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The flexibility of NiTi based endodontic files is improved by heat treatment, leading to lower risk of failure, ledges, and canal transportation during the preparation of curved root canals. The aim of this study is to investigate and clearly highlight the influence of every parameter of heat treatment on the flexibility of NiTi wires and thus of endodontic instruments. A full factorial Design of Experiment (DoE) and a designed bending-torsion bench following the ISO 3630-1 standard were used for this investigation. Temperature, holding time, and cooling method were selected as contributing factors, while maximum bending moment, hysteresis size, and stiffness during martensitic transformation were selected as outputs. Regression analysis was performed to estimate the relationship between contributing and output variables to assess how the experimentation fits with the model. The experimental results showed that wires heated at 425 °C for 30 min are more flexible. Moreover, heat treatment temperature is the most critical factor influencing the flexibility and hysteresis size of the NiTi wire followed by the holding time, while the cooling method has a negligible effect. The regression analysis showed that the model is effective at predicting the relationship between contributing factors, bending moment response, and hysteresis size.
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OBJECTIVE: Radiotherapy (RT) against head and neck squamous cell carcinomas (HNSCC) may lead to severe toxicity in 30-40% of patients. The normal tissue complication probability (NTCP) models, based on dosimetric data refined the normal tissue dose/volume tolerance guidelines. In parallel, the radiation-induced nucleoshuttling (RIANS) of the Ataxia-Telangiectasia Mutated protein (pATM) is a predictive approach of individual intrinsic radiosensitivity. Here, we combined NTCP with RADIODTECT©, a blood assay derived from the RIANS model, to predict RT toxicity in HNSCC patients. METHODS: RADIODTECT© cutoff values (i.e. 57.8 ng/mL for grade⩾2 toxicity and 46 ng/mL for grade⩾3 toxicity) have been previously assessed. Validation was performed on a prospective cohort of 36 HNSCC patients treated with postoperative RT. Toxicity was graded with the Common Terminology Criteria for Adverse Events (CTCAE) scale and two criteria were considered: grade⩾2 oral mucositis (OM2), grade⩾3 mucositis (OM3) and grade⩾2 dysphagia (DY2), grade⩾3 dysphagia (DY3). pATM quantification was assessed in lymphocytes of HNSCC patients. The discrimination power of the pATM assay was evaluated through the Area Under the Receiver Operator Characteristics Curve (AUC-ROC). Two previously described NTCP models were considered, including the dose to the oral cavity and the mean dose to the parotid glands (OM2 and OM3) and the dose to the oral cavity, to the larynx and the volume of pharyngeal constrictor muscles (DY2 and DY3). RESULTS: Combining NTCP models with RADIODTECT© blood test improved the AUC-ROC. Considering the prediction of mucositis, AUC-ROCNTCP+RADIODTECT©=0.80 was for OM2, and AUC-ROCNTCP+RADIODTECT©=0.78 for OM3. Considering the prediction of acute dysphagia, AUC-ROCNTCP+RADIODTECT©=0.71 for DY2 and for DY3. CONCLUSIONS: Combining NTCP models with a radiosensitivity biomarker might significantly improve the prediction of toxicities for HNSCC patients.
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Transtornos de Deglutição , Neoplasias de Cabeça e Pescoço , Mucosite , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Projetos Piloto , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/complicações , Transtornos de Deglutição/etiologia , Estudos Prospectivos , Disprósio , Dosagem Radioterapêutica , Tolerância a Radiação/genética , Biomarcadores , ProbabilidadeRESUMO
Unlike Quality by Testing approach, where products were tested only after drug manufacturing, Quality by Design (QbD) is a proactive control quality paradigm, which handles risks from the early development steps. In QbD, regression models built from experimental data are used to predict a risk mapping called Design Space in which the developers can identify values of critical input factors leading to acceptable probabilities to meet the efficacy and safety specifications for the expected product. These empirical models are often limited to quantitative responses. Moreover, in practice the smallness and incompleteness of datasets degrade the quality of predictions. In this study, a Bayesian approach including variable selection, parameter estimation and model quality assessment is proposed and assessed using a real case study devoted to the development of a Cationic Nano-Lipid Structures for siRNA Transfection. Two original model structures are also included to describe both binary and percentage response variables. The results confirm the practical relevance and applicability of the Bayesian implementation of the QbD analysis.
