A copper-loaded self-assembled nanoparticle for disturbing the tumor redox balance and triple anti-tumor therapy.

Both chemodynamic therapy and photodynamic therapy, based on the production of reactive oxygen (ROS), have excellent potential in cancer therapy. However, the abnormal redox homeostasis in tumor cells, especially the overexpressed glutathione (GSH) could scavenge ROS and reduce the anti-tumor efficiency. Therefore, it is essential to develop a simple and effective tumor-specific drug delivery system for modulating the tumor microenvironment (TME) and achieving synergistic therapy at the tumor site. In this study, self-assembled nanoparticles (named CDZP NPs) were developed using copper ion (Cu2+), doxorubicin (Dox), zinc phthalocyanine (ZnPc) and a trace amount of poly(2-(di-methylamino)ethylmethacrylate)-poly[(R)-3-hydroxybutyrate]-poly(2-(dimethylamino)ethylmethacrylate) (PDMAEMA-PHB-PDMAEMA) through chelation, π-π stacking and hydrophobic interaction. These triple factor-responsive (pH, laser and GSH) nanoparticles demonstrated unique advantages through the synergistic effect. Highly controllable drug release ensured its effectiveness at the tumor site, Dox-induced chemotherapy and ZnPc-mediated fluorescence (FL) imaging exhibited the distribution of nanoparticles. Meanwhile, Cu2+-mediated GSH-consumption not only reduced the intracellular ROS elimination but also produced Cu+ to catalyze hydrogen peroxide (H2O2) and generated hydroxyl radicals (˙OH), thereby enhancing the chemodynamic and photodynamic therapy. Herein, this study provides a green and relatively simple method for preparing multifunctional nanoparticles that can effectively modulate the TME and improve synergetic cancer therapy.

Quality by Design Framework Applied to GMMA Purification.

In recent years, Generalized Modules for Membrane Antigens (GMMA) have received increased attention as an innovative vaccine platform against bacterial pathogens, particularly attractive for low- and middle-income countries because of manufacturing simplicity. The assessment of critical quality attributes (CQAs), product-process interactions, identification of appropriate in process analytical methods, and process modeling is part of a robust quality by design (QbD) framework to support further development and control of manufacturing processes. QbD implementation in the context of the GMMA platform will ensure robust manufacturing of batches with desired characteristics, facilitating technical transfer to local manufacturers, regulatory approval, and commercialization of vaccines based on this technology. Here, we summarize the methodology suggested, applied to a first step of GMMA manufacturing process.

Molecular Signature of Monocytes Shaped by the Shigella sonnei 1790-Generalized Modules for Membrane Antigens Vaccine.

Shigellosis, an acute gastroenteritis infection caused by Shigella species, remains a public health burden in developing countries. Recently, many outbreaks due to Shigella sonnei multidrug-resistant strains have been reported in high-income countries, and the lack of an effective vaccine represents a major hurdle to counteract this bacterial pathogen. Vaccine candidates against Shigella sonnei are under clinical development, including a Generalized Modules for Membrane Antigens (GMMA)-based vaccine. The mechanisms by which GMMA-based vaccines interact and activate human immune cells remain elusive. Our previous study provided the first evidence that both adaptive and innate immune cells are targeted and functionally shaped by the GMMA-based vaccine. Here, flow cytometry and confocal microscopy analysis allowed us to identify monocytes as the main target population interacting with the S. sonnei 1790-GMMA vaccine on human peripheral blood. In addition, transcriptomic analysis of this cell population revealed a molecular signature induced by 1790-GMMA mostly correlated with the inflammatory response and cytokine-induced processes. This also impacts the expression of genes associated with macrophages' differentiation and T cell regulation, suggesting a dual function for this vaccine platform both as an antigen carrier and as a regulator of immune cell activation and differentiation.

Effect of immersion in disinfectants on the color stability of denture base resins and artificial teeth obtained by 3D printing.

