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BACKGROUND: This study aimed to explore whether explainable Artificial Intelligence methods can be fruitfully used to improve the medical management of patients suffering from complex diseases, and in particular to predict the death risk in hospitalized patients with SARS-Cov-2 based on admission data. METHODS: This work is based on an observational ambispective study that comprised patients older than 18 years with a positive SARS-Cov-2 diagnosis that were admitted to the hospital Azienda Ospedaliera "SS Antonio e Biagio e Cesare Arrigo", Alessandria, Italy from February, 24 2020 to May, 31 2021, and that completed the disease treatment inside this structure. The patients'medical history, demographic, epidemiologic and clinical data were collected from the electronic medical records system and paper based medical records, entered and managed by the Clinical Study Coordinators using the REDCap electronic data capture tool patient chart. The dataset was used to train and to evaluate predictive ML models. RESULTS: We overall trained, analysed and evaluated 19 predictive models (both supervised and unsupervised) on data from 824 patients described by 43 features. We focused our attention on models that provide an explanation that is understandable and directly usable by domain experts, and compared the results against other classical machine learning approaches. Among the former, JRIP showed the best performance in 10-fold cross validation, and the best average performance in a further validation test using a different patient dataset from the beginning of the third COVID-19 wave. Moreover, JRIP showed comparable performances with other approaches that do not provide a clear and/or understandable explanation. CONCLUSIONS: The ML supervised models showed to correctly discern between low-risk and high-risk patients, even when the medical disease context is complex and the list of features is limited to information available at admission time. Furthermore, the models demonstrated to reasonably perform on a dataset from the third COVID-19 wave that was not used in the training phase. Overall, these results are remarkable: (i) from a medical point of view, these models evaluate good predictions despite the possible differences entitled with different care protocols and the possible influence of other viral variants (i.e. delta variant); (ii) from the organizational point of view, they could be used to optimize the management of health-care path at the admission time.
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COVID-19 , Humanos , COVID-19/diagnóstico , SARS-CoV-2 , Teste para COVID-19 , Inteligência Artificial , Aprendizado de Máquina , Estudos RetrospectivosRESUMO
BACKGROUND: Nowadays, the inception of computer modeling and simulation in life science is a matter of fact. This is one of the reasons why regulatory authorities are open in considering in silico trials evidence for the assessment of safeness and efficacy of medicinal products. In this context, mechanistic Agent-Based Models are increasingly used. Unfortunately, there is still a lack of consensus in the verification assessment of Agent-Based Models for regulatory approval needs. VV&UQ is an ASME standard specifically suited for the verification, validation, and uncertainty quantification of medical devices. However, it can also be adapted for the verification assessment of in silico trials for medicinal products. RESULTS: Here, we propose a set of automatic tools for the mechanistic Agent-Based Model verification assessment. As a working example, we applied the verification framework to an Agent-Based Model in silico trial used in the COVID-19 context. CONCLUSIONS: Using the described verification computational workflow allows researchers and practitioners to easily perform verification steps to prove Agent-Based Models robustness and correctness that provide strong evidence for further regulatory requirements.
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COVID-19 , Simulação por Computador , Consenso , Coleta de Dados , Humanos , IncertezaRESUMO
Agent-based models (ABMs) are a powerful class of computational models widely used to simulate complex phenomena in many different application areas. However, one of the most critical aspects, poorly investigated in the literature, regards an important step of the model credibility assessment: solution verification. This study overcomes this limitation by proposing a general verification framework for ABMs that aims at evaluating the numerical errors associated with the model. A step-by-step procedure, which consists of two main verification studies (deterministic and stochastic model verification), is described in detail and applied to a specific mission critical scenario: the quantification of the numerical approximation error for UISS-TB, an ABM of the human immune system developed to predict the progression of pulmonary tuberculosis. Results provide indications on the possibility to use the proposed model verification workflow to systematically identify and quantify numerical approximation errors associated with UISS-TB and, in general, with any other ABMs.
