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Article ; Online: Immunometabolic Adaptation of CD19-Targeted CAR T Cells in the Central Nervous System Microenvironment of Patients Promotes Memory Development.

Goldberg, Lior / Haas, Eric R / Urak, Ryan / Vyas, Vibhuti / Pathak, Khyatiben V / Garcia-Mansfield, Krystine / Pirrotte, Patrick / Singhal, Jyotsana / Figarola, James L / Aldoss, Ibrahim / Forman, Stephen J / Wang, Xiuli

Cancer research

2024 Volume 84, Issue 7, Page(s) 1048–1064

Abstract: Metabolic reprogramming is a hallmark of T-cell activation, and metabolic fitness is fundamental for T-cell-mediated antitumor immunity. Insights into the metabolic plasticity of chimeric antigen receptor (CAR) T cells in patients could help identify ... ...

Abstract	Metabolic reprogramming is a hallmark of T-cell activation, and metabolic fitness is fundamental for T-cell-mediated antitumor immunity. Insights into the metabolic plasticity of chimeric antigen receptor (CAR) T cells in patients could help identify approaches to improve their efficacy in treating cancer. Here, we investigated the spatiotemporal immunometabolic adaptation of CD19-targeted CAR T cells using clinical samples from CAR T-cell-treated patients. Context-dependent immunometabolic adaptation of CAR T cells demonstrated the link between their metabolism, activation, differentiation, function, and local microenvironment. Specifically, compared with the peripheral blood, low lipid availability, high IL15, and low TGFβ in the central nervous system microenvironment promoted immunometabolic adaptation of CAR T cells, including upregulation of a lipolytic signature and memory properties. Pharmacologic inhibition of lipolysis in cerebrospinal fluid led to decreased CAR T-cell survival. Furthermore, manufacturing CAR T cells in cerebrospinal fluid enhanced their metabolic fitness and antileukemic activity. Overall, this study elucidates spatiotemporal immunometabolic rewiring of CAR T cells in patients and demonstrates that these adaptations can be exploited to maximize the therapeutic efficacy of CAR T cells. Significance: The spatiotemporal immunometabolic landscape of CD19-targeted CAR T cells from patients reveals metabolic adaptations in specific microenvironments that can be exploited to maximize the therapeutic efficacy of CAR T cells.
MeSH term(s)	Humans ; Immunotherapy, Adoptive ; Neoplasms ; T-Lymphocytes ; Central Nervous System/metabolism ; Antigens, CD19/metabolism ; Receptors, Antigen, T-Cell ; Tumor Microenvironment
Chemical Substances	Antigens, CD19 ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2024-02-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-23-2299
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Article ; Online: Changes in proteomic cargo of circulating extracellular vesicles in response to lifestyle intervention in adolescents with hepatic steatosis.

DiStefano, Johanna K / Piras, Ignazio S / Wu, Xiumei / Sharma, Ritin / Garcia-Mansfield, Krystine / Willey, Maya / Lovell, Brooke / Pirrotte, Patrick / Olson, Micah L / Shaibi, Gabriel Q

Clinical nutrition ESPEN

2024 Volume 60, Page(s) 333–342

Abstract: Background: Recent studies suggest that proteomic cargo of extracellular vesicles (EVs) may play a role in metabolic improvements following lifestyle interventions. However, the relationship between changes in liver fat and circulating EV-derived ... ...