PURPOSE: To evaluate the effect of immersion in disinfecting solutions on the color stability of denture base resins and artificial teeth obtained by 3D printing. MATERIALS AND METHODS: Forty discs (15 × 3 mm) were obtained for each group: Lucitone 550 and Cosmos Denture 3D (denture base resins), Duralay and Cosmos TEMP 3D (artificial teeth resins). The discs were immersed in disinfectant solutions: Corega Tabs, 2% chlorhexidine digluconate, 0.25% sodium hypochlorite, and distilled water. Color measurements were obtained with a spectrophotometer before immersion in disinfectants and after the simulated periods of 6 and 12 months. Data (ΔE00 ) were submitted to mixed three-way ANOVA and Bonferroni post-test. RESULTS: For denture base resins, Cosmos Denture 3D showed greater color change regardless of the solution and immersion time. The immersion time of 6 months influenced the color change of the denture base resins regardless of the disinfectant solution. For the artificial teeth resins, the immersion time of 12 months showed a significant color change when compared to 6 months. Cosmos TEMP 3D showed greater color change for all solutions, except for 0.25% sodium hypochlorite. Duralay resin showed greater color change in 2% chlorhexidine, regardless of immersion time. CONCLUSIONS: For denture base resins, the immersion time significantly changed the color regardless of the solution. For artificial teeth resins, Cosmos TEMP 3D showed greater color changes in all solutions when compared to Duralay, except for 0.25% sodium hypochlorite. Chlorhexidine digluconate significantly changed the color of Duralay.

The Genie Is Out of the Bottle: What ChatGPT Can and Cannot Do for Medical Professionals.

ChatGPT is a cutting-edge artificial intelligence technology that was released for public use in November 2022. Its rapid adoption has raised questions about capabilities, limitations, and risks. This article presents an overview of ChatGPT, and it highlights the current state of this technology for the medical field. The article seeks to provide a balanced perspective on what the model can and cannot do in three specific domains: clinical practice, research, and medical education. It also provides suggestions on how to optimize the use of this tool.

Extending the Affinity Range of Weak Affinity Chromatography for the Identification of Weak Ligands Targeting Membrane Proteins.

The identification of weak-affinity ligands targeting membrane proteins is of great interest in Fragment-Based Drug Design (FBDD). Recently, miniaturized weak affinity chromatography (WAC) has been proposed as a valuable tool to study interactions between small ligands and wild-type membrane proteins embedded in so-called nanodisc biomimetic membranes immobilized on GMA-co-EDMA monoliths in situ-synthesized in capillary columns (less than one microliter in volume). In this proof-of-concept study, the achievable affinity range was limited to medium affinity (low micromolar range). The present work investigates different strategies to extend the affinity range towards low affinities, either by increasing the density of membrane proteins on the chromatographic support or by reducing non-specific interactions with the monolith. The combination of the use of a new and more hydrophilic monolithic support (poly(DHPMA-co-MBA)) and a multilayer nanodisc grafting process (up to three layers) allows a significant increase in the membrane protein density by a more than three-fold factor (up to 5.4 pmol cm-1). Such an increase in protein density associated with reduced non-specific interactions makes it possible to extend the range of detectable affinity, as demonstrated by the identification and characterization of affinities of very low-affinity ligands (Kd values of several hundred micromolar) for the adenosine receptor AA2AR used as a model protein, which was not possible before. The affinity was confirmed by competition experiments.

Preparation and characterization of slow-release fertilizers loaded guar gum-g-poly methylmethacrylate-cl-polylactic acid (Gg-g-PMMA-cl-PLA) hydrogel and its effect on wheat growth.

