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| 1 | Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade显示文摘 | Clifford R Jack David S Knopman William J Jagust Leslie M Shaw Paul S Aisen Michael W Weiner Ronald C Petersen John Q Trojanowski | 2010 | Lancet Neurology2010，，1： | 4 |
| 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 | Central obesity and the aging brain显示文摘 | Jagust W Harvey D Mungas D | 2005 | Arch Neurol2005，62，10： | 1 |
| 4 | Results from a phase I safety trial of hAADC gene therapy for Parkinson disease显示文摘 | EBERLING J L JAGUST W J CHRISTINE C W | 2008 | Neurology2008，70，21： | 1 |
| 5 | Central obesity and the aging brain显示文摘 | Jagust W Harvey D Mungas D | 2005 | Arch Neurol2005，62，10： | 1 |
| 6 | Neuropsy- chological characteristics of mild cognitive impairment subgroups 显示文摘 | Lopez OL Becker JT Jagust W J ctal | 2006 | J Neurol Neurosurg Psychiatry2006，77，2： | 1 |
| 7 | Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers 显示文摘 | Jack CR Jr Knopman DS Jagust WJ | 2013 | Lancet Neurol2013，12，2： | 1 |
| 8 | Tracking pathophysiologieal processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers显示文摘 | Jack CR Jr Knopman DS Jagust WJ | 2013 | Lancet Neurol2013，12，2： | 1 |
| 9 | Amyloid imaging in aging and dementia:testing the amyloid hypothesis in vivo显示文摘 | Rabinovici GD Jagust WJ | | 0，，01： | 1 |
| 10 | The diagnosis of dementia with single photon emission computed tomography 显示文摘 | Jagust W Budinger T Reed B | 1987 | Arch Neurol1987，44，1： | 1 |
| 11 | Volumetric MRI predicts rate of cognitive decline related to AD and cerebrovascular disease 显示文摘 | Mungas D Reed B R Jagust W J | 2002 | Neurology2002，59，126： | 1 |
| 12 | Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 2显示文摘 | Lopez OL Jagust WJ Dulberg C | 2003 | Arch Neurol2003，60，10： | 1 |
| 13 | The Alzheimer's Disease Neuroimaging Initiative positron emission tomog- raphy core显示文摘 | Jagust WJ Bandy D Chen K | 2010 | Alzheimers Dement2010，6，3： | 1 |
| 14 | Relationships between bio-markers in aging and dementia 显示文摘 | Jagust WJ Landau SM Shaw LM | 2009 | Neurology2009，73，： | 1 |
| 15 | Mapping brain beta-amyloid 显示文摘 | Jagust WJ | 2009 | Curr Opin Neu?rol2009，22，： | 1 |
| 16 | Central obesity and the aging brain显示文摘 | Jagust W Harvey D Mungas D | 2005 | Arch Neuro2005，62，10： | 1 |
| 17 | Brain imaging in the study of Alzheimer's disease 显示文摘 | REIMAN E M JAGUST W J | 2012 | Neuroimage2012，61，2： | 1 |
| 18 | Comparing positron emission tomography imaging and cerebrospinal fluid measurements of β‐amyloid显示文摘 | Susan M. Landau Ming Lu Abhinay D. Joshi Michael Pontecorvo Mark A. Mintun John Q. Trojanowski Leslie M. Shaw William J. Jagust | 2013 | Ann Neurol2013，，： | 1 |
| 19 | MRI predictors of cognition in subcortical ischemic vascular disease and Alzheimer's disease显示文摘 | Mungas D Jagust WJ Reed BR | 2001 | Neurology2001，57，12： | 1 |
| 20 | Prevalence and classification of mild cognitive impairment in the Cardiovas- cular Health Study Cognition Study: part l显示文摘 | Lopez OL Jagust WJ DeKosky ST | 2003 | Arch Neurol2003，60，10： | 1 |
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