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Teorema de Bayes , RNA Interferente Pequeno/genética , Controle de QualidadeRESUMO
mRNA vaccines have recently proved to be highly effective against SARS-CoV-2. Key to their success is the lipid-based nanoparticle (LNP), which enables efficient mRNA expression and endows the vaccine with adjuvant properties that drive potent antibody responses. Effective cancer vaccines require long-lived, qualitative CD8 T cell responses instead of antibody responses. Systemic vaccination appears to be the most effective route, but necessitates adaptation of LNP composition to deliver mRNA to antigen-presenting cells. Using a design-of-experiments methodology, we tailored mRNA-LNP compositions to achieve high-magnitude tumor-specific CD8 T cell responses within a single round of optimization. Optimized LNP compositions resulted in enhanced mRNA uptake by multiple splenic immune cell populations. Type I interferon and phagocytes were found to be essential for the T cell response. Surprisingly, we also discovered a yet unidentified role of B cells in stimulating the vaccine-elicited CD8 T cell response. Optimized LNPs displayed a similar, spleen-centered biodistribution profile in non-human primates and did not trigger histopathological changes in liver and spleen, warranting their further assessment in clinical studies. Taken together, our study clarifies the relationship between nanoparticle composition and their T cell stimulatory capacity and provides novel insights into the underlying mechanisms of effective mRNA-LNP-based antitumor immunotherapy.
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COVID-19 , Vacinas Anticâncer , Nanopartículas , Animais , Imunização/métodos , Imunoterapia , RNA Mensageiro/metabolismo , SARS-CoV-2/genética , Baço , Distribuição Tecidual , Vacinação/métodosRESUMO
Quality-by-Design (QbD) guidance is a risk-based and proactive approach to drug development proposed in the early 2000s and now widely used in the pharmaceutical field in compliance with the ICH Q8-Q11 guidelines. Analytical Quality by Design (AQbD), introduced in 2010, is the adaptation of the QbD paradigm for the development of analytical methods. AQbD aims at optimizing the accuracy and robustness of analysis results by identifying and controlling critical analytical variables and method parameters over the entire protocol, including biological sample preparation, measurement technology and statistical analysis. Nevertheless, much remains to be done for a clear understanding and an efficient implementation of this new paradigm in practice. The first objective of this review is to propose a global clarification of the Analytical Quality by Design approach by reviewing its terminology and steps and by clarifying its relationships with the well-established QbD paradigm and ICH guidelines. Two new templates of documents have been proposed: a form designed for the definition of the analytical target profile and a connection matrix between expected metrological properties and analytical attributes. Finally, the open challenges in the characterization of nano-enabled medicinal products are examined from the AQbD angle.
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Desenvolvimento de Medicamentos , Projetos de PesquisaRESUMO
Breast cancer is one of the leading causes of cancer-related death among females worldwide. A major challenge is to develop innovative therapy in order to treat breast cancer subtypes resistant to current treatment. In the present study, we examined the effects of two Troglitazone derivatives Δ2-TGZ and AB186. Previous studies showed that both compounds induce apoptosis, nevertheless AB186 was a more potent agent. The kinetic of cellular events was investigated by real-time cell analysis system (RTCA) in MCF-7 (hormone dependent) and MDA-MB-231 (triple negative) breast cancer (TNBC) cells, followed by cell morphology analysis by immuno-localization. Both compounds induced a rapid modification of both impedance-based signals and cellular morphology. This process was associated with an inhibition of cell migration measured by wound healing and transwell assays in TNBC MDA-MB-231 and Hs578T cells. In order to identify cytoplasmic targets of AB186, we performed surface plasmon resonance (SPR) and pull-down analyses. Subsequently, 6 cytoskeleton components were identified as potential targets. We further validated α-tubulin as one of the direct targets of AB186. In conclusion, our results suggested that AB186 could be promising to develop novel therapeutic strategies to treat aggressive forms of breast cancer such as TNBC.
