Combination of IFN-gamma with STING agonist and PD-1 immune checkpoint blockade: a potential immunotherapy for gastric cancer.

Suppression of the cGAS-STING pathway is an immune escape mechanism in cancer cells. The critical role of this pathway in gastric cancer (GC) is not fully understood. Herein, we evaluated the effect of the interferon-gamma (IFN-gamma), STING agonist, PD-1 immune checkpoint blockade, and their combination on the cGAS-STING pathway in GC. Expression of cGAS and STING in tumor tissue samples and adjacent normal tissue (ANT) biopsies of fifty new GC patients was evaluated by quantitative real-time PCR (qRT-PCR). Moreover, cGAS and STING expression levels were examined in Peripheral Blood Mononuclear Cells (PBMC) samples of forty GC patients and twenty-five healthy subjects. The apoptosis rate of cancer cells was analyzed by Annexin V-FITC/PI. Cell proliferation was measured by the BrdU assay. Also, IFN-ß levels were evaluated in the supernatants of the treated groups. The cGAS expression was decreased in patients with distant metastasis. Co-cultures treated with IFN-gamma showed an elevated level of cGAS and STING expressions in PBMC and cancer cells. The rate of apoptosis increased in all the treatment groups. In addition, the rate of proliferation in PBMCs increased in different treated groups. The main role of PBMCs in cytotoxicity was determined by a comparative analysis of the viability of cells treated with all treatments, both with and without PBMCs. The production of IFN-ß was elevated in all treated groups. The current study suggests that a combination therapy using IFN-gamma, STING agonist, and anti-PD-1 antibody can provide a promising approach to the treatment of GC.

Oleuropein induces apoptosis in gastric cancer cell lines by regulating mir-34a, mir-21, and related genes: An experimental and bioinformatic study.

Gastric Cancer (GC) is one of the most prevalent malignancies worldwide. Oleuropein, as a natural phenolic compound with anti-cancer characteristics, is a good option with low side effects to overcome the adverse impact of conventional treatments in cancer. This research evaluated Oleuropein's anti-cancer and apoptotic activities and the anti-migratory effects by modulating potential target genes in epithelial-mesenchymal transition (EMT). Bioinformatic analysis was performed to predict possible Oleuropein's target genes. Then the importance of these genes was shown by UALCAN, Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA) datasets in gastric cancer. Finally, the association between the selected genes was shown by Cytoscape network analysis. The MTT assay, DAPI staining, flow cytometry, and real-time PCR were applied in the current study. The results showed that the viability of cells was decreased, and the apoptosis rate increased in the Oleuropein-treated group. These findings revealed that Oleuropein regulated the expression of the apoptotic and metastatic genes and microRNAs in GC cells.

Persistent diazinon induced neurotoxicity: The effect on inhibitory avoidance memory performance, amyloid precursor proteins, and TNF-α levels in the prefrontal cortex of rats.

INTRODUCTION: Organophosphate pesticides (Ops) like diazinon (DZN) have well-known neurotoxic effects and low-level chronic exposure has been linked to detrimental neurobehavioral impairments and memory deficits. However, it's not entirely clear how DZN-induced biological changes, particularly in the prefrontal cortex (PFC) contribute to these effects. The purpose of this study is to investigate the impact of DZN exposure on inhibitory avoidance (IA) memory function, amyloid precursor expression (APP), and proinflammatory tumor necrosis factor-α (TNF-α) levels in the rat cortex. MATERIALS AND METHODS: Rats were divided into 4 groups and recived 2 mg/kg DZN for 5-days or 12-weeks and two control groups recived the same volume of vehicle. IA memory was assesed using the shuttle box apparatus. Rats were sacrificed and the prefrontal cortex PFC were removed. Real-time PCR and Western blotting were used to messure TNF-α, and amyloid protein precursors gene expression and protein levels. RESULTS: Our findings indicated that DZN caused body weight loss and a notable decline in performance on the IA memory. Additionally, 5-days exposure increased APP and APLP2 protein levels in the PFC, while 12-weeks exposure decreased these levels. Furthermore, expression of APP and APLP2 gens were decreased in PFC. TNF-α levels increased as a result of 5-days exposure to DZN, but these levels dropped to normal after 12-weeks administration, and this observation was significant. CONCLUSION: Taken together, exposure to low doses of DZN leads to disturbances in IA memory performance and also alternations in amyloid beta precursors that can be related to increased risk of Alzheimer's disease.

