scholarly journals Long-term cultivation using ineffective MDM2 inhibitor concentrations alters the drug sensitivity profiles of PL21 leukaemia cells

2020 ◽  
Vol 1 ◽  
Author(s):  
Martin Michaelis ◽  
Florian Rothweiler ◽  
Constanze Schneider ◽  
Tamara Rothenburger ◽  
Marco Mernberger ◽  
...  
Keyword(s):  
Therapy Response ◽  
Loss Of Function ◽  
Leukaemia Cell Line ◽  
Anti Cancer ◽  
Increased Sensitivity ◽  
Inhibitor Resistance ◽  
Mutant Cells ◽  
Mdm2 Inhibitor ◽  
Selection Of

AbstractAcquired MDM2 inhibitor resistance is commonly caused by loss-of-function TP53 mutations. In addition to the selection of TP53-mutant cells by MDM2 inhibitors, MDM2 inhibitor-induced DNA damage may promote the formation of TP53 mutations. Here, we cultivated 12 sublines of the intrinsically MDM2 inhibitor-resistant TP53 wild-type acute myeloid leukaemia cell line PL21 for 52 passages in the presence of ineffective concentrations of the MDM2 inhibitor nutlin-3 but did not observe loss-of-function TP53 mutations. This suggests that MDM2 inhibitors select TP53-mutant cells after mutations have occurred, but do not directly promote TP53 mutations. Unexpectedly, many sublines displayed increased sensitivity to the anti-cancer drugs cytarabine, doxorubicin, or gemcitabine. Consequently, therapies can affect the outcome of next-line treatments, even in the absence of a therapy response. This finding is conceptually novel. A better understanding of such processes will inform the design of improved therapy protocols in the future.

scholarly journals Exploring the Anti-Cancer Mechanism of Novel 3,4′-Substituted Diaryl Guanidinium Derivatives

2020 ◽  
Vol 13 (12) ◽  
pp. 485
Author(s):  
Viola Previtali ◽  
Helene B. Mihigo ◽  
Rebecca Amet ◽  
Anthony M. McElligott ◽  
Daniela M. Zisterer ◽  
...  
Keyword(s):  
Cell Line ◽  
Promyelocytic Leukaemia ◽  
Lead Compound ◽  
Leukaemia Cell Line ◽  
Structure Activity ◽  
Allosteric Mechanism ◽  
Anti Cancer ◽  
Mcf10a Cells ◽  
Lipophilic Groups ◽  
Selection Of

We previously identified a guanidinium-based lead compound that inhibited BRAF through a hypothetic type-III allosteric mechanism. Considering the pharmacophore identified in this lead compound (i.e., “lipophilic group”, “di-substituted guanidine”, “phenylguanidine polar end”), several modifications were investigated to improve its cytotoxicity in different cancer cell lines. Thus, several lipophilic groups were explored, the di-substituted guanidine was replaced by a secondary amine and the phenyl ring in the polar end was substituted by a pyridine. In a structure-based design approach, four representative derivatives were docked into an in-house model of an active triphosphate-containing BRAF protein, and the interactions established were analysed. Based on these computational studies, a variety of derivatives was synthesized, and their predicted drug-like properties calculated. Next, the effect on cell viability of these compounds was assessed in cell line models of promyelocytic leukaemia and breast, cervical and colorectal carcinomas. The potential of a selection of these compounds as apoptotic agents was assessed by screening in the promyelocytic leukaemia cell line HL-60. The toxicity against non-tumorigenic epithelial MCF10A cells was also investigated. These studies allowed for several structure-activity relationships to be derived. Investigations on the mechanism of action of representative compounds suggest a divergent effect on inhibition of the MAPK/ERK signalling pathway.

