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Article: N-cadherin dynamically regulates pediatric glioma cell migration in complex environments.

Kim, Dayoung / Olson, James M / Cooper, Jonathan A

bioRxiv : the preprint server for biology

2024

Abstract: Pediatric high-grade gliomas are highly invasive and essentially incurable. Glioma cells migrate between neurons and glia, along axon tracts, and through extracellular matrix surrounding blood vessels and underlying the pia. Mechanisms that allow ... ...

Abstract	Pediatric high-grade gliomas are highly invasive and essentially incurable. Glioma cells migrate between neurons and glia, along axon tracts, and through extracellular matrix surrounding blood vessels and underlying the pia. Mechanisms that allow adaptation to such complex environments are poorly understood. N-cadherin is highly expressed in pediatric gliomas and associated with shorter survival. We found that inter-cellular homotypic N-cadherin interactions differentially regulate glioma migration according to the microenvironment, stimulating migration on cultured neurons or astrocytes but inhibiting invasion into reconstituted or astrocyte-deposited extracellular matrix. N-cadherin localizes to filamentous connections between migrating leader cells but to epithelial-like junctions between followers. Leader cells have more surface and recycling N-cadherin, increased YAP1/TAZ signaling, and increased proliferation relative to followers. YAP1/TAZ signaling is dynamically regulated as leaders and followers change position, leading to altered N-cadherin levels and organization. Together, the results suggest that pediatric glioma cells adapt to different microenvironments by regulating N-cadherin dynamics and cell-cell contacts.
Language	English
Publishing date	2024-01-11
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.04.535599
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Article ; Online: N-cadherin dynamically regulates pediatric glioma cell migration in complex environments.

Kim, Dayoung / Olson, James M / Cooper, Jonathan A

The Journal of cell biology

2024 Volume 223, Issue 6

Abstract	Pediatric high-grade gliomas are highly invasive and essentially incurable. Glioma cells migrate between neurons and glia, along axon tracts, and through extracellular matrix surrounding blood vessels and underlying the pia. Mechanisms that allow adaptation to such complex environments are poorly understood. N-cadherin is highly expressed in pediatric gliomas and associated with shorter survival. We found that intercellular homotypic N-cadherin interactions differentially regulate glioma migration according to the microenvironment, stimulating migration on cultured neurons or astrocytes but inhibiting invasion into reconstituted or astrocyte-deposited extracellular matrix. N-cadherin localizes to filamentous connections between migrating leader cells but to epithelial-like junctions between followers. Leader cells have more surface and recycling N-cadherin, increased YAP1/TAZ signaling, and increased proliferation relative to followers. YAP1/TAZ signaling is dynamically regulated as leaders and followers change position, leading to altered N-cadherin levels and organization. Together, the results suggest that pediatric glioma cells adapt to different microenvironments by regulating N-cadherin dynamics and cell-cell contacts.
MeSH term(s)	Child ; Humans ; Astrocytes ; Axons ; Cadherins/metabolism ; Cell Movement ; Glioma/metabolism ; Glioma/pathology ; Tumor Microenvironment
Chemical Substances	Cadherins ; CDH2 protein, human
Language	English
Publishing date	2024-03-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.202401057
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Article ; Online: Carboplatin During Craniospinal Radiotherapy for Children With Group 3 Medulloblastoma-A New Standard of Care?-Reply.

Leary, Sarah E S / Li, Yimei / Olson, James M

JAMA oncology

2021 Volume 8, Issue 2, Page(s) 302–303

MeSH term(s)	Carboplatin/adverse effects ; Cerebellar Neoplasms/drug therapy ; Cerebellar Neoplasms/radiotherapy ; Child ; Combined Modality Therapy ; Cranial Irradiation/adverse effects ; Humans ; Medulloblastoma/drug therapy ; Medulloblastoma/radiotherapy ; Standard of Care
Chemical Substances	Carboplatin (BG3F62OND5)
Language	English
Publishing date	2021-11-27
Publishing country	United States
Document type	Letter ; Comment
ISSN	2374-2445
ISSN (online)	2374-2445
DOI	10.1001/jamaoncol.2021.6526
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Article ; Online: Therapeutic opportunities for medulloblastoma come of age.

Olson, James M

Cancer cell

2014 Volume 25, Issue 3, Page(s) 267–269

Abstract: In this issue of Cancer Cell, Kool and colleagues reveal clear genetically defined subclasses of the sonic hedgehog (SHH) subclass of medulloblastoma. This molecular dissection of the SHH subclass is not simply a cutting-edge advance; the data have ... ...

