scholarly journals Targeting Cellular DNA Damage Responses in Cancer: An In Vitro-Calibrated Agent-Based Model Simulating Monolayer and Spheroid Treatment Responses to ATR-Inhibiting Drugs

2021 ◽  
Vol 83 (10) ◽  
Author(s):  
Sara Hamis ◽  
James Yates ◽  
Mark A. J. Chaplain ◽  
Gibin G. Powathil
Keyword(s):  
Dna Damage ◽  
Drug Development ◽  
Agent Based Model ◽  
Agent Based ◽  
Preclinical Drug Development ◽  
Dna Damage Responses ◽  
Treatment Responses ◽  
Cellular Dna

AbstractWe combine a systems pharmacology approach with an agent-based modelling approach to simulate LoVo cells subjected to AZD6738, an ATR (ataxia–telangiectasia-mutated and rad3-related kinase) inhibiting anti-cancer drug that can hinder tumour proliferation by targeting cellular DNA damage responses. The agent-based model used in this study is governed by a set of empirically observable rules. By adjusting only the rules when moving between monolayer and multi-cellular tumour spheroid simulations, whilst keeping the fundamental mathematical model and parameters intact, the agent-based model is first parameterised by monolayer in vitro data and is thereafter used to simulate treatment responses in in vitro tumour spheroids subjected to dynamic drug delivery. Spheroid simulations are subsequently compared to in vivo data from xenografts in mice. The spheroid simulations are able to capture the dynamics of in vivo tumour growth and regression for approximately 8 days post-tumour injection. Translating quantitative information between in vitro and in vivo research remains a scientifically and financially challenging step in preclinical drug development processes. However, well-developed in silico tools can be used to facilitate this in vitro to in vivo translation, and in this article, we exemplify how data-driven, agent-based models can be used to bridge the gap between in vitro and in vivo research. We further highlight how agent-based models, that are currently underutilised in pharmaceutical contexts, can be used in preclinical drug development.

scholarly journals Bridging in vitro and in vivo research via an agent-based modelling approach: predicting tumour responses to an ATR-inhibiting drug

2019 ◽  
Author(s):  
Sara Hamis ◽  
James Yates ◽  
Mark AJ Chaplain ◽  
Gibin G Powathil
Keyword(s):  
Drug Development ◽  
Quantitative Information ◽  
Agent Based Model ◽  
Agent Based ◽  
Lovo Cells ◽  
Preclinical Drug Development ◽  
Development Processes ◽  
Modelling Approach

AbstractTranslating quantitative information between in vitro and in vivo research remains a scientifically and financially challenging step in preclinical drug development processes. However, well-developed in silico tools can be used to facilitate this in vitro to in vivo translation, and we here propose using a data-driven, agent-based model to bridge the gap between in vitro and in vivo research. The agent-based model used in this study is governed by a set of empirically observable rules, and by adjusting only the rules when moving between in vitro and in vivo simulations, whilst keeping the fundamental mathematical model and parameters intact, the agent-based model can first be parameterised by in vitro data and thereafter be used to predict in vivo treatment responses.As a proof-of-concept, this modelling approach is here validated against data pertaining to LoVo cells subjected to the ATR (ataxia telangiectasia mutated and rad3-related kinase) inhibiting drug AZD6738, but the modelling approach has the potential to be expanded to other applications. In this article we also highlight how agent-based models, that are currently underutilised in pharmaceutical contexts, can be used in preclinical drug development.

scholarly journals 570 The AHR-p27 axis modulates DNA damage responses in UV-irradiated keratinocytes in vitro and in vivo

2016 ◽  
Vol 136 (5) ◽  
pp. S101 ◽  
Author(s):  
S. Shaik ◽  
M. Pollet ◽  
J. Krutmann ◽  
T. Haarmann-Stemmann
Keyword(s):  
Dna Damage ◽  
Dna Damage Responses

scholarly journals S1P lyase regulates DNA damage responses in vitro and in vivo

2011 ◽  
Vol 25 (S1) ◽  
Author(s):  
Julie Deane Saba ◽  
Ashok Kumar ◽  
Babak Oskouian ◽  
Henrik Fyrst ◽  
Meng Zhang
Keyword(s):  
Dna Damage ◽  
Dna Damage Responses ◽  
S1p Lyase

scholarly journals Autophagy-Based Unconventional Secretory for AIM2 Inflammasome Drives DNA Damage Resistance During Intervertebral Disc Degeneration

2021 ◽  
Vol 9 ◽  
Author(s):  
Shuai Li ◽  
Zhiwei Liao ◽  
Rongjin Luo ◽  
Yu Song ◽  
Kun Wang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Damage Resistance ◽  
Unconventional Secretion ◽  
Underlying Mechanisms ◽  
Cellular Dna