Women's Participation in Politics: Ukrainian Case

2014 ◽  
Vol 2013 (3) ◽  
pp. 53-66
Author(s):  
Skovikov Alexey
Keyword(s):  
Political Culture ◽  
Separation Of Powers ◽  
Party Competition ◽  
Political Life ◽  
Ruling Class ◽  
Political Actors ◽  
Women's Participation ◽  
Democratic Transformation ◽  
Selection Of

AbstractThe international practices takes into account the question of women's participation in the political life of modern Ukraine. The selection of the state was due to the dynamic process of democratic transformation - the separation of powers, the formation of multi-party competition among political actors in the electoral process, the activity women in the various institutions of civil society. The position was claimed on the basis of empirical data range of academic institutions and reputable sociological centers, and also interviews with experts who said that the creation of real conditions for self-realization by women's interest in politics is only possible for long term. The process is controversial and caused by political culture, traditions and interests of the ruling class represented mainly by men.

Evidence for a single mechanism gating perceptual and long-term memory information into working memory

2020 ◽  
Author(s):  
Sam Verschooren ◽  
Yoav Kessler ◽  
Tobias Egner
Keyword(s):  
Working Memory ◽  
Long Term Memory ◽  
Sources Of Information ◽  
Term Memory ◽  
Source Selection ◽  
Single Mechanism ◽  
Gating Mechanism ◽  
Opening And Closing ◽  
Selection Of

An influential view of working memory (WM) holds that its’ contents are controlled by a selective gating mechanism that allows for relevant perceptual information to enter WM when opened, but shields WM contents from interference when closed. In support of this idea, prior studies using the reference-back paradigm have established behavioral costs for opening and closing the gate between perception and WM. WM also frequently requires input from long-term memory (LTM), but it is currently unknown whether a similar gate controls the selection of LTM representations into WM, and how WM gating of perceptual vs. LTM sources of information relate to each other. To address these key theoretical questions, we devised a novel version of the reference-back paradigm, where participants switched between gating perceptual and LTM information into WM. We observed clear evidence for gate opening and closing costs in both cases. Moreover, the pattern of costs associated with gating and source-switching indicated that perceptual and LTM information is gated into WM via a single gate, and rely on a shared source-selection mechanism. These findings extend current models of WM gating to encompass LTM information, and outline a new functional WM architecture.

scholarly journals A Multi-Attribute Decision Method under Uncertainty Environment Conditions—The Green Supplier Evaluation Perspective

2021 ◽  
Vol 18 (1) ◽  
pp. 344
Author(s):  
Hao Xu ◽  
Liuxin Chen ◽  
Qiongfang Li ◽  
Jianchao Yang
Keyword(s):  
Environmental Pollution ◽  
Evaluation Method ◽  
External Environment ◽  
Environmental Indicators ◽  
Supplier Evaluation ◽  
Uncertain Environment ◽  
Green Suppliers ◽  
Uncertainty Environment ◽  
Selection Of

Due to the continuous changes of political environment, consumption habits, technological progress and other factors, the external environment of enterprises is full of uncertainty. The turbulence of external environment is not conducive to the long-term operation and development of enterprises, but also brings great challenges to the selection of suppliers. This makes the competition of enterprises focus on how to choose long-term cooperation suppliers in the uncertain external environment. In addition, due to the deterioration of the global environment, governments pay more and more attention to environmental pollution, and consumers are more and more inclined to green consumption, which makes many companies pay more and more attention to environmental indicators when selecting suppliers. In the case of external environment turbulence and serious environmental pollution, the evaluation and selection of green suppliers in uncertain environment is particularly important for the long-term development of enterprises. What’s more, when the supplier’s capability gap is small, the decision-maker often hesitates among several suppliers. In this paper, the hesitant fuzzy is used to describe the hesitant psychology of decision-makers in selecting suppliers, the variance fluctuation is used to describe the characteristics of hesitant fuzzy numbers, and the probability is used to measure the uncertainty of the environment. A green supplier evaluation model under the uncertainty environment is proposed, which comprehensively evaluates the green suppliers under the uncertain environment. Furthermore, it is compared with other methods that do not consider the uncertainty and the adaptability of evaluation method and right confirmation method, so as to reflect the influence of uncertainty to green supplier evaluation and the importance of adaptability of evaluation method and right confirmation method.

