer Cell, 23(6), 839-852. doi:10.1016/j.ccr.2013.04.008Kunath, T., Saba-El-Leil, M. K., Almousailleakh, M., Wray, J., Meloche, S., & Smith, A. (2007). FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment. Development, 134(16), 2895-2902. doi:10.1242/dev.02880Lanner, F., & Rossant, J. (2010). The role of FGF/Erk signaling in pluripotent cells. Development, 137(20), 3351-3360. doi:10.1242/dev.050146Li, W., & Ding, S. (2010). Small molecules that modulate embryonic stem cell fate and somatic cell reprogramming. Trends in Pharmacological Sciences, 31(1), 36-45. doi:10.1016/j.tips.2009.10.002Lin, Y., Yang, Y., Li, W., Chen, Q., Li, J., Pan, X., … Wang, Y.-J. (2012). Reciprocal Regulation of Akt and Oct4 Promotes the Self-Renewal and Survival of Embryonal Carcinoma Cells. Molecular Cell, 48(4), 627-640. doi:10.1016/j.molcel.2012.08.030Llames, S., García-Pérez, E., Meana, Á., Larcher, F., & del Río, M. (2015). Feeder Layer Cell Actions and Applications. Tissue Engineering Part B: Reviews, 21(4), 345-353. doi:10.1089/ten.teb.2014.0547Manning, B. D., & Cantley, L. C. (2007). AKT/PKB Signaling: Navigating Downstream. Cell, 129(7), 1261-1274. doi:10.1016/j.cell.2007.06.009Morgani, S. M., Canham, M. A., Nichols, J., Sharov, A. A., Migueles, R. P., Ko, M. S. H., & Brickman, J. M. (2013). Totipotent Embryonic Stem Cells Arise in Ground-State Culture Conditions. Cell Reports, 3(6), 1945-1957. doi:10.1016/j.celrep.2013.04.034Murakami, M., & Hirano, T. (2008). Intracellular zinc homeostasis and zinc signaling. Cancer Science, 99(8), 1515-1522. doi:10.1111/j.1349-7006.2008.00854.xMurray, P., & Edgar, D. (2001). The regulation of embryonic stem cell differentiation by leukaemia inhibitory factor (LIF). Differentiation, 68(4-5), 227-234. doi:10.1046/j.1432-0436.2001.680410.xNair, G., Abranches, E., Guedes, A. M. V., Henrique, D., & Raj, A. (2015). Heterogeneous lineage marker expression in naive embryonic stem cells is mostly due to spontaneous differentiation. Scientific Reports, 5(1). doi:10.1038/srep13339Niwa, H. (2007). How is pluripotency determined and maintained? Development, 134(4), 635-646. doi:10.1242/dev.02787Niwa, H., Burdon, T., Chambers, I., & Smith, A. (1998). Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes & Development, 12(13), 2048-2060. doi:10.1101/gad.12.13.2048Ohtsuka, S., & Dalton, S. (2007). Molecular and biological properties of pluripotent embryonic stem cells. Gene Therapy, 15(2), 74-81. doi:10.1038/sj.gt.3303065Oshimori, N., & Fuchs, E. (2012). The Harmonies Played by TGF-β in Stem Cell Biology. Cell Stem Cell, 11(6), 751-764. doi:10.1016/j.stem.2012.11.001Pera, M. F., & Tam, P. P. L. (2010). Extrinsic regulation of pluripotent stem cells. Nature, 465(7299), 713-720. doi:10.1038/nature09228Rose-John, S. (2002). GP130 stimulation and the maintenance of stem cells. Trends in Biotechnology, 20(10), 417-419. doi:10.1016/s0167-7799(02)02056-5Saxe, J. P., Tomilin, A., Schöler, H. R., Plath, K., & Huang, J. (2009). Post-Translational Regulation of Oct4 Transcriptional Activity. PLoS ONE, 4(2), e4467. doi:10.1371/journal.pone.0004467Schugar, R. C., Robbins, P. D., & Deasy, B. M. (2007). Small molecules in stem cell self-renewal and differentiation. Gene Therapy, 15(2), 126-135. doi:10.1038/sj.gt.3303062Shao, Y., Wolf, P. G., Guo, S., Guo, Y., Gaskins, H. R., & Zhang, B. (2017). Zinc enhances intestinal epithelial barrier function through the PI3K/AKT/mTOR signaling pathway in Caco-2 cells. The Journal of Nutritional Biochemistry, 43, 18-26. doi:10.1016/j.jnutbio.2017.01.013Singhal, P. K., Sassi, S., Lan, L., Au, P., Halvorsen, S. C., Fukumura, D., … Seed, B. (2015). Mouse embryonic fibroblasts exhibit extensive developmental and phenotypic diversity. Proceedings of the National Academy of Sciences, 113(1), 122-127. doi:10.1073/pnas.1522401112Stewart, M. H., Bendall, S. C., & Bhatia, M. (2008). Deconstructing human embryonic stem cell cultures: niche regulation of self-renewal and pluripotency. Journal of Molecular Medicine, 86(8), 875-886. doi:10.1007/s00109-008-0356-9Tamm, C., Pijuan Galitó, S., & Annerén, C. (2013). A Comparative Study of Protocols for Mouse Embryonic Stem Cell Culturing. PLoS ONE, 8(12), e81156. doi:10.1371/journal.pone.0081156Taylor, K. M., Hiscox, S., Nicholson, R. I., Hogstrand, C., & Kille, P. (2012). Protein Kinase CK2 Triggers Cytosolic Zinc Signaling Pathways by Phosphorylation of Zinc Channel ZIP7. Science Signaling, 5(210), ra11-ra11. doi:10.1126/scisignal.2002585Taylor, K. M., Vichova, P., Jordan, N., Hiscox, S., Hendley, R., & Nicholson, R. I. (2008). ZIP7-Mediated Intracellular Zinc Transport Contributes to Aberrant Growth Factor Signaling in Antihormone-Resistant Breast Cancer Cells. Endocrinology, 149(10), 4912-4920. doi:10.1210/en.2008-0351Tremml, G., Singer, M., & Malavarca, R. (2008). Culture of Mouse Embryonic Stem Cells. Current Protocols in Stem Cell Biology, 5(1). doi:10.1002/9780470151808.sc01c04s5Wang, E. S., Reyes, N. A., Melton, C., Huskey, N. E., Momcilovic, O., Goga, A., … Oakes, S. A. (2015). Fas-Activated Mitochondrial Apoptosis Culls Stalled Embryonic Stem Cells to Promote Differentiation. Current Biology, 25(23), 3110-3118. doi:10.1016/j.cub.2015.10.020Watanabe, S., Umehara, H., Murayama, K., Okabe, M., Kimura, T., & Nakano, T. (2006). Activation of Akt signaling is sufficient to maintain pluripotency in mouse and primate embryonic stem cells. Oncogene, 25(19), 2697-2707. doi:10.1038/sj.onc.1209307Weinberger, L., Ayyash, M., Novershtern, N., & Hanna, J. H. (2015). Dynamic stem cell states: naive to primed pluripotency in rodents and humans. doi:10.1101/030676West, J. A., Park, I.-H., Daley, G. Q., & Geijsen, N. (2006). In vitro generation of germ cells from murine embryonic stem cells. Nature Protocols, 1(4), 2026-2036. doi:10.1038/nprot.2006.303Wichterle, H., Lieberam, I., Porter, J. A., & Jessell, T. M. (2002). Directed Differentiation of Embryonic Stem Cells into Motor Neurons. Cell, 110(3), 385-397. doi:10.1016/s0092-8674(02)00835-8Xu, Z., Robitaille, A. M., Berndt, J. D., Davidson, K. C., Fischer, K. A., Mathieu, J., … Moon, R. T. (2016). Wnt/β-catenin signaling promotes self-renewal and inhibits the primed state transition in naïve human embryonic stem cells. Proceedings of the National Academy of Sciences, 113(42), E6382-E6390. doi:10.1073/pnas.1613849113Yamaguchi, H., & Wang, H.-G. (2001). The protein kinase PKB/Akt regulates cell survival and apoptosis by inhibiting Bax conformational change. Oncogene, 20(53), 7779-7786. doi:10.1038/sj.onc.1204984Yamasaki, S., Sakata-Sogawa, K., Hasegawa, A., Suzuki, T., Kabu, K., Sato, E., … Hirano, T. (2007). Zinc is a novel intracellular second messenger. Journal of Cell Biology, 177(4), 637-645. doi:10.1083/jcb.200702081Yiangou, L., Ross, A. D. B., Goh, K. J., & Vallier, L. (2018). Human Pluripotent Stem Cell-Derived Endoderm for Modeling Development and Clinical Applications. Cell Stem Cell, 22(4), 485-499. doi:10.1016/j.stem.2018.03.016Yu, J. S. L., & Cui, W. (2016). Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development, 143(17), 3050-3060. doi:10.1242/dev.137075Zhou, J., Wulfkuhle, J., Zhang, H., Gu, P., Yang, Y., Deng, J., … Zhang, Y. (2007). Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proceedings of the National Academy of Sciences, 104(41), 16158-16163. doi:10.1073/pnas.0702596104Ziomek, C. A., Lepire, M. L., & Torres, I. (1990). A highly fluorescent simultaneous azo dye technique for demonstration of nonspecific alkaline phosphatase activity. Journal of Histochemistry & Cytochemistry, 38(3), 437-442. doi:10.1177/38.3.168934