Reported side-effects following Oxford/AstraZeneca COVID-19 vaccine in the north-west province, Iran: A cross-sectional study.

While the vaccination was introduced as a promising tool to control the Coronavirus disease 2019 (COVID-19) pandemic, concerns about vaccine-related side effects had grown. Due to the widespread administration of the COVID-19 vaccine worldwide for the first time, it was necessary to evaluate the safety and potential side effects in recipients. This study aims to assess, the incidence of adverse effects following Oxford-AstraZeneca vaccination and identify their related factors. In this cross-sectional survey-based study, 453 volunteers participated, including 235 men and 218 women. The reported adverse reactions from recipients of the ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccine were collected by using a questionnaire. The findings showed that the incidence of adverse reactions, such as neurological, systematic, gastrointestinal, respiratory, and local symptoms were significantly higher after the first dose compared to the second dose. Systematic symptoms were the most prevalent reported side effects after the first and second dose injection. The demographical study of participants showed that individuals aged 18-34 and females were more prone to present adverse events following vaccination. However, no significant relationship was found between the occurrence of side effects and the recipients' body mass index. Despite the life-saving role of vaccination against SARS-CoV-2, it may have some adverse reactions in recipients. The severity and frequency of side effects were different. So, they were dependent on several factors, including gender and age. Altogether, post-vaccination adverse reactions were mild and tolerable.

Adverse Effects Reported and Insights Following Sinopharm COVID-19 Vaccination.

Vaccines are promising strategies for controlling COVID-19; however, COVID-19 vaccine side effects play a central role in public confidence in the vaccine and its uptake process. This study aimed to provide evidence on the post-vaccination early side effects of the BBIBP-CorV (Sinopharm) vaccine. This cross-sectional survey-based study was conducted between November 2021 and January 2022 among recipients of the BBIBP-CorV vaccine, using a questionnaire-based survey. Our final sample consisted of 657 participants, including 392 women. Among the study cases, only 103 (15.7%) participants received one dose of vaccine, and the rest received both doses (N = 554, 84.3%). Systemic symptoms (first dose: N = 187, both doses: N = 128) were the most commonly reported events after vaccination, and among them, injection site pain (first dose: 19.3%, both doses: 12.9%) was the most prevalent adverse effect. All reporting events were mild and resolved in less than 3 days without hospitalization. Among the participants, females and young people aged 35-65 were more prone to manifest side effects (N = 169, 53.3%) after the vaccine injection. Furthermore, our results revealed that the recipients who were suffering from underlying diseases, including diabetes, renal disorder, and respiratory illness, reported fewer adverse responses after vaccination in comparison with healthy individuals. Vaccination against SARS-CoV-2 may lead to some adverse reactions in recipients. However, the frequency of post-vaccination early side effects differed in people, but all responses were slight and temporary.

Irradiated oocysts in combination with inulin adjuvant-induced potent immune responses against Eimeria tenella infection in broiler chickens.

Coccidiosis is the leading parasitic disease in poultry. One of the most critical Eimeria species, Eimeria tenella, lives inside the cecal epithelial cells and induces bloody coccidiosis. The present study evaluated the effect of radiation-attenuated E. tenella oocytes mixed with inulin adjuvant on broiler chicken. Initially, the effect of irradiation on oocyst attenuation was confirmed. Then, one-day-old broilers (n = 90) were divided into nine groups on seven days of age as follow: Group 1 (400 attenuated oocysts + 1.00 mg of adjuvant), group 2 (400 attenuated oocysts + 0.50 mg adjuvant), group 3 (200 attenuated oocysts + 1.00 mg of adjuvant), group 4 (200 attenuated oocysts + 0.50 mg adjuvant), group 5 (1.00 mg adjuvant), group 6 (400 attenuated oocysts), group 7 (commercial vaccine), group 8 (negative control) and group 9 (blank). On day 21, we performed a challenge with E. tenella oocytes and investigated oocyst output and average weekly weight throughout the study. At the end of the study, we evaluated macroscopic lesion, histology, cytokine level and leukogram status. The results showed a statistically significant difference among groups. Furthermore, the optimal dose was 400 irradiated oocysts and 1.00 mg of inulin. Moreover, an X-ray could reduce the virulence of E. tenella oocytes. Inulin alone or combined with attenuated oocysts showed an acceptable effect on evaluated parameters.