Optimal adaptive inspection and maintenance for redundant systems

2021 ◽  
pp. 1748006X2110201
Author(s):  
Chaochao Lin ◽  
Matteo Pozzi
Keyword(s):  
Engineering Systems ◽  
Discounted Cost ◽  
Markov Decision ◽  
Inspection And Maintenance ◽  
And Performance ◽  
Partially Observable ◽  
Series Systems ◽  
Selection Of ◽  
Redundant Systems

Optimal exploration of engineering systems can be guided by the principle of Value of Information (VoI), which accounts for the topological important of components, their reliability and the management costs. For series systems, in most cases higher inspection priority should be given to unreliable components. For redundant systems such as parallel systems, analysis of one-shot decision problems shows that higher inspection priority should be given to more reliable components. This paper investigates the optimal exploration of redundant systems in long-term decision making with sequential inspection and repairing. When the expected, cumulated, discounted cost is considered, it may become more efficient to give higher inspection priority to less reliable components, in order to preserve system redundancy. To investigate this problem, we develop a Partially Observable Markov Decision Process (POMDP) framework for sequential inspection and maintenance of redundant systems, where the VoI analysis is embedded in the optimal selection of exploratory actions. We investigate the use of alternative approximate POMDP solvers for parallel and more general systems, compare their computation complexities and performance, and show how the inspection priorities depend on the economic discount factor, the degradation rate, the inspection precision, and the repair cost.

scholarly journals AB0994 NEW ALTERNATIVE IN THE TREATMENT OF PATIENT WITH MUTATION OF GEN LACC1

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1790.2-1790
Author(s):  
R. M. Alcobendas ◽  
C. Quintana ◽  
J. Arostegui ◽  
C. Udaondo ◽  
S. Murias Loza ◽  
...  
Keyword(s):  
Chart Review ◽  
Loss Of Function ◽  
Acute Phase Reactants ◽  
Reactive Protein ◽  
Inflammatory Parameters ◽  
Whole Exome ◽  
Multiple Treatments ◽  
Clinical Chart ◽  
Clinical Worsening

Background:Few patients have been described in the literature with mutations in the Lacasa Domain containing one (LACC1) gene. Its clinical presentation usually associates sustained systemic inflammation associated with chronic polyarticular erosive arthritis. Until now, there have been multiple treatments described to try to control the disease, however, they are generally unsuccessful in the long term.Objectives:Describe the clinical course of a patient as well as the different treatments usedMethods:Clinical chart reviewResults:Female 18-year-old born from a consanguineous Moroccan couple. Mother, brother and sister with similar conditions. She started at 3 years with fever, anemia, intense elevation of acute phase reactants and symmetric polyarthritis (knees, elbows, carps, shoulders, hands and ankles). Subsequent whole exome sequencing identified c.128_129delGT mutation in the LACC1/FAMIN gene. During the course of her illness, she has received treatment with oral, intravenous and infiltrated corticosteroid, methotrexate and etanercept, without getting adequate control of the disease. In 2016, she started treatment with tocilizumab (8 mg / kg every two weeks), obtaining an acceptable control of the disease (requiring periodic infiltrations every 2-3 months due to persistent arthritis). Nonetheless, in April 2019, she consulted for clinical worsening of the arthritis and laboratory test (C reactive protein 99.7 mg / L, erythrosedimentation rate 53 mm / h, leukocytes 13,500/µL and neutrophils 10,930/µL). At that time, she discontinued therapy with tocilizumab and started tofacitinib 5 mg every 12 hours with good evolution. Since its introduction, it has not required joint infiltration again and the inflammatory parameters (persistently elevated previously) have normalized.Conclusion:The jak kinasa inhibitors may be a treatment option in those patients with bad response to conventional therapy.References:[1]Rabionet R, Remesal A, Mensa-Vilaró A, Murías S, Alcobendas R, González-Roca E, Ruiz-Ortiz E, Antón J, Iglesias E, Modesto C, Comas D, Puig A, Drechsel O, Ossowski S, Yagüe J, Merino R, Estivill X, Arostegui JI. Biallelic loss-of-function LACC1/FAMIN Mutations Presenting as Rheumatoid Factor-Negative Polyarticular Juvenile Idiopathic Arthritis. Sci Rep. 2019 Mar 14;9(1):4579Disclosure of Interests:None declared

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