In vivo CAR T-cell generation in non-human primates using lentiviral vectors displaying a multi-domain fusion ligand.

Chimeric antigen receptor (CAR) T-cell therapies have demonstrated transformative efficacy in treating B-cell malignancies. However, high cost and manufacturing complexities hinder their widespread use. To overcome these hurdles, we have developed the VivoVecTM platform, a lentiviral vector capable of generating CAR T-cells in vivo. Here we describe the incorporation of T cell activation and costimulatory signals onto the surface of VivoVecTM particles (VVPs) in the form of a multi-domain fusion protein and show enhanced in vivo transduction and improved CAR-T cell antitumor functionality. Furthermore, in the absence of lymphodepleting chemotherapy, administration of VVPs into non-human primates resulted in the robust generation of anti-CD20 CAR T-cells and the complete depletion of B cells for more than 10 weeks. These data validate the VivoVecTM platform in a translationally relevant model and support its transition into human clinical testing, offering a paradigm shift in the field of CAR T-cell therapies.

Yield and Selectivity Improvement in the Synthesis of Carbonated Linseed Oil by Catalytic Conversion of Carbon Dioxide.

Carbonation of epoxidized linseed oil (CELO) containing five-membered cyclic carbonate (CC5) groups has been optimized to 95% by reacting epoxidized linseed oil (ELO) with carbon dioxide (CO2) and tetrabutylammonium bromide (TBAB) as catalysts. The effect of reaction variables (temperature, CO2 pressure, and catalyst concentration) on the reaction parameters (conversion, carbonation and selectivity) in an autoclave system was investigated. The reactions were monitored, and the products were characterized by Fourier Transform Infrared Spectroscopy (FT-IR), carbon-13 nuclear magnetic resonance (13C-NMR) and proton nuclear magnetic resonance (1H-NMR) spectroscopies. The results showed that when carrying out the reaction at high temperature (from 90 °C to 120 °C) and CO2 pressure (60-120 psi), the reaction's conversion improves; however, the selectivity of the reaction decreases due to the promotion of side reactions. Regarding the catalyst, increasing the TBAB concentration from 2.0 to 5.0 w/w% favors selectivity. The presence of a secondary mechanism is based on the formation of a carboxylate ion, which was formed due to the interaction of CO2 with the catalyst and was demonstrated through 13C-NMR and FT-IR. The combination of these factors makes it possible to obtain the largest conversion (96%), carbonation (95%), and selectivity (99%) values reported until now, which are obtained at low temperature (90 °C), low pressure (60 psi) and high catalyst concentration (5.0% TBAB).

Therapeutic targeting of Notch signaling and immune checkpoint blockade in a spontaneous, genetically heterogeneous mouse model of T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer derived from the malignant transformation of T-cell progenitors. Outcomes remain poor for T-ALL patients who have either primary resistance to standard-of-care chemotherapy or disease relapse. Notably, there are currently no targeted therapies available in T-ALL. This lack of next-generation therapies highlights the need for relevant preclinical disease modeling to identify and validate new targets and treatment approaches. Here, we adapted a spontaneously arising, genetically heterogeneous, thymic transplantation-based murine model of T-ALL, recapitulating key histopathological and genetic features of the human disease, to the preclinical testing of targeted and immune-directed therapies. Genetic engineering of the murine Notch1 locus aligned the spectrum of Notch1 mutations in the mouse model to that of human T-ALL and confirmed aberrant, recombination-activating gene (RAG)-mediated 5' Notch1 recombination events as the preferred pathway in murine T-ALL development. Testing of Notch1-targeting therapeutic antibodies demonstrated T-ALL sensitivity to different classes of Notch1 blockers based on Notch1 mutational status. In contrast, genetic ablation of Notch3 did not impact T-ALL development. The T-ALL model was further applied to the testing of immunotherapeutic agents in fully immunocompetent, syngeneic mice. In line with recent clinical experience in T-cell malignancies, programmed cell death 1 (PD-1) blockade alone lacked anti-tumor activity against murine T-ALL tumors. Overall, the unique features of the spontaneous T-ALL model coupled with genetic manipulations and the application to therapeutic testing in immunocompetent backgrounds will be of great utility for the preclinical evaluation of novel therapies against T-ALL.

Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling.

