Natural killer cell-derived exosomes for cancer immunotherapy: innovative therapeutics art.

Chimeric antigen receptor natural killer cells (CAR-NK) promote off-the-shelf cellular therapy for solid tumors and malignancy.However,, the development of CAR-NK is due to their immune surveillance uncertainty and cytotoxicity challenge was restricted. Natural killer cell-derived exosome (NK-Exo) combine crucial targeted cellular therapies of NK cell therapies with unique non-toxic Exo as a self-origin shuttle against cancer immunotherapy. This review study covers cytokines, adoptive (autologous and allogenic) NK immunotherapy, stimulatory and regulatory functions, and cell-free derivatives from NK cells. The future path of NK-Exo cytotoxicity and anti-tumor activity with considering non-caspase-independent/dependent apoptosis and Fas/FasL pathway in cancer immunotherapy. Finally, the significance and implication of NK-Exo therapeutics through combination therapy and the development of emerging approaches for the purification and delivery NK-Exo to severe immune and tumor cells and tissues were discussed in detail.

Recent advances in the roles of exosomal microRNAs (exomiRs) in hematologic neoplasms: pathogenesis, diagnosis, and treatment.

In clinical diagnosis, the capability of exosomes to serve as biomarkers is one of the most important biological functions of exosomes. The superior stability of exosome biomarkers makes them superior to those isolated from traditional samples such as serum and urine. Almost all body fluids contain exosomes, which contain proteins, nucleic acids, and lipids. Several molecular components of exosomes, including exosome proteins and microRNAs (miRNAs), are promising diagnostic biomarkers. These exosomes may carry genetic information by containing messenger RNA (mRNA) and miRNA. The miRNAs are small noncoding RNAs that regulate protein-coding genes by acting as translational repressors. It has been shown that miRNAs are mis-expressed in a range of conditions, including hematologic neoplasms. Additionally, miRNAs found within exosomes have been linked with specific diseases, including hematologic neoplasms. Numerous studies suggest that circulating exosomes contain miRNAs similar to those found in parental cancer cells. Exosomes contain miRNAs that are released by almost all kinds of cells. MiRNAs are packaged into exosomes and delivered to recipient cells, and manipulate its function. It has been recognized that exosomes are new therapeutic targets for immunotherapy and biomedicine of cancers. The current review discusses the current evidence around exosomal miRNAs involved in the pathogenesis, diagnosis, and treatment of hematologic neoplasms. Video Abstract.

B lymphocytes in COVID-19: a tale of harmony and discordance.

B lymphocytes play a vital role in the human defense against viral infections by producing specific antibodies. They are also critical for the prevention of infectious diseases by vaccination, and their activation influences the efficacy of the vaccination. Since the beginning of coronavirus disease 2019 (COVID-19), which became the main concern of the world health system, many efforts have been made to treat and prevent the disease. However, for the development of successful therapeutics and vaccines, it is necessary to understand the interplay between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, and the immune system. The innate immune system provides primary and nonspecific defense against the virus, but within several days after infection, a virus-specific immune response is provided first by antibody-producing B cells, which are converted after the resolution of disease to memory B cells, which provide long-term immunity. Although a failure in B cell activation or B cell dysfunction can cause a severe form of the disease and also lead to vaccination inefficiency, some individuals with B cell immunodeficiency have shown less production of the cytokine IL-6, resulting in a better disease outcome. In this review, we present the latest findings on the interaction between SARS-CoV-2 and B lymphocytes during COVID-19 infection.

Reactogenicity within the first week after Sinopharm, Sputnik V, AZD1222, and COVIran Barekat vaccines: findings from the Iranian active vaccine surveillance system.