Abstract	Background: Recent studies suggest that proteomic cargo of extracellular vesicles (EVs) may play a role in metabolic improvements following lifestyle interventions. However, the relationship between changes in liver fat and circulating EV-derived protein cargo following intervention remains unexplored. Methods: The study cohort comprised 18 Latino adolescents with obesity and hepatic steatosis (12 males/6 females; average age 13.3 ± 1.2 y) who underwent a six-month lifestyle intervention. EV size distribution and concentration were determined by light scattering intensity; EV protein composition was characterized by liquid chromatography tandem-mass spectrometry. Results: Average hepatic fat fraction (HFF) decreased 23% by the end of the intervention (12.5% [5.5] to 9.6% [4.9]; P = 0.0077). Mean EV size was smaller post-intervention compared to baseline (120.2 ± 16.4 nm to 128.4 ± 16.5 nm; P = 0.031), although the difference in mean EV concentration (1.1E+09 ± 4.1E+08 particles/mL to 1.1E+09 ± 1.8E+08 particles/mL; P = 0.656)) remained unchanged. A total of 462 proteins were identified by proteomic analysis of plasma-derived EVs from participants pre- and post-intervention, with 113 proteins showing differential abundance (56 higher and 57 lower) between the two timepoints (adj-p <0.05). Pathway analysis revealed enrichment in complement cascade, initial triggering of complement, creation of C4 and C2 activators, and regulation of complement cascade. Hepatocyte-specific EV affinity purification identified 40 proteins with suggestive (p < 0.05) differential abundance between pre- and post-intervention samples. Conclusions: Circulating EV-derived proteins, particularly those associated with the complement cascade, may contribute to improvements in liver fat in response to lifestyle intervention.
MeSH term(s)	Male ; Female ; Humans ; Adolescent ; Child ; Proteomics/methods ; Extracellular Vesicles/chemistry ; Extracellular Vesicles/metabolism ; Chromatography, Liquid ; Proteins/metabolism ; Mass Spectrometry
Chemical Substances	Proteins
Language	English
Publishing date	2024-02-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2405-4577
ISSN (online)	2405-4577
DOI	10.1016/j.clnesp.2024.02.024
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Article ; Online: Subgroup-Enriched Pathways and Kinase Signatures in Medulloblastoma Patient-Derived Xenografts.

Leskoske, Kristin L / Garcia-Mansfield, Krystine / Sharma, Ritin / Krishnan, Aparna / Rusert, Jessica M / Mesirov, Jill P / Wechsler-Reya, Robert J / Pirrotte, Patrick

Journal of proteome research

2022 Volume 21, Issue 9, Page(s) 2124–2136

Abstract: Medulloblastoma (MB) is the most common malignant pediatric brain tumor. MB is classified into four primary molecular subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4), and further genomic and proteomic subtypes have been ... ...

Abstract	Medulloblastoma (MB) is the most common malignant pediatric brain tumor. MB is classified into four primary molecular subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4), and further genomic and proteomic subtypes have been reported. Subgroup heterogeneity and few actionable mutations have hindered the development of targeted therapies, especially for G3 MB, which has a particularly poor prognosis. To identify novel therapeutic targets for MB, we performed mass spectrometry-based deep expression proteomics and phosphoproteomics in 20 orthotopic patient-derived xenograft (PDX) models of MB comprising SHH, G3, and G4 subgroups. We found that the proteomic profiles of MB PDX tumors are closely aligned with those of primary human MB tumors illustrating the utility of PDX models. SHH PDXs were enriched for NFκB and p38 MAPK signaling, while G3 PDXs were characterized by MYC activity. Additionally, we found a significant association between actinomycin D sensitivity and increased abundance of MYC and MYC target genes. Our results highlight several candidate pathways that may serve as targets for new MB therapies. Mass spectrometry data are available via ProteomeXchange with identifier PXD035070.
MeSH term(s)	Animals ; Brain Neoplasms/genetics ; Cerebellar Neoplasms/genetics ; Cerebellar Neoplasms/metabolism ; Cerebellar Neoplasms/pathology ; Child ; Disease Models, Animal ; Hedgehog Proteins/genetics ; Hedgehog Proteins/metabolism ; Hedgehog Proteins/therapeutic use ; Heterografts ; Humans ; Medulloblastoma/genetics ; Medulloblastoma/metabolism ; Medulloblastoma/pathology ; Proteomics
Chemical Substances	Hedgehog Proteins
Language	English
Publishing date	2022-08-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.2c00203
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Article: Subgroup-Enriched Pathways and Kinase Signatures in Medulloblastoma Patient-Derived Xenografts

Leskoske, Kristin L. / Garcia-Mansfield, Krystine / Sharma, Ritin / Krishnan, Aparna / Rusert, Jessica M. / Mesirov, Jill P. / Wechsler-Reya, Robert J. / Pirrotte, Patrick

