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| 1 | Optimized Nonbismuth Quadruple Therapies Cure Most Patients With Helicobacter pylori Infection in Populations With High Rates of Antibiotic Resistance显示文摘 | Javier Molina–Infante Marco Romano Miguel Fernandez–Bermejo Alessandro Federico Antonietta G. Gravina Liliana Pozzati Elena Garcia–Abadia Gema Vinagre–Rodriguez Carmen Martinez–Alcala Moises Hernandez–Alonso Agnese Miranda Maria Rosaria Iovene Carmen Pazo | 2013 | Gastroenterology2013，，1： | 8 |
| 2 | Glutathione metabolism is essential for self-renewal and chemoresistance of pancreatic cancer stem cells显示文摘BACKGROUND Cellular metabolism regulates stemness in health and disease.A reduced redox state is essential for self-renewal of normal and cancer stem cells(CSCs).However,while stem cells rely on glycolysis,different CSCs,including pancreatic CSCs,favor mitochondrial metabolism as their dominant energy-producing pathway.This suggests that powerful antioxidant networks must be in place to detoxify mitochondrial reactive oxygen species(ROS)and maintain stemness in oxidative CSCs.Since glutathione metabolism is critical for normal stem cell function and CSCs from breast,liver and gastric cancer show increased glutathione content,we hypothesized that pancreatic CSCs also rely on this pathway for ROS detoxification.AIM To investigate the role of glutathione metabolism in pancreatic CSCs.METHODS Primary pancreatic cancer cells of patient-derived xenografts(PDXs)were cultured in adherent or CSC-enriching sphere conditions to determine the role of glutathione metabolism in stemness.Real-time polymerase chain reaction(PCR)was used to validate RNAseq results involving glutathione metabolism genes in adherent vs spheres,as well as the expression of pluripotency-related genes following treatment.Public TCGA and GTEx RNAseq data from pancreatic cancer vs normal tissue samples were analyzed using the webserver GEPIA2.The glutathione-sensitive fluorescent probe monochlorobimane was used to determine glutathione content by fluorimetry or flow cytometry.Pharmacological inhibitors of glutathione synthesis and recycling[buthionine-sulfoximine(BSO)and 6-Aminonicotinamide(6-AN),respectively]were used to investigate the impact of glutathione depletion on CSC-enriched cultures.Staining with propidium iodide(cell cycle),Annexin-V(apoptosis)and CD133(CSC content)were determined by flow cytometry.Self-renewal was assessed by sphere formation assay and response to gemcitabine treatment was used as a readout for chemoresistance.RESULTS Analysis of our previously published RNAseq dataset E-MTAB-3808 revealed upregulation of genes involved in the KEGG(Kyoto Encyclopedia of Genes and Genomes)Pathway Glutathione Metabolism in CSC-enriched cultures compared to their differentiated counterparts.Consistently,in pancreatic cancer patient samples the expression of most of these up-regulated genes positively correlated with a stemness signature defined by NANOG,KLF4,SOX2 and OCT4 expression(P<10-5).Moreover,3 of the upregulated genes(MGST1,GPX8,GCCT)were associated with reduced disease-free survival in patients[Hazard ratio(HR)2.2-2.5;P=0.03-0.0054],suggesting a critical role for this pathway in pancreatic cancer progression.CSC-enriched sphere cultures also showed increased expression of different glutathione metabolism-related genes,as well as enhanced glutathione content in its reduced form(GSH).Glutathione depletion with BSO induced cell cycle arrest and apoptosis in spheres,and diminished the expression of stemness genes.Moreover,treatment with either BSO or the glutathione recycling inhibitor 6-AN inhibited self-renewal and the expression of the CSC marker CD133.GSH content in spheres positively correlated with intrinsic resistance to gemcitabine treatment in different PDXs r=0.96,P=5.8×1011).Additionally,CD133+cells accumulated GSH in response to gemcitabine,which was abrogated by BSO treatment(P<0.05).Combined treatment with BSO and gemcitabine-induced apoptosis in CD133+cells to levels comparable to CD133-cells and significantly diminished self-renewal(P<0.05),suggesting that chemoresistance of CSCs is partially dependent on GSH metabolism.CONCLUSION Our data suggest that pancreatic CSCs depend on glutathione metabolism.Pharmacological targeting of this pathway showed that high GSH content is essential to maintain CSC functionality in terms of self-renewal and chemoresistance. | Petra Jagust Sonia Alcala Bruno Sainz Jr Christopher Heeschen Patricia Sancho | 2020 | World Journal of Stem Cells2020，12，11： | 2 |
