scholarly journals Multiscale Modelling and Analysis of Tumour Growth and Treatment Strategies

2021 ◽  
Author(s):  
◽  
Sara Hamis
Keyword(s):  
Tumour Growth ◽  
Treatment Strategies ◽  
Sensitivity Analyses ◽  
Mathematical Framework ◽  
Cancer Therapies ◽  
Agent Based ◽  
Damage Repair ◽  
Novel Drugs ◽  
Parameter Perturbations ◽  
Treatment Responses

A multiscale, agent-based mathematical framework is here used to capture the multiscale nature of solid tumours. Tumour dynamics and treatment responses are modelled and simulated in silico. Details regarding cell cy-cle progression, tumour growth and oxygen distribution are included in the mathematical framework. Treatment responses to conventional anti-cancer therapies, such as chemotherapy and radiotherapy, as well as to more novel drugs, such as hypoxia-activated prodrugs and DNA-damage repair inhibit-ing drugs, are studied. Uncertainty and sensitivity analyses techniques are discussed in order to mitigate model uncertainty and interpret model sen-sitivity to parameter perturbations. This thesis furthermore discusses the role of mathematical modelling in current cancer research.

scholarly journals PARP Power: A Structural Perspective on PARP1, PARP2, and PARP3 in DNA Damage Repair and Nucleosome Remodelling

2021 ◽  
Vol 22 (10) ◽  
pp. 5112
Author(s):  
Lotte van Beek ◽  
Éilís McClay ◽  
Saleha Patel ◽  
Marianne Schimpl ◽  
Laura Spagnolo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Binding ◽  
Parp Inhibitors ◽  
Covalent Modification ◽  
Activation Mechanism ◽  
Cancer Therapies ◽  
Damage Repair ◽  
Complementary Role ◽  
Functional Understanding

Poly (ADP-ribose) polymerases (PARP) 1-3 are well-known multi-domain enzymes, catalysing the covalent modification of proteins, DNA, and themselves. They attach mono- or poly-ADP-ribose to targets using NAD+ as a substrate. Poly-ADP-ribosylation (PARylation) is central to the important functions of PARP enzymes in the DNA damage response and nucleosome remodelling. Activation of PARP happens through DNA binding via zinc fingers and/or the WGR domain. Modulation of their activity using PARP inhibitors occupying the NAD+ binding site has proven successful in cancer therapies. For decades, studies set out to elucidate their full-length molecular structure and activation mechanism. In the last five years, significant advances have progressed the structural and functional understanding of PARP1-3, such as understanding allosteric activation via inter-domain contacts, how PARP senses damaged DNA in the crowded nucleus, and the complementary role of histone PARylation factor 1 in modulating the active site of PARP. Here, we review these advances together with the versatility of PARP domains involved in DNA binding, the targets and shape of PARylation and the role of PARPs in nucleosome remodelling.

scholarly journals Public health impact of delaying second dose of BNT162b2 or mRNA-1273 covid-19 vaccine: simulation agent based modeling study

BMJ ◽  
2021 ◽  
pp. n1087
Author(s):  
Santiago Romero-Brufau ◽  
Ayush Chopra ◽  
Alex J Ryu ◽  
Esma Gel ◽  
Ramesh Raskar ◽  
...  
Keyword(s):  
Hospital Admissions ◽  
Vaccination Strategy ◽  
Population Based ◽  
Agent Based Modeling ◽  
Sensitivity Analyses ◽  
Agent Based ◽  
Cumulative Mortality ◽  
Vaccination Rates ◽  
Dose Strategy ◽  
Modeling Study

AbstractObjectiveTo estimate population health outcomes with delayed second dose versus standard schedule of SARS-CoV-2 mRNA vaccination.DesignSimulation agent based modeling study.SettingSimulated population based on real world US county.ParticipantsThe simulation included 100 000 agents, with a representative distribution of demographics and occupations. Networks of contacts were established to simulate potentially infectious interactions though occupation, household, and random interactions.InterventionsSimulation of standard covid-19 vaccination versus delayed second dose vaccination prioritizing the first dose. The simulation runs were replicated 10 times. Sensitivity analyses included first dose vaccine efficacy of 50%, 60%, 70%, 80%, and 90% after day 12 post-vaccination; vaccination rate of 0.1%, 0.3%, and 1% of population per day; assuming the vaccine prevents only symptoms but not asymptomatic spread (that is, non-sterilizing vaccine); and an alternative vaccination strategy that implements delayed second dose for people under 65 years of age, but not until all those above this age have been vaccinated.Main outcome measuresCumulative covid-19 mortality, cumulative SARS-CoV-2 infections, and cumulative hospital admissions due to covid-19 over 180 days.ResultsOver all simulation replications, the median cumulative mortality per 100 000 for standard dosing versus delayed second dose was 226 v 179, 233 v 207, and 235 v 236 for 90%, 80%, and 70% first dose efficacy, respectively. The delayed second dose strategy was optimal for vaccine efficacies at or above 80% and vaccination rates at or below 0.3% of the population per day, under both sterilizing and non-sterilizing vaccine assumptions, resulting in absolute cumulative mortality reductions between 26 and 47 per 100 000. The delayed second dose strategy for people under 65 performed consistently well under all vaccination rates tested.ConclusionsA delayed second dose vaccination strategy, at least for people aged under 65, could result in reduced cumulative mortality under certain conditions.

