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1.
Cell Rep Med ; : 101663, 2024 Jul 23.
Article in English | MEDLINE | ID: mdl-39094577

ABSTRACT

The current targeted therapy for BRAFV600E-mutant lung cancer consists of a dual blockade of RAF/MEK kinases often combining dabrafenib/trametinib (D/T). This regimen extends survival when compared to single-agent treatments, but disease progression is unavoidable. By using whole-genome CRISPR screening and RNA sequencing, we characterize the vulnerabilities of both persister and D/T-resistant cellular models. Oxidative stress together with concomitant induction of antioxidant responses is boosted by D/T treatment. However, the nature of the oxidative damage, the choice of redox detoxification systems, and the resulting therapeutic vulnerabilities display stage-specific differences. Persister cells suffer from lipid peroxidation and are sensitive to ferroptosis upon GPX4 inhibition in vivo. Biomarkers of lipid peroxidation are detected in clinical samples following D/T treatment. Acquired alterations leading to mitogen-activated protein kinase (MAPK) reactivation enhance cystine transport to boost GPX4-independent antioxidant responses. Similarly to BRAFV600E-mutant melanoma, histone deacetylase (HDAC) inhibitors decrease D/T-resistant cell viability and extend therapeutic response in vivo.

2.
Molecules ; 29(14)2024 Jul 22.
Article in English | MEDLINE | ID: mdl-39065020

ABSTRACT

A major limitation preventing the use of surface-enhanced Raman scattering (SERS) in routine analyses is the signal variability due to the heterogeneity of metallic nanoparticles used as SERS substrates. This study aimed to robustly optimise a synthesis process of silver nanoparticles to improve the measured SERS signal repeatability and the protocol synthesis repeatability. The process is inspired by a chemical reduction method associated with microwave irradiation to guarantee better controlled and uniform heating. The innovative Quality by Design strategy was implemented to optimise the different parameters of the process. A preliminary investigation design was firstly carried out to evaluate the influence of four parameters selected by means of an Ishikawa diagram. The critical quality attributes were to maximise the intensity of the SERS response and minimise its variance. The reaction time, temperature and stirring speed are critical process parameters. These were optimised using an I-optimal design. A robust operating zone covering the optimal reaction conditions (3.36 min-130 °C-600 rpm) associated with a probability of success was modelled. Validation of this point confirmed the prediction with intra- and inter-batch variabilities of less than 15%. In conclusion, this study successfully optimised silver nanoparticles by a rapid, low cost and simple technique enhancing the quantitative perspectives of SERS.

3.
Plast Reconstr Surg ; 2023 Jun 14.
Article in English | MEDLINE | ID: mdl-37314374

ABSTRACT

BACKGROUND: Aesthetic soft tissue filler injections for lip enhancement are highly popular and are performed throughout the world. When injecting lips with cannulas, as the cannula is advanced, resistance is perceived in consistent locations potentially indicating boundaries between intralabial compartments. OBJECTIVE: To investigate whether intra-labial compartments exist and (if so) to describe their volumes, location, boundaries, and dimensions. METHODS: This cadaveric study investigated a total of n = 20 (13 males, 7 females) human body donors with a mean age at death of 61.9 (23.9) years and a mean body mass index of 24.3 (3.7) kg/m 2. The investigated cohort included n = 11 Caucasian, n = 8 Asian, and n = 1 African American donors. Dye injections simulating minimally invasive lip treatments were conducted. RESULTS: Independent of gender or race, 6 anterior and 6 posterior compartments in the upper and lower lip were identified, for a total of 24 lip compartments. Compartment boundaries were formed by vertically oriented septations that were found in consistent locations. The anterior compartments had volumes ranging from 0.30 - 0.39 cc whereas the posterior compartment volume ranged from 0.44 - 0.52 cc. Centrally, the compartment volumes were larger and decreased gradually towards the oral commissure. CONCLUSION: The volume and the size of each of the 24 compartments contribute to the overall appearance and shape of the lips. To achieve a natural and lip-shape preserving aesthetic outcome it may be preferable to administer the volumizing product using a compartment-respecting injection approach.

4.
J Pharm Biomed Anal ; 233: 115475, 2023 Sep 05.
Article in English | MEDLINE | ID: mdl-37235958

ABSTRACT

Surface-enhanced Raman scattering (SERS) is a vibrational widely used technique thanks to its multiple advantages such as its high specificity and sensitivity. The Raman signal exaltation comes from the use of metallic nanoparticles (Nps) acting as antennas by amplifying the Raman scattering. Controlling the Nps synthesis is a major point for the implementation of SERS in routine analysis and especially in quantitative applications. Effectively, nature, size and shape of these Nps considerably influence the SERS response intensity and repeatability. The Lee-Meisel protocol is the most common synthesis route used by the SERS community due to the low cost, rapidity and ease of manufacturing. However, this process leads to a significant heterogeneity in terms of particle size and shape. In this context, this study aimed to synthesize repeatable and homogeneous silver nanoparticles (AgNps) by chemical reduction. The Quality by Design strategy from quality target product profile to early characterization design was considered to optimize this reaction. The first step of this strategy aimed to highlight critical parameters by the means of an early characterization design. Based on an Ishikawa diagram, five process parameters were studied: the reaction volume as categorical variable and the temperature, the time of reaction, the trisodium citrate concentration and pH as continuous variables. A D-Optimal design of 35 conditions was performed. Three critical quality attributes were selected to maximize the SERS intensity, minimize the variation coefficient on SERS intensities and the polydispersity index of the AgNps. Considering these factors, it appeared that concentration, pH and time of reaction were identified as having a critical impact on the Nps formation and can then be considered for the further optimization step.