Intervertebral disc degeneration (IDD) is the primary cause of low back pain. Stress-induced DNA damage is closely relevant to the pathogenesis of IDD; however, the underlying mechanisms remain unclear. This study investigated the role of the absent in melanoma 2 (AIM2) inflammasome as a DNA damage sensor in nucleus pulposus (NP) cells. We found that the level of AIM2 increased in degenerated discs and was correlated to the degree of IDD. Knockdown of AIM2 ameliorated H2O2-induced DNA damage and apoptosis in NP cells in vitro, and retarded the progression of IDD in vivo. Furthermore, the induction of autophagy protected against cellular DNA damage via the unconventional secretion of AIM2. We further identified the Golgi re-assembly and stacking protein 55 (GRASP55) as mediator of the transport and secretion of AIM2 via an autophagic pathway. Taken together, our researches illustrate the role and regulatory mechanism of the AIM2 inflammasome during IDD. Targeting the AIM2 inflammasome may offer a promising therapeutic strategy for patients with IDD.

Technological Advances in Preclinical Drug Evaluation: The Role of -Omics Methods

2020 ◽  
Vol 27 (8) ◽  
pp. 1337-1349 ◽  
Author(s):  
Sandra Kraljević Pavelić ◽  
Elitza Markova-Car ◽  
Marko Klobučar ◽  
Lana Sappe ◽  
Radan Spaventi
Keyword(s):  
Drug Development ◽  
Drug Evaluation ◽  
Legal Aspects ◽  
Drug Candidates ◽  
Technological Advances ◽  
Preclinical Drug Development ◽  
New Chemical Entities ◽  
Speed Up

Preclinical drug development is an essential step in the drug development process where the evaluation of new chemical entities occurs. In particular, preclinical drug development phases include deep analysis of drug candidates’ interactions with biomolecules/targets, their safety, toxicity, pharmacokinetics, metabolism by use of assays in vitro and in vivo animal assays. Legal aspects of the required procedures are well-established. Herein, we present a comprehensive summary of current state-of-the art approaches and techniques used in preclinical studies. In particular, we will review the potential of new, -omics methods and platforms for mechanistic evaluation of drug candidates and speed-up of the preclinical evaluation steps.

scholarly journals In Silico Modeling of Biofilm Formation by Nontypeable Haemophilus influenzae In Vivo

mSphere ◽  
2019 ◽  
Vol 4 (4) ◽  
Author(s):  
Jonathan R. Brown ◽  
Joseph Jurcisek ◽  
Vinal Lakhani ◽  
Ali Snedden ◽  
William C. Ray ◽  
...  
Keyword(s):  
Haemophilus Influenzae ◽  
In Silico ◽  
Biofilm Formation ◽  
Host Responses ◽  
Model Parameters ◽  
Agent Based Model ◽  
Content Type ◽  
Agent Based

ABSTRACT Biofilms formed by nontypeable Haemophilus influenzae (NTHI) bacteria play an important role in multiple respiratory tract diseases. Visual inspection of the morphology of biofilms formed during chronic infections shows distinct differences from biofilms formed in vitro. To better understand these differences, we analyzed images of NTHI biofilms formed in the middle ears of Chinchilla lanigera and developed an in silico agent-based model of the formation of NTHI biofilms in vivo. We found that, as in vitro, NTHI bacteria are organized in self-similar patterns; however, the sizes of NTHI clusters in vivo are more than 10-fold smaller than their in vitro counterparts. The agent-based model reproduced these patterns and suggested that smaller clusters occur due to elimination of planktonic NTHI cells by the host responses. Estimation of model parameters by fitting simulation results to imaging data showed that the effects of several processes in the model change during the course of the infection. IMPORTANCE Multiple respiratory illnesses are associated with formation of biofilms within the human airway by NTHI. However, a substantial amount of our understanding of the mechanisms that underlie NTHI biofilm formation is obtained from in vitro studies. Our in silico model that describes biofilm formation by NTHI within the middle ears of Chinchilla lanigera will help isolate processes potentially responsible for the differences between the morphologies of biofilms formed in vivo versus those formed in vitro. Thus, the in silico model can be used to glean mechanisms that underlie biofilm formation in vivo and connect those mechanisms to those obtained from in vitro experiments. The in silico model developed here can be extended to investigate potential roles of specific host responses (e.g., mucociliary clearance) on NTHI biofilm formation in vivo. The developed computational tools can also be used to analyze and describe biofilm formation by other bacterial species in vivo.

Photoprotection of maqui berry against ultraviolet B-induced photodamage in vitro and in vivo

2020 ◽  
Vol 11 (3) ◽  
pp. 2749-2762 ◽  
Author(s):  
Ling Chen ◽  
Gao Zhou ◽  
Xiao-Shan Meng ◽  
Hui-Ying Fu ◽  
Qi-Gui Mo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Ultraviolet B ◽  
Uvb Irradiation ◽  
Maqui Berry ◽  
Berry Extracts ◽  
Cellular Dna

Maqui berry extracts could ameliorate oxidative stress, cellular DNA damage, and inflammation induced by UVB-irradiation in vitro and in vivo.

