Progress and pitfalls of gene editing technology in CAR-T cell therapy: a state-of-the-art review.

CAR-T cell therapy has shown remarkable promise in treating B-cell malignancies, which has sparked optimism about its potential to treat other types of cancer as well. Nevertheless, the Expectations of CAR-T cell therapy in solid tumors and non-B cell hematologic malignancies have not been met. Furthermore, safety concerns regarding the use of viral vectors and the current personalized production process are other bottlenecks that limit its widespread use. In recent years the use of gene editing technology in CAR-T cell therapy has opened a new way to unleash the latent potentials of CAR-T cell therapy and lessen its associated challenges. Moreover, gene editing tools have paved the way to manufacturing CAR-T cells in a fully non-viral approach as well as providing a universal, off-the-shelf product. Despite all the advantages of gene editing strategies, the off-target activity of classical gene editing tools (ZFNs, TALENs, and CRISPR/Cas9) remains a major concern. Accordingly, several efforts have been made in recent years to reduce their off-target activity and genotoxicity, leading to the introduction of advanced gene editing tools with an improved safety profile. In this review, we begin by examining advanced gene editing tools, providing an overview of how these technologies are currently being applied in clinical trials of CAR-T cell therapies. Following this, we explore various gene editing strategies aimed at enhancing the safety and efficacy of CAR-T cell therapy.

The paths and challenges of "off-the-shelf" CAR-T cell therapy: An overview of clinical trials.

The advent of chimeric antigen receptor T cells (CAR-T cells) has made a tremendous revolution in the era of cancer immunotherapy, so that since 2017 eight CAR-T cell products have been granted marketing authorization. All of these approved products are generated from autologous sources, but this strategy faces several challenges such as time-consuming and expensive manufacturing process and reduced anti-tumor potency of patients' T cells due to the disease or previous therapies. The use of an allogeneic source can overcome these issues and provide an industrial, scalable, and standardized manufacturing process that reduces costs and provides faster treatment for patients. Nevertheless, for using allogeneic CAR-T cells, we are faced with the challenge of overcoming two formidable impediments: severe life-threatening graft-versus-host-disease (GvHD) caused by allogeneic CAR-T cells, and allorejection of allogeneic CAR-T cells by host immune cells which is called "host versus graft" (HvG). In this study, we reviewed recent registered clinical trials of allogeneic CAR-T cell therapy to analyze different approaches to achieve a safe and efficacious "off-the-shelf" source for chimeric antigen receptor (CAR) based immunotherapy.

Comparison of Maturity in Auditory-Visual Multisensory Processes With Sound-Induced Flash Illusion Test in Children and Adults.

Multi-sensory neural pathways of auditory-visual maturation develop before birth in humans. Maturation levels of multi-sensory brain pathways are very different in children in comparison to adults. Auditory sensory neural maturation occurs earlier than visual sensory neural maturation. Auditory-visual multi-sensory processing can assess using objective (event-related potential tests) and subjective (behavioral tests). In this study, we use the sound-induced flash illusion (SIFI) test as a subjective test. The results of the SIFI test show that when the test is complex, the younger children performed not as accurately as the older ones. This difference occurs due to the complexity in the auditory-visual multi-sensory pathway maturation. Therefore, it is necessary to evaluate and analyze the results of different age groups with their normative data.

Can Pitch Mismatch Be Diagnosed in Children Who Use Electric-Acoustic Stimulation?

Introduction Pitch mismatch is one of the most important problems of users of bimodal cochlear implants, which affects their life satisfaction. Children with acquired hearing loss cannot explain their pitch mismatch problems, as they have had no auditory experience. This study tries to diagnose pitch mismatch in these children through the sound-induced flash illusion test. Materials and methods In this study, 20 children with a bimodal cochlear implant and 20 children with normal hearing, within the age range of 8 to 13 years old, were examined using the sound-induced flash illusion test. In this test, participants received one flash with one to four beep sounds, and they were asked to indicate the number of perceived flashes. Results The results revealed that in the bimodal implantation group, when the flash was provided with one beep, at certain frequencies, children expressed that they saw two flashes. However, the results were not the same in children with normal hearing. Conclusion The results indicated that at frequencies where the auditory information of the hearing aids and those of the cochlear implants overlap, pitch mismatch develops, which can significantly affect the auditory performance of bimodal users.

