Progress of antibody-drug conjugates (ADCs) targeting c-Met in cancer therapy; insights from clinical and preclinical studies.

The cell-surface receptor tyrosine kinase c-mesenchymal-epithelial transition factor (c-Met) is overexpressed in a wide range of solid tumors, making it an appropriate target antigen for the development of anticancer therapeutics. Various antitumor c-Met-targeting therapies (including monoclonal antibodies [mAbs] and tyrosine kinases) have been developed for the treatment of c-Met-overexpressing tumors, most of which have so far failed to enter the clinic because of their efficacy and complications. Antibody-drug conjugates (ADCs), a new emerging class of cancer therapeutic agents that harness the target specificity of mAbs to deliver highly potent small molecules to the tumor with the minimal damage to normal cells, could be an attractive therapeutic approach to circumvent these limitations in patients with c-Met-overexpressing tumors. Of great note, there are currently nine c-Met-targeting ADCs being examined in different phases of clinical studies as well as eight preclinical studies for treating various solid tumors. The purpose of this study is to present a broad overview of clinical- and preclinical-stage c-Met-targeting ADCs.

A New Approach in the Early Electrochemical Diagnosis of Hepatitis B Virus Infection using Carbon-based Nanomaterials.

The importance of early diagnosis of hepatitis B virus infection to treat and follow up this disease has led to many advances in diagnostic techniques and materials. Conventional diagnostic tests are not very useful, especially in the early stages of infection; it is therefore suggested that nanomaterials can enhance them by changing and strengthening their performance for a more accurate and rapid diagnosis. Electrochemical immunosensors with unique features such as miniaturization, low cost, specificity, and simplicity have become a convenient and vital tool in the rapid diagnosis of hepatitis B. Different strategies have been presented, such as graphene oxide and gold nanorods [GO-GNRs], graphene oxide [GO], copper metal-organic framework/ electrochemically reduced graphene oxide [Cu-MOF/ErGO] composite, label-free graphene oxide/Fe3O4/Prussian Blue [GO/Fe3O4/PB] immunosensor, and graphene oxide-ferrocene-CS/Au [ GO-Fc-CS/Au] nanoparticle layered electrochemical immunosensor. In this review, we discuss a group of the most widely used nanostructures, such as graphene and carbon nanotubes, which are used to develop electrochemical immunosensors for the early diagnosis of the hepatitis B virus.

The Seroprevalence of Hepatitis A in Patients with Positive Human Immunodeficiency Virus.

Background: Hepatitis A virus (HAV) can have severe manifestations in adult patients with other liver diseases, particularly in those infected with human immunodeficiency virus (HIV). This study aimed to measure immunity against HAV in HIV-positive individuals to determine the necessity of vaccination against HAV in this population. Methods: This cross-sectional study investigated 171 HIV-positive patients aged 18 years or older who were tested for serum IgG anti-viral hepatitis A antibody. The prevalence and its determinants were analyzed based on patient data. Results: The average age of the patients was 44.2 years old. The prevalence of HAV antibody positivity was 97.7%. The prevalence was higher in patients older than 30 years. There was a close association between hepatitis C virus (HCV) infection (P=0.002). There were no significant correlations between antibody levels and sex, marital status, employment status, education level, economic status, smoking status, drug use status, and physical activity level. The mean and median CD4+ counts in patients with positive (reactive) antibody (Ab) levels were 458 and 404±294, respectively, while the mean and median CD4+ counts in patients with non-reactive antibody levels were 806 and 737±137, respectively, in those who tested negative for anti-HAV Ab (P=0.05). Conclusion: The prevalence of anti-hepatitis A IgG antibodies in people with HIV was very high in Shiraz. There is an increasing trend in the number of older patients and those with HCV infections. The negative association with CD4 was borderline in this study, which needs to be confirmed in larger groups.

Sporadic Lymphangioleiomyomatosis Disease: A Case Report.