BACKGROUND: This study aimed to evaluate the reactogenicity effects of COVID-19 vaccines, used in Iran. METHODS: At least 1000 people were followed up with phone calls or self-report in a mobile application within 7 days after vaccination. Local and systemic reactogenicities were reported overall and by subgroups. RESULTS: The presence of one or more local and systemic adverse effects after the first dose of vaccines was 58.9% [(95% Confidence Intervals): 57.5-60.3)] and 60.5% (59.1-61.9), respectively. These rates were reduced to 53.8% (51.2-55.0) and 50.8% (48.8-52.7) for the second dose. The most common local adverse effect reported for all vaccines was pain in the injection site. During the first week after the first dose of vaccines, the frequency of the pain for Sinopharm, AZD1222, Sputnik V, and Barekat was 35.5%, 86.0%, 77.6%, and 30.9%, respectively. The same rates after the second dose were 27.3%, 66.5%, 63.9%, and 49.0%. The most common systemic adverse effect was fatigue. In the first dose, it was 30.3% for Sinopharm, 67.4% for AZD1222, 47.6% for Sputnik V, and 17.1% for Barekat. These rates were reduced to 24.6%, 37.1%, 36.5%, and 19.5%, in the second dose of vaccines. AZD1222 had the highest local and systemic adverse effects rates. The odds ratio of local adverse effects of the AZD1222 vaccine compared to the Sinopharm vaccine were 8.73 (95% CI 6.93-10.99) in the first dose and 4.14 (95% CI 3.32-5.17) in the second dose. Barekat and Sinopharm had the lowest frequency of local and systemic adverse effects. Compared to Sinopharm, systemic adverse effects were lower after the first dose of Barekat (OR = 0.56; 95% CI 0.46-0.67). Reactogenicity events were higher in women and younger people. Prior COVID-19 infection increased the odds of adverse effects only after the first dose of vaccines. CONCLUSIONS: Pain and fatigue were the most common reactogenicities of COVID-19 vaccination. Reactogenicities were less common after the second dose of the vaccines. The adverse effects of AZD1222 were greater than those of other vaccines.

Quantum Bohmian-Inspired Potential to Model Non-Gaussian Time Series and Its Application in Financial Markets.

We have implemented quantum modeling mainly based on Bohmian mechanics to study time series that contain strong coupling between their events. Compared to time series with normal densities, such time series are associated with rare events. Hence, employing Gaussian statistics drastically underestimates the occurrence of their rare events. The central objective of this study was to investigate the effects of rare events in the probability densities of time series from the point of view of quantum measurements. For this purpose, we first model the non-Gaussian behavior of time series using the multifractal random walk (MRW) approach. Then, we examine the role of the key parameter of MRW, λ, which controls the degree of non-Gaussianity, in quantum potentials derived for time series. Our Bohmian quantum analysis shows that the derived potential takes some negative values in high frequencies (its mean values), then substantially increases, and the value drops again for rare events. Thus, rare events can generate a potential barrier in the high-frequency region of the quantum potential, and the effect of such a barrier becomes prominent when the system transverses it. Finally, as an example of applying the quantum potential beyond the microscopic world, we compute quantum potentials for the S&P financial market time series to verify the presence of rare events in the non-Gaussian densities and demonstrate deviation from the Gaussian case.

Exosomes as bio-inspired nanocarriers for RNA delivery: preparation and applications.

Nanocarriers as drug/biomolecule delivery systems have been significantly developed during recent decades. Given the stability, reasonable delivery efficiency, and safety of nanocarriers, there are several barriers in the fulfillment of successful clinical application of these delivery systems. These challenges encouraged drug delivery researchers to establish innovative nanocarriers with longer circulation time, high stability, and high compatibility. Exosomes are extracellular nanometer-sized vesicles released through various cells. These vesicles serve as nanocarriers, possessing great potential to overcome some obstacles encountered in gene and drug delivery due to their natural affinity to recipient cells and the inherent capability to shuttle the genes, lipids, proteins, and RNAs between cells. So far, there has been a lot of valuable research on drug delivery by exosomes, but research on RNA delivery, especially mRNA, is very limited. Since mRNA-based vaccines and therapies have recently gained particular prominence in various diseases, it is essential to find a suitable delivery system due to the large size and destructive nature of these nucleic acids. That's why we're going to take a look at the unique features of exosomes and their isolation and loading methods, to embrace this idea that exosome-mediated mRNA-based therapies would be introduced as a very efficient strategy in disease treatment within the near future.