A Novel Camptothecin Derivative 3j Inhibits Nsclc Proliferation Via Induction of Cell Cycle Arrest By Topo I-Mediated DNA Damage

2019 ◽  
Vol 19 (3) ◽  
pp. 365-374 ◽  
Author(s):  
Yang Liu ◽  
Jingyin Zhang ◽  
Shuyun Feng ◽  
Tingli Zhao ◽  
Zhengzheng Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Flow Cytometry ◽  
Dna Damage ◽  
Cyclin D ◽  
Dna Relaxation ◽  
Cycle Arrest ◽  
H460 Cell ◽  
H1975 Cell

Objective: The aim of this study is to investigate the inhibitory effect of camptothecin derivative 3j on Non-Small Cell Lung Cancer (NSCLCs) cells and the potential anti-tumor mechanisms. Background: Camptothecin compounds are considered as the third largest natural drugs which are widely investigated in the world and they suffered restriction because of serious toxicity, such as hemorrhagic cystitis and bone marrow suppression. Methods: Using cell proliferation assay and S180 tumor mice model, a series of 20(S)-O-substituted benzoyl 7- ethylcamptothecin compounds were screened and evaluated the antitumor activities in vitro and in vivo. Camptothecin derivative 3j was selected for further study using flow cytometry in NSCLCs cells. Cell cycle related protein cyclin A2, CDK2, cyclin D and cyclin E were detected by Western Blot. Then, computer molecular docking was used to confirm the interaction between 3j and Topo I. Also, DNA relaxation assay and alkaline comet assay were used to investigate the mechanism of 3j on DNA damage. Results: Our results demonstrated that camptothecin derivative 3j showed a greater antitumor effect in eleven 20(S)-O-substituted benzoyl 7-ethylcamptothecin compounds in vitro and in vivo. The IC50 of 3j was 1.54± 0.41 µM lower than irinotecan with an IC50 of 13.86±0.80 µM in NCI-H460 cell, which was reduced by 8 fold. In NCI-H1975 cell, the IC50 of 3j was 1.87±0.23 µM lower than irinotecan (IC50±SD, 5.35±0.38 µM), dropped by 1.8 fold. Flow cytometry analysis revealed that 3j induced significant accumulation in a dose-dependent manner. After 24h of 3j (10 µM) treatment, the percentage of NCI-H460 cell in S-phase significantly increased (to 93.54 ± 4.4%) compared with control cells (31.67 ± 3.4%). Similarly, the percentage of NCI-H1975 cell in Sphase significantly increased (to 83.99 ± 2.4%) compared with control cells (34.45 ± 3.9%) after treatment with 10µM of 3j. Moreover, increased levels of cyclin A2, CDK2, and decreased levels of cyclin D, cyclin E further confirmed that cell cycle arrest was induced by 3j. Furthermore, molecular docking studies suggested that 3j interacted with Topo I-DNA and DNA-relaxation assay simultaneously confirmed that 3j suppressed the activity of Topo I. Research on the mechanism showed that 3j exhibited anti-tumour activity via activating the DNA damage response pathway and suppressing the repair pathway in NSCLC cells. Conclusion: Novel camptothecin derivative 3j has been demonstrated as a promising antitumor agent and remains to be assessed in further studies.

Protective effect of argan oil on DNA damage in vivo and in vitro

Biomarkers ◽  
2021 ◽  
pp. 1-9
Author(s):  
Habiba Bouchab ◽  
Abbas Ishaq ◽  
Riad EL Kebbaj ◽  
Boubker Nasser ◽  
Gabriele Saretzki
Keyword(s):  
Dna Damage ◽  
Protective Effect ◽  
Argan Oil

scholarly journals Detecting apoptosis as a clinical endpoint for proof of a clinical principle

2020 ◽  
Author(s):  
Piero Zollet ◽  
Timothy E.Yap ◽  
M Francesca Cordeiro
Keyword(s):  
Drug Development ◽  
Therapeutic Response ◽  
Imaging Techniques ◽  
Brain Diseases ◽  
Promising Strategy ◽  
Sight Loss ◽  
Apoptosis Detection ◽  
Novel Therapeutic Strategies

The transparent eye media represent a window through which to observe changes occurring in the retina during pathological processes. In contrast to visualising the extent of neurodegenerative damage that has already occurred, imaging an active process such as apoptosis has the potential to report on disease progression and therefore the threat of irreversible functional loss in various eye and brain diseases. Early diagnosis in these conditions is an important unmet clinical need to avoid or delay irreversible sight loss. In this setting, apoptosis detection is a promising strategy with which to diagnose, provide prognosis, and monitor therapeutic response. Additionally, monitoring apoptosis in vitro and in vivo has been shown to be valuable for drug development in order to assess the efficacy of novel therapeutic strategies both in the pre-clinical and clinical setting. Detection of Apoptosing Retinal Cells (DARC) technology is to date the only tool of its kind to have been tested in clinical trials, with other new imaging techniques under investigation in the fields of neuroscience, ophthalmology and drug development. We summarize the transitioning of techniques detecting apoptosis from bench to bedside, along with the future possibilities they encase.

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