Abstract	In this issue of Cancer Cell, Kool and colleagues reveal clear genetically defined subclasses of the sonic hedgehog (SHH) subclass of medulloblastoma. This molecular dissection of the SHH subclass is not simply a cutting-edge advance; the data have profound impact on clinical trial design and decision-making.
MeSH term(s)	Animals ; Clonal Evolution/genetics ; Genetic Variation/genetics ; Humans ; Leukemia, Myeloid, Acute/genetics
Language	English
Publishing date	2014-03-20
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccr.2014.03.003
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Article: Miniproteins as a Powerful Modality in Drug Development.

Crook, Zachary R / Nairn, Natalie W / Olson, James M

Trends in biochemical sciences

2020 Volume 45, Issue 4, Page(s) 332–346

Abstract: Miniproteins are a diverse group of protein scaffolds characterized by small (1-10 kDa) size, stability, and versatility in drug-like roles. Coming largely from native sources, they have been widely adopted into drug development pipelines. While their ... ...

Abstract	Miniproteins are a diverse group of protein scaffolds characterized by small (1-10 kDa) size, stability, and versatility in drug-like roles. Coming largely from native sources, they have been widely adopted into drug development pipelines. While their structures and capabilities are diverse, the approaches to their utilization share more similarities with each other than with more widely used modalities (e.g., antibodies or small molecules). In this review, we highlight recent advances in miniprotein-based approaches to otherwise poorly addressed clinical needs, including structure-based and functional characterization. We also summarize their unique screening strategies and pharmacology considerations. Through a greater understanding of the unique properties that make them attractive for drug design, miniproteins can be effectively utilized against targets that are intractable by other approaches.
MeSH term(s)	Animals ; Drug Development ; Humans ; Proteins/chemistry ; Proteins/metabolism
Chemical Substances	Proteins
Language	English
Publishing date	2020-01-31
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	194216-5
ISSN	1362-4326 ; 0968-0004 ; 0376-5067
ISSN (online)	1362-4326
ISSN	0968-0004 ; 0376-5067
DOI	10.1016/j.tibs.2019.12.008
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Book ; Conference proceedings: Self-inference processes

Olson, James M.

[rev. papers presented at the Sixth Ontario Symposium on Personality and Social Psychology, held at the University of Western Ontario, June 4 - 5, 1988]

(The Ontario symposium ; 6)

1990

Event/congress	Ontario Symposium on Personality and Social Psychology (6, 1988, LondonOntario)
Author's details	ed. by James M. Olson
Series title	The Ontario symposium ; 6
Collection
Keywords	Self Concept / congresses ; Selbstbeobachtung
Subject	Introspektion ; Selbstwahrnehmung
Language	English
Size	XI, 339 S. : graph. Darst.
Publisher	Erlbaum
Publishing place	Hillsdale, NJ u.a.
Publishing country	United States
Document type	Book ; Conference proceedings
HBZ-ID	HT003783857
ISBN	0-8058-0551-6 ; 978-0-8058-0551-2
Database	Catalogue ZB MED Medicine, Health

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1996 A 5062	order for loan	Magazin

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Article ; Online: Mammalian Surface Display Screening of Diverse Cystine-Dense Peptide Libraries for Difficult-to-Drug Targets.

Crook, Zachary R / Sevilla, Gregory P / Mhyre, Andrew J / Olson, James M

Methods in molecular biology (Clifton, N.J.)

2019 Volume 2070, Page(s) 363–396

Abstract: Many diseases are mediated by targets that are not amenable to conventional small-molecule drug approaches. While antibody-based drugs have undeniable utility, peptides of the 1-9 kDa size range (10-80 amino acids) have drawn interest as alternate drug ... ...