The evaluation of the MMP-2/TIMP-1 ratio in peptic ulcer and its association with refractory helicobacter pylori infection.

BACKGROUND: Helicobacter pylori (H. pylori) is one of the leading causes of peptic ulcers, and its treatment is a worldwide challenge. Matrix metalloproteinases and their inhibitors influence the development and healing of peptic ulcers. This study aimed to evaluate the ratios of matrix metalloproteinase-2 (MMP-2) to tissue inhibitor of metalloproteinase-1 (TIMP-1) in patients with peptic ulcers that are sensitive or resistant to H. pylori treatment and compare them with healthy individuals. METHODS: In this study, 95 patients were included and divided into two groups sensitive (41 patients) and resistant to treatment (54 patients). The results were compared with a control group of 20 participants with normal endoscopy and H. pylori-negative. After obtaining written informed consent, five ml of venous blood was taken to determine their serum MMP-2 and TIMP-1 levels using an enzyme-linked immunosorbent assay. RESULTS: In patients with H. pylori-induced peptic ulcers, the MMP-2/TIMP-1 ratio was significantly higher than the healthy controls (P < 0.05). MMP-2 level was associated with patients' response to treatment (P < 0.05). The MMP-2/TIMP-1 ratio was higher in patients with simultaneous gastric and duodenal ulcers (P < 0.05). CONCLUSION: It seems that peptic ulcer disease caused by infection with H. pylori increases the MMP-2/TIMP-1 ratio in patients with peptic ulcers. However, it might not be a good predictor of refractory H. pylori-induced peptic ulcer disease.

A novel water-soluble thiosemicarbazone Schiff base ligand and its complexes as potential anticancer agents and cellular fluorescence imaging.

A novel fluorescent ligand (H2LCl⋅1.5CH3OH, 1) was synthesized and metal complexes of 1 with Mn(II), Fe(III), Ni(II), Cu(II), and Zn(II) were obtained as Mn(HL)2Cl2 (2), Fe(HL)2Cl3⋅3H2O (3), Ni(L)(HL)Cl⋅8H2O (4), Cu(HL)Cl2⋅4H2O (5), Zn(H2L)Cl3 (6), respectively. These compounds were identified by spectroscopic methods, elemental analysis, molar conductivity, and single-crystal X-ray crystallography. According to the crystal structure of 4 nickel (II), center is surrounded by two ligands in a distorted octahedral geometry. The ligand and its complexes are soluble in water and have excellent stability. In vitro anti-proliferative activity of these compounds was evaluated against human breast adenocarcinoma (MCF-7) and human lipo-sarcoma (SW-872) as cancer cells and human fibroblasts (HFF-2) as normal cells by MTT assay. Interestingly, complex 5 exhibited excellent activity against both cancer cells with low IC50 value 22.18 ± 0.35 µg/mL (35.66 ± 0.56 µM) for SW-872 and 79.41 ± 3.54 µg/mL (127.6 ± 5.69 µM) for MCF-7 among the compounds and in comparison with paclitaxel (PTX) which acts finely. Morphological changes were evaluated by flow cytometry that revealed apoptosis is the main cause of cell death. Likewise, cell cycle studies indicated the cell cycle arrest in the G1 and S phases for complex 5 against MCF-7 and SW-872 cancer cells, while complex 6 could arrest the MCF-7 and SW-872 cells in G2 and G1 phases, respectively. All of the compounds are fluorescent which enabled us to monitor the uptake and intracellular distribution in living human cancer cells by fluorescence microscopy.

Association of carbapenem and multidrug resistance with the expression of efflux pump-encoding genes in Pseudomonas aeruginosa clinical isolates.