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Neoplasias de Mama Triplo Negativas , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Tubulina (Proteína)RESUMO
BACKGROUND AND PURPOSE: HERG blocking drugs known for their propensity to trigger Torsades de Pointes (TdP) were reported to induce a sympatho-vagal coactivation and to enhance High Frequency heart rate (HFHR) and QT oscillations (HFQT) in telemetric data. The present work aimed to characterize the underlying mechanism(s) leading to these autonomic changes. EXPERIMENTAL APPROACH: Effects of 15 torsadogenic hERG blocking drugs (astemizole, chlorpromazine, cisapride, droperidol, ibutilide, dofetilide, haloperidol, moxifloxacin, pimozide, quinidine, risperidone, sotalol, sertindole, terfenadine, and thioridazine) were assessed by telemetry in beagle dogs. Haemodynamic effects on diastolic and systolic arterial pressure were analysed from the first doses causing QTc prolongation and/or HFQT oscillations enhancement. Autonomic control changes were analysed using the high frequency autonomic modulation (HFAM) model. KEY RESULTS: Except for moxifloxacin and quinidine, all torsadogenic hERG blockers induced parasympathetic activation or sympatho-vagal coactivation combined with enhancement of HFQT oscillations. These autonomic effects result from reflex compensatory mechanisms in response to mild haemodynamic side effects. These haemodynamic mechanisms were characterized by transient HR acceleration during HF oscillations. A phenomenon of concealed QT prolongation was unmasked for several torsadogenic hERG blockers under ß-adrenoceptor blockade with atenolol. Resulting enhancement of HFQT oscillations was shown to contribute directly to triggering dofetilide-induced ventricular arrhythmias. CONCLUSION AND IMPLICATIONS: This work supports for the first time a contribution of haemodynamic side properties to ventricular arrhythmias triggered by torsadogenic hERG blocking drugs. These haemodynamic side effects may constitute a second component of their arrhythmic profile, acting as a trigger alongside their intrinsic arrhythmogenic electrophysiological properties.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Síndrome do QT Longo , Torsades de Pointes , Animais , Arritmias Cardíacas/induzido quimicamente , Cães , Eletrocardiografia , Canais de Potássio Éter-A-Go-Go/fisiologia , Frequência Cardíaca , Síndrome do QT Longo/induzido quimicamente , Moxifloxacina/efeitos adversos , Quinidina , Reflexo , Torsades de Pointes/induzido quimicamenteRESUMO
Radiation therapy (RT), either alone or in combination with surgery and/or chemotherapy is a keystone of cancers treatment. Early toxicity is common, sometimes leading to discontinuation of treatment. Recent studies stressed the role of the phosphorylated ATM (pATM) protein in RT-toxicity genesis and its ability in predicting individual radiosensitivity (IRS) in fibroblasts. Here we assessed the reliability of the pATM quantification in lymphocytes to predict IRS. A first retrospective study was performed on 150 blood lymphocytes of patients with several cancer types. Patients were divided into 2 groups, according to the grade of experienced toxicity. The global quantity of pATM molecules was assessed by ELISA on lymphocytes to determine the best threshold value. Then, the binary assay was assessed on a validation cohort of 36 patients with head and neck cancers. The quantity of pATM molecules in each sample of the training cohort was found in agreement with the observed Common Terminology Criteria for Adverse Events (CTCAE) grades with an AUC = 0.71 alone and of 0.77 combined to chemotherapy information. In the validation cohort, the same test was conducted with the following performances: sensitivity = 0.84, specificity = 0.54, AUC = 0.70 and 0.72 combined to chemotherapy. This study provides the basis of an easy to perform assay for clinical use.
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Biomaterials applied to the epicardium have been studied intensively in recent years for different therapeutic purposes. Their mechanical influence on the heart, however, has not been clearly identified. Most biomaterials for epicardial applications are manufactured as membranes or cardiac patches that have isotropic geometry, which is not well suited to myocardial wall motion. Myocardial wall motion during systole and diastole produces a complex force in different directions. Membrane or cardiac patches that cannot adapt to these specific directions will exert an inappropriate force on the heart, at the risk of overly restricting or dilating it. Accurately characterizing the mechanical properties of the myocardial wall is thus essential, through analysis of muscle orientation and elasticity. In this study, we investigated the Hertz contact theory for characterizing cardiac tissue, using nanoindentation measurements to distinguish different patterns in the local myocardium. We then evaluated the predictive accuracy of this model using Finite Element Analysis (FEA) to mimic the diastolic phase of the heart. Our results, extracted from instrumented nanoindentation experiments in a liquid environment using five pig hearts, revealed variations in elasticity according to the local orientation of the myocardial tissue. In addition, applying the Finite Element Method (FEM) in our model based on transverse isotropy and local tissue orientation proved able to accurately simulate the passive filling of a left ventricle (LV) in a representative 3D geometry. Our model enables improved understanding of the underlying mechanical properties of the LV wall and can serve as a guide for designing and manufacturing biomedical material better adapted to the local epicardial tissue.