scholarly journals Diagnosis, Prevention, Treatment and Surveillance of Anthracycline-Induced Cardiovascular Toxicity in Pediatric Cancer Survivors

Hearts ◽  
2021 ◽  
Vol 2 (1) ◽  
pp. 45-60
Author(s):  
Valerie Curren ◽  
Niti Dham ◽  
Christopher Spurney
Keyword(s):  
Pediatric Cancer ◽  
Systolic Function ◽  
Treatment Strategies ◽  
Significant Risk ◽  
Imaging Biomarkers ◽  
Cancer Therapies ◽  
Cardiovascular Toxicity ◽  
Treatment Protocols ◽  
Mechanisms Of Toxicity ◽  
Pediatric Cancer Survivors

Advances in pediatric cancer therapies have dramatically improved the likelihood of survival. As survivors are aging, however, we are now understanding that treatment carries a significant risk of cardiovascular toxicity, which can develop immediately, or even many years after completing therapy. Anthracycline derivates are some of the most commonly used agents in pediatric oncology treatment protocols, which have a dose-dependent correlation with the development of cardiac toxicity. As we learn more about the mechanisms of toxicity, we are developing prevention strategies, including improvements in surveillance, to improve early diagnosis of heart disease. Current survivorship surveillance protocols often include screening echocardiograms to evaluate systolic function by measuring the ejection fraction or fractional shortening. However, these measurements alone are not enough to capture early myocardial changes. The use of additional imaging biomarkers, serum biomarkers, electrocardiograms, as well as cholesterol and blood pressure screening, are key to the early detection of cardiomyopathy and cardiovascular disease. Medical treatment strategies are the same as those used for heart failure from other causes, but earlier recognition and implementation can lead to improved long term outcomes.

scholarly journals Bioactive compounds from Lactarius deterrimus interfere with the invasive potential of gastric cancer cells

2021 ◽  
Author(s):  
Kamila Król ◽  
Maciej Pudełek ◽  
Gracjana Krzysiek-Mączka ◽  
Mateusz Wierdak ◽  
Bożena Muszyńska ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Bioactive Compounds ◽  
Treatment Strategies ◽  
Cancer Therapies ◽  
Invasive Potential ◽  
Gastric Cancer Cells ◽  
Ags Cells ◽  
Phenolic Fraction ◽  
Atp Production ◽  
Cytoskeleton Rearrangements

Stomach cancer is the 4th most common cancer diagnosed worldwide. Despite intensive research on its etiopathology, its treatment strategies have not changed in the last 50 years. Mushrooms have recently attracted much attention as the source of bioactive compounds that can potentially complement cancer therapies. Here, we extracted a phenolic fraction from Lactarius deterrimus and analyzed its composition and bioactivity against the gastric cancer (AGS) cells. The complexity of L. deterrimus compounds was revealed by an HPLC assay, and was accompanied by cytostatic, cytotoxic and anti-invasive effects of the L. deterrimus extract (LDE). These are illustrated by inhibition of the AGS cells’ proliferation, metabolic activity and motility, and by induction of the cytoskeleton rearrangements. Apparently, these effects are exerted via activation of intracellular oxidative stress and decreased ATP production in AGS cells that could not be compensated by induction of autophagy. Less severe LDE effects were seen on physiology of normal gastric fibroblasts; however, inhibition of their motility indicates that LDE can interfere with gastric cancer development via an effect on stromal cells. Along with the observed synergy of LDE and cisplatin/5-fluorouracil effects on AGS cells, our data show the potential of LDE for supplementation of the gastric cancer therapy.

scholarly journals The Public Health Impact of Delaying a Second Dose of the BNT162b2 or mRNA-1273 COVID-19 Vaccine