Abstract	Many diseases are mediated by targets that are not amenable to conventional small-molecule drug approaches. While antibody-based drugs have undeniable utility, peptides of the 1-9 kDa size range (10-80 amino acids) have drawn interest as alternate drug scaffolds This is born of a desire to identify compounds with the advantages of antibody-based therapeutics (affinity, potency, specificity, and ability to disrupt protein:protein interactions) without all of their liabilities (large size, expensive manufacturing, and necessity of humanization). Of these alternate scaffolds, cystine-dense peptides (CDPs) have several specific benefits. Due to their stable intra-chain disulfide bridges, CDPs often demonstrate resistance to heat and proteolysis, along with low immunogenicity. These properties do not require chemical modifications, permitting CDP screening by conventional genetic means. The cystine topology of a typical CDP requires an oxidative environment, and we have found that the mammalian secretory pathway is most effective at allowing diverse CDPs to achieve a stable fold. As such, high-diversity screens to identify CDPs that interact with targets of interest can be efficiently conducted using mammalian surface display. In this protocol, we present the theory and tools to conduct a mammalian surface display screen for CDPs that bind with targets of interest, including the steps to validate binding and mature the affinity of preliminary candidates. With these methods, CDPs of all kinds can be brought to bear against targets that would benefit from a peptide-based intervention.
MeSH term(s)	Animals ; Cell Line ; Cell Surface Display Techniques ; Disulfides/chemistry ; Disulfides/metabolism ; Drug Delivery Systems ; Drug Discovery ; Humans ; Peptide Library ; Protein Engineering
Chemical Substances	Disulfides ; Peptide Library
Language	English
Publishing date	2019-10-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-9853-1_21
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Article ; Online: Laboratory information management software for engineered mini-protein therapeutic workflow.

Brusniak, Mi-Youn / Ramos, Hector / Lee, Bernard / Olson, James M

BMC bioinformatics

2019 Volume 20, Issue 1, Page(s) 343

Abstract: Background: Protein based therapeutics are one of the fastest growing classes of novel medical interventions in areas such as cancer, infectious disease, and inflammation. Protein engineering plays an important role in the optimization of desired ... ...

Abstract	Background: Protein based therapeutics are one of the fastest growing classes of novel medical interventions in areas such as cancer, infectious disease, and inflammation. Protein engineering plays an important role in the optimization of desired therapeutic properties such as reducing immunogenicity, increasing stability for storage, increasing target specificity, etc. One category of protein therapeutics is nature-inspired bioengineered cystine-dense peptides (CDPs) for various biological targets. These engineered proteins are often further modified by synthetic chemistry. For example, candidate mini-proteins can be conjugated into active small molecule drugs. We refer to modified mini-proteins as "Optides" (Optimized peptides). To efficiently serve the multidisciplinary lab scientists with varied therapeutic portfolio research goals in a non-commercial setting, a cost effective extendable laboratory information management system (LIMS) is/was needed. Results: We have developed a LIMS named Optide-Hunter for a generalized engineered protein compounds workflow that tracks entities and assays from creation to preclinical experiments. The implementation and custom modules are built using LabKey server, which is an Open Source platform for scientific data integration and analysis. Optide-Hunter contains a compound registry, in-silico assays, high throughput production, large-scale production, in vivo assays and data extraction from a specimen-tracking database. It is used to store, extract, and view data for various therapeutics projects. Optide-Hunter also includes external processing stand-alone software (HPLCPeakClassifierApp) for automated chromatogram classification. The HPLCPeakClassifierApp is used for pre-processing of HPLC data prior to loading to Optide-Hunter. The custom implementation is done using data transformation modules in R, SQL, javascript, and java and is Open Source to assist new users in customizing it for their unique workflows. Instructions for exploring a deployed version of Optide-Hunter can be found at https://www.labkey.com/case%20study/optide-hunter CONCLUSION: The Optide-Hunter LIMS system is designed and built to track the process of engineering, producing and prioritizing protein therapeutic candidates. It can be easily adapted and extended for use in small or large research laboratories where multidisciplinary scientists are collaborating to engineer compounds for potential therapeutic or protein science applications. Open Source exploration of Optide-Hunter can help any bioinformatics scientist adapt, extend, and deploy an equivalent system tailored to each laboratory's workflow.
MeSH term(s)	Automation ; Humans ; Information Management ; Laboratories ; Protein Engineering ; Proteins/therapeutic use ; Software ; User-Computer Interface ; Workflow
Chemical Substances	Proteins
Language	English
Publishing date	2019-06-17
Publishing country	England
Document type	Journal Article
ZDB-ID	2041484-5
ISSN	1471-2105 ; 1471-2105
ISSN (online)	1471-2105
ISSN	1471-2105
DOI	10.1186/s12859-019-2935-x
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Article ; Online: Systemically administered low-affinity HER2 CAR T cells mediate antitumor efficacy without toxicity.

Shabaneh, Tamer Basel / Stevens, Andrew R / Stull, Sylvia M / Shimp, Kristen R / Seaton, Brandon W / Gad, Ekram A / Jaeger-Ruckstuhl, Carla A / Simon, Sylvain / Koehne, Amanda L / Price, Jason P / Olson, James M / Hoffstrom, Benjamin G / Jellyman, David / Riddell, Stanley R

Journal for immunotherapy of cancer

2024 Volume 12, Issue 2

Abstract: Background: The paucity of tumor-specific targets for chimeric antigen receptor (CAR) T-cell therapy of solid tumors necessitates careful preclinical evaluation of the therapeutic window for candidate antigens. Human epidermal growth factor receptor 2 ( ... ...

