Current approaches in glioblastoma multiforme immunotherapy.

Glioblastoma multiform (GBM) is the most prevalent CNS (central nervous system) tumor in adults, with an average survival length shorter than 2 years and rare metastasis to organs other than CNS. Despite extensive attempts at surgical resecting, the inherently permeable nature of this disease has rendered relapse nearly unavoidable. Thus, immunotherapy is a feasible alternative, as stimulated immune cells can enter into the remote and inaccessible tumor cells. Immunotherapy has revolutionized patient upshots in various malignancies and might introduce different effective ways for GBM patients. Currently, researchers are exploring various immunotherapeutic strategies in patients with GBM to target both the innate and acquired immune responses. These approaches include reprogrammed tumor-associated macrophages, the use of specific antibodies to inhibit tumor progression and metastasis, modifying tumor-associated macrophages with antibodies, vaccines that utilize tumor-specific dendritic cells to activate anti-tumor T cells, immune checkpoint inhibitors, and enhanced T cells that function against tumor cells. Despite these findings, there is still room for improving the response faults of the many currently tested immunotherapies. This study aims to review the currently used immunotherapy approaches with their molecular mechanisms and clinical application in GBM.

Advances in immune checkpoint-based immunotherapies for multiple sclerosis: rationale and practice.

Beyond the encouraging results and broad clinical applicability of immune checkpoint (ICP) inhibitors in cancer therapy, ICP-based immunotherapies in the context of autoimmune disease, particularly multiple sclerosis (MS), have garnered considerable attention and hold great potential for developing effective therapeutic strategies. Given the well-established immunoregulatory role of ICPs in maintaining a balance between stimulatory and inhibitory signaling pathways to promote immune tolerance to self-antigens, a dysregulated expression pattern of ICPs has been observed in a significant proportion of patients with MS and its animal model called experimental autoimmune encephalomyelitis (EAE), which is associated with autoreactivity towards myelin and neurodegeneration. Consequently, there is a rationale for developing immunotherapeutic strategies to induce inhibitory ICPs while suppressing stimulatory ICPs, including engineering immune cells to overexpress ligands for inhibitory ICP receptors, such as program death-1 (PD-1), or designing fusion proteins, namely abatacept, to bind and inhibit the co-stimulatory pathways involved in overactivated T-cell mediated autoimmunity, and other strategies that will be discussed in-depth in the current review. Video Abstract.

Molecular diagnosis, phylogenetic analysis, and antifungal susceptibility profiles of Candida species isolated from neutropenic oncological patients.

BACKGROUND: Neutropenia is the most important cause of life-threatening invasive fungal infections (IFIs). Here, we studied the frequency and antifungal susceptibility profiles of Candida species that colonized or caused infections among neutropenic patients with solid or hematological malignancies. METHODS: A total of 362 clinical samples were collected from 138 patients. After initial isolation using a mix of mycological methods, isolates were screened using chromogenic culture media. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was applied for molecular identification. Positive or suspected cases were confirmed using the reference method of sequencing. Antifungal susceptibility testing for voriconazole and caspofungin was carried out using the microbroth dilution method. An in-silico assay was applied for phylogenetic analysis. RESULTS: Thirty-four Candida strains were isolated. C. albicans (47.06%) and C. glabrata (29.41%) were the most frequent strains. Antifungal treatment reduced the chance of Candida colonization by almost 76% in neutropenic patients (OR: 1.759; 95% CI: 1.349 to 2.390; p value: 0.000). An unusual and non-resistant strain, C. lambica, was reported from the bloodstream of a 56-year-old man with hematologic malignancy (HM). Eight isolates were non-susceptible, and one isolate was resistant to voriconazole. Also, four isolates were non-susceptible to caspofungin. CONCLUSION: We can conclude that there is a cause-and-effect relationship between neutropenia, HM background, and Candida species separated from neutropenic patients, which can lead to possible infections. Further and repetitive studies are recommended using different molecular methods for better prediction and management of fungal infections in neutropenic patients.

Current status of skin cancers with a focus on immunology and immunotherapy.