Tumor-promoting myeloid cells in the pathogenesis of human oncoviruses: potential targets for immunotherapy.

Oncoviruses, known as cancer-causing viruses, are typically involved in cancer progression by inhibiting tumor suppressor pathways and uncontrolled cell division. Myeloid cells are the most frequent populations recruited to the tumor microenvironment (TME) and play a critical role in cancer development and metastasis of malignant tumors. Tumor-infiltrating myeloid cells, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), tumor-associated dendritic cells (TADCs), and tumor-associated neutrophils (TANs) exert different states from anti-tumorigenic to pro-tumorigenic phenotypes in TME. Although their role in the anti-tumorigenic state is well introduced, their opposing roles, pro-tumorigenic activities, such as anti-inflammatory cytokine and reactive oxygen species (ROS) production, should not be ignored since they result in inflammation, tumor progression, angiogenesis, and evasion. Since the blockade of these cells had promising results against cancer progression, their inhibition might be helpful in various cancer immunotherapies. This review highlights the promoting role of tumor-associated myeloid cells (TAMCs) in the pathophysiology of human virus tumorigenesis.

COVID-19 cases, hospitalizations and deaths after vaccination: a cohort event monitoring study, Islamic Republic of Iran.

Objective: To investigate the incidence of coronavirus disease 2019 (COVID-19) cases, hospitalizations and deaths in Iranians vaccinated with either AZD1222 Vaxzevria, CovIran® vaccine, SARS-CoV-2 Vaccine (Vero Cell), Inactivated (lnCoV) or Sputnik V. Methods: We enrolled individuals 18 years or older receiving their first COVID-19 vaccine dose between April 2021 and January 2022 in seven Iranian cities. Participants completed weekly follow-up surveys for 17 weeks (25 weeks for AZD1222) to report their COVID-19 status and hospitalization. We used Cox regression models to assess risk factors for contracting COVID-19, hospitalization and death. Findings: Of 89 783 participants enrolled, incidence rates per 1 000 000 person-days were: 528.2 (95% confidence interval, CI: 514.0-542.7) for contracting COVID-19; 55.8 (95% CI: 51.4-60.5) for hospitalization; and 4.1 (95% CI: 3.0-5.5) for death. Compared with SARS-CoV-2 Vaccine (Vero Cell), hazard ratios (HR) for contracting COVID-19 were: 0.70 (95% CI: 0.61-0.80) with AZD1222; 0.73 (95% CI: 0.62-0.86) with Sputnik V; and 0.73 (95% CI: 0.63-0.86) with CovIran®. For hospitalization and death, all vaccines provided similar protection 14 days after the second dose. History of COVID-19 protected against contracting COVID-19 again (HR: 0.76; 95% CI: 0.69-0.84). Diabetes and respiratory, cardiac and renal disease were associated with higher risks of contracting COVID-19 after vaccination. Conclusion: The rates of contracting COVID-19 after vaccination were relatively high. SARS-CoV-2 Vaccine (Vero Cell) provided lower protection against COVID-19 than other vaccines. People with comorbidities had higher risks of contracting COVID-19 and hospitalization and should be prioritized for preventive interventions.

Molecular variants of SARS-CoV-2: antigenic properties and current vaccine efficacy.

An ongoing pandemic of newly emerged SARS-CoV-2 has puzzled many scientists and health care policymakers around the globe. The appearance of the virus was accompanied by several distinct antigenic changes, specifically spike protein which is a key element for host cell entry of virus and major target of currently developing vaccines. Some of these mutations enable the virus to attach to receptors more firmly and easily. Moreover, a growing number of trials are demonstrating higher transmissibility and, in some of them, potentially more serious forms of illness related to novel variants. Some of these lineages, especially the Beta variant of concern, were reported to diminish the neutralizing activity of monoclonal and polyclonal antibodies present in both convalescent and vaccine sera. This could imply that these independently emerged variants could make antiviral strategies prone to serious threats. The rapid changes in the mutational profile of new clades, especially escape mutations, suggest the convergent evolution of the virus due to immune pressure. Nevertheless, great international efforts have been dedicated to producing efficacious vaccines with cutting-edge technologies. Despite the partial decrease in vaccines efficacy against worrisome clades, most current vaccines are still effective at preventing mild to severe forms of disease and hospital admission or death due to coronavirus disease 2019 (COVID-19). Here, we summarize existing evidence about newly emerged variants of SARS-CoV-2 and, notably, how well vaccines work against targeting new variants and modifications of highly flexible mRNA vaccines that might be required in the future.

