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.

Tokyo's COVID-19: An urban perspective on factors influencing infection rates in a global city.

This research investigates the relationship between COVID-19 and urban factors in Tokyo. To understand the spread dynamics of COVID-19, the study examined 53 urban variables (including population density, socio-economic status, housing conditions, transportation, and land use) in 53 municipalities of Tokyo prefecture. Using spatial models, the study analysed the patterns and predictors of COVID-19 infection rates. The findings revealed that COVID-19 cases were concentrated in central Tokyo, with clustering levels decreasing after the outbreaks. COVID-19 infection rates were higher in areas with a greater density of retail stores, restaurants, health facilities, workers in those sectors, public transit use, and telecommuting. However, household crowding was negatively associated. The study also found that telecommuting rate and housing crowding were the strongest predictors of COVID-19 infection rates in Tokyo, according to the regression model with time-fixed effects, which had the best validation and stability. This study's results could be useful for researchers and policymakers, particularly because Japan and Tokyo have unique circumstances, as there was no mandatory lockdown during the pandemic.

Exosomal non-coding RNAs: Emerging therapeutic targets in atherosclerosis.

Atherosclerosis is an LDL-driven and inflammatory disorder of the sub-endothelial space. Available data have proposed that various factors could affect atherosclerosis pathogenesis, including inflammation, oxidation of LDL particles, endothelial dysfunction, foam cell formation, proliferation, and migration of vascular smooth muscle cells (VSMCs). In addition, other research indicated that the crosstalk among atherosclerosis-induced cells is a crucial factor in modulating atherosclerosis. Extracellular vesicles arenanoparticleswith sizes ranging from 30 to 150 nm, playing an important role in various pathophysiological situations. Exosomes, asa form of extracellular vesicles, could affect the crosstalk between sub-endothelial cells. They can transport bioactive components like proteins, lipids, RNA, and DNA. As an important cargo in exosomes, noncoding RNAs (ncRNAs) including microRNAs, long noncoding RNAs, and circular RNAs could modulate cellular functions by regulating the transcription, epigenetic alteration, and translation. The current work aimed to investigate the underlying molecular mechanisms of exosomal ncRNA as well as their potential as a diagnostic biomarker and therapeutic target in atherosclerosis.

Effects of the built environment and human factors on the spread of COVID-19: A systematic literature review.

Soon after its emergence, COVID-19 became a global problem. While different types of vaccines and treatments are now available, still non-pharmacological policies play a critical role in managing the pandemic. The literature is enriched enough to provide comprehensive, practical, and scientific insights to better deal with the pandemic. This research aims to find out how the built environment and human factors have affected the transmission of COVID-19 on different scales, including country, state, county, city, and urban district. This is done through a systematic literature review of papers indexed on the Web of Science and Scopus. Initially, these databases returned 4264 papers, and after different stages of screening, we found 166 relevant papers and reviewed them. The empirical papers that had at least one case study and analyzed the effects of at least one built environment factor on the spread of COVID-19 were selected. Results showed that the driving forces can be divided into seven main categories: density, land use, transportation and mobility, housing conditions, demographic factors, socio-economic factors, and health-related factors. We found that among other things, overcrowding, public transport use, proximity to public spaces, the share of health and services workers, levels of poverty, and the share of minorities and vulnerable populations are major predictors of the spread of the pandemic. As the most studied factor, density was associated with mixed results on different scales, but about 58 % of the papers reported that it is linked with a higher number of cases. This study provides insights for policymakers and academics to better understand the dynamic roles of the non-pharmacological driving forces of COVID-19 at different levels.

Medroxyprogesterone acetate attenuates demyelination, modulating microglia activation, in a cuprizone neurotoxic demyelinating mouse model.