2021 ◽  
Author(s):  
Santiago Romero-Brufau ◽  
Ayush Chopra ◽  
Alex J Ryu ◽  
Esma Gel ◽  
Ramesh Raskar ◽  
...  
Keyword(s):  
Vaccination Strategy ◽  
Population Level ◽  
Health Impact ◽  
Vaccination Rate ◽  
Agent Based Modeling ◽  
Sensitivity Analyses ◽  
Agent Based ◽  
Cumulative Mortality ◽  
Vaccination Rates ◽  
The Public

AbstractObjectivesTo estimate population health outcomes under delayedsecond dose versus standard schedule SARS-CoV-2 mRNA vaccination.DesignAgent-based modeling on a simulated population of 100,000 based on a real-world US county. The simulation runs were replicated 10 times. To test the robustness of these findings, simulations were performed under different estimates for single-dose efficacy and vaccine administration rates, and under the possibility that a vaccine prevents only symptoms but not asymptomatic spread.Settingpopulation level simulation.Participants100,000 agents are included in the simulation, with a representative distribution of demographics and occupations. Networks of contacts are established to simulate potentially infectious interactions though occupation, household, and random interactionsInterventionswe simulate standard Covid-19 vaccination, versus delayed-second-dose vaccination prioritizing first dose. Sensitivity analyses include first-dose vaccine efficacy of 70%, 80% and 90% after day 12 post-vaccination; vaccination rate of 0.1%, 0.3%, and 1% of population per day; assuming the vaccine prevents only symptoms but not asymptomatic spread; and an alternative vaccination strategy that implements delayed-second-dose only for those under 65 years of age.Main outcome measurescumulative Covid-19 mortality over 180 days, cumulative infections and hospitalizations.ResultsOver all simulation replications, the median cumulative mortality per 100,000 for standard versus delayed second dose was 226 vs 179; 233 vs 207; and 235 vs 236; for 90%, 80% and 70% first-dose efficacy, respectively. The delayed-second-dose strategy was optimal for vaccine efficacies at or above 80%, and vaccination rates at or below 0.3% population per day, both under sterilizing and non-sterilizing vaccine assumptions, resulting in absolute cumulative mortality reductions between 26 and 47 per 100,000. The delayed-second-dose for those under 65 performed consistently well under all vaccination rates tested.ConclusionsA delayed-second-dose vaccination strategy, at least for those under 65, could result in reduced cumulative mortality under certain conditions.

scholarly journals Quantitative in vivo analyses reveal a complex pharmacogenomic landscape in lung adenocarcinoma

2020 ◽  
Author(s):  
Chuan Li ◽  
Wen-Yang Lin ◽  
Hira Rizvi ◽  
Hongchen Cai ◽  
Christopher D. McFarland ◽  
...  
Keyword(s):  
Cancer Therapies ◽  
Genetic Determinants ◽  
Patient Response ◽  
Large Patient ◽  
Treatment Responses ◽  
Effective Use ◽  
The Relationship ◽  
Robust Statistical Methods ◽  
Therapeutic Responses

Abstract:The lack of knowledge about the relationship between tumor genotypes and therapeutic responses remains one of the most important gaps in enabling the effective use of cancer therapies. Here, we couple a multiplexed and quantitative platform with robust statistical methods to enable pharmacogenomic mapping of lung cancer treatment responses in vivo. We uncover a surprisingly complex map of genotype-specific therapeutic responses, with over 20% of possible interactions showing significant resistance or sensitivity. We validate one of these interactions - the resistance of Keap1 mutant tumors to platinum therapy - using a large patient response dataset. Our results highlight the importance of understanding the genetic determinants of treatment responses in the development of precision therapies and define a strategy to identify such determinants.

scholarly journals Acute Myeloid Leukemia and Acute Promyelocytic Leukemia

Hematology ◽  
2003 ◽  
Vol 2003 (1) ◽  
pp. 82-101 ◽  
Author(s):  
Bob Löwenberg ◽  
James D. Griffin ◽  
Martin S. Tallman
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Promyelocytic Leukemia ◽  
Tyrosine Kinases ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Treatment Strategies ◽  
Promyelocytic Leukemia ◽  
Remission Induction ◽  
Novel Drugs ◽  
Acute Myeloid