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Materiais Biocompatíveis , Ventrículos do Coração , Animais , Simulação por Computador , Modelos Cardiovasculares , Estresse Mecânico , SuínosRESUMO
Health product development has been lately tainted by wariness in manufacturers, which has reduced trust in the system. It also affects Digital Health were patients' big data flows generated by numerous sensors are subject to increased security and confidentiality to lower the risks incurred. Our aim is to increase trust in the system again by implementing a dedicated Blockchain solution where data are automatically stored, and where each actor in the development process can access and host them. Blockchain has its downside, such as a subefficient management of big data flows. This study is a first step toward defining a Blockchain solution that will not deteriorate the Quality of Service in this particular context by using the Quality by Design approach. We will mainly focus on the time to consensus attribute which affects both of them. From our experiments' results generated after running screening design and surface response design on a practical Byzantine Fault Tolerance (pBFT) simulator, we find that the transmission time and the message processing time are the most impacting factors.
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Segurança Computacional , Confidencialidade , Big Data , Blockchain , Consenso , HumanosRESUMO
Cheyne-Stokes respiration (CSR) is a sleep-disordered breathing characterized by recurrent central apneas alternating with hyperventilation exhibiting a crescendo-decrescendo pattern of tidal volume. This respiration is reported in patients with heart failure, stroke or damage in respiratory centers. It increases mortality for patients with severe heart failure as it has adverse impacts on the cardiac function. Early stage of CSR, also called periodic breathing, is often undiagnosed as it only provokes hypopneas instead of apneas, which are much more difficult to detect. This paper demonstrates the proof of concept of a new method devoted to the early detection of CSR. The proposed approach relies on a signal demodulation technique applied to ventilation signals measured on 15 patients with chronic heart failure whose respiration goes from normal to severe CSR. Based on a modulation index and its instantaneous frequency, oscillation zones are detected and classified into three categories: CSR, periodic breathing and no abnormal pattern. The modulation index is used as an efficient indicator to quantify the degree of certainty of the pathology for each patient. Results show high correlation with experts' annotations with sensitivity and specificity values of 87.1% and 89.8% respectively. A final decision leads to a classification which is confirmed by the experts' conclusions.
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Algoritmos , Respiração de Cheyne-Stokes/diagnóstico , Respiração de Cheyne-Stokes/etiologia , Insuficiência Cardíaca/complicações , Modelagem Computacional Específica para o Paciente , Idoso , Respiração de Cheyne-Stokes/fisiopatologia , Diagnóstico Precoce , Humanos , Masculino , Pessoa de Meia-Idade , Polissonografia/métodos , Respiração , Estudos Retrospectivos , Sensibilidade e Especificidade , Apneia do Sono Tipo Central/fisiopatologia , Volume de Ventilação PulmonarRESUMO
An early dialogue between nanomedicine developers and regulatory authorities are of utmost importance to anticipate quality and safety requirements for these innovative health products. In order to stimulate interactions between the various communities involved in a translation of nanomedicines to clinical applications, the European Commission's Joint Research Centre hosted a workshop titled "Bridging communities in the field of Nanomedicine" in Ispra/Italy on the 27th -28th September 2017. Experts from regulatory bodies, research institutions and industry came together to discuss the next generation of nanomedicines and their needs to obtain regulatory approval. The workshop participants came up with recommendations highlighting methodological gaps that should be addressed in ongoing projects addressing the regulatory science of nanomedicines. In addition, individual opinions of experts relevant to progress of the regulatory science in the field of nanomedicine were summarised in the format of a survey.
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Nanomedicina , Tomada de Decisões , Sistemas de Apoio a Decisões Clínicas , Humanos , Inquéritos e QuestionáriosRESUMO
PURPOSE: The ability to identify, before treatment, those patients who will overreact to radiation therapy would have sound positive clinical implications. By focusing on DNA double-strand breaks recognition and repair proteins after irradiation, we recently demonstrated that the maximal number of phosphorylated ATM (pATM) nuclear foci in the first hour (pATMmax) after ex vivo irradiation correlated with postradiation therapy toxicity severity. We performed additional analyses of our whole collection of fibroblast lines to refine the predictive performance of our assay. METHODS AND MATERIALS: Immunofluorescence experiments were performed on 117 primary skin fibroblast lines irradiated at 2 Gy. The toxicity response was split into 2 binary classes: 0 if the toxicity grade was <2 and 1 otherwise. To assess the relationship between the quantity of pATMmax foci and toxicity grade, we applied a correlation and then a supervised classification analysis. Training data sets from 13 radiosensitive patients randomly drawn using a random undersampling technique were constituted. Receiver operating characteristic analyses were performed using a Monte-Carlo method to estimate the optimal threshold and discriminate the responses for each data set. The discrimination cutoff was estimated as the maximum value of the 104 thresholds computed from each training subset. RESULTS: As expected, we confirmed a quasi-linear dependence between toxicity and pATMmax (Pearson correlation coefficient -0.85; P < 2.2e-16). When taken as a binary predictive assay with the optimal cutoff value of 34.5 pATM foci/cell, our assay showed outstanding predictive performance (sensitivity, specificity, negative predictive value, positive predictive value, and area under the curve: 100%, 92%, 100%, 99%, and 0.987, respectively). CONCLUSIONS: The results of these experiments allowed us to identify pATMmax as a high-performance predictive parameter of patients with postradiation therapy overreactions. Additional studies are in progress to confirm that this radiosensitivity assay reaches the same performance level in any condition to adapt clinical practice.