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Tuberculose , HumanosRESUMO
BACKGROUND: Multiple Sclerosis (MS) represents nowadays in Europe the leading cause of non-traumatic disabilities in young adults, with more than 700,000 EU cases. Although huge strides have been made over the years, MS etiology remains partially unknown. Furthermore, the presence of various endogenous and exogenous factors can greatly influence the immune response of different individuals, making it difficult to study and understand the disease. This becomes more evident in a personalized-fashion when medical doctors have to choose the best therapy for patient well-being. In this optics, the use of stochastic models, capable of taking into consideration all the fluctuations due to unknown factors and individual variability, is highly advisable. RESULTS: We propose a new model to study the immune response in relapsing remitting MS (RRMS), the most common form of MS that is characterized by alternate episodes of symptom exacerbation (relapses) with periods of disease stability (remission). In this new model, both the peripheral lymph node/blood vessel and the central nervous system are explicitly represented. The model was created and analysed using Epimod, our recently developed general framework for modeling complex biological systems. Then the effectiveness of our model was shown by modeling the complex immunological mechanisms characterizing RRMS during its course and under the DAC administration. CONCLUSIONS: Simulation results have proven the ability of the model to reproduce in silico the immune T cell balance characterizing RRMS course and the DAC effects. Furthermore, they confirmed the importance of a timely intervention on the disease course.
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Sistema Imunitário/fisiologia , Modelos Biológicos , Esclerose Múltipla Recidivante-Remitente/imunologia , Interface Usuário-Computador , Algoritmos , Daclizumabe/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/patologia , Processos EstocásticosRESUMO
BACKGROUND: In 2018, about 10 million people were found infected by tuberculosis, with approximately 1.2 million deaths worldwide. Despite these numbers have been relatively stable in recent years, tuberculosis is still considered one of the top 10 deadliest diseases worldwide. Over the years, Mycobacterium tuberculosis has developed a form of resistance to first-line tuberculosis treatments, specifically to isoniazid, leading to multi-drug-resistant tuberculosis. In this context, the EU and Indian DBT funded project STriTuVaD-In Silico Trial for Tuberculosis Vaccine Development-is supporting the identification of new interventional strategies against tuberculosis thanks to the use of Universal Immune System Simulator (UISS), a computational framework capable of predicting the immunity induced by specific drugs such as therapeutic vaccines and antibiotics. RESULTS: Here, we present how UISS accurately simulates tuberculosis dynamics and its interaction within the immune system, and how it predicts the efficacy of the combined action of isoniazid and RUTI vaccine in a specific digital population cohort. Specifically, we simulated two groups of 100 digital patients. The first group was treated with isoniazid only, while the second one was treated with the combination of RUTI vaccine and isoniazid, according to the dosage strategy described in the clinical trial design. UISS-TB shows to be in good agreement with clinical trial results suggesting that RUTI vaccine may favor a partial recover of infected lung tissue. CONCLUSIONS: In silico trials innovations represent a powerful pipeline for the prediction of the effects of specific therapeutic strategies and related clinical outcomes. Here, we present a further step in UISS framework implementation. Specifically, we found that the simulated mechanism of action of RUTI and INH are in good alignment with the results coming from past clinical phase IIa trials.
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Biologia Computacional/métodos , Tuberculose/imunologia , Interface Usuário-Computador , Antituberculosos/uso terapêutico , Sistema Imunitário/imunologia , Isoniazida/uso terapêutico , Resultado do Tratamento , Tuberculose/tratamento farmacológico , Tuberculose/metabolismo , Tuberculose/prevenção & controle , Vacinas contra a Tuberculose/imunologiaRESUMO
BACKGROUND: SARS-CoV-2 is a severe respiratory infection that infects humans. Its outburst entitled it as a pandemic emergence. To get a grip on this outbreak, specific preventive and therapeutic interventions are urgently needed. It must be said that, until now, there are no existing vaccines for coronaviruses. To promptly and rapidly respond to pandemic events, the application of in silico trials can be used for designing and testing medicines against SARS-CoV-2 and speed-up the vaccine discovery pipeline, predicting any therapeutic failure and minimizing undesired effects. RESULTS: We present an in silico platform that showed to be in very good agreement with the latest literature in predicting SARS-CoV-2 dynamics and related immune system host response. Moreover, it has been used to predict the outcome of one of the latest suggested approach to design an effective vaccine, based on monoclonal antibody. Universal Immune System Simulator (UISS) in silico platform is potentially ready to be used as an in silico trial platform to predict the outcome of vaccination strategy against SARS-CoV-2. CONCLUSIONS: In silico trials are showing to be powerful weapons in predicting immune responses of potential candidate vaccines. Here, UISS has been extended to be used as an in silico trial platform to speed-up and drive the discovery pipeline of vaccine against SARS-CoV-2.