Pulmonary Lymphangioleiomyomatosis (LAM) is a rare disease of the lung and lymphatic system that primarily affects women of childbearing age. LAM is a progressive disease with a terrible prognosis, which worsens over time and is extremely difficult to treat. In this study, we discuss the case of a 31-year-old woman with LAM who was initially misdiagnosed with leiomyoma and the way that led to a true diagnosis and effective treatment. Following a precise diagnosis based on comprehensive clinical data and particular immunohistochemical tests, sirolimus treatment was initiated, and the patient entirely responded to the treatment. This case report demonstrated that LAM is an uncommon condition that is challenging to diagnose, which causes its treatment to be delayed.

Prevalence of Pseudomonas aeruginosa and its antibiotic resistance in patients who have received Hematopoietic Stem-Cell Transplantation; A globally Systematic Review.

Gram-negative bacteria are infectious and life-threatening agents after hematopoietic stem cell transplantation (HSCT). So, this study aimed to investigate the prevalence of Pseudomonas aeruginosa and its antibiotic resistance in patients who have received Hematopoietic Stem-Cell Transplantation through a systematic review. The systematic search was done with key words; Pseudomonas aeruginosa, hematopoietic stem cell transplantation from 2000 to the end of July 2023 in Google Scholar and PubMed/Medline, Scopus, and Web of Science. Twelve studies were able to include our study. Quality assessment of studies was done by Appraisal tool for Cross-Sectional Studies. The most of the included studies were conducted as allo-HSCT. Infections such as respiratory infection, urinary infection and bacteremia have occurred. The rate of prevalence with P. aeruginosa has varied between 3 and 100%. The average age of the participants was between 1 and 74 years. The rate of prevalence of P. aeruginosa resistant to several drugs has been reported to be variable, ranging from 20 to 100%. The highest antibiotic resistance was reported against cefotetan (100%), and the lowest was related to tobramycin (1.8%) followed by amikacin, levofloxacin and ciprofloxacin with the prevalence of 16.6%. Our findings showed a high prevalence and antibiotic resistance rate of P. aeruginosa in Hematopoietic stem cell transplantation. Therefore, more serious health measures should be taken in patients after transplantation.

Effect of Mir-4270 Inhibitor and Mimic on Viability and Stemness in Gastric Cancer Stem-Like Cells Derived from MKN-45 Cell Line.

Background: MicroRNAs (miRNAs) are significant regulatory factors in stem cell proliferation, and change in miRNA expression influences the cancer stem cell viability and gene expression. Herein, we evaluated the effect of the hsa-miR-4270 inhibitor and its mimic on the expression of stem cell markers in gastric cancer (GC) stem-like cells. Methods: GC stem-like cells were isolated from the MKN-45 cell line by a non-adherent surface system. The cells were confirmed by differentiation assays using dexamethasone and insulin as adipogenesis-inducing agents and also Staurosporine as a neural-inducing agent. Isolated GC stem-like cells were treated with different concentrations (0, 15, 20, 25, 30, 40, 50, and 60 nM) of hsa-miR-4270 inhibitor and its mimic. The quantity of cell viability was determined by trypan blue method. Transcription of the stem cell marker genes, including CD44, OCT3/4, SOX2, Nanog, and KLF4, was evaluated by real-time RT-PCR. Results: The results showed that GC stem-like cells were differentiated into both adipose cells using dexamethasone and insulin and neural cells by Staurosporine. Treatment of GC stem-like cells with hsa-miR-4270 inhibitor decreased cell viability and downregulated OCT3/4, CD44, and Nanog to 86%, 79%, and 91% respectively. Also, SOX2 and KLF4 were overexpressed to 8.1- and 1.94-folds, respectively. However, hsa-miR-4270 mimic had opposite effects on the cell viability and gene expression of the stem cell markers. Conclusion: The effect of hsa-miR-4270 inhibitor and its mimic on the expression of the stem cell markers in GCSCs indicated that hsa-miR-4270 stimulates the stemness property of GCSCs, likely through stimulating the development of gastric stem cells.