The level of CD147 expression correlates with cyclophilin-induced signalling and chemotaxis

<p>Abstract</p> <p>Background</p> <p>Previous studies identified CD147 as the chemotactic receptor on inflammatory leukocytes for extracellular cyclophilins (eCyp). However, CD147 is not known to associate with signal transducing molecules, so other transmembrane proteins, such as proteoglycans, integrins, and CD98, were suggested as receptor or co-receptor for eCyp. CD147 is ubiquitously expressed on many cell types, but relationship between the level of CD147 expression and cellular responses to eCyp has never been analyzed. Given the role of eCyp in pathogenesis of many diseases, it is important to know whether cellular responses to eCyp are regulated at the level of CD147 expression.</p> <p>Results</p> <p>Here, we manipulated CD147 expression levels on HeLa cells using RNAi and investigated the signalling and chemotactic responses to eCypA. Both Erk activation and chemotaxis correlated with the level of CD147 expression, with cells exhibiting low level expression being practically unresponsive to eCypA.</p> <p>Conclusions</p> <p>Our results provide the first demonstration of a chemotactic response of HeLa cells to eCypA, establish a correlation between the level of CD147 expression and the magnitude of cellular responses to eCypA, and indicate that CD147 may be a limiting factor in the receptor complex determining cyclophilin-induced Erk activation and cell migration.</p

Pharmacokinetic Characteristics, Pharmacodynamic Effect and In Vivo Antiviral Efficacy of Liver-Targeted Interferon Alpha

Work carried out by JM was funded by the National Institutes of Health (NIH). NIH contract number is HHSN272201000039I/HHSN27200001/ A19