In order to reduce the harmful effects of synthetic non-biodegradable hydrogel, biopolymers have attracted attention, particularly for use in slow-release fertilizers. The current attempt intends to develop a hydrogel from biopolymers for sustainable release of water and nutrients in soil. Here, guar gum is used as a polysaccharide, MMA as a monomer, KPS as an initiator, and Polylactic acid as a cross-linker. Further investigation is done to study synthesized hydrogel in the development of wheat crop. Biodegradation study shows that it's environmentally favorable and degradable, contributing nutrients to the soil as it decomposes. Fertilizer release studies in soil and water show that the timing of the nutrient release is delayed, improving soil water holding capacity and retention studies. The agronomic parameters show that fertilizers-loaded hydrogel has a positive effect on physiological, morphological characteristics like shoot length, root length, number of shoots and roots, shoot weight and root weight, chlorophyll content, and most notably, fruiting efficiency is enhanced as compared with commercially available hydrogel. ATR-FTIR, SEM-EDX, TGA-DTA, and XRD analysis used to confirm successful loading of fertilizers and biodegradation of hydrogel. The encouraging findings suggested that this hydrogel could be used as a multifunctional, fertilizers-loaded hydrogel in crop production.

Comparison of Mechanical Properties of Three Tissue Conditioners: An Evaluation In Vitro Study.

Introduction: Tissue conditioners have been widely used in various clinical applications in dentistry, such as treating inflamed alveolar ridges, temporarily relining partial and complete dentures, and the acquisition of functional impressions for denture fabrication. This study aimed to investigate the mechanical properties of the most prevalent tissue conditioner materials on the market, including Tissue Conditioners (TC), Visco Gel (VG), and FITT (F). Materials and Methods: The three tissue conditioners, TC, VG, and F, were assessed based on the parameters mentioned above. The following tests were performed based on the ISO 10139-1 and ISO 10139-2 requirements: Shore A hardness, denture plate adhesion, sorption, water solubility, and contraction after 1 and 3 days in water. Additional tests are described in the literature, such as ethanol content and gelling time. The tests were carried out by storing the materials in water at 37 °C for 7 days. Results: The gel times of all tested materials exceeded 5 min (TC = 300 [s], VG = 350 [s]). In vitro, phthalate-free materials exhibited higher dissolution in water after 14 days (VG = -260.78 ± 11.31 µg/mm2) compared to F (-76.12 ± 7.11 µg/mm2) and experienced faster hardening when stored in distilled water (F = 33.4 ± 0.30 Sh. A, VG = 59.2 ± 0.60 Sh. A). They also showed greater contractions. The connection of all materials to the prosthesis plate was consistent at 0.11 MPa. The highest counterbalance after 3 days was observed in TC = 3.53 ± 1.12%. Conclusions: Materials containing plasticizers that are not phthalates have worse mechanical properties than products containing these substances. Since phthalates are not allowed to be used indefinitely in medical devices, additional research is necessary, especially in vivo, to develop safe materials with superior functional properties to newer-generation alternatives. In vitro results often do not agree fully with those of in vivo outcomes.

Tailoring the Morphology of Monodisperse Mesoporous Silica Particles Using Different Alkoxysilanes as Silica Precursors.

The hard template method for the preparation of monodisperse mesoporous silica microspheres (MPSMs) has been established in recent years. In this process, in situ-generated silica nanoparticles (SNPs) enter the porous organic template and control the size and pore parameters of the final MPSMs. Here, the sizes of the deposited SNPs are determined by the hydrolysis and condensation rates of different alkoxysilanes in a base catalyzed sol-gel process. Thus, tetramethyl orthosilicate (TMOS), tetraethyl orthosilicate (TEOS), tetrapropyl orthosilicate (TPOS) and tetrabutyl orthosilicate (TBOS) were sol-gel processed in the presence of amino-functionalized poly (glycidyl methacrylate-co-ethylene glycol dimethacrylate) (p(GMA-co-EDMA)) templates. The size of the final MPSMs covers a broad range of 0.5-7.3 µm and a median pore size distribution from 4.0 to 24.9 nm. Moreover, the specific surface area can be adjusted between 271 and 637 m2 g-1. Also, the properties and morphology of the MPSMs differ according to the SNPs. Furthermore, the combination of different alkoxysilanes allows the individual design of the morphology and pore parameters of the silica particles. Selected MPSMs were packed into columns and successfully applied as stationary phases in high-performance liquid chromatography (HPLC) in the separation of various water-soluble vitamins.

Effects of methacryloyloxydecyl dihydrogen phosphate on bonding of tri-n-butylborane-initiated resin to human enamel.

