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.
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.
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.
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.
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.
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.
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.
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 10
thresholds computed from each training subset.
As expected, we confirmed a quasi-linear dependence between toxicity and pATMmax (Pearson correlation coefficient -0.85; P < 2.2e
). 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).
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.
Systems with bifurcations may experience abrupt irreversible and often unwanted shifts in their performance, called critical transitions. For many systems like climate, economy, ecosystems it is ...highly desirable to identify indicators serving as early warnings of such regime shifts. Several statistical measures were recently proposed as early warnings of critical transitions including increased variance, autocorrelation and skewness of experimental or model-generated data. The lack of automatized tool for model-based prediction of critical transitions led to designing DyGloSA - a MATLAB toolbox for dynamical global parameter sensitivity analysis (GPSA) of ordinary differential equations models. We suggest that the switch in dynamics of parameter sensitivities revealed by our toolbox is an early warning that a system is approaching a critical transition. We illustrate the efficiency of our toolbox by analyzing several models with bifurcations and predicting the time periods when systems can still avoid going to a critical transition by manipulating certain parameter values, which is not detectable with the existing SA techniques. DyGloSA is based on the SBToolbox2 and contains functions, which compute dynamically the global sensitivity indices of the system by applying four main GPSA methods: eFAST, Sobol's ANOVA, PRCC and WALS. It includes parallelized versions of the functions enabling significant reduction of the computational time (up to 12 times). DyGloSA is freely available as a set of MATLAB scripts at http://bio.uni.lu/systems_biology/software/dyglosa. It requires installation of MATLAB (versions R2008b or later) and the Systems Biology Toolbox2 available at www.sbtoolbox2.org. DyGloSA can be run on Windows and Linux systems, -32 and -64 bits.
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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