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Vacinas contra COVID-19 , COVID-19 , Modelos Imunológicos , SARS-CoV-2/imunologia , Software , COVID-19/imunologia , COVID-19/prevenção & controle , Biologia Computacional/métodos , Simulação por Computador , HumanosRESUMO
BACKGROUND: The STriTuVaD project, funded by Horizon 2020, aims to test through a Phase IIb clinical trial one of the most advanced therapeutic vaccines against tuberculosis. As part of this initiative, we have developed a strategy for generating in silico patients consistent with target population characteristics, which can then be used in combination with in vivo data on an augmented clinical trial. RESULTS: One of the most challenging tasks for using virtual patients is developing a methodology to reproduce biological diversity of the target population, ie, providing an appropriate strategy for generating libraries of digital patients. This has been achieved through the creation of the initial immune system repertoire in a stochastic way, and through the identification of a vector of features that combines both biological and pathophysiological parameters that personalise the digital patient to reproduce the physiology and the pathophysiology of the subject. CONCLUSIONS: We propose a sequential approach to sampling from the joint features population distribution in order to create a cohort of virtual patients with some specific characteristics, resembling the recruitment process for the target clinical trial, which then can be used for augmenting the information from the physical the trial to help reduce its size and duration.
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Biologia Computacional/métodos , Tuberculose/imunologia , Interface Usuário-Computador , Anticorpos Antibacterianos/metabolismo , Sistema Imunitário/fisiologia , Tuberculose/metabolismo , Tuberculose/patologia , Tuberculose/prevenção & controleRESUMO
INTRODUCTION: A new body of evidence depicts the applications of artificial intelligence and systems biology in vaccine design and development. The combination of both approaches shall revolutionize healthcare, accelerating clinical trial processes and reducing the costs and time involved in drug research and development. AREAS COVERED: This review explores the basics of artificial intelligence and systems biology approaches in the vaccine development pipeline. The topics include a detailed description of epitope prediction tools for designing epitope-based vaccines and agent-based models for immune system response prediction, along with a focus on their potentiality to facilitate clinical trial phases. EXPERT OPINION: Artificial intelligence and systems biology offer the opportunity to avoid the inefficiencies and failures that arise in the classical vaccine development pipeline. One promising solution is the combination of both methodologies in a multiscale perspective through an accurate pipeline. We are entering an 'in silico era' in which scientific partnerships, including a more and more increasing creation of an 'ecosystem' of collaboration and multidisciplinary approach, are relevant for addressing the long and risky road of vaccine discovery and development. In this context, regulatory guidance should be developed to qualify the in silico trials as evidence for intelligent vaccine development.
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Inteligência Artificial , Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Desenvolvimento de Medicamentos/métodos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Biologia de Sistemas , Vacinas Virais/normas , COVID-19 , Vacinas contra COVID-19 , Infecções por Coronavirus/terapia , Humanos , Pneumonia Viral/terapia , SARS-CoV-2 , Vacinas Virais/uso terapêuticoRESUMO
As of today, 20 disease-modifying drugs (DMDs) have been approved for the treatment of relapsing multiple sclerosis (MS) and, based on their efficacy, they can be grouped into moderate-efficacy DMDs and high-efficacy DMDs. The choice of the drug mostly relies on the judgment and experience of neurologists and the evaluation of the therapeutic response can only be obtained by monitoring the clinical and magnetic resonance imaging (MRI) status during follow up. In an era where therapies are focused on personalization, this study aims to develop a modeling infrastructure to predict the evolution of relapsing MS and the response to treatments. We built a computational modeling infrastructure named Universal Immune System Simulator (UISS), which can simulate the main features and dynamics of the immune system activities. We extended UISS to simulate all the underlying MS pathogenesis and its interaction with the host immune system. This simulator is a multi-scale, multi-organ, agent-based simulator with an attached module capable of simulating the dynamics of specific biological pathways at the molecular level. We simulated six MS patients with different relapsing-remitting courses. These patients were characterized based on their age, sex, presence of oligoclonal bands, therapy, and MRI lesion load at the onset. The simulator framework is made freely available and can be used following the links provided in the availability section. Even though the model can be further personalized employing immunological parameters and genetic information, we generated a few simulation scenarios for each patient based on the available data. Among these simulations, it was possible to find the scenarios that realistically matched the real clinical and MRI history. Moreover, for two patients, the simulator anticipated the timing of subsequent relapses, which occurred, suggesting that UISS may have the potential to assist MS specialists in predicting the course of the disease and the response to treatment.