This study investigated the effect of 10-methacryloyloxydecyl dihydrogen phosphate (MDP) in methyl methacrylate (MMA) monomer on the adhesion of tri-n-butylborane (TBB)-initiated resins (MDP/MMA-TBB resins) to human enamel. Enamel surface conditions were either polished only or phosphatized surfaces. The 1.0, 1.7, and 2.0 mol% MDP/MMA-TBB resins, 4-methacryloxyethyl trimellitate anhydride (4-META)/MMA-TBB resin and MMA-TBB resin were prepared as luting materials. The shear bond strength was determined before and after thermocycles, and the results were compared using non-parametric statistical analyses (each, n=15). The MDP/MMA-TBB resins showed significantly better bond durability to enamel than other resins with or without etching. The 1.7 and 2.0 mol% MDP/MMA-TBB resins were suggested to be the optimum MDP concentrations from pre- and post-thermocycling results for the non-etched specimens. The TBB initiator resin including MDP was shown to be effective in bonding to human enamel, and this effect was enhanced in combination with phosphate treatment.

Exploring the Role of GMMA Components in the Immunogenicity of a 4-Valent Vaccine against Shigella.

Shigellosis is the leading cause of diarrheal disease, especially in children of low- and middle-income countries, and is often associated with anti-microbial resistance. Currently, there are no licensed vaccines widely available against Shigella, but several candidates based on the O-antigen (OAg) portion of lipopolysaccharides are in development. We have proposed Generalized Modules for Membrane Antigens (GMMA) as an innovative delivery system for OAg, and a quadrivalent vaccine candidate containing GMMA from S. sonnei and three prevalent S. flexneri serotypes (1b, 2a and 3a) is moving to a phase II clinical trial, with the aim to elicit broad protection against Shigella. GMMA are able to induce anti-OAg-specific functional IgG responses in animal models and healthy adults. We have previously demonstrated that antibodies against protein antigens are also generated upon immunization with S. sonnei GMMA. In this work, we show that a quadrivalent Shigella GMMA-based vaccine is able to promote a humoral response against OAg and proteins of all GMMA types contained in the investigational vaccine. Proteins contained in GMMA provide T cell help as GMMA elicit a stronger anti-OAg IgG response in wild type than in T cell-deficient mice. Additionally, we observed that only the trigger of Toll-like Receptor (TLR) 4 and not of TLR2 contributed to GMMA immunogenicity. In conclusion, when tested in mice, GMMA of a quadrivalent Shigella vaccine candidate combine both adjuvant and carrier activities which allow an increase in the low immunogenic properties of carbohydrate antigens.

Preparation of miniaturized hydrophilic affinity monoliths: Towards a reduction of non-specific interactions and an increased target protein density.

In affinity chromatography, non-specific interactions between the ligands and the affinity column may affect the results, leading to misinterpretations during the investigation of protein-ligand interactions (detection of false positives in ligand screening, lack of specificity in purification). Such non-specific interactions may arise both from the underlying support or from the target protein itself. If the second ones are protein-dependent (and cannot be studied in a general framework), the first ones occur in the same way regardless of the immobilized target. We propose a methodology to identify the origin of such non-specific interactions with the underlying material of the affinity column. This methodology relies on the systematic investigation of the retention behavior of a set of 41 low-molecular weight compounds covering a wide chemical space (net charge, log D, functionality). We first demonstrate that the main source of non-specific interactions on the most commonly used GMA-co-EDMA monolith comes from hydrophobic effects. To reduce such non-specific interactions, we developed a new hydrophilic glycidyl methacrylate-based monolith by replacing the EDMA crosslinker by the more hydrophilic NN' Methylenebisacrylamide (MBA). Optimization of the synthesis parameters (monomer content, initiation type, temperature) has focused on the reduction of non-specific interaction with the monolithic support while maximizing the amount of protein that can be grafted onto the monolith at the issue of its synthesis. The retention data of the 41 test solutes on the new poly(GMA-co-MBA) monolith shows a drastic reduction of non-specific interactions except for cationic compounds. The particular behavior of cationic compounds is due to their electrostatic interactions with carboxylic groups resulting from the partial acidic hydrolysis of amide groups of MBA during the epoxide ring opening step. So, the ring opening step in acidic media was replaced by a hot water treatment to avoid side reaction on MBA. The new monolith poly(GMA-co-MBA) not only has improved hydrophilic surface properties but also a higher protein density (16 ± 0.8 pmol cm-1 instead of 8 ± 0.3 pmol cm-1). To highlight the benefits of this new hydrophilic monolith for affinity chromatographic studies, frontal affinity chromatography experiments were conducted on these monoliths grafted with con A.