| 3 | 苏禄-苏拉威西海:环境与社会经济状况:对未来的预测及作出改进的政策选择显示文摘苏禄-苏拉威西海,及相邻的印度尼西亚海和南海,位于世界热带海洋生物多样性的中心。苏禄-苏拉威西海由3个人口众多的发展中国家——菲律宾、印度尼西亚和马来西亚所包围,该海及其毗连的沿海和陆地生态系养育着大约3300万人口,其中大部分人口的生计主要依赖于该海的可再生自然资源。由于人口的快速增长(平均年增长率大于2%,至2035年可望翻一番),广泛的贫困,加上不断增长的国际市场的需求和快速的技术变化,以及管理效能低下和在当地居民中,特别是在菲律宾和印度尼西亚某些地区,缺乏法律意识和/或认同,这些资源正经历着严重的冲击。这些关键性的根源造成了非法行为和腐败的产生,引起了资源枯竭和集水流域、河流、湖泊、河口、沿岸水域及海洋等水域的生态系统严重退化。苏禄-苏拉威西海形成了一个重要的地缘政治核心,断断续续的边界、移民、分离主义运动、海盗及非法捕捞造成了环境退化,人类苦难,政治不稳定,以及阻碍了三边对各种介入强有力的相互支持。本文分析了对环境和社会经济状况的各种影响及其产生的根源,提出了至2020年对未来状况的预测,以及推荐通过可持续的管理和发展的各种政策选择,以便作出改进。 | Lyndon DeVantier Angel Alcala Clive Wilkinson 郭家梁 | 2004 | AMBIO-人类环境杂志2004，33，1： | 2 |
| 4 | Neuroendocrine small cell carcinoma of the bladder显示文摘 | Cuesta Alcala JA Ripa Saldias L Aldave VJ | 2002 | Arch Esp Urol2002，55，： | 2 |
| 5 | Contact deformation regimes around sharp indentations and the concept of the characteristic strain显示文摘 | Mata M Angtada M Alcala J | 2002 | Journal of Materials Research2002，17，5： | 1 |
| 6 | Sphericalindentation of compositionally graded material: Theoryand experiment 显示文摘 | Suresh S Giannakopoulos A E Alcala J | 1997 | Acta Materialia1997，45，： | 1 |
| 7 | Mechanical property evaluation through sharp indentations in elastoplastic and fully plastic contact regimes显示文摘 | Mata M Alcala J | 2003 | Journal of Materials Research2003，18，7： | 1 |
| 8 | A review of recent, unconventional applications of ion mobility spectrome- try(IMS)显示文摘 | Armenta S Alcala M Blanco M | 2011 | Analytica Chimica Acta2011，703，11： | 1 |
| 9 | A study in glycation of a therapeutic recombinant humanized monoclonal antibody: where it is, how it got there, and how it affeets charge-based behavior 显示文摘 | Quan C Alcala E Petkovska I | 2008 | Anal Biochem2008，373，2： | 1 |
| 10 | Protein composition of bovine lens cortical fiber cell membranes 显示文摘 | Alcala J Lieska N Maisel H | 1975 | Exp Eye Res1975，21，6： | 1 |
| 11 | Neuroproteetive effects of brimonidine treatment in a rodent model of isehemie optic neuropathy显示文摘 | Danylkova NO Alcala SR Pomeranz HD | 2007 | Exp Eye Res2007，84，2： | 1 |
| 12 | Reconstruction-based contribution for process monitoring显示文摘 | Alcala C Qin S | 2009 | Automatica2009，45，7： | 1 |
| 13 | Genetic learning of accurate and compact fuzzy rule based systems based on the 2- tuples linguistic representation 显示文摘 | ALCALA R ALCALA-FDEZ J HERRERA F | 2007 | International Journal of Approximate Reasoning2007，44，1： | 1 |
| 14 | Antologia显示文摘 | Ocana Sierra J Alcala Romero F Coronel A | 1974 | Dermatologica1974，4，： | 1 |
| 15 | Effect of relaxation and primary nanocrystallization on the mechanical properties of Cu60Zr22Ti18 bulk metallic glass显示文摘 | Concustell A Alcala G Mato S Woodcock T G Gebert A Eckert J Baro M D | 2005 | Intermetallics2005，13，： | 1 |
| 16 | In vitro activities of linezolid against clinical isolates of Mycobacterium tuberculosis that are susceptible or resistant to first-line antituberculous drugs 显示文摘 | Alcala L Ruiz-Serrano M J Perez-Femandez Turegano C | 2003 | Antimicrob Agents Chemother2003，47，1： | 1 |
| 17 | Statins improve visual field alteration related to hypereholesterolemia 显示文摘 | Alcala A Jansen Stellez T Gomez Huelgas R | 2010 | Athroselerosis2010，269，2： | 1 |
| 18 | LSOX5 regulates RhoB expression in the neural tube and promotes generation of the neural crest显示文摘 | Perez - Alcala S Nieto MA Barbas JA | 2004 | Development2004，131，： | 1 |
| 19 | Engineering of Escherichia coli beta-galactosidase for solvent display of a functional scFv antibody fragment显示文摘 | Alcala P Ferrer-Miralles N Villaverde A | 2003 | FEBS Lett2003，533，13： | 1 |
| 20 | Fatigue and static crack propagation in yttria-stabilized tetraged zirconia polycrystal:crack groeth micromechainisms and precracking effects显示文摘 | Alcala J | 1997 | J Am Ceram Soc1997，80，11： | 1 |
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