Abstract	Background: The paucity of tumor-specific targets for chimeric antigen receptor (CAR) T-cell therapy of solid tumors necessitates careful preclinical evaluation of the therapeutic window for candidate antigens. Human epidermal growth factor receptor 2 (HER2) is an attractive candidate for CAR T-cell therapy in humans but has the potential for eliciting on-target off-tumor toxicity. We developed an immunocompetent tumor model of CAR T-cell therapy targeting murine HER2 (mHER2) and examined the effect of CAR affinity, T-cell dose, and lymphodepletion on safety and efficacy. Methods: Antibodies specific for mHER2 were generated, screened for affinity and specificity, tested for immunohistochemical staining of HER2 on normal tissues, and used for HER2-targeted CAR design. CAR candidates were evaluated for T-cell surface expression and the ability to induce T-cell proliferation, cytokine production, and cytotoxicity when transduced T cells were co-cultured with mHER2+ tumor cells in vitro. Safety and efficacy of various HER2 CARs was evaluated in two tumor models and normal non-tumor-bearing mice. Results: Mice express HER2 in the same epithelial tissues as humans, rendering these tissues vulnerable to recognition by systemically administered HER2 CAR T cells. CAR T cells designed with single-chain variable fragment (scFvs) that have high-affinity for HER2 infiltrated and caused toxicity to normal HER2-positive tissues but exhibited poor infiltration into tumors and antitumor activity. In contrast, CAR T cells designed with an scFv with low-affinity for HER2 infiltrated HER2-positive tumors and controlled tumor growth without toxicity. Toxicity mediated by high-affinity CAR T cells was independent of tumor burden and correlated with proliferation of CAR T cells post infusion. Conclusions: Our findings illustrate the disadvantage of high-affinity CARs for targets such as HER2 that are expressed on normal tissues. The use of low-affinity HER2 CARs can safely regress tumors identifying a potential path for therapy of solid tumors that exhibit high levels of HER2.
MeSH term(s)	Mice ; Humans ; Animals ; Xenograft Model Antitumor Assays ; Cell Line, Tumor ; T-Lymphocytes ; Immunotherapy, Adoptive ; Mice, Inbred Strains
Language	English
Publishing date	2024-02-07
Publishing country	England
Document type	Journal Article
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2023-008566
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Article ; Online: Preclinical pediatric brain tumor models for immunotherapy: Hurdles and a way forward.

Mishra, Deepak Kumar / Popovski, Dean / Morris, Shelli M / Bondoc, Andrew / Senthil Kumar, Shiva / Girard, Emily J / Rutka, James / Fouladi, Maryam / Huang, Annie / Olson, James M / Drissi, Rachid

Neuro-oncology

2023 Volume 26, Issue 2, Page(s) 226–235

Abstract: Brain tumors are the most common solid tumor in children and the leading cause of cancer-related deaths. Over the last few years, improvements have been made in the diagnosis and treatment of children with Central Nervous System tumors. Unfortunately, ... ...

Abstract	Brain tumors are the most common solid tumor in children and the leading cause of cancer-related deaths. Over the last few years, improvements have been made in the diagnosis and treatment of children with Central Nervous System tumors. Unfortunately, for many patients with high-grade tumors, the overall prognosis remains poor. Lower survival rates are partly attributed to the lack of efficacious therapies. The advent and success of immune checkpoint inhibitors (ICIs) in adults have sparked interest in investigating the utility of these therapies alone or in combination with other drug treatments in pediatric patients. However, to achieve improved clinical outcomes, the establishment and selection of relevant and robust preclinical pediatric high-grade brain tumor models is imperative. Here, we review the information that influenced our model selection as we embarked on an international collaborative study to test ICIs in combination with epigenetic modifying agents to enhance adaptive immunity to treat pediatric brain tumors. We also share challenges that we faced and potential solutions.
MeSH term(s)	Humans ; Child ; Brain Neoplasms/therapy ; Brain Neoplasms/pathology ; Immunotherapy ; Central Nervous System Neoplasms/therapy
Language	English
Publishing date	2023-09-15
Publishing country	England
Document type	Review ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2028601-6
ISSN	1523-5866 ; 1522-8517
ISSN (online)	1523-5866
ISSN	1522-8517
DOI	10.1093/neuonc/noad170
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