Dual Blockade of PD-1 and LAG3 Immune Checkpoints Increases Dendritic Cell Vaccine Mediated T Cell Responses in Breast Cancer Model.

PURPOSE: Increasing the efficiency of unsuccessful immunotherapy methods is one of the most important research fields. Therefore, the use of combination therapy is considered as one of the ways to increase the effectiveness of the dendritic cell (DC) vaccine. In this study, the inhibition of immune checkpoint receptors such as LAG3 and PD-1 on T cells was investigated to increase the efficiency of T cells in response to the DC vaccine. METHODS: We used trimethyl chitosan-dextran sulfate-lactate (TMC-DS-L) nanoparticles (NPs) loaded with siRNA molecules to quench the PD-1 and LAG3 checkpoints' expression. RESULTS: Appropriate physicochemical characteristics of the generated NPs led to efficient inhibition of LAG3 and PD-1 on T cells, which was associated with increased survival and activity of T cells, ex vivo. Also, treating mice with established breast tumors (4T1) using NPs loaded with siRNA molecules in combination with DC vaccine pulsed with tumor lysate significantly inhibited tumor growth and increased survival in mice. These ameliorative effects were associated with increased anti-tumor T cell responses and downregulation of immunosuppressive cells in the tumor microenvironment and spleen. CONCLUSION: These findings strongly suggest that TMC-DS-L NPs loaded with siRNA could act as a novel tool in inhibiting the expression of immune checkpoints in the tumor microenvironment. Also, combination therapy based on inhibition of PD-1 and LAG3 in combination with DC vaccine is an effective method in treating cancer that needs to be further studied.

Combination Cancer Immunotherapy with Dendritic Cell Vaccine and Nanoparticles Loaded with Interleukin-15 and Anti-beta-catenin siRNA Significantly Inhibits Cancer Growth and Induces Anti-Tumor Immune Response.

PURPOSE: The invention and application of new immunotherapeutic methods can compensate for the inefficiency of conventional cancer treatment approaches, partly due to the inhibitory microenvironment of the tumor. In this study, we tried to inhibit the growth of cancer cells and induce anti-tumor immune responses by silencing the expression of the ß-catenin in the tumor microenvironment and transmitting interleukin (IL)-15 cytokine to provide optimal conditions for the dendritic cell (DC) vaccine. METHODS: For this purpose, we used folic acid (FA)-conjugated SPION-carboxymethyl dextran (CMD) chitosan (C) nanoparticles (NPs) to deliver anti-ß-catenin siRNA and IL-15 to cancer cells. RESULTS: The results showed that the codelivery of ß-catenin siRNA and IL-15 significantly reduced the growth of cancer cells and increased the immune response. The treatment also considerably stimulated the performance of the DC vaccine in triggering anti-tumor immunity, which inhibited tumor development and increased survival in mice in two different cancer models. CONCLUSIONS: These findings suggest that the use of new nanocarriers such as SPION-C-CMD-FA could be an effective way to use as a novel combination therapy consisting of ß-catenin siRNA, IL-15, and DC vaccine to treat cancer.

The PI3K/AKT signaling pathway in cancer: Molecular mechanisms and possible therapeutic interventions.

The human body consists of countless cells with the possibility of excessive and uncontrolled proliferation under certain dysregulated circumstances that could cause abnormal states such as cancer. Phosphatidylinositol 3 kinase (PI3K) and its downstream target, Protein kinase B or AKT, play a critical role in cell survival, proliferation, differentiation, migration, and metabolism. Research studies have examined the aberrant expression of signaling molecules that regulate PI3K/AKT pathway with the purpose of target discovery. The present review aims to recapitulate the relationship between the PI3K/AKT signaling pathway and factors contributing to initiation and development of various cancers. In addition, therapeutic interventions regulating this signaling pathway have been summarized.