Investigating the Effects of Hearing Loss and Hearing Aid Digital Delay on Sound-Induced Flash Illusion.

BACKGROUND AND OBJECTIVES: The integration of auditory-visual speech information improves speech perception; however, if the auditory system input is disrupted due to hearing loss, auditory and visual inputs cannot be fully integrated. Additionally, temporal coincidence of auditory and visual input is a significantly important factor in integrating the input of these two senses. Time delayed acoustic pathway caused by the signal passing through digital signal processing. Therefore, this study aimed to investigate the effects of hearing loss and hearing aid digital delay circuit on sound-induced flash illusion. SUBJECTS AND METHODS: A total of 13 adults with normal hearing, 13 with mild to moderate hearing loss, and 13 with moderate to severe hearing loss were enrolled in this study. Subsequently, the sound-induced flash illusion test was conducted, and the results were analyzed. RESULTS: The results showed that hearing aid digital delay and hearing loss had no detrimental effect on sound-induced flash illusion. CONCLUSIONS: Transmission velocity and neural transduction rate of the auditory inputs decreased in patients with hearing loss. Hence, the integrating auditory and visual sensory cannot be combined completely. Although the transmission rate of the auditory sense input was approximately normal when the hearing aid was prescribed. Thus, it can be concluded that the processing delay in the hearing aid circuit is insufficient to disrupt the integration of auditory and visual information.

Acid-treated Fe-doped TiO2 as a high performance photocatalyst used for degradation of phenol under visible light irradiation.

The photocatalytic activity of Fe-doped TiO2 nanoparticles is significantly increased by an acid-treatment process. The photocatalyst nanoparticles were prepared using sol-gel method with 0.5 mol% ratio of Fe:Ti in acidic pH of 3. The nanoparticles were structurally characterized by means of X-ray diffraction (XRD), high-resolution transmission electron microscope (HRTEM), energy-dispersive X-ray spectroscopy (EDX), X-ray photoelectron spectroscopy (XPS) and diffuse reflectance spectroscopy (DRS). It was observed that the photocatalytic activity suffered from an iron oxide contaminating layer deposited on the surface of the nanoparticles. This contamination layer was removed using an HCl acid-treatment process. The photocatalytic activity using 500 mg/L of Fe0.5-TiO2 in a 10 mg/L of phenol solution increased significantly from 33% to 57% (about 73% increase in the performance), within 90 min of reaction time under visible light irradiation. This significant improvement was achieved by removing the iron oxide contamination layer from the surface of the nanoparticles and adjusting pH to mild acidic and basic pHs.

Study of enzymatic degradation and water absorption of composites carboxymethyl cellulose and poly (ϵ-caprolactone) containing SiO2nanoparticle by cellulase.

This study investigates the effect of Poly (ϵ-Caprolactone (PCL) and Nano-SiO2content within the Carboxymethyl Cellulose (CMC) blends on the rate and extent of carboxymethyl cellulose enzymatic hydrolysis using the enzyme cellulase. The results reveal that blends with Nano-SiO2content at 5 wt% exhibit a significantly reduced rate and extent of CMC hydrolysis. This may be attributed to interactions between CMC and SiO2that prevent further enzymatic attack on the remaining CMC phases within the blend. The total solids that remained after 2880 min were 44.8 wt.% (CMC: PCL); 62.7 wt.% (CMC: PCL: 1% Nano-SiO2); 69.8 wt.% (CMC: PCL: 3% Nano-SiO2); 73.1 wt.% (CMC: PCL: 5% Nano-SiO2). Enzymatic degradation behaviour of CMC: PCL: Nano-SiO2was based on the determinations of water resistance, weight loss and the reducing sugars. The degraded residues have been examined by scanning electronic microscopy (SEM) and UV-Vis spectroscopy.