Skin cancer is one of the most widespread cancers, with a significant global health effect. UV-induced DNA damage in skin cells triggers them to grow and proliferate out of control, resulting in cancer development. Two common types of skin cancer include melanoma skin cancer (MSC) and non-melanoma skin cancer (NMSC). Melanoma is the most lethal form of skin cancer, and NMSC includes basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and other forms. The incidence of skin cancer is increasing in part owing to a demographic shift toward an aging population, which is more prone to NMSC, imposing a considerable financial strain on public health services. The introduction of immunostimulatory approaches for cancer cell eradication has led to significant improvements in skin cancer treatment. Over the last three decades, monoclonal antibodies have been used as powerful human therapeutics besides scientific tools, and along with the development of monoclonal antibody production and design procedures from chimeric to humanized and then fully human monoclonal antibodies more than 6 monoclonal antibodies have been approved by the food and drug administration (FDA) and have been successful in skin cancer treatment. In this review, we will discuss the epidemiology, immunology, and therapeutic approaches of different types of skin cancer.

The current landscape of CAR T-cell therapy for solid tumors: Mechanisms, research progress, challenges, and counterstrategies.

The successful outcomes of chimeric antigen receptor (CAR) T-cell therapy in treating hematologic cancers have increased the previously unprecedented excitement to use this innovative approach in treating various forms of human cancers. Although researchers have put a lot of work into maximizing the effectiveness of these cells in the context of solid tumors, few studies have discussed challenges and potential strategies to overcome them. Restricted trafficking and infiltration into the tumor site, hypoxic and immunosuppressive tumor microenvironment (TME), antigen escape and heterogeneity, CAR T-cell exhaustion, and severe life-threatening toxicities are a few of the major obstacles facing CAR T-cells. CAR designs will need to go beyond the traditional architectures in order to get over these limitations and broaden their applicability to a larger range of malignancies. To enhance the safety, effectiveness, and applicability of this treatment modality, researchers are addressing the present challenges with a wide variety of engineering strategies as well as integrating several therapeutic tactics. In this study, we reviewed the antigens that CAR T-cells have been clinically trained to recognize, as well as counterstrategies to overcome the limitations of CAR T-cell therapy, such as recent advances in CAR T-cell engineering and the use of several therapies in combination to optimize their clinical efficacy in solid tumors.

Prognostic significance and therapeutic potentials of immune checkpoints in osteosarcoma.

Although there exist manifold strategies for cancer treatment, researchers are obliged to develop novel treatments based on the challenges that arise. One of these recent treatment approaches is cancer immunotherapy, which enjoys various types of strategies itself. However, one of the most significant methods, in this regard, is employing immune checkpoint proteins (ICPs). Bone sarcomas have several subtypes, with the most common ones being chordoma, chondrosarcoma, Ewing sarcoma, and osteosarcoma. Although many aggressive treatment approaches, including radiotherapy, chemotherapy, and surgical resection, have been employed over the last decades, significantly improved outcomes have not been observed for Ewing sarcoma or osteosarcoma patients. Additionally, chordoma and chdrosarcoma resist against both radiation and chemotherapy. Accordingly, elucidating how recent therapies could affect bone sarcomas is necessary. Checkpoint inhibitors have attracted great attention for the treatment of several cancer types, including bone sarcoma. Herein, the recent advances of current immune checkpoint targets, such as anti-PD-1/PD-L1 and anti-CTLA-4 blockade, for the treatment of bone sarcoma have been reviewed.

Co-stimulatory agonists: An insight into the immunotherapy of cancer.

Immune checkpoint pathways consist of stimulatory pathways, which can function like a strong impulse to promote T helper cells or killer CD8+ cells activation and proliferation. On the other hand, inhibitory pathways keep self-tolerance of the immune response. Increasing immunological activity by stimulating and blocking these signaling pathways are recognized as immune checkpoint therapies. Providing the best responses of CD8+ T cell needs the activation of T cell receptor along with the co-stimulation that is generated via stimulatory checkpoint pathways ligation including Inducible Co-Stimulator (ICOS), CD40, 4-1BB, GITR, and OX40. In cancer, programmed cell death receptor-1 (PD-1), Programmed cell death ligand-1(PD-L1) and Cytotoxic T Lymphocyte-Associated molecule-4 (CTLA-4) are the most known inhibitory checkpoint pathways, which can hinder the immune responses which have specifically anti-tumor characteristics and attenuate T cell activation and also cytokine production. The use of antagonistic monoclonal antibodies (mAbs) that block CTLA-4 or PD-1 activation is used in a variety of malignancies. It has been reported that they can lead to an increase in T cells and thereby strengthen anti-tumor immunity. Agonists of stimulatory checkpoint pathways can induce strong immunologic responses in metastatic patients; however, for achieving long-lasting benefits for the wide range of patients, efficient combinatorial therapies are required. In the present review, we focus on the preclinical and basic research on the molecular and cellular mechanisms by which immune checkpoint inhibitor blockade or other approaches with co-stimulatory agonists work together to improve T-cell antitumor immunity.