Recent advances in mRNA-LNP therapeutics: immunological and pharmacological aspects.

In the last decade, the development of messenger RNA (mRNA) therapeutics by lipid nanoparticles (LNP) leads to facilitate clinical trial recruitment, which improves the efficacy of treatment modality to a large extent. Although mRNA-LNP vaccine platforms for the COVID-19 pandemic demonstrated high efficiency, safety and adverse effects challenges due to the uncontrolled immune responses and inappropriate pharmacological interventions could limit this tremendous efficacy. The current study reveals the interplay of immune responses with LNP compositions and characterization and clarifies the interaction of mRNA-LNP therapeutics with dendritic, macrophages, neutrophile cells, and complement. Then, pharmacological profiles for mRNA-LNP delivery, including pharmacokinetics and cellular trafficking, were discussed in detail in cancer types and infectious diseases. This review study opens a new and vital landscape to improve multidisciplinary therapeutics on mRNA-LNP through modulation of immunopharmacological responses in clinical trials.

Narrow-band transmission filter based on 1D-PCs with a defect layer.

A narrow-band transmission filter based on one-dimensional photonic crystals with SiO2/titaniumdioxide(TiO2) layers is grown by sol-gel spin-coating processing. The structural and optical properties of fabricated samples are characterized by an atomic force microscope, scanning electron microscope, and UV-visible spectroscopy. Specific wavelength transmission and bandgap in the optical filter with and without a defect layer have been investigated by engineering the layer thickness and defect layer material. For three fabricated optical filters, it is found that the maximum transmission for the TiO2 and InP defect layers reaches 58.09% and 42.21%, respectively. The layer thickness is fixed just by tuning the rotational speed of the spin-coater.

Long-Term Persistence of Anti-SARS-COV-2 IgG Antibodies.

Antibodies against severe acute respiratory syndrome coronavirus-2 (Anti-SARS-COV-2) can be detected in patients with COVID-19 in 7 to 10 days post onset of symptoms (POS). However, there is no firm evidence of the long-term persistence of these antibodies in recovered COVID-19 patients. Therefore, this study aimed to evaluate the stability of anti-SARS-COV-2 IgG in recovered COVID-19 patients in a 15-month follow-up testing. Thirty hospitalized patients with real-time PCR-confirmed SARS-COV-2 infections were included in the study and five serum samples (1st, 2nd, 3rd, 4th, and 5th) were collected from each participant. The serum levels of N and S specific anti-SARS-COV-2 IgG and IgM antibodies were evaluated by the immunoassay technique at the same time. To determine the correlation between levels of anti-SARS-CoV-2 IgG/IgM with severity of disease, neutrophil-to-lymphocyte ratio (NLR %), and the serum levels of C-reactive protein were evaluated using an automated analyzer and turbidimetry assays, respectively. The mean serum level of anti-SARS-CoV-2 IgG antibody was at the highest level up to 90 days and then decreased significantly 1 year POS (P < 0.0001). However, it was still detectable in a 15-month follow-up testing. There were no significant differences in the mean levels of IgG antibody in patients with mild, moderate, and severe diseases. The results from this study suggest that the titer of anti-SARS-COV-2 IgG antibody is detectable at high levels up to 3 months and then decreases over time. However, these antibodies can be reliably detected in up to 15 months, and they may persist for a long time.

Exosomes for mRNA delivery: a novel biotherapeutic strategy with hurdles and hope.