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Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Imunofluorescência , Tolerância a Radiação , Radioterapia , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Humanos , Análise Multivariada , Fosforilação/efeitos da radiação , Aprendizado de Máquina Supervisionado , Resultado do TratamentoRESUMO
Pharmaceutical Quality-by-Design is a risk-based approach of drug development relying on the understanding of both the product and the process. This state of the art analyzes 24 studies published during the last ten years. A risk modeling of the nanomaterial formulation and manufacturing is firstly presented. After a brief history of the QbD approach, its basic components are recalled in a second part. The most critical material attributes, process parameters, quality variables and measurement technologies are reviewed. Specific deficiencies are also emphasized such as the absence of prior risk assessment, production scale-up, process analytical technology and control strategy. Finally, perspectives and development priorities are drawn to improve the implementation of this integrative approach of quality and safety in nanomedicine.
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Descoberta de Drogas/métodos , Nanotecnologia/métodos , Animais , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Nanomedicina/métodos , Medição de RiscoRESUMO
Despite recent progress in conventional therapeutic approaches, the vast majority of glioblastoma recur locally, indicating that a more aggressive local therapy is required. Interstitial photodynamic therapy (iPDT) appears as a very promising and complementary approach to conventional therapies. However, an optimal fractionation scheme for iPDT remains the indispensable requirement. To achieve that major goal, we suggested following iPDT tumor response by a non-invasive imaging monitoring. Nude rats bearing intracranial glioblastoma U87MG xenografts were treated by iPDT, just after intravenous injection of AGuIX® nanoparticles, encapsulating PDT and imaging agents. Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS) allowed us an original longitudinal follow-up of post-treatment effects to discriminate early predictive markers. We successfully used conventional MRI, T2 star (T2*), Diffusion Weighted Imaging (DWI) and MRS to extract relevant profiles on tissue cytoarchitectural alterations, local vascular disruption and metabolic information on brain tumor biology, achieving earlier assessment of tumor response. From one day post-iPDT, DWI and MRS allowed us to identify promising markers such as the Apparent Diffusion Coefficient (ADC) values, lipids, choline and myoInositol levels that led us to distinguish iPDT responders from non-responders. All these responses give us warning signs well before the tumor escapes and that the growth would be appreciated.
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Monitoramento de Medicamentos/métodos , Glioblastoma/diagnóstico , Glioblastoma/terapia , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética/métodos , Fotoquimioterapia , Prótons , Animais , Meios de Contraste/administração & dosagem , Modelos Animais de Doenças , Xenoenxertos , Estudos Longitudinais , Nanopartículas/administração & dosagem , Fármacos Fotossensibilizantes/administração & dosagem , Ratos Nus , Resultado do TratamentoRESUMO
OBJECTIVE: Photodynamic therapy (PDT) is an alternative treatment for cancer, which involves the administration of a photosensitizing agent that is activated by light at a specific wavelength. This illumination causes after a sequence of photoreactions, the production of reactive oxygen species responsible for the death of the tumor cells but also the degradation of the photosensitizing agent, which then loose the fluorescence properties. The phenomenon is commonly known as the photobleaching process and can be considered as a therapy efficiency indicator. METHODS: This paper presents the design and validation of a real-time controller able to track a preset photobleaching trajectory by modulating the light impulses width during the treatment sessions. RESULTS: This innovative solution was validated by in vivo experiments that have shown a significantly improvement of reproducibility of the interindividual photobleaching kinetic. CONCLUSION: We believe that this approach could lead to personalized PDT modalities. SIGNIFICANCE: This work may open new perspectives in the control and optimization of photodynamic treatments.
