Engineering Next-Generation CAR-T Cells for Better Toxicity Management

Immunoadoptive therapy with genetically modified T lymphocytes expressing chimeric antigen receptors (CARs) has revolutionized the treatment of patients with hematologic cancers. Although clinical outcomes in B-cell malignancies are impressive, researchers are seeking to enhance the activity, persistence, and also safety of CAR-T cell therapy—notably with a view to mitigating potentially serious or even life-threatening adverse events like on-target/off-tumor toxicity and (in particular) cytokine release syndrome. A variety of safety strategies have been developed by replacing or adding various components (such as OFF- and ON-switch CARs) or by combining multi-antigen-targeting OR-, AND- and NOT-gate CAR-T cells. This research has laid the foundations for a whole new generation of therapeutic CAR-T cells. Here, we review the most promising CAR-T cell safety strategies and the corresponding preclinical and clinical studies.     

Functional Insights into Silymarin as an Antiviral Agent against Enterovirus A71 (EV-A71)

Enterovirus A71 (EV-A71) is a major neurovirulent agent capable of causing severe hand, foot and mouth disease (HFMD) associated with neurological complications and death. Currently, no FDA-approved antiviral is available for the treatment of EV-A71 infections. The flavonoid silymarin was shown to exert virucidal effects, but the binding site on the capsid was unknown. In this study, the ligand interacting site of silymarin was determined in silico and validated in vitro. Moreover, the potential of EV-A71 to develop resistance against silymarin was further evaluated. Molecular docking of silymarin with the capsid of EV-A71 indicated that silymarin binds to viral protein 1 (VP1) of EV-A71, specifically at the GH loop of VP1. The in vitro binding of silymarin with VP1 of EV-A71 was validated using recombinant VP1 through ELISA competitive binding assay. Continuous passaging of EV-A71 in the presence of silymarin resulted in the emergence of a mutant carrying a substitution of isoleucine by threonine (I97T) at position 97 of the BC loop of EV-A71. The mutation was speculated to overcome the inhibitory effects of silymarin. This study provides functional insights into the underlying mechanism of EV-A71 inhibition by silymarin, but warrants further in vivo evaluation before being developed as a potential therapeutic agent.     

HMDCS-UV: A concept study of Hybrid Monitoring,Detection and Cleaning System for Unmanned Vehicles

This paper proposes a modular system of precision agriculture to automate sprayers, optimizing the application of pesticides through a robotic system based on computer vision and individual nozzle on/off control. The system uses low-cost equipment such as Arduino boards, solenoid valves, pressure and flow sensors, smartphone, webcam, and Raspberry Pi. The motivation is to reduce the amount of pesticides applied in crops, not just for potential savings for the farmers, but also for environment protection issues, as well as for food safety. The system can be used in any crop planted in rows such as onion, soybean, corn, beans, and rice. The results show that our system can detect lines in plantations and can be used to retrofit conventional boom sprayers, so it is an important step to develop a kit capable of upgrade a conventional sprayer to a fully autonomous robotic sprayer even at affordable cost in the context of small and medium size farms.

     

Characterization of Magnesium‐Doped Hydroxyapatite Prepared by Sol‐Gel Process

Pure and doped hydroxyapatite (HA) nanocrystalline powders (Ca_10‐xMg_x(PO₄)₆OH₂) were synthesized using sol‐gel process. For this, calcium nitrate tetrahydrate, magnesium nitrate hexahydrate, and phosphorous pentoxide were used as precursors for Ca, Mg, and P, respectively. Calculated amounts of magnesium ions (Mg⁺²) especially from 0 to 10% (molar ratio) were incorporated as dopant into the calcium sol solution. The structure and morphology of the gels obtained after mixing the phosphorous and (calcium + magnesium) sol solution were different, and their condensations in time depend on the quantities of magnesium added. The several powders resulting from the gels dried and sintered at 500°C for 1 h were characterized by thermogravimetry (TG), Fourier transform infrared spectroscopy (FTIR), X‐ray diffraction (XRD), and inductively coupled plasma (ICP). Additionally, their agglomeration, morphology, and particle size were investigated using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The specific surface area of each sample was measured by the Brunauer–Emmett–Teller (BET) gas adsorption technique. The results of XRD, FTIR, and ICP values ranged between 0.45 and 2.11 mg/L indicated that the magnesium added in the calcium solution was incorporated in the lattice structure of HA so prepared, while those obtained by SEM and TEM confirmed the influence of Mg on their morphology (needle and irregular shape) and crystallite size, which is about 30–60 nm. The as‐prepared powders had a specific surface area ranged between 6.37 and 27.60 m²/g.     

