Identifying SCC Lesions Capable of Spontaneous Regression by Using Immunohistochemistry: A Systematic Review and Meta-Analysis.

INTRODUCTION: Keratoacanthoma (KA) and squamous cell carcinoma (SCC) are two cutaneous conditions with morphological resemblance, which can complicate the diagnosis in some cases. Using immunohistochemistry staining of biomarkers could be beneficial in resolving this obstacle. OBJECTIVES: We investigated a variety of biomarkers assessed in different studies in order to find the most important and helpful biomarkers for differentiation between SCC and lesions capable of spontaneous regression. METHODS: MEDLINE via PubMed and Google Scholar database were used to identify relevant literature up to 15 June 2022. The aim of our analyses was to determine the capability of biomarkers to distinguish between SCC and lesions capable of spontaneous regression using calculated individual and pooled odds ratios (OR) and 95% confidence intervals (CI) and I2 tests. RESULTS: Six potential biomarkers were CD10 with pooled OR= 0.006 (95% CI: 0.001-0.057) and I2=0%; COX-2 with pooled OR=0.089 (95% CI: 0.029-0.269) and I2=17.1%; elastic fibers with pooled OR= 6.69 (95% CI: 2.928-15.281) and I2=0%; IMP-3 with pooled OR=0.145 (95% CI: 0.021-1.001) and I2=44.5%; P53 with pooled OR=0.371 (95% CI: 0.188-0.733) and I2=55.9%; AT1R with OR=0.026 (95% CI: 0.006-0.107). CONCLUSIONS: We suggest the utilization of the following IHC biomarkers for discrimination between lesions with spontaneous regression such as KA and SCC: CD10, COX-2, and elastic fibers.

Dental stem cells improve memory and reduce cell death in rat seizure model.

Epilepsy is a common neurological disorder that significantly affects the quality of life of patients. In this study, we aim to evaluate the effectiveness of dental pulp stem cell (DPSC) transplantation in decreasing inflammation and cell death in brain cells, thus reducing seizure damage. We induced seizures in rats using intraperitoneal injections of pentylenetetrazole (PTZ). In the PTZ + DPSC group, we conducted bilateral hippocampal transplantation of DPSCs in PTZ-lesioned rat models. After 1 month, we performed post-graft analysis and measured some behavioral factors, such as working memory and long-term memory, using a T-maze test and passive avoidance test, respectively. We investigated the immunohistopathology and distribution of astrocyte cells through light microscopy and Sholl analysis. Additionally, we employed the Voronoi tessellation method to estimate the spatial distribution of the cells in the hippocampus. Compared to the control group, we observed a reduction in astrogliosis, astrocyte process length, the number of branches, and intersections distal to the soma in the hippocampus of the PTZ + DPSC group. Further analysis indicated that the grafted DPSCs decreased the expression of caspase-3 in the hippocampus of rats with induced seizures. Moreover, the DPSCs transplant protected hippocampal pyramidal neurons against PTZ toxicity and improved the spatial distribution of the hippocampal neurons. Our findings suggest that DPSCs transplant can be an effective modifier of astrocyte reactivation and inflammatory responses.

Hydrogel-encapsulated extracellular vesicles for the regeneration of spinal cord injury.

Spinal cord injury (SCI) is a critical neurological condition that may impair motor, sensory, and autonomous functions. At the cellular level, inflammation, impairment of axonal regeneration, and neuronal death are responsible for SCI-related complications. Regarding the high mortality and morbidity rates associated with SCI, there is a need for effective treatment. Despite advances in SCI repair, an optimal treatment for complete recovery after SCI has not been found so far. Therefore, an effective strategy is needed to promote neuronal regeneration and repair after SCI. In recent years, regenerative treatments have become a potential option for achieving improved functional recovery after SCI by promoting the growth of new neurons, protecting surviving neurons, and preventing additional damage to the spinal cord. Transplantation of cells and cells-derived extracellular vesicles (EVs) can be effective for SCI recovery. However, there are some limitations and challenges related to cell-based strategies. Ethical concerns and limited efficacy due to the low survival rate, immune rejection, and tumor formation are limitations of cell-based therapies. Using EVs is a helpful strategy to overcome these limitations. It should be considered that short half-life, poor accumulation, rapid clearance, and difficulty in targeting specific tissues are limitations of EVs-based therapies. Hydrogel-encapsulated exosomes have overcome these limitations by enhancing the efficacy of exosomes through maintaining their bioactivity, protecting EVs from rapid clearance, and facilitating the sustained release of EVs at the target site. These hydrogel-encapsulated EVs can promote neuroregeneration through improving functional recovery, reducing inflammation, and enhancing neuronal regeneration after SCI. This review aims to provide an overview of the current research status, challenges, and future clinical opportunities of hydrogel-encapsulated EVs in the treatment of SCI.

Role of SARS-CoV-2-induced cytokine storm in multi-organ failure: Molecular pathways and potential therapeutic options.

Coronavirus disease 2019 (COVID-19) outbreak has become a global public health emergency and has led to devastating results. Mounting evidence proposes that the disease causes severe pulmonary involvement and influences different organs, leading to a critical situation named multi-organ failure. It is yet to be fully clarified how the disease becomes so deadly in some patients. However, it is proven that a condition called "cytokine storm" is involved in the deterioration of COVID-19. Although beneficial, sustained production of cytokines and overabundance of inflammatory mediators causing cytokine storm can lead to collateral vital organ damages. Furthermore, cytokine storm can cause post-COVID-19 syndrome (PCS), an important cause of morbidity after the acute phase of COVID-19. Herein, we aim to explain the possible pathophysiology mechanisms involved in COVID-19-related cytokine storm and its association with multi-organ failure and PCS. We also discuss the latest advances in finding the potential therapeutic targets to control cytokine storm wishing to answer unmet clinical demands for treatment of COVID-19.