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Monitoramento de Medicamentos/métodos , Neoplasias Experimentais/química , Neoplasias Experimentais/tratamento farmacológico , Fotodegradação/efeitos da radiação , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/química , Animais , Sistemas Computacionais , Relação Dose-Resposta à Radiação , Quimioterapia Assistida por Computador/métodos , Cinética , Luz , Fármacos Fotossensibilizantes/efeitos da radiação , Doses de Radiação , Radiometria/métodos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
This article addresses the in silico-in vitro prediction issue of organometallic nanoparticles (NPs)-based radiosensitization enhancement. The goal was to carry out computational experiments to quickly identify efficient nanostructures and then to preferentially select the most promising ones for the subsequent in vivo studies. To this aim, this interdisciplinary article introduces a new theoretical Monte Carlo computational ranking method and tests it using 3 different organometallic NPs in terms of size and composition. While the ranking predicted in a classical theoretical scenario did not fit the reference results at all, in contrast, we showed for the first time how our accelerated in silico virtual screening method, based on basic in vitro experimental data (which takes into account the NPs cell biodistribution), was able to predict a relevant ranking in accordance with in vitro clonogenic efficiency. This corroborates the pertinence of such a prior ranking method that could speed up the preclinical development of NPs in radiation therapy.
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Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Método de Monte Carlo , Nanopartículas/administração & dosagem , Radiossensibilizantes/farmacocinética , Simulação por Computador , Humanos , Técnicas In Vitro , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Nanoestruturas/química , Distribuição Tecidual , Células Tumorais CultivadasRESUMO
The increase of computational environments dedicated to the simulation of nanoparticles (NP)-X-Rays interactions has opened new perspectives in computer-aided-design of nanostructured materials for biomedical applications. Several published studies have shown a crucial need of standardization of these numerical simulations. That is why, a robustness multivariate analysis was performed in this paper. A gold nanoparticle (GNP) of 100 nm diameter was selected as a standard nanosystem activated by a X-ray source placed just below the NP. Two response variables were examined: the dose enhancement in seven different spatial regions of interest around the NP and the duration of the experiments. Nine factors were pre-identified as potentially critical. A Plackett-Burman design of numerical experiments was applied to estimate and test the effects of each simulation factors on the examined responses. Four factors-the working volume, the spatial resolution, the spatial cutoff, and the computational mode (parallelization)-do not significantly affect the dose deposition results and none except the last one may reduce the computational duration. The energy cutoff may cause significant variations of the dose enhancement in some specific regions of interest: the higher the cutoff, the closer the secondary particles will stop from the GNP. By contrast, the Auger effect as well as the choice of the physical medium and the fluence level clearly appear as critical simulation parameters. Consequently, these four factors may be compulsory examined before comparing and interpreting any simulation results coming from different simulation sessions.
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Ouro/química , Nanopartículas Metálicas/química , Modelos Teóricos , Radiossensibilizantes/química , Simulação por Computador , Imageamento Tridimensional , Radioterapia , Planejamento da Radioterapia Assistida por ComputadorRESUMO
This review focuses on the radiosensitization strategies that use high-Z nanoparticles. It does not establish an exhaustive list of the works in this field but rather propose constructive criticisms pointing out critical factors that could improve the nano-radiation therapy. Whereas most reviews show the chemists and/or biologists points of view, the present analysis is also seen through the prism of the medical physicist. In particular, we described and evaluated the influence of X-rays energy spectra using a numerical analysis. We observed a lack of standardization in preclinical studies that could partially explain the low number of translation to clinical applications for this innovative therapeutic strategy. Pointing out the critical parameters of high-Z nanoparticles radiosensitization, this review is expected to contribute to a larger preclinical and clinical development.
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Nanopartículas/administração & dosagem , Radiossensibilizantes/administração & dosagem , Radioterapia/métodos , Animais , Avaliação Pré-Clínica de Medicamentos , Radiação Eletromagnética , Raios XRESUMO
System identification is a data-driven modeling approach more and more used in biology and biomedicine. In this application context, each assay is always repeated to estimate the response variability. The inference of the modeling conclusions to the whole population requires to account for the inter-individual variability within the modeling procedure. One solution consists in using random effects models but up to now no similar approach exists in the field of dynamical system identification. In this article, we propose a new solution based on an ARX (Auto Regressive model with eXternal inputs) structure using the EM (Expectation-Maximisation) algorithm for the estimation of the model parameters. Simulations show the relevance of this solution compared with a classical procedure of system identification repeated for each subject.