The influence of bleeding,extra water and superplasticizer on the SCC plastic shrinkage cracking: case of hot weather

Self-compacting concrete (SCC) is a new material able to be put in place without vibration. However, this advantage is offset by some drawbacks, such as plastic shrinkage, one of the causes of cracking in concrete. Furthermore, the presence of fines absorbs a large amount of water and therefore minimizes bleeding. This paper endeavours to provide a better understanding of the appearance of plastic shrinkage cracking, and to justify his relation with bleeding phenomena. Five SCC formulas with different W/C ratios were prepared and compared to the same range of ordinary concrete (OC) in terms of restrained shrinkage (cracking width). At the same time, a study of cracks’ propagation over time (cracking length) was conducted on the equivalent mortars (mOCe, mSCCe). Mixtures were placed in different hot environmental conditions. The results showed that bleeding significantly reduces cracking length and has no effect on cracking width. In the second part, extra water and superplasticizer was proposed as a solution to prevent SCC cracking and findings show the addition of 10% of water reduces cracking length and a slightly lower addition of superplasticizer reduces SCC’s crack width.     

Big Data: from collection to visualization

Organisations are increasingly relying on Big Data to provide the opportunities to discover correlations and patterns in data that would have previously remained hidden, and to subsequently use this new information to increase the quality of their business activities. In this paper we present a ‘story’ of Big Data from the initial data collection and to the end visualization, passing by the data fusion, and the analysis and clustering tasks. For this, we present a complete work flow on (a) how to represent the heterogeneous collected data using the high performance RDF language, how to perform the fusion of the Big Data in RDF by resolving the issue of entity disambiguity and how to query those data to provide more relevant and complete knowledge and (b) as the data are received in data streams, we propose batchStream, a Micro-Batching version of the growing neural gas approach, which is capable of clustering data streams with a single pass over the data. The batchStream algorithm allows us to discover clusters of arbitrary shapes without any assumptions on the number of clusters. This Big Data work flow is implemented in the Spark platform and we demonstrate it on synthetic and real data.     

HPV Lesions and Other Issues in the Oral Cavity Treatment and Removal without Pain

Due to different oral and dental conditions, oral mucosa lesions such as those caused by the human papilloma virus and temporomandibular joint pathologies often have to be treated by surgical, ablative or extractive procedures. The treatment and control of pain and inflammation during these procedures is essential to guarantee the patient’s well-being. For the foregoing reason, a hydrogel based on sodium alginate and hyaluronic acid containing 2% of ketorolac tromethamine has been developed. We characterized it physically, mechanically and morphologically. The rheological results suggest that the formulation can be easily and gently applied. Ex vivo permeation studies show that Ketorolac Tromethamine is able to penetrate through the buccal and sublingual mucosae, in addition to being retained in the mucosae’s structure. Through an in vitro test, we were able to evaluate the role that saliva plays in the bioavailability of the drug, observing that more than half of the applied dose is eliminated in an hour. The histological and cytotoxic studies performed on pigs in vivo showed the excellent safety profile of the formulation, as well as its high tolerability. In parallel, a biomimetic artificial membrane (PermeaPad^®) was evaluated, and it showed a high degree of correlation with the oral and sublingual mucosa.     

The web from a complex adaptive systems perspective

The web continues to grow at a phenomenal rate, and the amount of information on the web is overwhelming. Finding the relevant information remains a big challenge. Due to its wide distribution, its openness and high dynamics, the web is a complex system, for which we have to imagine mechanisms of content maintaining, filtering and organizing that are able to deal with its evolving dynamics and distribution. Integrating mechanisms of self-organization of the web content is an attractive perspective, to match with these requirements. Self-organized complex systems can be programmed using situated multi-agent systems with a coupling between the agents' social organization and spatial organization. This paper explores the web from a complex adaptive system (CAS) perspective. It reviews some characteristic behaviors of CASs and shows how the web exhibits similar behaviors. We propose a model and a prototype of a system that addresses the dynamic web content organization, adopting the CAS vision and using the multi-agent paradigm.     

High solids content emulsion polymerisation without intermediate seeds. Part II. In situ generation of bimodal latices

A process for the production of high solid content latexes with low viscosity that does not require the use of intermediate seeds is developed. It is shown that the second population of a bimodal latex can be generated by controlled homogeneous nucleation through the use of a combination of an initiator that generates charged free radicals and a mixed surfactant system that is very rich in non-ionic surfactant. The process was shown to be reproducible, and was used to produce a latex with a solid content of almost 77% (v/v) and a viscosity of 1.5 Pa s at a shear rate of 20 s⁻¹.