Efflux pumps play an important role in the emergence of antibiotic-resistant Pseudomonas aeruginosa strains. The present study aimed to assess the expression of the MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM efflux pumps in carbapenem-resistant and multidrug-resistant (MDR) P. aeruginosa strains isolated from clinical specimens between June 2019 and January 2022 in Ardabil city. The presence of efflux pump-encoding genes, i.e. mexA, mexC, mexE, and mexY, was assessed using the polymerase chain reaction (PCR) technique in 48 carbapenem-resistant and MDR P. aeruginosa strains. Real-time reverse transcription PCR was employed to evaluate the expression levels of mexA, mexC, mexE, and mexY genes. All 48 carbapenem-resistant and MDR P. aeruginosa strains harbored efflux pump-encoding genes including mexA, mexC, mexE, and mexY according to the PCR results. Overexpression of the MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM efflux pumps was detected in 75% (n = 36), 83.3% (n = 40), 10.4% (n = 5) and 41.6% (n = 20) of the clinical isolates of P. aeruginosa, respectively. This study revealed that the presence and overexpression of efflux pumps are associated with the emergence of carbapenem-resistant and MDR P. aeruginosa strains. Therefore, research on efflux pump inhibitors of P. aeruginosa will be a worthwhile endeavor to increase the clinical efficiency of available antibiotics and prevent ensuing treatment failure.

Partners in crime: Autoantibodies complicit in COVID-19 pathogenesis.

Autoantibodies (AABs) play a critical role in the pathogenesis of autoimmune diseases (AIDs) and serve as a diagnostic and prognostic tool in assessing these complex disorders. Viral infections have long been recognized as a principal environmental factor affecting the production of AABs and the development of autoimmunity. COVID-19 has primarily been considered a hyperinflammatory syndrome triggered by a cytokine storm. In the following, the role of maladaptive B cell response and AABs became more apparent in COVID-19 pathogenesis. The current review will primarily focus on the role of extrafollicular B cell response, Toll-like receptor-7 (TLR-7) activation, and neutrophil extracellular traps (NETs) formation in the development of AABs following SARS-CoV-2 infection. In the following, this review will clarify how these AABs dysregulate immune response to SARS-CoV-2 by disrupting cytokine function and triggering neutrophil hyper-reactivity. Finally, the pathologic effects of these AABs will be further described in COVID-19 associate clinical manifestations, including venous and arterial thrombosis, a multisystem inflammatory syndrome in children (MIS-C), acute respiratory distress syndrome (ARDS), and recently described post-acute sequelae of COVID-19 (PASC) or long-COVID.

The effect of convalescent plasma on the treatment of COVID-19 patients in Ardabil, Iran.

BACKGROUND: Infection with COVID-19 has resulted in considerable mortality all around the world. This study aimed to investigate the effect of convalescent plasma on the treatment of hospitalized patients with COVID-19 in Imam Khomeini Hospital at Ardabil, Iran. MATERIALS AND METHODS: In this quasi-experimental clinical trial, patients over 18 years of age with polymerase chain reaction-positive COVID-19 were admitted based on the clinical criteria of respiratory distress with hypoxia (O2 saturation <90) and tachypnea (R Relative Risk (RR) >24) with moderate-to-severe lung involvement and in the 1st week of respiratory disease who were not intubated were nonrandomly assigned to two groups: convalescent plasma therapy (CPT) group (197 cases) and control group (200 cases). We used the Chi-square, t-test, Fisher's exact test, and Pearson's correlation coefficient for statistical analysis. RESULTS: Analyses revealed that length of stay in hospital was significantly lower in the CPT group as compared to the control group (P = 0.001). Twenty-four cases (22.0%) in the CPT group and 85 cases (78.0%) in the control group needed intubation. Furthermore, mortality was 17 cases (18.3%) in the CPT group and 76 cases (81.7%) in the control group, the difference of which was also found to be statistically significant (P < 0.05). CONCLUSIONS: It seems that CPT can be used as an alternative treatment at the early stages of COVID-19 to prevent the progress of the disease, reduce the need for intubation and consequently the length of stay in hospital, and finally, decrease mortality.

Cognitive Impairment and Neurodegenerative Diseases Development Associated with Organophosphate Pesticides Exposure: a Review Study.