Abstract The therapeutic approach to the patient with acute myeloid leukemia (AML) currently evolves toward new frontiers. This is particularly apparent from the entree of high-throughput diagnostic technologies and the identification of prognostic and therapeutic targets, the introduction of therapies in genetically defined subgroups of AML, as well as the influx of investigational approaches and novel drugs into the pipeline of clinical trials that target pathogenetic mechanisms of the disease. In Section I, Dr. Bob Löwenberg reviews current issues in the clinical practice of the management of adults with AML, including those of older age. Dr. Löwenberg describes upcoming possibilities for predicting prognosis in defined subsets by molecular markers and reviews experimental strategies to improve remission induction and postinduction treatment. In Section II, Dr. James Griffin reviews the mechanisms that lead to activation of tyrosine kinases by mutations in AML, the consequences of that activation for the cell, and the opportunities for targeted therapy and discusses some examples of developing novel drugs (tyrosine kinase inhibitors) and their effectiveness in AML (FLT3). In Section III, Dr. Martin Tallman describes the evaluation and management of patients with acute promyelocytic leukemia, a notable example of therapeutic progress in a molecularly defined entity of leukemia. Dr. Tallman focuses on the molecular genetics of APL, current curative treatment strategies and approaches for patients with relapsed and refractory disease. In addition, areas of controversy regarding treatment are addressed.

scholarly journals The effect of CELLFOODTM on radiotherapy or combined chemoradiotherapy: preclinical evidence

2019 ◽  
Vol 11 ◽  
pp. 175883591987834
Author(s):  
Barbara Nuvoli ◽  
Bruno Amadio ◽  
Giancarlo Cortese ◽  
Serena Benedetti ◽  
Barbara Antoniani ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumour Growth ◽  
Human Cancer ◽  
Combined Treatment ◽  
Treatment Strategies ◽  
Phosphoglycerate Kinase ◽  
Immunohistochemical Analysis ◽  
Chemotherapy Treatment ◽  
Human Cancer Cell Lines

Background: Based on previous observations that the nutraceutical CELLFOOD™ (CF), the ‘physiological modulator’ that aimed to make oxygen available ‘on demand’, inhibits the growth of cancer cells, this study was designed to investigate the role of CF in the regulation of hypoxia-inducible factor 1 alpha (HIF1α) and its correlated proteins, phosphoglycerate kinase 1 and vascular endothelial growth factor. Our idea was that CF, acting on HIF1α, in combination with current anticancer therapies could improve their effectiveness. Methods: To evaluate the effect of CF in association with radiotherapy and chemotherapy, different human cancer cell lines and mice with mesothelioma were analysed by tumour growth, clonogenic assay, western blot and immunohistochemical analysis. Results: CF in combination with radiation with or without cisplatin increases the death rate of cancer cells. In vivo, 70% of mice treated with CF before the mesothelioma graft did not show any tumour growth, indicating a possible preventive effect of CF. Moreover, in mouse mesothelioma xenografts, CF improves the effect of radiotherapy also in combination with chemotherapy treatment. Immunohistochemical analysis of tumour explants showed that HIF1α expression was reduced by the combination of CF and radiotherapy treatment and even more by the combination of CF and radiotherapy and chemotherapy treatment. Mechanistically, CF increases the fraction of oxygenated cells, making the radiotherapy more effective with a greater production of reactive oxygen species (ROS) that in turn, reduce the HIF1α expression. This effect is amplified by further increase in ROS from chemotherapy. Conclusions: Collectively, results from preclinical trials suggest that CF could be a useful intervention to improve the efficacy of radiotherapy or combined treatment strategies and could be a promising treatment modality to counteract cancer.

scholarly journals Mathematically modelling inflammation as a promoter of tumour growth

2020 ◽  
Vol 37 (4) ◽  
pp. 491-514 ◽  
Author(s):  
Kathleen P Wilkie ◽  
Farjana Aktar
Keyword(s):  
Experimental Data ◽  
Growth Rate ◽  
Mouse Model ◽  
Tumour Growth ◽  
Surgical Removal ◽  
Cancer Therapies ◽  
Tumour Control ◽  
Small Tumour ◽  
Metastatic Burden ◽  
Anti Inflammatory

Abstract Inflammation is now known to play a significant role in tumour growth and progression. It is also difficult to adequately quantify systemic inflammation and the resulting localized effects in cancer. Here, we use experimental data to infer the possible contributions of inflammation in a mouse model of cancer. The model is validated by predicting tumour growth under anti-inflammatory treatments, and combination cancer therapies are explored. We then extend the model to consider simultaneous tumour implants at two distinct sites, which experimentally was shown to result in one large and one small tumour. We use this model to examine the role inflammation may play in the growth rate separation. Finally, we use this predictive two-tumour model to explore implications of inflammation on metastases, surgical removal of the primary and adjuvant anti-inflammatory treatments. This work suggests that improved tumour control can be obtained by targeting both the cancer and host, through anti-inflammatory treatments, including reduced metastatic burden post-surgical removal of primary tumours.

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