Subject(s)
Metal Nanoparticles , Metal Nanoparticles/chemistry , Silver/chemistry , Spectrum Analysis, Raman/methods , Particle Size
5.
Talanta ; 224: 121866, 2021 Mar 01.
Article in English | MEDLINE | ID: mdl-33379076

ABSTRACT

With the fast growth of bioanalytical surface-enhanced Raman scattering (SERS), analytical methods have had to adapt to the complex nature of biological samples. In particular, interfering species and protein adsorption onto the SERS substrates have been addressed by sample preparation steps, such as precipitation or extraction, and by smart SERS substrate functionalisation. These additional handling steps however result in irreversible sample alteration, which in turn prevents sample monitoring over time. A new methodology, that enables near real-time, non-invasive and non-destructive SERS monitoring of biological samples, is therefore proposed. It combines solid SERS substrates, benefitting from liquid immersion resistance for extended periods of time, with an original protein filtering device and an on-field detection by means of a handheld Raman analyser. The protein removal device aims at avoiding protein surface fouling on the SERS substrate. It consists of an ultracentrifugation membrane fixed under a cell culture insert for multi-well plates. The inside of the insert is dedicated to containing biological samples. The solid SERS substrate and a simple medium, without any protein, are placed under the insert. By carefully selecting the membrane molecular weight cutoff, selective diffusion of small analytes through the device could be achieved whereas larger proteins were retained inside the insert. Non-invasive SERS spectral acquisition was then carried out through the bottom of the multi-well plate. The diffusion of a SERS probe, 2-mercaptopyridine, and of a neurotransmitter having a less intense SERS signal, serotonin, were first successfully monitored with the device. Then, the latter was applied to distinguish between subclones of cancerous cells through differences in metabolite production. This promising methodology showed a high level of versatility, together with the capability to reduce cellular stress and contamination hazards.


Subject(s)
Proteins , Spectrum Analysis, Raman , Surface Properties
6.
Talanta ; 214: 120888, 2020 Jul 01.
Article in English | MEDLINE | ID: mdl-32278435

ABSTRACT

This paper addresses the issue of pharmaceutical solid dosage form quantitation using handheld Raman spectrophotometers. The two spectrophotometers used are designed with different technologies: one allows getting a more representative sampling with the Orbital Raster Scanning technology and the other one allows setting acquisition parameters. The goal was to evaluate which technology could provide the best analytical results. Several parameters were optimized to get the lowest prediction error in the end. The main objective of this study was to evaluate if this kind of instrument would be able to identify substandard medicines. For that purpose, two case-study were explored. At first, a full ICH Q2 (R1) compliant validation was performed for moderate Raman scatterer active pharmaceutical ingredient (API) in a specific formulation. It was successfully validated in the ±15% relative total error acceptance limits, with a RMSEP of 0.85% (w/w). Subsequently, it was interesting to evaluate the influence of excipients when the API is a high Raman scatterer. For that purpose, a multi-formulation model was developed and successfully validated with a RMSEP of 2.98% (w/w) in the best case. These two studies showed that thanks to the optimization of acquisition parameters, Raman handheld spectrophotometers methods were validated for two different case-study and could be applied to identify substandard medicines.

7.
Fed Pract ; 34(3): 41-44, 2017 Mar.
Article in English | MEDLINE | ID: mdl-30766266

ABSTRACT

A retrospective review found that obesity did not impact the lipid-lowering effectiveness of simvastatin therapy.

8.
Ann Pharmacother ; 49(5): 506-14, 2015 May.
Article in English | MEDLINE | ID: mdl-25712443

ABSTRACT

BACKGROUND: Fracture absolute risk assessment (FARA) is recommended for guiding osteoporosis treatment decisions in males. The best strategy for applying FARA in the clinic setting is not known. OBJECTIVES: We compared 2 FARA tools for use with electronic health records (EHRs) to determine which would more accurately identify patients known to be high risk for fracture. Tools evaluated were an adaptation of the World Health Organization's Fracture Risk Assessment Tool used with electronic data (eFRAX) and the Veterans Affairs (VA)-based tool, VA-FARA. METHODS: We compared accuracies of VA-FARA and eFRAX for correctly classifying male veterans who fractured and who were seen in the VA's Sierra Pacific Network in 2002-2013. We then matched those cases to nonfracture controls to compare odds of fracture in patients classified as high risk by either tool. RESULTS: Among 8740 patients, the mean (SD) age was 67.0 (11.1) years. Based on risk factors present in the EHR, VA-FARA correctly classified 40.1% of fracture patients as high risk (33.0% and 34.6% for hip and any major fracture, respectively); eFRAX classified 17.4% correctly (17.4% for hip and 0.2% for any major fracture). Compared with non-high-risk patients, those classified as high risk by VA-FARA were 35% more likely to fracture (95% CI = 23%-47%; P < 0.01) compared with 17% for eFRAX (95% CI = 5%-32%; P < 0.01). CONCLUSIONS: VA-FARA is more predictive of first fracture than eFRAX using EHR data. Decision support tools based on VA-FARA may improve early identification and care of men at risk.


Subject(s)
Fractures, Bone/diagnosis , Medical Informatics Applications , Osteoporosis/diagnosis , Aged , Aged, 80 and over , Bone Density , Case-Control Studies , Fractures, Bone/etiology , Humans , Male , Middle Aged , Osteoporosis/complications , Retrospective Studies , Risk Assessment , Risk Factors , Veterans
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