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Simulação por Computador/tendências , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/terapia , Progressão da Doença , Feminino , Humanos , Masculino , Esclerose Múltipla Recidivante-Remitente/patologiaRESUMO
Herein, we assess the gene expression changes activated in thyroid tumors through a computational approach, using the MapReduce algorithm. Through this predictive analysis, we identified the TfR1 gene as a critical mediator of thyroid tumor progression. Then, we investigated the effect of TfR1 gene silencing through small interfering RNA (siRNA) in the expression of extracellular signal-regulated kinase 1/2 (Erk1/2) pathway and c-Myc in human differentiated follicular and undifferentiated anaplastic thyroid cancer. The expression levels of cyclin D1, p53, and p27, proteins involved in cell cycle progression, were also evaluated. The effect of TfR1 gene silencing through siRNA on the apoptotic pathway activation was also tested. Computational prediction and in vitro studies demonstrate that TfR1 plays a key role in thyroid cancer and that its downregulation was able to inhibit the ERK pathway, reducing also c-Myc expression, which blocks the cell cycle and activates the apoptotic pathway. We demonstrate that TfR1 plays a crucial role for a rapid and transient activation of the ERK signaling pathway, which induces a deregulation of genes involved in the aberrant accumulation of intracellular free iron and in drug resistance. We also suggest that TfR1 might represent an important target for thyroid cancer therapy.
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Different research communities have developed various approaches to assess the credibility of predictive models. Each approach usually works well for a specific type of model, and under some epistemic conditions that are normally satisfied within that specific research domain. Some regulatory agencies recently started to consider evidences of safety and efficacy on new medical products obtained using computer modelling and simulation (which is referred to as In Silico Trials); this has raised the attention in the computational medicine research community on the regulatory science aspects of this emerging discipline. But this poses a foundational problem: in the domain of biomedical research the use of computer modelling is relatively recent, without a widely accepted epistemic framing for model credibility. Also, because of the inherent complexity of living organisms, biomedical modellers tend to use a variety of modelling methods, sometimes mixing them in the solution of a single problem. In such context merely adopting credibility approaches developed within other research communities might not be appropriate. In this paper we propose a theoretical framing for assessing the credibility of a predictive models for In Silico Trials, which accounts for the epistemic specificity of this research field and is general enough to be used for different type of models.
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Pesquisa Biomédica/normas , Simulação por Computador/normas , Pesquisa Biomédica/métodos , Humanos , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Multiple Sclerosis (MS) is an immune-mediated inflammatory disease of the Central Nervous System (CNS) which damages the myelin sheath enveloping nerve cells thus causing severe physical disability in patients. Relapsing Remitting Multiple Sclerosis (RRMS) is one of the most common form of MS in adults and is characterized by a series of neurologic symptoms, followed by periods of remission. Recently, many treatments were proposed and studied to contrast the RRMS progression. Among these drugs, daclizumab (commercial name Zinbryta), an antibody tailored against the Interleukin-2 receptor of T cells, exhibited promising results, but its efficacy was accompanied by an increased frequency of serious adverse events. Manifested side effects consisted of infections, encephalitis, and liver damages. Therefore daclizumab has been withdrawn from the market worldwide. Another interesting case of RRMS regards its progression in pregnant women where a smaller incidence of relapses until the delivery has been observed. RESULTS: In this paper we propose a new methodology for studying RRMS, which we implemented in GreatSPN, a state-of-the-art open-source suite for modelling and analyzing complex systems through the Petri Net (PN) formalism. This methodology exploits: (a) an extended Colored PN formalism to provide a compact graphical description of the system and to automatically derive a set of ODEs encoding the system dynamics and (b) the Latin Hypercube Sampling with PRCC index to calibrate ODE parameters for reproducing the real behaviours in healthy and MS subjects.To show the effectiveness of such methodology a model of RRMS has been constructed and studied. Two different scenarios of RRMS were thus considered. In the former scenario the effect of the daclizumab administration is investigated, while in the latter one RRMS was studied in pregnant women. CONCLUSIONS: We propose a new computational methodology to study RRMS disease. Moreover, we show that model generated and calibrated according to this methodology is able to reproduce the expected behaviours.