Journal of proteome research. 2022 Aug. 17, v. 21, no. 9

2022

Abstract	Medulloblastoma (MB) is the most common malignant pediatric brain tumor. MB is classified into four primary molecular subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4), and further genomic and proteomic subtypes have been reported. Subgroup heterogeneity and few actionable mutations have hindered the development of targeted therapies, especially for G3 MB, which has a particularly poor prognosis. To identify novel therapeutic targets for MB, we performed mass spectrometry-based deep expression proteomics and phosphoproteomics in 20 orthotopic patient-derived xenograft (PDX) models of MB comprising SHH, G3, and G4 subgroups. We found that the proteomic profiles of MB PDX tumors are closely aligned with those of primary human MB tumors illustrating the utility of PDX models. SHH PDXs were enriched for NFκB and p38 MAPK signaling, while G3 PDXs were characterized by MYC activity. Additionally, we found a significant association between actinomycin D sensitivity and increased abundance of MYC and MYC target genes. Our results highlight several candidate pathways that may serve as targets for new MB therapies. Mass spectrometry data are available via ProteomeXchange with identifier PXD035070.
Keywords	brain neoplasms ; genomics ; humans ; mass spectrometry ; mitogen-activated protein kinase ; prognosis ; proteome ; proteomics ; research ; xenotransplantation
Language	English
Dates of publication	2022-0817
Size	p. 2124-2136.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.2c00203
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Article ; Online: CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma.

Thieme, Elana / Bruss, Nur / Sun, Duanchen / Dominguez, Edward C / Coleman, Daniel / Liu, Tingting / Roleder, Carly / Martinez, Melissa / Garcia-Mansfield, Krystine / Ball, Brian / Pirrotte, Patrick / Wang, Lili / Xia, Zheng / Danilov, Alexey V

Molecular cancer

2023 Volume 22, Issue 1, Page(s) 64

Abstract: Diffuse large B-cell lymphoma (DLBCL) exhibits significant genetic heterogeneity which contributes to drug resistance, necessitating development of novel therapeutic approaches. Pharmacological inhibitors of cyclin-dependent kinases (CDK) demonstrated ... ...

Abstract	Diffuse large B-cell lymphoma (DLBCL) exhibits significant genetic heterogeneity which contributes to drug resistance, necessitating development of novel therapeutic approaches. Pharmacological inhibitors of cyclin-dependent kinases (CDK) demonstrated pre-clinical activity in DLBCL, however many stalled in clinical development. Here we show that AZD4573, a selective inhibitor of CDK9, restricted growth of DLBCL cells. CDK9 inhibition (CDK9i) resulted in rapid changes in the transcriptome and proteome, with downmodulation of multiple oncoproteins (eg, MYC, Mcl-1, JunB, PIM3) and deregulation of phosphoinotiside-3 kinase (PI3K) and senescence pathways. Following initial transcriptional repression due to RNAPII pausing, we observed transcriptional recovery of several oncogenes, including MYC and PIM3. ATAC-Seq and ChIP-Seq experiments revealed that CDK9i induced epigenetic remodeling with bi-directional changes in chromatin accessibility, suppressed promoter activation and led to sustained reprograming of the super-enhancer landscape. A CRISPR library screen suggested that SE-associated genes in the Mediator complex, as well as AKT1, confer resistance to CDK9i. Consistent with this, sgRNA-mediated knockout of MED12 sensitized cells to CDK9i. Informed by our mechanistic findings, we combined AZD4573 with either PIM kinase or PI3K inhibitors. Both combinations decreased proliferation and induced apoptosis in DLBCL and primary lymphoma cells in vitro as well as resulted in delayed tumor progression and extended survival of mice xenografted with DLBCL in vivo. Thus, CDK9i induces reprogramming of the epigenetic landscape, and super-enhancer driven recovery of select oncogenes may contribute to resistance to CDK9i. PIM and PI3K represent potential targets to circumvent resistance to CDK9i in the heterogeneous landscape of DLBCL.
MeSH term(s)	Animals ; Mice ; Apoptosis ; Cell Line, Tumor ; Epigenesis, Genetic ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Lymphoma, Large B-Cell, Diffuse/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Transcription Factors/genetics ; Cyclin-Dependent Kinase 9/antagonists & inhibitors ; Drug Resistance, Neoplasm
Chemical Substances	Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Transcription Factors ; Cdk9 protein, mouse (EC 2.7.11.22) ; Cyclin-Dependent Kinase 9 (EC 2.7.11.22)
Language	English
Publishing date	2023-03-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2091373-4
ISSN	1476-4598 ; 1476-4598
ISSN (online)	1476-4598
ISSN	1476-4598
DOI	10.1186/s12943-023-01762-6
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Article ; Online: Proteomics and mathematical modeling of longitudinal CSF differentiates fast versus slow ALS progression.