Clinical data reported a reduction of Multiple sclerosis (MS) symptoms during pregnancy when progesterone levels are high. Medroxyprogesterone acetate (MPA) is a synthetic progestin contraceptive with unknown neuroprotective effects. This study investigated the effect of a contraceptive dose of MPA on microglia polarization and neuroinflammation in the neurotoxic cuprizone (CPZ)-induced demyelinating mouse model of MS. Mice received 1 mg of MPA weekly, achieving similar serum concentrations in human contraceptive users. Results revealed that MPA therapy significantly reduced the demyelination in the corpus callosum. In addition, MPA treatment induced a significant reduction in microglia M1-markers (iNOS, IL-1ß and TNF-α) while M2-markers (Arg-1, IL-10 and TGF-ß) were significantly increased. Moreover, MPA resulted in a significant decrease in the number of iNOS positive cells (M1), whereas TREM-2 positive cells (M2) significantly increased. Furthermore, MPA decreased the protein expression levels of NF-κB and NLRP3 inflammasome as well as mRNA expression levels of the downstream product IL-18. In summary, MPA reduces the level of demyelination and has an anti-inflammatory role in CNS demyelination by inducing M2 microglia polarization and suppressing the M1 phenotype through the inhibition of NF-κB and NLRP3 inflammasome. Our results suggest that MPA should be a suitable contraceptive pharmacological agent in demyelinating diseases.

Smart City and Crisis Management: Lessons for the COVID-19 Pandemic.

COVID-19 shocked cities around the world and revealed the vulnerability of urban lives and functions. Most cities experienced a catastrophic disturbance that has lasted for a long time. Planning plays a critical role in responding efficiently to this crisis and enabling rapid functional recovery in the post-disaster era. Cities that have implemented digitalization initiatives and programs are likely to have more capacity to react appropriately. Specifically, digitalized cities could ensure the well-being of their residents and maintain continuity of urban functions. This research aims to analyze the role of technology in crisis management in the last two decades and provide appropriate policy recommendations for dealing with the COVID-19 pandemic. Systematic literature review and subjective content analysis are employed to investigate the effects of technology on community well-being and making cities more resilient in past crises. This study shows that different technology-driven policies and actions enable crisis management, enhance community well-being, and increase urban resilience. Technology has enhanced coping and recovery capacities by increasing participation and social connectedness, enhancing physical and mental health and maintaining the functionality of education and economic systems. These have been achieved through various solutions and technologies such as social media, telehealth, tracking and monitoring systems, sensors and locational applications, teleworking systems, etc. These solutions and technologies have also been used during the COVID-19 pandemic to enhance community well-being and sustain urban functions. However, technology deployment might have adverse effects such as social exclusion, digital divide, privacy and confidentiality violation, political bias and misinformation dissemination, and inefficient remote working and education. It is suggested that to mitigate these side effects, policymakers should liberate the process of digitalization, increase the accessibility to digital services, and enhance digital literacy.

Genetic polymorphisms and epigenetic regulation of survivin encoding gene, BIRC5, in multiple sclerosis patients.

BACKGROUND: The persistent the inflammatory condition in multiple sclerosis (MS) may due to the aberrant regulation of the elimination of the pathogenic autoreactive lymphocytes through apoptosis. Survivin, encoded by the BIRC5 gene, has been indicated to be involved in the regulation of apoptosis. This survey intended to investigate the genetic and microRNA mediated regulation of survivin in relapsing-remitting MS (RRMS) disease. RESULTS: It was observed that the C allele (OR = 1.38, 95% CI = 1.05-1.348, P = 0.022) and CC genotype (OR = 1.84, 95% CI = 1.06-3.19; P = 0.029) in the rs9904341 polymorphism increased the disease risk. Furthermore, miR-34a was significantly downregulated (Fold change = 0.41, P = 0.001) in the PBMCs from RRMS subjects. Survivin mRNA expression in PBMCs and serum survivin level were increased in RRMS patients in comparison to the controls. Downregulation of miR-34a was negatively correlated with increased survivin level. CONCLUSION: Although the genetic polymorphism of BIRC5 gene was associated with the disease risk, miR-34a was suggested to be involved in the regulation of survivin in the RRMS patients.