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Simulação por Computador , Esclerose Múltipla Recidivante-Remitente , Biologia Computacional , Progressão da Doença , Feminino , Humanos , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Gravidez , RecidivaRESUMO
BACKGROUND: Tuberculosis (TB) represents a worldwide cause of mortality (it infects one third of the world's population) affecting mostly developing countries, including India, and recently also developed ones due to the increased mobility of the world population and the evolution of different new bacterial strains capable to provoke multi-drug resistance phenomena. Currently, antitubercular drugs are unable to eradicate subpopulations of Mycobacterium tuberculosis (MTB) bacilli and therapeutic vaccinations have been postulated to overcome some of the critical issues related to the increase of drug-resistant forms and the difficult clinical and public health management of tuberculosis patients. The Horizon 2020 EC funded project "In Silico Trial for Tuberculosis Vaccine Development" (STriTuVaD) to support the identification of new therapeutic interventions against tuberculosis through novel in silico modelling of human immune responses to disease and vaccines, thereby drastically reduce the cost of clinical trials in this critical sector of public healthcare. RESULTS: We present the application of the Universal Immune System Simulator (UISS) computational modeling infrastructure as a disease model for TB. The model is capable to simulate the main features and dynamics of the immune system activities i.e., the artificial immunity induced by RUTI® vaccine, a polyantigenic liposomal therapeutic vaccine made of fragments of Mycobacterium tuberculosis cells (FCMtb). Based on the available data coming from phase II Clinical Trial in subjects with latent tuberculosis infection treated with RUTI® and isoniazid, we generated simulation scenarios through validated data in order to tune UISS accordingly to STriTuVaD objectives. The first case simulates the establishment of MTB latent chronic infection with some typical granuloma formation; the second scenario deals with a reactivation phase during latent chronic infection; the third represents the latent chronic disease infection scenario during RUTI® vaccine administration. CONCLUSIONS: The application of this computational modeling strategy helpfully contributes to simulate those mechanisms involved in the early stages and in the progression of tuberculosis infection and to predict how specific therapeutical strategies will act in this scenario. In view of these results, UISS owns the capacity to open the door for a prompt integration of in silico methods within the pipeline of clinical trials, supporting and guiding the testing of treatments in patients affected by tuberculosis.
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Simulação por Computador , Vacinas contra a Tuberculose/imunologia , Tuberculose/imunologia , Biologia Computacional , Humanos , Mycobacterium tuberculosis/imunologia , SoftwareRESUMO
BACKGROUND: In recent years, the study of immune response behaviour using bottom up approach, Agent Based Modeling (ABM), has attracted considerable efforts. The ABM approach is a very common technique in the biological domain due to high demand for a large scale analysis tools for the collection and interpretation of information to solve biological problems. Simulating massive multi-agent systems (i.e. simulations containing a large number of agents/entities) requires major computational effort which is only achievable through the use of parallel computing approaches. RESULTS: This paper explores different approaches to parallelising the key component of biological and immune system models within an ABM model: pairwise interactions. The focus of this paper is on the performance and algorithmic design choices of cell interactions in continuous and discrete space where agents/entities are competing to interact with one another within a parallel environment. CONCLUSIONS: Our performance results demonstrate the applicability of these methods to a broader class of biological systems exhibiting typical cell to cell interactions. The advantage and disadvantage of each implementation is discussed showing each can be used as the basis for developing complete immune system models on parallel hardware.