Complement-mediated serum bactericidal activity of antibodies elicited by the Shigella sonnei GMMA vaccine in adults from a shigellosis-endemic country: Exploratory analysis of a Phase 2a randomized study.

Shigella is associated with a significant burden of disease worldwide among individuals of all ages and is the major cause of moderate and severe diarrhea in children under five years of age in low- and middle-income countries. Several candidate vaccines against Shigella species are currently under clinical development. The investigational 1790GAHB vaccine against Shigella sonnei is based on GMMA (Generalized Modules for Membrane Antigens) technology. The vaccine was well tolerated and induced high antibody levels in early-phase clinical trials in both Shigella-endemic and non-endemic settings. The present analysis assessed the bactericidal activity of antibodies induced by 1790GAHB in healthy Kenyan adults during a phase 2a, controlled, randomized study (NCT02676895). Participants received two doses of 1790GAHB 4 weeks apart containing either 1.5/25 µg or 6/100 µg O antigen/protein, or active comparator vaccines (Control). Serum bactericidal activity (SBA) against S. sonnei was assessed at pre-vaccination (D1), 28 days post-first dose (D29) and 28 days post-second dose (D57), using a luminescence-based assay. Most participants had SBA titers above the lower limit of quantification of the assay at D1. SBA geometric mean titers increased 3.4-fold in the 1.5/25 µg group and 6.3-fold in the 6/100 µg group by D29 and were maintained at D57. There was no increase in SBA geometric mean titers in the Control group. A strong correlation was observed between SBA titers and anti-S. sonnei lipopolysaccharide serum immunoglobulin G antibody concentrations (Pearson correlation coefficient = 0.918), indicating that SBA can effectively complement enzyme-linked immunosorbent assay data by indicating the functionality of 1790GAHB-induced antibodies.

Alternating Methyl Methacrylate/n-Butyl Acrylate Copolymer Prepared by Atom Transfer Radical Polymerization.

Poly(methyl methacrylate/n-butyl acrylate) [P(MMA/BA)] copolymer with an alternating structure was synthesized via an activator regenerated by electron transfer (ARGET) atom transfer radical (co)polymerization (ATRP) of 2-ethylfenchyl methacrylate (EFMA) and n-butyl acrylate (BA) with subsequent postpolymerization modifications (PPM). Due to the steric hindrance of the bulky pendant group of EFMA, as well as the low reactivity ratio of BA in copolymerization with methacrylates, copolymerization of EFMA and BA generated a copolymer with a high content of alternating dyads. A subsequent PPM procedure of the alternating EFMA/BA copolymer was comprised of the hydrolysis of a tertiary ester by trifluoroacetic acid and methylation by (trimethylsilyl)diazomethane. After the modifications, the architecture of the obtained alternating MMA/BA copolymers was compared with gradient and statistical copolymers with overall similar compositions, molecular weights, and dispersities. 13C NMR indicated the absence of either MMA/MMA/MMA or BA/BA/BA sequences, in contrast to an abundance of homotriads in either the statistical or especially in the gradient copolymer. All three copolymers had similar glass transition temperatures, as measured by differential scanning calorimetry (DSC), but the alternating copolymer had the narrowest range of glass transition.

Synthesis of Starch-Grafted Polymethyl Methacrylate via Free Radical Polymerization Reaction and Its Application for the Uptake of Methylene Blue.