Immune checkpoints and reproductive immunology: Pioneers in the future therapy of infertility related Disorders?

As co-stimulatory receptors, immune checkpoint molecules are found on the surface of various immune cells and transduce inhibitory signals following ligand binding. The most studied members in this regard include PD-1, TIM-3, and CTLA-4. The physiological part immune checkpoints possess is the prevention of dangerous immune attacks towards self-antigens throughout an immune response, which takes place through the negative regulation of the effector immune cells, through the induction of T-cell exhaustion, for instance. It has recently been suggested that each checkpoint reduces immunoactivation via distinct intracellular mechanisms of signaling. Regulators of immune checkpoints are supposed to participate actively in immune defense mechanisms against infections, preventing autoimmunity, transplantation, and tumor immune evasion. In pregnancy, as an active immunotolerance mechanism which is also natural, the maternal immune system encounters two simultaneous challenges; in addition to accepting the semi-allogeneic fetus, the maternal immune system should also prevent infections. In this regard, the part immune checkpoint molecules possess is particularly interesting. Herein, the current understanding of such part in reproductive immunology is described.

Current applications and prospects of nanoparticles for antifungal drug delivery.

Currently, the significance of fungi as human pathogens is not medically concealed in the world. Consequently, suitable recognition and treatment of such infections are of great importance and necessitate the need for comprehensive information in this regard. The introduction of new antifungals and their use today, especially in the last two decades, have revolutionized the treatment of fungal infections. On the other hand, increasing drug resistance in the world has overshadowed such developments. The use of NPs results in the treatment of fungal infections and owing to their specific properties, these particles, unlike the pure antibiotics, can exert a greater inhibitory power although with less concentration compared with conventional drugs. Important reasons that have led to the use of antifungal drugs in delivery systems include reduced drug efficacy, limited penetration through tissue, poor aqueous solubility, decreased bioavailability, and poor drug pharmacokinetics. It is therefore hoped that unfavorable properties of antifungal drugs be mitigated via their incorporation into different types of NPs. This review summarizes the different types of NPs as delivery systems of antifungal as well as their advantages over pure drugs.

Platelet lysate: a promising candidate in regenerative medicine.

Human platelet lysate has attracted much interest from many researchers as it is growth-factor rich for cell expansion, which is employed as a new therapeutic strategy. Not only are human platelet lysates used for cell therapy, but they are also used for the completion of basal media in mesenchymal stem cell cultures. Due to the presence of a large number of growth factors, platelet lysates have potential roles in wound healing, treatment of ocular graft-versus-host disease, osteoarthritis, Parkinson's disease, tendon regeneration, infertility, androgenetic alopecia, nerve repair and regenerative tissue, such as bone regeneration. In this review, we summarize that platelet lysates could be valuable candidates for the treatment of a variety of diseases in regenerative medicine.

Current progress in cancer immunotherapy based on natural killer cells.

One of the most common diseases in the present era is cancer. The common treatment methods used to control cancer include surgery, chemotherapy, and radiotherapy. Despite progress in the treatment of cancers, there still is no definite therapeutic approach. Among the currently proposed strategies, immunotherapy is a new approach that can provide better outcomes compared with existing therapies. Employing natural killer (NK) cells is one of the means of immunotherapy. As innate lymphocytes, NK cells are capable of rapidly responding to cancer cells without being sensitized or restricted to the cognate antigen in advance, as compared to T cells that are tumor antigen-specific. Latest insights into the biology of NK cells have clarified the underlying molecular mechanisms of NK cell maturation and differentiation, as well as controlling their effector functions through the investigation of the ligands and receptors engaged in recognizing cancer cells by NK cells. Elucidating the fact that NK cells recognize cancer cells could similarly show the mechanism through which cancer cells possibly avoid NK cell-dependent immune surveillance. Additionally, the expectations for novel immunotherapies by targeting NK cells have increased through the latest clinical outcomes of T-cell-targeted cancer immunotherapy. For this emerging method, researchers are still attempting to develop protocols for conferring the best proliferation and expansion medium, activation pathways, utilization dosage, transferring methods, as well as reducing possible side effects in cancer therapy. This study reviews the NK cells, their proliferation and expansion methods, and their recent applications in cancer immunotherapy.

