Search results for "Bridged Bicyclo Compounds"
showing 10 items of 47 documents
Roles of TP53 in determining therapeutic sensitivity, growth, cellular senescence, invasion and metastasis.
2016
TP53 is a critical tumor suppressor gene that regulates cell cycle progression, apoptosis, cellular senescence and many other properties critical for control of normal cellular growth and death. Due to the pleiotropic effects that TP53 has on gene expression and cellular physiology, mutations at this tumor suppressor gene result in diverse physiological effects. T53 mutations are frequently detected in numerous cancers. The expression of TP53 can be induced by various agents used to treat cancer patients such as chemotherapeutic drugs and ionizing radiation. Radiation will induce Ataxia telangiectasia mutated (ATM) and other kinases that results in the phosphorylation and activation of TP53…
Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial.
2020
Abstract Ibrutinib, obinutuzumab, and venetoclax demonstrate synergy in preclinical models of mantle cell lymphoma (MCL). OAsIs (NCT02558816), a single-arm multicenter prospective phase 1/2 trial, aimed to determine the maximum tolerated dose of venetoclax in combination with fixed doses of ibrutinib and obinutuzumab, in relapsed MCL patients. At the venetoclax MTD, extension cohorts were opened for relapsed and untreated patients. Safety and efficacy were secondary objectives. Minimal residual disease (MRD) was assessed by allele-specific oligonucleotide quantitative polymerase chain reaction. Between 14 October 2015 and 29 May 2018, 48 patients were enrolled. No dose-limiting toxicity was…
Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomis…
2020
Background Venetoclax is a highly selective, potent, oral BCL-2 inhibitor, which induces apoptosis in multiple myeloma cells. Venetoclax plus bortezomib and dexamethasone has shown encouraging clinical efficacy with acceptable safety and tolerability in a phase 1 trial. The aim of this study was to evaluate venetoclax plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Methods In this randomised, double-blind, multicentre, phase 3 trial, patients aged 18 years or older with relapsed or refractory multiple myeloma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received one to three previous therapies were enrolled from …
A possible desensitized state conformation of the human α7 nicotinic receptor: A molecular dynamics study
2017
International audience; The determination of the conformational states corresponding to diverse functional roles of ligand gated ion channels is subject of intense investigation with various techniques, from X-rays structure determination to electrophysiology and computational modeling. Even with a certain number of structures becoming recently available, only few major structural features distinguishing conductive open channel from the non conductive resting protein have been highlighted, while high-resolution details are still missing. The characterization of the desensitized conformation(s) is even more complex, and only few specific characteristics have been identified. Furthermore, exp…
Statins and the squalene synthase inhibitor zaragozic acid stimulate the non-amyloidogenic pathway of amyloid-beta protein precursor processing by su…
2010
Cholesterol-lowering drugs such as statins influence the proteolytic processing of the amyloid-beta protein precursor (AbetaPP) and are reported to stimulate the activity of alpha-secretase, the major preventive secretase of Alzheimer's disease. Statins can increase the alpha-secretase activity by their cholesterol-lowering properties as well as by impairment of isoprenoids synthesis. In the present study, we elucidate the contribution of these pathways in alpha-secretase activation. We demonstrate that zaragozic acid, a potent inhibitor of squalene synthase which blocks cholesterol synthesis but allows synthesis of isoprenoids, also stimulates alpha-secretase activity. Treatment of human n…
Coupling between agonist and chloride ionophore sites of the GABA(A) receptor: agonist/antagonist efficacy of 4-PIOL.
2000
Eight gamma-aminobutyric acid (GABA) mimetics were tested on their ability to differentiate native GABA(A) receptor subtypes present in various rat brain regions. In rat brain cryostat sections, little regional variations by the agonistic actions of muscimol, thiomuscimol, 4,5,6,7-tetrahydroisoazolo(5,4-c)pyridin-3-ol, piperidine-4-sulphonic acid, taurine and beta-alanine on [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding to GABA(A) receptor channels were found. They were very similar to those found for GABA itself and indicated no direct correlation with single subunit distributions for any of these compounds. Only the low-efficacy GABA mimetic 5-(4-piperidyl)isoxazol-3-ol (4-PIOL…
Behavioral effects of different enriched environments in mice treated with the cholinergic agonist PNU-282987.
2013
Abstract Environmental enrichment is an experimental model in which rodents are housed in complex environments that favor lower levels of anxiety-like behavior. PNU-282987 (PNU) is a α7 nicotinic acetylcholine receptor agonist with beneficial effects on learning though its effects on anxiety are unclear. Our main aim was to carry out a study of its effects in NMRI ( n = 96) mice reared in different environments: environmental enrichment (EE), Marlau™ cages (MC) and standard environment (SE). After a 4-month period, mice received acute treatment of PNU (2.5, 5 and 10 mg/kg) and were evaluated in the elevated plus-maze (EPM) and hole-board (HB). In the EPM, both EE and MC reared mice showed …
Exploring kainate receptor pharmacology using molecular dynamics simulations.
2010
Ionotropic glutamate receptors (iGluRs) are enticing targets for pharmaceutical research; however, the search for selective ligands is a laborious experimental process. Here we introduce a purely computational procedure as an approach to evaluate ligand–iGluR pharmacology. The ligands are docked into the closed ligand-binding domain and during the molecular dynamics (MD) simulation the bi-lobed interface either opens (partial agonist/antagonist) or stays closed (agonist) according to the properties of the ligand. The procedure is tested with closely related set of analogs of the marine toxin dysiherbaine bound to GluK1 kainate receptor. The modeling is set against the abundant binding data …
Altered atypical coupling of γ-aminobutyrate type A receptor agonist and convulsant binding sites in subunit-deficient mouse lines
2001
We searched for subunit correlations for GABA(A) receptor-associated atypically GABA-insensitive [35S]TBPS binding. The homomeric beta3 subunit receptors could be excluded, as GABA-insensitive [35S]TBPS binding was present in beta3-/- mice. Localization of GABA-insensitive [35S]TBPS binding correlated best with those of delta, alpha4 and alpha6 subunit mRNAs. The amounts of GABA-insensitive [35S]TBPS binding components were increased in delta-/- mice, but dramatically reduced in alpha6-/- mice, suggesting a role for alpha6 but excluding delta subunits.
Chemical composition of essential oils of Anthemis secundiramea Biv. subsp. secundiramea (Asteraceae) collected wild in Sicily and their activity on …
2016
In the present study, the chemical composition of the essential oil from the aerial parts of Anthemis secundiramea Biv. subsp. secundiramea L. collected in Sicily was evaluated by GC and gas chromatography–mass spectrometry. The main components of A. secundiramea were (Z)-lyratyl acetate (14.6%), (Z)-chrysanthenyl acetate (9.9%), (Z)-chrysanthenol (8.7%) and (E)-chrysanthenyl acetate (7.7%). The comparing with other studied oils of genus Anthemis belonging to the same clade is discussed. Antibacterial and antifungal activities against some micro-organisms infesting historical art craft, were also determined.