The contribution of gut-brain axis to development of neurological symptoms in COVID-19 recovered patients: A hypothesis and review of literature.

The gut microbiota undergoes significant alterations in response to viral infections, particularly the novel SARS-CoV-2. As impaired gut microbiota can trigger numerous neurological disorders, we suggest that the long-term neurological symptoms of COVID-19 may be related to intestinal microbiota disorders in these patients. Thus, we have gathered available information on how the virus can affect the microbiota of gastrointestinal systems, both in the acute and the recovery phase of the disease, and described several mechanisms through which this gut dysbiosis can lead to long-term neurological disorders, such as Guillain-Barre syndrome, chronic fatigue, psychiatric disorders such as depression and anxiety, and even neurodegenerative diseases such as Alzheimer's and Parkinson's disease. These mechanisms may be mediated by inflammatory cytokines, as well as certain chemicals such as gastrointestinal hormones (e.g., CCK), neurotransmitters (e.g., 5-HT), etc. (e.g., short-chain fatty acids), and the autonomic nervous system. In addition to the direct influences of the virus, repurposed medications used for COVID-19 patients can also play a role in gut dysbiosis. In conclusion, although there are many dark spots in our current knowledge of the mechanism of COVID-19-related gut-brain axis disturbance, based on available evidence, we can hypothesize that these two phenomena are more than just a coincidence and highly recommend large-scale epidemiologic studies in the future.

Hypoxia-sensitive miRNA regulation via CRISPR/dCas9 loaded in hybrid exosomes: A novel strategy to improve embryo implantation and prevent placental insufficiency during pregnancy.

Assisted reproductive techniques as a new regenerative medicine approach have significantly contributed to solving infertility problems that affect approximately 15% of couples worldwide. However, the success rate of an in vitro fertilization (IVF) cycle remains only about 20%-30%, and 75% of these losses are due to implantation failure (the crucial rate-limiting step of gestation). Implantation failure and abnormal placenta formation are mainly caused by defective adhesion, invasion, and angiogenesis. Placental insufficiency endangers both the mother's and the fetus's health. Therefore, we suggested a novel treatment strategy to improve endometrial receptivity and implantation success rate. In this strategy, regulating mir-30d expression as an upstream transcriptomic modifier of the embryo implantation results in modified expression of the involved genes in embryonic adhesion, invasion, and angiogenesis and consequently impedes implantation failure. For this purpose, "scaffold/matrix attachment regions (S/MARs)" are employed as non-viral episomal vectors, transfecting into trophoblasts by exosome-liposome hybrid carriers. These vectors comprise CRISPR/dCas9 with a guide RNA to exclusively induce miR-30d gene expression in hypoxic stress conditions. In order to avoid concerns about the fetus's genetic manipulation, our vector would be transfected specifically into the trophoblast layer of the blastocyst via binding to trophoblast Erb-B4 receptors without entering the inner cell mass. Additionally, S/MAR episomal vectors do not integrate with the original cell DNA. As an on/off regulatory switch, a hypoxia-sensitive promoter (HRE) is localized upstream of dCas9. The miR-30d expression increases before and during the implantation and placental insufficiency conditions and is extinguished after hypoxia elimination. This hypothesis emphasizes that improving the adhesion, invasion, and angiogenesis in the uterine microenvironment during pregnancy will result in increased implantation success and reduced placental insufficiency, as a new insight in translational medicine.

Developing Cytokine Storm-Sensitive Therapeutic Strategy in COVID-19 Using 8P9R Chimeric Peptide and Soluble ACE2.

Currently, the COVID-19 pandemic is an international challenge, largely due to lack of effective therapies. Pharmacotherapy has not yet been able to find a definitive treatment for COVID-19. Since SARS-CoV-2 affects several organs, treatment strategies that target the virus in a wider range are expected to be ultimately more successful. To this end, a two-step treatment strategy has been presented. In the first phase of the disease, when the patient is newly infected with the virus and the cytokine storm has not yet been developed, a chimeric peptide is used to inhibit virus entry into the host cell cytosol (by inhibiting endosomal pH acidification) and viral replication. After the virus entry and decrease of angiotensin converting enzyme 2 (ACE2) level, some people are unable to properly compensate for the ACE2 pathway and progress toward the cytokine storm. In the beginning of the cytokine storm, sACE2 protein is very effective in regulating the immune system toward the anti-inflammatory pathway, including M2 macrophages. Hence, the genes of 8P9R chimeric peptide and sACE2 would be inserted in an episomal vector with a separate promoter for each gene: the chimeric peptide gene promoter is a CMV promoter, while the sACE2 gene promoter is a NF-κB-sensitive promoter. The NF-κB-sensitive promoter induces the expression of sACE2 gene soon after elevation of NF-κB which is the main transcription factor of inflammatory genes. Thus, as the expression of inflammatory cytokines increases, the expression of sACE2 increases simultaneously. In this condition, sACE2 can prevent the cytokine storm by inhibiting the pro-inflammatory pathways. To deliver the designed vector to the target cells, mesenchymal stem cell-derived (MSC-derived) exosome-liposome hybrids are used. Herein, the strategy can be considered as a personalized clinical therapy for COVID-19, that can prevent morbidity and mortality in the future.