Over the past decade, therapeutic messenger RNAs (mRNAs) have emerged as a highly promising new class of drugs for protein replacement therapies. Due to the recent developments, the incorporation of modified nucleotides in synthetic mRNAs can lead to maximizing protein expression and reducing adverse immunogenicity. Despite these stunning improvements, mRNA therapy is limited by the need for the development of safe and efficient carriers to protect the mRNA integrity for in vivo applications. Recently, leading candidates for in vivo drug delivery vehicles are cell-derived exosomes, which have fewer immunogenic responses. In the current study, the key hurdles facing mRNA-based therapeutics, with an emphasis on recent strategies to overcoming its immunogenicity and instability, were highlighted. Then the immunogenicity and toxicity of exosomes derived from various cell sources were mentioned in detail. Finally, an overview of the recent strategies in using exosomes for mRNA delivery in the treatment of multiple diseases was stated.

Neurological manifestations of COVID-19: with emphasis on Iranian patients.

The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has instigated a global pandemic as a formidable and highly contagious infectious disease. Although the respiratory system remains the most frequently affected organ, several case reports have revealed that the complications are not merely limited to the respiratory system, and neurotropic and neuroinvasive properties have also been observed, leading to neurological diseases. In the present paper, it was intended to review the possible neuroinvasive routes of SARS-CoV-2 and its mechanisms that may cause neurological damage. Additionally, the neurological manifestations of COVID-19 across the globe were discussed with emphasis on Iran, while highlighting the impact of SARS-CoV-2 on the central and peripheral nervous systems.

The tumorigenic and therapeutic functions of exosomes in colorectal cancer: Opportunity and challenges.

Most cells release extracellular vesicles (EVs) mediating intercellular communication via transferring various biomolecules including proteins, nucleic acids, and lipids. A subset of EVs is exosomes that promote tumorigenesis. Different tumour cells such as colorectal cancer (CRC) cells produce exosomes that participate in the progression of CRC. Exosomes cargo including proteins and miRNAs not only support proliferation and metastasis of tumour cells but also mediate chemoresistance, immunomodulation and angiogenesis. In addition, as exosomes are present in most body fluids, they can hold the great capacity for clinical usage in early diagnosis and prognosis of CRC. Exosomes from CRC (CRC-Exo) differentially contain proteins and miRNAs that make them a promising candidate for CRC diagnosis by a simple liquid-biopsy. Despite hopeful results, some challanges about exosomes terminology and definition remains to be clarified in further experiments. In addition, there are little clinical trials regarding the application of exosomes in CRC treatment, therefore additional studies are essential focusing on exosome biology and translation of preclinical findings into the clinic. The present study discusses the key role of exosomes in CRC progression and diagnosis. Furthermore, it describes the opportunity and challenges associated with using exosomes as tumour markers.

Nanoparticle-mediated synergistic chemoimmunotherapy for tailoring cancer therapy: recent advances and perspectives.

Nowadays, a potent challenge in cancer treatment is considered the lack of efficacious strategy, which has not been able to significantly reduce mortality. Chemoimmunotherapy (CIT) as a promising approach in both for the first-line and relapsed therapy demonstrated particular benefit from two key gating strategies, including chemotherapy and immunotherapy to cancer therapy; therefore, the discernment of their participation and role of potential synergies in CIT approach is determinant. In this study, in addition to balancing the pros and cons of CIT with the challenges of each of two main strategies, the recent advances in the cancer CIT have been discussed. Additionally, immunotherapeutic strategies and the immunomodulation effect induced by chemotherapy, which boosts CIT have been brought up. Finally, harnessing and development of the nanoparticles, which mediated CIT have expatiated in detail.

Adverse effects of brimonidine eye drop in children: A case series.

WHAT IS KNOWN AND OBJECTIVE: Brimonidine is increasingly used in the treatment of intraocular hypertension. CASE SUMMARY: We report on five paediatric patients suffering from brimonidine eye drop intoxication. The most frequent signs of the intoxication were a lowered level of consciousness and hypotonia. Other complications were apnea, bradycardia, hypotension and seizure. One of the patients needed cardiopulmonary resuscitation. Apnea in one of the cases was resistant to naloxone. Pupils were unremarkable in two cases. WHAT IS NEW AND CONCLUSION: Brimonidine is potentially lethal for young infants. The absence of miosis and absence of response to naloxone is not a reason to rule out brimonidine poisoning.