Vu, Lucas / Garcia-Mansfield, Krystine / Pompeiano, Antonio / An, Jiyan / David-Dirgo, Victoria / Sharma, Ritin / Venugopal, Vinisha / Halait, Harkeerat / Marcucci, Guido / Kuo, Ya-Huei / Uechi, Lisa / Rockne, Russell C / Pirrotte, Patrick / Bowser, Robert

Annals of clinical and translational neurology

2023 Volume 10, Issue 11, Page(s) 2025–2042

Abstract: Objective: Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease with a complex etiology that lacks biomarkers predicting disease progression. The objective of this study was to use longitudinal cerebrospinal fluid (CSF) samples to identify ... ...

Abstract	Objective: Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease with a complex etiology that lacks biomarkers predicting disease progression. The objective of this study was to use longitudinal cerebrospinal fluid (CSF) samples to identify biomarkers that distinguish fast progression (FP) from slow progression (SP) and assess their temporal response. Methods: We utilized mass spectrometry (MS)-based proteomics to identify candidate biomarkers using longitudinal CSF from a discovery cohort of SP and FP ALS patients. Immunoassays were used to quantify and validate levels of the top biomarkers. A state-transition mathematical model was created using the longitudinal MS data that also predicted FP versus SP. Results: We identified a total of 1148 proteins in the CSF of all ALS patients. Pathway analysis determined enrichment of pathways related to complement and coagulation cascades in FPs and synaptogenesis and glucose metabolism in SPs. Longitudinal analysis revealed a panel of 59 candidate markers that could segregate FP and SP ALS. Based on multivariate analysis, we identified three biomarkers (F12, RBP4, and SERPINA4) as top candidates that segregate ALS based on rate of disease progression. These proteins were validated in the discovery and a separate validation cohort. Our state-transition model determined that the overall variance of the proteome over time was predictive of the disease progression rate. Interpretation: We identified pathways and protein biomarkers that distinguish rate of ALS disease progression. A mathematical model of the CSF proteome determined that the change in entropy of the proteome over time was predictive of FP versus SP.
MeSH term(s)	Humans ; Amyotrophic Lateral Sclerosis ; Proteome/metabolism ; Proteomics/methods ; Biomarkers/cerebrospinal fluid ; Disease Progression ; Retinol-Binding Proteins, Plasma
Chemical Substances	Proteome ; Biomarkers ; RBP4 protein, human ; Retinol-Binding Proteins, Plasma
Language	English
Publishing date	2023-08-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2740696-9
ISSN	2328-9503 ; 2328-9503
ISSN (online)	2328-9503
ISSN	2328-9503
DOI	10.1002/acn3.51890
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Article: Defining the Caprin-1 Interactome in Unstressed and Stressed Conditions

Vu, Lucas / Ghosh, Asmita / Tran, Chelsea / Tebung, Walters Aji / Sidibé, Hadjara / Garcia-Mansfield, Krystine / David-Dirgo, Victoria / Sharma, Ritin / Pirrotte, Patrick / Bowser, Robert / Vande Velde, Christine

Journal of proteome research. 2021 May 03, v. 20, no. 6

2021

Abstract: Cytoplasmic stress granules (SGs) are dynamic foci containing translationally arrested mRNA and RNA-binding proteins (RBPs) that form in response to a variety of cellular stressors. It has been debated that SGs may evolve into cytoplasmic inclusions ... ...