A significant body of literature emphasizes the role of insecticide, particularly organophosphates (OPs), as the major environmental factor in the etiology of neurodegenerative diseases. This review aims to study the relationship between OP insecticide exposure, cognitive impairment, and neurodegenerative disease development. Human populations, especially in developing countries, are frequently exposed to OPs due to their extensive applications. The involvement of various signaling pathways in OP neurotoxicity are reported, but the OP-induced cognitive impairment and link between OP exposure and the pathophysiology of neurodegenerative diseases are not clearly understood. In the present review, we have therefore aimed to come to new conclusions which may help to find protective and preventive strategies against OP neurotoxicity and may establish a possible link between organophosphate exposure, cognitive impairment, and OP-induced neurotoxicity. Moreover, we discuss the findings obtained from animal and human research providing some support for OP-induced cognitive impairment and neurodegenerative disorders.

DNA methylation changes and inflammaging in aging-associated diseases.

Aging as an inevitable phenomenon is associated with pervasive changes in physiological functions. There is a relationship between aging and the increase of several chronic diseases. Most age-related disorders are accompanied by an underlying chronic inflammatory state, as demonstrated by local infiltration of inflammatory cells and greater levels of proinflammatory cytokines in the bloodstream. Within inflammaging, many epigenetic events, especially DNA methylation, change. During the aging process, due to aberrations of DNA methylation, biological processes are disrupted, leading to the emergence or progression of a variety of human diseases, including cancer, neurodegenerative disorders, cardiovascular disease and diabetes. The focus of this review is on DNA methylation, which is involved in inflammaging-related activities, and how its dysregulation leads to human disorders.

Aging as a natural process is associated with variation in physiological functions. One of the hallmarks of aging is epigenetic changes, which are directly involved in the aging process and aging-related diseases. DNA methylation is one of the epigenetic changes during aging. Consequently, changes in DNA methylation affect various cellular processes and cause age-related diseases. This review discusses the role of DNA methylation in aging processes and age-related diseases.

Serum Brain-Derived Neurotrophic Factor (BDNF) in COVID-19 Patients and its Association with the COVID-19 Manifestations.

COVID-19 is a systematic disease that frequently implies neurological and non-neurological manifestations, predominantly by inducing hypoxia. Brain-derived neurotrophic factor (BDNF) is a key factor in regulating functions of nervous and respiratory systems and has been strongly related to hypoxia. Therefore, this study planned to investigate BDNF association with the COVID-19 manifestations especially neurological impairments and the infection-induced hypoxia. We enrolled sixty-four COVID-19 patients and twenty-four healthy individuals in this study. Patients were divided into two groups, with and without neurological manifestations, and their serum BDNF levels were measured by enzyme-linked immunosorbent assay (ELISA). COVID-19 patients had significantly lower BDNF levels than healthy individuals (p = 0.023). BDNF levels were significantly lower in patients with neurological manifestations compared to healthy individuals (p = 0.010). However, we did not observe a statistically significant difference in BDNF levels between patients with and without neurological manifestations (p = 0.175). BDNF's levels were significantly lower in patients with CNS manifestations (p = 0.039) and higher in patients with fever (p = 0.03) and dyspnea (p = 0.006). Secondly, BDNF levels have a significant negative association with oxygen therapy requirement (p = 0.015). These results strongly suggest the critical association between dysregulated BDNF and hypoxia in promoting COVID-19 manifestations, particularly neurological impairments.

The role of IL-1 family of cytokines and receptors in pathogenesis of COVID-19.

A global pandemic has erupted as a result of the new brand coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This pandemic has been consociated with widespread mortality worldwide. The antiviral immune response is an imperative factor in confronting the recent coronavirus disease 2019 (COVID-19) infections. Meantime, cytokines recognize as crucial components in guiding the appropriate immune pathways in the restraining and eradication of the virus. Moreover, SARS-CoV-2 can induce uncontrolled inflammatory responses characterized by hyper-inflammatory cytokine production, which causes cytokine storm and acute respiratory distress syndrome (ARDS). As excessive inflammatory responses are contributed to the severe stage of the COVID-19 disease, therefore, the pro-inflammatory cytokines are regarded as the Achilles heel during COVID-19 infection. Among these cytokines, interleukin (IL-) 1 family cytokines (IL-1, IL-18, IL-33, IL-36, IL-37, and IL-38) appear to have a strong inflammatory role in severe COVID-19. Hence, understanding the underlying inflammatory mechanism of these cytokines during infection is critical for reducing the symptoms and severity of the disease. Here, the possible mechanisms and pathways involved in inflammatory immune responses are discussed.