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Simulação por Computador , Sistema Imunitário , Modelos Imunológicos , Algoritmos , Humanos , Biologia de SistemasRESUMO
The 2nd Computational Methods for the Immune System function Workshop has been held in Madrid in conjunction with the IEEE International Conference on Bioinformatics and Biomedicine (BIBM 2018) in Madrid, Spain, from December 3 to 6, 2018. The workshop has been obtained 100% more submissions in respect to the first edition, highlighting a growing interest for the treated topics. The best papers (9) have been selected for extension in this special issue, with themes about immune system and disease simulation, computer-aided design of novel candidate vaccines, methods for the analysis of immune system involved diseases based on statistical methods, meta-heuristics and game theory, and modelling strategies for improving the simulation of the immune system dynamics.
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Biologia Computacional , Simulação por Computador , Sistema Imunitário , HumanosRESUMO
BACKGROUND: DNA methylation is an epigenetic mechanism of genomic regulation involved in the maintenance of homeostatic balance. Dysregulation of DNA methylation status is one of the driver alterations occurring in neoplastic transformation and cancer progression. The identification of methylation hotspots associated to gene dysregulation may contribute to discover new prognostic and diagnostic biomarkers, as well as, new therapeutic targets. RESULTS: We present EpiMethEx (Epigenetic Methylation and Expression), a R package to perform a large-scale integrated analysis by cyclic correlation analyses between methylation and gene expression data. For each gene, samples are segmented according to the expression levels to select genes that are differentially expressed. This stratification allows to identify CG methylation probesets modulated among gene-stratified samples. Subsequently, the methylation probesets are grouped by their relative position in gene sequence to identify wide genomic methylation events statically related to genetic modulation. CONCLUSIONS: The beta-test study showed that the global methylation analysis was in agreement with scientific literature. In particular, this analysis revealed a negative association between promoter hypomethylation and overexpression in a wide number of genes. Less frequently, this overexpression was sustained by intragenic hypermethylation events.
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Biologia Computacional/métodos , Metilação de DNA/genética , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Software , Ilhas de CpG/genética , Humanos , Melanoma/genéticaRESUMO
MOTIVATION: Val600Glu (V600E) mutation is the most common BRAF mutation detected in thyroid cancer. Hence, recent research efforts have been performed trying to explore several inhibitors of the V600E mutation-containing BRAF kinase as potential therapeutic options in thyroid cancer refractory to standard interventions. Among them, vemurafenib is a selective BRAF inhibitor approved by Food and Drug Administration for clinical practice. Unfortunately, vemurafenib often displays limited efficacy in poorly differentiated and anaplastic thyroid carcinomas probably because of intrinsic and/or acquired resistance mechanisms. In this view, cancer stem cells (CSCs) may represent a possible mechanism of resistance to vemurafenib, due to their self-renewal and chemo resistance properties. RESULTS: We present a computational framework to suggest new potential targets to overcome drug resistance. It has been validated with an in vitro model based upon a spheroid-forming method able to isolate thyroid CSCs that may mimic resistance to vemurafenib. Indeed, vemurafenib did not inhibit cell proliferation of BRAF V600E thyroid CSCs, but rather stimulated cell proliferation along with a paradoxical over-activation of ERK and AKT pathways. The computational model identified a fundamental role of mitogen-activated protein kinase 8 (MAP3K8), a serine/threonine kinase expressed in thyroid CSCs, in mediating this drug resistance. To confirm model prediction, we set a suitable in vitro experiment revealing that the treatment with MAP3K8 inhibitor restored the effect of vemurafenib in terms of both DNA fragmentation and poly (ADP-ribose) polymerase cleavage (apoptosis) in thyroid CSCs. Moreover, MAP3K8 expression levels may be a useful marker to predict the response to vemurafenib. AVAILABILITY AND IMPLEMENTATION: The model is available in GitHub repository visiting the following URL: https://github.com/francescopappalardo/MAP3K8-Thyroid-Spheres-V-3.0. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Células-Tronco Neoplásicas , Antineoplásicos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Indóis , Proteína Quinase 8 Ativada por Mitógeno , Mutação , Proteínas Proto-Oncogênicas B-raf , Sulfonamidas , VemurafenibRESUMO
Personalized target therapies represent one of the possible treatment strategies to fight the ongoing battle against cancer. New treatment interventions are still needed for an effective and successful cancer therapy. In this scenario, we simulated and analyzed the dynamics of BRAF V600E melanoma patients treated with BRAF inhibitors in order to find potentially interesting targets that may make standard treatments more effective in particularly aggressive tumors that may not respond to selective inhibitor drugs. To this aim, we developed a continuous Petri Net model that simulates fundamental signalling cascades involved in melanoma development, such as MAPK and PI3K/AKT, in order to deeply analyze these complex kinase cascades and predict new crucial nodes involved in melanomagenesis. The model pointed out that some microRNAs, like hsa-mir-132, downregulates expression levels of p120RasGAP: under high concentrations of p120RasGAP, MAPK pathway activation is significantly decreased and consequently also PI3K/PDK1/AKT activation. Furthermore, our analysis carried out through the Genomic Data Commons (GDC) Data Portal shows the evidence that hsa-mir-132 is significantly associated with clinical outcome in melanoma cancer genomic data sets of BRAF-mutated patients. In conclusion, targeting miRNAs through antisense oligonucleotides technology may suggest the way to enhance the action of BRAF-inhibitors.