In this research, a new biodegradable and eco-friendly adsorbent, starch-grafted polymethyl methacrylate (St-g-PMMA) was synthesized. The St-g-PMMA was synthesized by a free radical polymerization reaction in which methyl methacrylate (MMA) was grafted onto a starch polymer chain. The reaction was performed in water in the presence of a potassium persulfate (KPS) initiator. The structure and different properties of the St-g-PMMA was explored by FT-IR, 1H NMR, TGA, SEM and XRD. After characterization, the St-g-PMMA was used for the removal of MB dye. Different adsorption parameters, such as effect of adsorbent dose, effect of pH, effect of initial concentration of dye solution, effect of contact time and comparative adsorption study were investigated. The St-g-PMMA showed a maximum removal percentage (R%) of 97% towards MB. The other parameters, such as the isothermal and kinetic models, were fitted to the experimental data. The results showed that the Langmuir adsorption and pseudo second order kinetic models were best fitted to experimental data with a regression coefficient of R2 = 0.93 and 0.99, respectively.

Osteomyelitis and Gentamicin-PMMA Chains.

ABSTRACT: In chronic osteomyelitis, effective local antibiotic therapy after surgical debridement can be achieved by implantation of gentamicin-PMMA chains. The gentamicin concentrations at the site of infection are higher than that after systemic application of the same antibiotic. The appearance of this treatment is a particular aspect from a radiological point of view. Even if this is rare, these images deserve to be known when looking for osteomyelitis. We report a case of a 21-year-old man from Russia who had a bone scan in the context of chronic osteomyelitis persisting since a shin splints operation in a context of bilateral trauma in his country with antibiotic beads application.

Aza-Quasi-Favorskii Reaction: Construction of Highly Substituted Aziridines through a Concerted Multibond Rearrangement Process.

A new molecular rearrangement, the aza-Quasi-Favorskii rearrangement, has been developed for the construction of highly substituted aziridines. Electron-deficient O-sulfonyl oximes react readily with α,α-disubstituted acetophenone-derived enolates to furnish highly substituted aziridines via this unprecedented domino process. In-depth computational studies reveal an asynchronous yet concerted nitrenoid-type rearrangement pathway.

Influence of Test Specimen Geometry and Water Soaking on the In Vitro Cytotoxicity of Orthocryl®, Orthocryl® LC, Loctite® EA 9483 and Polypropylene.

Depending on their composition, plastics have a cytotoxic potential that needs to be evaluated before they are used in dentistry, e.g., as orthodontic removable appliances. Relevant guidelines set out requirements that a potential new resin in the medical field must meet, with a wide scope for experimental design. In the present study, test specimens of different geometries consisting of varying polymers (Orthocryl®, Orthocryl® LC, Loctite® EA 9483, Polypropylene) were soaked for different periods of time, then transferred to cell culture medium for 24 h, which was subsequently used for 24-h cultivation of A549 cells, followed by cytotoxicity assays (WST-1, Annexin V-FITC-propidium iodide (PI) flow cytometry). In this context, a reduction in the cytotoxic effect of the eluates of test specimens prepared from Orthocryl® LC and Loctite® EA 9483 was particularly evident in the Annexin V-FITC-PI assay when the soaking time was extended to 48 h and 168 h, respectively. Consistent with this, a reduced release of potentially toxic monomers into the cell culture medium, as measured by gas chromatography-mass spectrometry, was observed when the prior soaking time of test specimens of all geometries was extended. Remarkably, a significant increase in cytotoxic effect was observed in the WST-1 assay, which was accompanied by a higher release of monomers when the thickness of the test sample was increased from 0.5 to 1.0 mm, although an elution volume adapted to the surface area was used. However, further increasing the thickness to 3.0 mm did not lead to an increase in the observed cytotoxicity or monomer release. Test specimens made of polypropylene showed no toxicity under all test specimen sizes and soaking time conditions. Overall, it is recommended to perform toxicity studies of test specimens using different geometries and soaking times. Thereby, the influence of the different specimen thicknesses should also be considered. Finally, an extension of the test protocols proposed in ISO 10993-5:2009 should be considered, e.g., by flow cytometry or monomer analysis as well as fixed soaking times.