MicroRNA-143 act as a tumor suppressor microRNA in human lung cancer cells by inhibiting cell proliferation, invasion, and migration.

BACKGROUND/AIM: MicroRNAs play crucial roles in controlling cellular biological processes. miR-143 expression is usually downregulated in different cancers. In this study, we focused on exploring the role of miR143 in NSCLC development. METHODS: Bioinformatics analyses were used to detect the expression level of miR-143 in lung tumors. The cells were transfected by pCMV-miR-143 vectors. The efficacy of transfection was verified by Flow cytometry. The influence of miR-143 replacement on NSCLC cells migration, proliferation, and apoptosis was detected using wound-healing assay, MTT assay, and DAPI staining, respectively. RESULTS: MTT assay revealed that overexpression of miR143 inhibited cell growth and proliferation. Scratch assay results demonstrated that restoration of miR143 suppressed cell migration. The qRT-PCR assay was further used to detect the assumed relationship between miR143 and apoptotic and metastatic-related genes. CONCLUSION: The findings showed that miR-143 could reduce cell proliferation, invasion, and migration by reducing CXCR4, Vimentin, MMP-1, Snail-1, C-myc expression level, and increasing E-cadherin expression levels in lung cancer cells and might be a potential target in NSCLC's targeted therapy.

Hematological Parameters as Diagnostic Factors: Correlation with Severity of COVID-19.

Bachground and aim: Coronavirus disease 2019(COVID-19), which is the pandemic of 21st century, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Prognostic factors play an essential role in predicting the patients who need more care. Therefore, the current study aimed to investigate the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) ratio as discriminated indexes in prognosis of patients with COVID-19. METHODS: Age, NLR, PLR, white blood cell (WBC), neutrophil count, lymphocyte count and platelet from 1007 hospitalized patients with COVID-19, who were admitted to two referring hospitals  in Ardabil, North Western Iran. All confirmed cases divided into non-severe and severe groups. RESULTS: 534 (53.4%) males and 473 (47.3 %) females with mean age of 52 years were enrolled in this study. Patients with severe COVID-19 have lower counts of lymphocyte, but have higher NLR, comparing to non-severe patients (P = 0.001). CONCLUSION: Elevated NLR can be assumed as an independent biomarker, which could provide a crucial indicator in the monitoring patients with COVID-19 on admission. Increased NLR was correlated with the severity of COVID-19. Assessment of NLR could be proposed to identify high risk individuals with COVID-19.

The tricks for fighting against cancer using CAR NK cells: A review.

Natural killer (NK) cells seem to be the most common innate lymphocyte subtypes, and they're known for their ability to guide anti-tumor and anti-viral responses, making them potentially therapeutic. Since NK cells lack polymorphic clonotypic receptors, they must rely on inhibitory receptors to develop, mature, and distinguish between "self" and "non-self." In the clinic, genetically engineered immune cells expressing a chimeric antigen receptor (CAR) that consists of an extracellular antigen recognizing domain connected to an intracellular signaling domain have gained interest. The U.S. food and drug administration (FDA) approved two CAR-T cells, anti-CD19 CARs, for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL). Nevertheless, CAR-T cell therapy is linked to a series of negative side effects, including fatal cytokine release syndrome (CRS) and tumor lysis syndrome (TLS), as well as a lack of regulatory control. CAR-transduced NK cells (CAR-NK) are thought to have many benefits, including clinical safety, the mechanisms by which they identify cancerous cells, and their abundance in clinical specimens, according to a growing number of studies. In pre-clinical and clinical trials, human primary NK cells and the NK-92 cell line were effectively transduced to express CARs against hematological cancers and solid tumors. Here, it is tried to summarize the development of CAR-NK cells, challenges and coping strategies, as well as managing the challenges and obstacles related to its protection, which promises to eliminate the shortcomings of conventional CARs.

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.