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Biologia Computacional/métodos , Melanoma/genética , MicroRNAs/genética , Neoplasias Cutâneas/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Modelos Genéticos , Transdução de Sinais/genéticaRESUMO
BACKGROUND: Human papillomavirus infection is a global social burden that, every year, leads to thousands new diagnosis of cancer. The introduction of a protocol of immunization, with Gardasil and Cervarix vaccines, has radically changed the way this infection easily spreads among people. Even though vaccination is only preventive and not therapeutic, it is a strong tool capable to avoid the consequences that this pathogen could cause. Gardasil vaccine is not free from side effects and the duration of immunity is not always well determined. This work aim to enhance the effects of the vaccination by using a new class of adjuvants and a different administration protocol. Due to their minimum side effects, their easy extraction, their low production costs and their proven immune stimulating activity, citrus-derived molecules are valid candidates to be administered as adjuvants in a vaccine formulation against Hpv. RESULTS: With the aim to get a stronger immune response against Hpv infection we built an in silico model that delivers a way to predict the best adjuvants and the optimal means of administration to obtain such a goal. Simulations envisaged that the use of Neohesperidin elicited a strong immune response that was then validated in vivo. CONCLUSIONS: We built up a computational infrastructure made by a virtual screening approach able to preselect promising citrus derived compounds, and by an agent based model that reproduces HPV dynamics subject to vaccine stimulation. This integrated methodology was able to predict the best protocol that confers a very good immune response against HPV infection. We finally tested the in silico results through in vivo experiments on mice, finding good agreement.
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Adjuvantes Farmacêuticos/uso terapêutico , Citrus/química , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/tratamento farmacológico , Vacinas contra Papillomavirus/uso terapêutico , Vacinação/métodos , Adjuvantes Farmacêuticos/farmacologia , Animais , Feminino , Humanos , Programas de Rastreamento , Vacinas contra Papillomavirus/farmacologiaRESUMO
MOTIVATION: Vaccines represent the most effective and cost-efficient weapons against a wide range of diseases. Nowadays new generation vaccines based on subunit antigens reduce adverse effects in high risk individuals. However, vaccine antigens are often poor immunogens when administered alone. Adjuvants represent a good strategy to overcome such hurdles, indeed they are able to: enhance the immune response; allow antigens sparing; accelerate the specific immune response; and increase vaccine efficacy in vulnerable groups such as newborns, elderly or immuno-compromised people. However, due to safety concerns and adverse reactions, there are only a few adjuvants approved for use in humans. Moreover, in practice current adjuvants sometimes fail to confer adequate stimulation. Hence, there is an imperative need to develop novel adjuvants that overcome the limitations of the currently available licensed adjuvants. RESULTS: We developed a computational framework that provides a complete pipeline capable of predicting the best citrus-derived adjuvants for enhancing the immune system response using, as a target disease model, influenza A infection. In silico simulations suggested a good immune efficacy of specific citrus-derived adjuvant (Beta Sitosterol) that was then confirmed in vivoAvailability: The model is available visiting the following URL: http://vaima.dmi.unict.it/AdjSim CONTACT: francesco.pappalardo@unict.it; fp@francescopappalardo.net.