Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA307839 | ENA |
REPOSITORIES: ENA
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Project description:This randomized phase I/II clinical trial is studying the side effects and best dose of gamma-secretase/notch signalling pathway inhibitor RO4929097 when given together with vismodegib and to see how well they work in treating patients with advanced or metastatic sarcoma. Vismodegib may slow the growth of tumor cells. Gamma-secretase/notch signalling pathway inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vismodegib together with gamma-secretase/notch signalling pathway inhibitor RO4929097 may be an effective treatment for sarcoma.
| 2091475 | ecrin-mdr-crc
Project description:Das2010 - Effect of a gamma-secretase
inhibitor on Amyloid-beta dynamics
This model is described in the article:
Modeling effect of a
?-secretase inhibitor on amyloid-? dynamics reveals significant
role of an amyloid clearance mechanism.
Das R, Nachbar RB, Edelstein-Keshet
L, Saltzman JS, Wiener MC, Bagchi A, Bailey J, Coombs D, Simon
AJ, Hargreaves RJ, Cook JJ.
Bull. Math. Biol. 2011 Jan; 73(1):
230-247
Abstract:
Aggregation of the small peptide amyloid beta (A?) into
oligomers and fibrils in the brain is believed to be a
precursor to Alzheimer's disease. A? is produced via multiple
proteolytic cleavages of amyloid precursor protein (APP),
mediated by the enzymes ?- and ?-secretase. In this study, we
examine the temporal dynamics of soluble (unaggregated) A? in
the plasma and cerebral-spinal fluid (CSF) of rhesus monkeys
treated with different oral doses of a ?-secretase inhibitor. A
dose-dependent reduction of A? concentration was observed
within hours of drug ingestion, for all doses tested. A?
concentration in the CSF returned to its predrug level over the
monitoring period. In contrast, A? concentration in the plasma
exhibited an unexpected overshoot to as high as 200% of the
predrug concentration, and this overshoot persisted as late as
72 hours post-drug ingestion. To account for these
observations, we proposed and analyzed a minimal physiological
model for A? dynamics that could fit the data. Our analysis
suggests that the overshoot arises from the attenuation of an
A? clearance mechanism, possibly due to the inhibitor. Our
model predicts that the efficacy of A? clearance recovers to
its basal (pretreatment) value with a characteristic time of
>48 hours, matching the time-scale of the overshoot. These
results point to the need for a more detailed investigation of
soluble A? clearance mechanisms and their interaction with
A?-reducing drugs.
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2024-09-02 | BIOMD0000000551 | BioModels
Project description:While amyloid-β (Aβ) plaques are considered a hallmark of Alzheimer's disease, clinical trials focused on targeting gamma secretase, an enzyme involved in aberrant Aβ peptide production, have not led to amelioration of AD symptoms or synaptic dysregulation. Screening strategies based on mechanistic, multi-omics approaches that go beyond pathological readouts can aid in the evaluation of therapeutics. Using early-onset Alzheimer's (EOFAD) disease patient lineage PSEN1A246E iPSC-derived neurons, we performed RNA-seq to characterize AD-associated endotypes, which are in turn used as a screening evaluation metric for two gamma secretase drugs, the inhibitor Semagacestat and the modulator BPN-15606.
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Project description:Gamma-secretase inhibitor plus fludarabine in CLL
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Project description:Human iPSC-derived thoracic spinal cord organoids were transplanted into spinal cord injury mice, and spinal cord tissue was collected after 7 weeks. The transplantation resulted in functional recovery and neural circuit remodeling in the injured mice.
2025-08-21 | GSE305911 | GEO
Project description:To determine genes in FL HSCs that are sensitive to Notch signagling, E14.5 FL cells were cultured on DL1( to stimulate Notch signaling). Cells were cultured in the presence of DMSO (vehicle control) or gamma secretase inhibitor (1uM) for 4 hrs or 10hrs. Gamma secretase inhibitor was used to inhibit Notch signaling. SLAM-LSKs were sorted and used for RNA preparation.
2014-01-28 | GSE53713 | GEO
Project description:We have investigated the role of the Notch pathway in the generation and maintenance of KrasG12V-driven non-small cell lung carcinomas (NSCLCs). We demonstrate by genetic means that γ-secretase and Rbpj activities are both essential in the formation of NSCLCs. Interestingly, pharmacologic treatment of mice carrying endogenous NSCLCs with a γ-secretase inhibitor (GSI) blocks cancer growth and induces partial regression. Treated cancers show a reduction in Hes1 levels, reduced phosphorylated Erk, decreased proliferation and higher apoptosis. We demonstrate that HES1 directly binds and represses the promoter of DUSP1, a dual phosphatase with activity against phospho-ERK, and this repression is relieved by GSI treatment both in mouse and human NSCLCs. Our data provide proof for the in vivo therapeutic potential of γ-secretase inhibitors in primary NSCLCs and provide a mechanistic explanation for its therapeutical effect. We have included 6 samples. 3 with vehicle and 3 with the gamma-secretase inhibitor DAPT and we compare both groups.
2012-12-01 | E-GEOD-38054 | biostudies-arrayexpress
Project description:The intramembrane protease gamma-secretase has broad physiological functions, but also contributes to Notch-dependent tumors and Alzheimer’s disease. To identify naturally short substrates and non-substrates of gamma-secretase, we used four human cell lines of different tissue origins, breast cancer MCF7 cells, cervix carcinoma HeLa cells, T cell leukemia Jurkat cells and lymphoma U937 macrophage-like cells. The cell lines were treated overnight with the established gamma-secretase inhibitor DAPT or DMSO as a control. The proteomes of membrane fractions were determined by nano-liquid chromatography-tandem mass spectrometry and label-free quantitative proteomics. TNFRSF12A, PTPRCAP and C16orf54 were identified as potential naturally short gamma-secretase substrates, whereas other proteins with a short ectodomain including ‘pituitary tumor-transforming gene 1-interacting protein’ (PTTG1IP) did not show an increased abundance upon DAPT treatment.
2024-05-24 | PXD045701 | Pride
Project description:Analysis of five Notch signaling-dependent human T-ALL cell lines (ALLSIL, DND41, HPBALL, KOPTK1, TALL-1) treated with gamma-secretase inhibitor (GSI) to block Notch signaling. Samples include parental cells, cells rescued by retroviral transduction with ICN (a GSI-independent form of activated Notch1), and cells retrovirally transduced with c-Myc (an important downstream target of Notch1). Results allow segregation of bona fide Notch targets from other genes affected by gamma-secretase inhibition as well as from targets downstream of c-Myc. Thirty samples were analyzed. Five human T-ALL cell lines (ALLSIL, DND41, HPBALL, KOPTK1, TALL-1) were treated with gamma-secretase inhibitor (1.0 micromolar compound E) vs. DMSO vehicle control for 12 hours. Each cell line was also retrovirally transduced with ICN or c-Myc, FACS sorted, and then treated with GSI vs. DMSO.
2011-07-31 | E-GEOD-29959 | biostudies-arrayexpress
Project description:We used DNA microarrays to compare RNA transcript expression from various glioma neurospheres after treatment with gamma-secretase inhibitor MRK003.
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