Probiotic intervention as a potential therapeutic for managing gestational disorders and improving pregnancy outcomes.

Recent molecular investigations have significantly developed our knowledge of the characteristics of the reproductive microbiome and their associations with host responses to provide an ideal milieu for the development of the embryo during the peri-implantation period and throughout pregnancy as well as to provide a successful in vitro fertilization and appropriate reproductive outcomes. In this context, the establishment of microbial homeostasis in the female reproductive tract, in various physiological periods, is a substantial challenge, which appears the application of probiotics can facilitate the achievement of this goal. So that, currently, probiotics due to its safe and natural features can be considered as a novel biotherapeutic approach. In this review, we comprehensively discuss the bacterial, fungal, and viral diversity detected in the reproductive tract, and their associations with the establishment of dysbiosis/eubiosis conditions as well as we present the significant outcomes on probiotic intervention as an efficient biotherapeutic strategy for management of gestational disorders and improve pregnancy outcomes.

Exome-first Approach Identified Novel Homozygous Dedicator of Cytokinesis 8 (DOCK8) Mutations in Three Unrelated Iranian Pedigrees Suspected with Hyper-IgE Syndrome.

The prevalence of primary immunodeficiency (PID) is rather high in Iran compared to the world average, mainly due to the high rate of consanguineous marriage. Despite that, little genetic information is available about primary immunodeficiencies in Iran. Autosomal recessive hyper IgE syndrome (AR-HIES) is a severe type of immunodeficiency, mainly caused by mutations in the dedicator of cytokinesis 8 (DOCK8). Rapid and precise diagnoses of patients suffering from AR-HIES can help to manage the patients and reach properly the treatment decision. However, in regions with low financial resources and limited expertise, deep phenotyping is uncommon. Therefore, an exome-first approach is helpful to make a genetic-based diagnosis. In the present study, whole-exome sequencing (WES) was applied to detect causative mutations in three unrelated primary immunodeficient patients with poor clinical information. One of the cases was a deceased patient with suspected hyper IgE syndrome (HIES) whose parents were subjected to WES. As a result, three novel pathogenic variants were detected in the DOCK8 gene, including two splicing sites (c.4241+1G>T and c.4886+1G>T) and one-stop-gain (c.4201G>T, p.Glu1401Ter) variants. Sanger sequencing confirmed the mutations' segregation in corresponding families. Further immunological investigations confirmed that HIES in the studied probands. The presence of frontal bossing and broad nose in one of the studied cases, in addition to the typical clinical presentation of DOCK8-AR-HIES, is notable. This work suggests that an exome-first approach can be a valuable alternative strategy for precise diagnosis of primary immunodeficiency patients.

Prospects for the involvement of cancer stem cells in the pathogenesis of osteosarcoma.

Osteosarcoma (OS) is one of the most common bone tumors in children and adolescents that cause a high rate of mortality in this age group and tends to be metastatic, in spite of chemotherapy and surgery. The main reason for this can be returned to a small group of malignant cells called cancer stem cells (CSCs). OS-CSCs play a key role in the resistance to treatment and relapse and metastasis through self-renewal and differentiation abilities. In this review, we intend to go through the different aspects of this malignant disease, including the cancer stem cell-phenotype, methods for isolating CSCs, signaling pathways, and molecular markers in this disease, and drugs showing resistance in treatment efforts of OS.

Nanoparticles and cancer therapy: Perspectives for application of nanoparticles in the treatment of cancers.

Rapid growth in nanotechnology toward the development of nanomedicine agents holds massive promise to improve therapeutic approaches against cancer. Nanomedicine products represent an opportunity to achieve sophisticated targeting strategies and multifunctionality. Nowadays, nanoparticles (NPs) have multiple applications in different branches of science. In recent years, NPs have repetitively been reported to play a significant role in modern medicine. They have been analyzed for different clinical applications, such as drug carriers, gene delivery to tumors, and contrast agents in imaging. A wide range of nanomaterials based on organic, inorganic, lipid, or glycan compounds, as well as on synthetic polymers has been utilized for the development and improvement of new cancer therapeutics. In this study, we discuss the role of NPs in treating cancer among different drug delivery methods for cancer therapy.

The potential of exosomes in the therapy of the cartilage and bone complications; emphasis on osteoarthritis.