Abstract	Cytoplasmic stress granules (SGs) are dynamic foci containing translationally arrested mRNA and RNA-binding proteins (RBPs) that form in response to a variety of cellular stressors. It has been debated that SGs may evolve into cytoplasmic inclusions observed in many neurodegenerative diseases. Recent studies have examined the SG proteome by interrogating the interactome of G3BP1. However, it is widely accepted that multiple baits are required to capture the full SG proteome. To gain further insight into the SG proteome, we employed immunoprecipitation coupled with mass spectrometry of endogenous Caprin-1, an RBP implicated in mRNP granules. Overall, we identified 1543 proteins that interact with Caprin-1. Interactors under stressed conditions were primarily annotated to the ribosome, spliceosome, and RNA transport pathways. We validated four Caprin-1 interactors that localized to arsenite-induced SGs: ANKHD1, TALIN-1, GEMIN5, and SNRNP200. We also validated these stress-induced interactions in SH-SY5Y cells and further determined that SNRNP200 also associated with osmotic- and thermal-induced SGs. Finally, we identified SNRNP200 in cytoplasmic aggregates in amyotrophic lateral sclerosis (ALS) spinal cord and motor cortex. Collectively, our findings provide the first description of the Caprin-1 protein interactome, identify novel cytoplasmic SG components, and reveal a SG protein in cytoplasmic aggregates in ALS patient neurons. Proteomic data collected in this study are available via ProteomeXchange with identifier PXD023271.
Keywords	RNA transport ; amyotrophic lateral sclerosis ; mass spectrometry ; motor cortex ; patients ; precipitin tests ; protein-protein interactions ; proteome ; proteomics ; research ; ribosomes ; spinal cord ; spliceosomes ; translation (genetics)
Language	English
Dates of publication	2021-0503
Size	p. 3165-3178.
Publishing place	American Chemical Society
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.1c00016
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Article ; Online: Proteomic analysis identifies plasma correlates of remote ischemic conditioning in the context of experimental traumatic brain injury.

Saber, Maha / Pathak, Khyati V / McGilvrey, Marissa / Garcia-Mansfield, Krystine / Harrison, Jordan L / Rowe, Rachel K / Lifshitz, Jonathan / Pirrotte, Patrick

Scientific reports

2020 Volume 10, Issue 1, Page(s) 12989

Abstract: Remote ischemic conditioning (RIC), transient restriction and recirculation of blood flow to a limb after traumatic brain injury (TBI), can modify levels of pathology-associated circulating protein. This study sought to identify TBI-induced molecular ... ...

Abstract	Remote ischemic conditioning (RIC), transient restriction and recirculation of blood flow to a limb after traumatic brain injury (TBI), can modify levels of pathology-associated circulating protein. This study sought to identify TBI-induced molecular alterations in plasma and whether RIC would modulate protein and metabolite levels at 24 h after diffuse TBI. Adult male C57BL/6 mice received diffuse TBI by midline fluid percussion or were sham-injured. Mice were assigned to treatment groups 1 h after recovery of righting reflex: sham, TBI, sham RIC, TBI RIC. Nine plasma metabolites were significantly lower post-TBI (six amino acids, two acylcarnitines, one carnosine). RIC intervention returned metabolites to sham levels. Using proteomics analysis, twenty-four putative protein markers for TBI and RIC were identified. After application of Benjamini-Hochberg correction, actin, alpha 1, skeletal muscle (ACTA1) was found to be significantly increased in TBI compared to both sham groups and TBI RIC. Thus, identified metabolites and proteins provide potential biomarkers for TBI and therapeutic RIC in order to monitor disease progression and therapeutic efficacy.
MeSH term(s)	Actins/blood ; Animals ; Biomarkers/blood ; Brain Injuries, Traumatic/blood ; Brain Injuries, Traumatic/therapy ; Disease Models, Animal ; Ischemic Preconditioning ; Male ; Mice ; Proteomics
Chemical Substances	Acta1 protein, mouse ; Actins ; Biomarkers
Language	English
Publishing date	2020-07-31
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-69865-4
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Article ; Online: Defining the Caprin-1 Interactome in Unstressed and Stressed Conditions.