Androgen receptor (AR) signaling is a distinctive feature of prostate carcinoma (PC) and represents the major therapeutic target for treating metastatic prostate cancer (mPC). Though highly effective, AR antagonism can produce tumors that bypass a functional requirement for AR, often through neuroendocrine (NE) transdifferentiation. Through the molecular assessment of mPCs over two decades, we find a phenotypic shift has occurred in mPC with the emergence of an AR-null NE-null phenotype. These "double-negative" PCs are notable for elevated FGF and MAPK pathway activity, which can bypass AR dependence. Pharmacological inhibitors of MAPK or FGFR repressed the growth of double-negative PCs in vitro and in vivo. Our results indicate that FGF/MAPK blockade may be particularly efficacious against mPCs with an AR-null phenotype.

Biosynthesis of Silver Nanoparticles on Orthodontic Elastomeric Modules: Evaluation of Mechanical and Antibacterial Properties.

In the present study, silver nanoparticles (AgNPs) were synthesized in situ on orthodontic elastomeric modules (OEM) using silver nitrate salts as metal-ion precursors and extract of the plant Hetheroteca inuloides (H. inuloides) as bioreductant via a simple and eco-friendly method. The synthesized AgNPs were characterized by UV-visible spectroscopy; scanning electron microscopy-energy-dispersive spectroscopy (SEM-EDS) and transmission electron microscopy (TEM). The surface plasmon resonance peak found at 472 nm confirmed the formation of AgNPs. SEM and TEM images reveal that the particles are quasi-spherical. The EDS analysis of the AgNPs confirmed the presence of elemental silver. The antibacterial properties of OEM with AgNPs were evaluated against the clinical isolates Streptococcus mutans, Lactobacillus casei, Staphylococcus aureus and Escherichia coli using agar diffusion tests. The physical properties were evaluated by a universal testing machine. OEM with AgNPs had shown inhibition halos for all microorganisms in comparison with OEM control. Physical properties increased with respect to the control group. The results suggest the potential of the material to combat dental biofilm and in turn decrease the incidence of demineralization in dental enamel, ensuring their performance in patients with orthodontic treatment.

A comparative study of natural, formaldehyde-treated and copolymer-grafted orange peel for Pb(II) adsorption under batch and continuous mode.

Natural, formaldehyde-treated and copolymer-grafted orange peels were evaluated as adsorbents to remove lead ions from aqueous solutions. The optimum pH for lead adsorption was found to be pH 5. The adsorption process was fast, reaching 99% of sorbent capacity in 10 min for the natural and treated biomasses and 20 min for the grafted material. The treated biomass showed the highest sorption rate and capacity in the batch experiments, with the results fitting well to a pseudo-first order rate equation. In the continuous test with the treated biomass, the capacity at complete exhaustion was 46.61 mg g(-1) for an initial concentration of 150 mg L(-1). Scanning electronic microscopy and energy dispersive X-ray spectroscopy indicated that the materials had a rough surface, and that the adsorption of the metal took place on the surface. Fourier transform infrared spectroscopy revealed that the functional groups responsible for metallic biosorption were the -OH, -COOH and -NH(2) groups on the surface. Finally, the thermogravimetric analysis indicates that a mass reduction of 80% can be achieved at 600 degrees C.

Textural, structural and electrical properties of TiO2 nanoparticles using Brij 35 and P123 as surfactants.

The effect of the use of the triblock copolymer Pluronic P123[(PEO)20(PPO)70(PEO)20, Aldrich] and the non-ionic polyoxyethylene-lauryl ether Brij 35 as surfactants on the textural, structural and electrical properties of nanosized TiO2 is analyzed in this work. The as-obtained samples were thermally treated at 400 °C to eliminate the surfactant, promote dehydroxylation and crystallize the sample. The TiO2 samples were characterized by thermal analysis, N2 physisorption, x-ray diffraction analysis, micro-Raman spectroscopy and scanning electron microscopy. To evaluate the TiO2 electrical features, I-V data were obtained. The x-ray diffraction results show that in the chemical synthesis using surfactants, the crystallite size is smaller than that of the commercial sample. The Raman spectroscopy results clearly indicate that, when P123 is used, the anatase phase of TiO2 is obtained, whereas when Brij 35 is used a mixture of the anatase and brookite phases is obtained. The specific surface area and crystallite size of the TiO2 prepared as indicated above are higher and smaller, respectively, than the corresponding properties found in commercial TiO2. The I-V plot showed a nonlinear behavior of the nanosized TiO2. The samples obtained with P123 showed the best electrical conductivity.