Osteoarthritis is a prevalent worldwide joint disease, which demonstrates a remarkable adverse effect on the patients' life modality. Medicinal agents, exclusively nonsteroidal anti-inflammatory drugs (NSAIDs), have been routinely applied in the clinic. But, their effects are restricted to pain control with insignificant effects on cartilage renovation, which would finally lead to cartilage destruction. In the field of regenerative medicine, many researchers have tried to use stem cells to repair tissues and other human organs. However, in recent years, with the discovery of extracellular microvesicles, especially exosomes, researchers have been able to offer more exciting alternatives on the subject. Exosomes and microvesicles are derived from different types of bone cells such as mesenchymal stem cells, osteoblasts, and osteoclasts. They are also recognized to play substantial roles in bone remodeling processes including osteogenesis, osteoclastogenesis, and angiogenesis. Specifically, exosomes derived from a mesenchymal stem cell have shown a great potential for the desired purpose. Exosomal products include miRNA, DNA, proteins, and other factors. At present, if it is possible to extract exosomes from various stem cells effectively and load certain products or drugs into them, they can be used in diseases, such as rheumatoid arthritis, osteoarthritis, bone fractures, and other diseases. Of course, to achieve proper clinical use, advances have to be made to establish a promising regenerative ability for microvesicles for treatment purposes in the orthopedic disorders. In this review, we describe the exosomes biogenesis and bone cell derived exosomes in the regenerate process of bone and cartilage remodeling.

Implications of exosomes as diagnostic and therapeutic strategies in cancer.

Exosomes offer a new perspective on the biology of cancer with both diagnostic and therapeutic concepts. Due to the cell-to-cell association, exosomes are involved in the progression, metastasis, and therapeutic efficacy of the tumor. They can be isolated from blood and other body fluids to determine the disease progression in the body, including cancer growth. In addition to being reservoirs of biochemical markers of cancer, exomes can be designed to restore tumor immunity. Tumor exosomes interact with different cells in the tumor microenvironment to confer beneficial modulations, responsible for stromal activity, angiogenesis, increased vascular permeability, and immune evasion. Exosomes also contribute to the metastasis with the aim of epithelial transmission to the mesenchyme and the formation of premetastatic niches. Moreover, exosomes protect cells against the cytotoxic effects of chemotherapeutic drugs and prevent the transmission of chemotherapy resistance to adjacent cells. Therefore, exosomes are essential for many fatal cancer agents, and understanding their origins and role in cancer is important. In this article, we attempted to clarify the potential of exosomes for the application in cancer diagnosis and therapy.

Insights into the roles of miRNAs; miR-193 as one of small molecular silencer in osteosarcoma therapy.

Today, cancer is one of the most common causes of death. Osteosarcoma (OS) is a tumor in long bones and its prevalence is high in teenagers and young people. Among the methods that used to treat cancer, one can name chemotherapy, surgery, and radiotherapy. Since these methods have some disadvantages and they are not absolutely successful, the use of microRNAs (miRNAs) is very useful in diagnosis and treatment of OS. MiRNAs are small non-coding RNA molecules, containing 18-25 nucleotides, which are involved in the regulation of gene expression via binding to messenger RNA (mRNA). These RNAs are divided into two classes of suppressors and oncogenes. During OS, there is aberrant expression of several miRNAs. Among these miRNAs are downregulation of miR-193 that has been associated with cancer occurrence. The aim of the current manuscript is to have overview on the treatment approaches of OS with special focus on miR-193.

Current antifungal drugs and immunotherapeutic approaches as promising strategies to treatment of fungal diseases.

Invasive candidiasis (IC) can affect individuals with various underlying diseases hospitalized in different parts of hospitals. In recent decades, IC has caused 27-55% mortality in general population. Although Candida albicans (C. albicans) is still the most common cause of IC, non-albicans infections such as C. krusei, C. glabrata, C. lusitaniae, C. tropicalis, and C. parapsilosis have been increased in recent years. Treatment of invasive fungal infections is challenging as the number of existing antifungals is limited and more problems include: toxicity, drug interactions, and drug resistance. These problems provide a clear rationale for the development of new immunotherapies to increase outcomes in patients with invasive fungal infections. Thus, the purpose of this paper is to complete review of the current and modern antifungal drugs in IC therapy and focus on the role of immunotherapy in preventing and controlling the disease. Therefore, we review the features of current research efforts directed towards devising safe and effective immunotherapeutic options for fungal infections, including work on antifungal vaccines, engineered T-cells, cytokines, monoclonal antibodies, and other agents.