Journal of proteome research

2021 Volume 20, Issue 6, Page(s) 3165–3178

Abstract	Cytoplasmic stress granules (SGs) are dynamic foci containing translationally arrested mRNA and RNA-binding proteins (RBPs) that form in response to a variety of cellular stressors. It has been debated that SGs may evolve into cytoplasmic inclusions observed in many neurodegenerative diseases. Recent studies have examined the SG proteome by interrogating the interactome of G3BP1. However, it is widely accepted that multiple baits are required to capture the full SG proteome. To gain further insight into the SG proteome, we employed immunoprecipitation coupled with mass spectrometry of endogenous Caprin-1, an RBP implicated in mRNP granules. Overall, we identified 1543 proteins that interact with Caprin-1. Interactors under stressed conditions were primarily annotated to the ribosome, spliceosome, and RNA transport pathways. We validated four Caprin-1 interactors that localized to arsenite-induced SGs: ANKHD1, TALIN-1, GEMIN5, and SNRNP200. We also validated these stress-induced interactions in SH-SY5Y cells and further determined that SNRNP200 also associated with osmotic- and thermal-induced SGs. Finally, we identified SNRNP200 in cytoplasmic aggregates in amyotrophic lateral sclerosis (ALS) spinal cord and motor cortex. Collectively, our findings provide the first description of the Caprin-1 protein interactome, identify novel cytoplasmic SG components, and reveal a SG protein in cytoplasmic aggregates in ALS patient neurons. Proteomic data collected in this study are available
MeSH term(s)	Cytoplasmic Granules ; DNA Helicases ; Humans ; Poly-ADP-Ribose Binding Proteins ; Proteomics ; RNA Helicases/genetics ; RNA Recognition Motif Proteins ; RNA-Binding Proteins/genetics
Chemical Substances	ANKHD1 protein, human ; Poly-ADP-Ribose Binding Proteins ; RNA Recognition Motif Proteins ; RNA-Binding Proteins ; DNA Helicases (EC 3.6.4.-) ; G3BP1 protein, human (EC 3.6.4.12) ; RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2021-05-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.1c00016
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Article ; Online: PTEN loss drives resistance to the neddylation inhibitor MLN4924 in glioblastoma and can be overcome with TOP2A inhibitors.

Ferdosi, Shayesteh R / Taylor, Brett / Lee, Matthew / Tang, Nanyun / Peng, Sen / Bybee, Rita / Reid, George / Hartman, Lauren / Garcia-Mansfield, Krystine / Sharma, Ritin / Pirrotte, Patrick / Ma, Jianhui / Parisian, Alison D / Furnari, Frank / Dhruv, Harshil D / Berens, Michael E

publication RETRACTED

Neuro-oncology

2022 Volume 24, Issue 11, Page(s) 1857–1868

Abstract: Background: Neddylation inhibition, affecting posttranslational protein function and turnover, is a promising therapeutic approach to cancer. We report vulnerability to MLN4924 or pevonedistat (a neddylation inhibitor) in a subset of glioblastoma (GBM) ... ...

Abstract	Background: Neddylation inhibition, affecting posttranslational protein function and turnover, is a promising therapeutic approach to cancer. We report vulnerability to MLN4924 or pevonedistat (a neddylation inhibitor) in a subset of glioblastoma (GBM) preclinical models and identify biomarkers, mechanisms, and signatures of differential response. Methods: GBM sequencing data were queried for genes associated with MLN4924 response status; candidates were validated by molecular techniques. Time-course transcriptomics and proteomics revealed processes implicated in MLN4924 response. Results: Vulnerability to MLN4924 is associated with elevated S-phase populations, re-replication, and DNA damage. Transcriptomics and shotgun proteomics depict PTEN signaling, DNA replication, and chromatin instability pathways as significant differentiators between sensitive and resistant models. Loss of PTEN and its nuclear functions is associated with resistance to MLN4924. Time-course proteomics identified elevated TOP2A in resistant models through treatment. TOP2A inhibitors combined with MLN4924 prove synergistic. Conclusions: We show that PTEN status serves as both a novel biomarker for MLN4924 response in GBM and reveals a vulnerability to TOP2A inhibitors in combination with MLN4924.
MeSH term(s)	Humans ; Apoptosis ; Cell Line, Tumor ; Cyclopentanes/pharmacology ; Cyclopentanes/therapeutic use ; Glioblastoma/drug therapy ; NEDD8 Protein/metabolism ; PTEN Phosphohydrolase/genetics ; Pyrimidines/pharmacology ; Topoisomerase II Inhibitors/pharmacology ; Topoisomerase II Inhibitors/therapeutic use ; Drug Resistance, Neoplasm
Chemical Substances	Cyclopentanes ; NEDD8 Protein ; pevonedistat (S3AZD8D215) ; PTEN Phosphohydrolase (EC 3.1.3.67) ; PTEN protein, human (EC 3.1.3.67) ; Pyrimidines ; Topoisomerase II Inhibitors
Language	English
Publishing date	2022-03-30
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Retracted Publication
ZDB-ID	2028601-6
ISSN	1523-5866 ; 1522-8517
ISSN (online)	1523-5866
ISSN	1522-8517
DOI	10.1093/neuonc/noac067
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