The effect of long-term exposure to toxic air pollutants on the increased risk of malignant brain tumors.

Toxic air pollutants are one of the most agent that have many acute, chronic and non-communicable diseases (NCDs) on human health under long or short-term exposure has been raised from the past to the present. The aim of this study was investigation effect of long-term exposure to toxic air pollutants on the increased risk of malignant brain tumors. Databases used to for searched were the PubMed, Web of Science, Springer and Science Direct (Scopus) and Google Scholar. 71 papers based on abstract and article text filtered. In the end after sieve we selected 7 papers. Identify all relevant studies published 1970-2022. The literature showed that exposure to toxic air pollutants and their respiration can cause disorders in different parts of the brain by transmission through the circulatory system and other mechanisms. Various unpleasant abnormalities are caused by the inhalation of toxic air pollutants in the human body that some of the most common of them include chronic lung disease, coronary heart disease and heart attacks, strokes and brain diseases (Parkinson's, Alzheimer's and multiple Sclerosis), cancers (liver, blood, prostate and brain) and eventually death. According to the finding brain health and proper functioning can be easily disrupted by various genetic or external factors such as air pollution, causing a wide range of abnormalities in the brain and malignant brain tumors. The results of this study showed that reducing the concentration of toxic pollutants in the air, that exposure to them play an increasing role in the development of brain diseases can slow down the process of abnormalities in the brain and will have significant impacts on reducing the number of people affected by them.

A Middle East systematic review and meta-analysis of prevalence and antibiotic susceptibility pattern in MRSA Staphylococcus aureus isolated from patients with cystic fibrosis.

BACKGROUND: This study aimed to determine the prevalence and antibiotic resistance patterns in Staphylococcus aureus isolated from patients with cystic fibrosis in Middle Eastern countries. METHODS: A systematic search was conducted in the PubMed, Web of Science (ISI), and Scopus databases for studies presenting the prevalence of MRSA strains, antibiotic resistance pattern in S. aureus strains isolated from patients who suffered from cystic fibrosis in Middle Eastern countries from 1999 to 10 June 2020. The following terms were used; prevalence, antibiotic resistance, antimicrobial drug resistance, drug resistance, Staphylococcus aureus, S. aureus, Methicillin-resistant Staphylococcus aureus, MRSA, cystic fibrosis, CF, and the Middle East. The meta-analysis was performed using Comprehensive Meta-analysis software (Version 3.3.070). RESULTS: Patients' age ranged from 1.6 to 18 years. Females were more than males. The prevalence of S. aureus was varied between 5.6 and 77.8%. The prevalence of S. aureus was varied between 5.6 and 77.8% in different countries. The combined prevalence of S. aureus in Middle East countries from 1999 to 2020 was reported by 40.9% (95% CI 29.6-53.1). The pooled prevalence of MRSA was reported at 18.6% (95% CI 1.1-82.6), Z = 0.9, I2 = 98.6, Q = 146.7. The highest combined resistance in S. aureus strains was reported to Penicillin G (94%), followed by Ciprofloxacin (54.9%). CONCLUSION: Regarding a quite prevalence of S. aureus and an intermediate prevalence of MRSA in CF patients, preventive measures and health policies should be implemented in the Middle East area to prevent the spread of infections caused by MRSA strains in CF patients.

Effect of Cytomegalovirus Recombinant Phosphoprotein 150 (pp150) on Maturation and Function of Murine Dendritic Cells: an In-Vitro Study.

BACKGROUND: Tegument protein pp150 of cytomegaloviruses (CMVs) plays a vital role in all stages of viral life cycle, representing the most important tegument protein candidate for HCMV treatment. However, the exact role of pp150 in immune regulation is yet to be elucidated. OBJECTIVE: To examine the effects of pp150 on the maturity and function of murine dendritic cells (DCs). METHODS: Maturity status (CD40, CD86, and MHC-II expression) and phagocytic capacity of DCs (dextran uptake assay) were characterized. Gene expression profiles of ROR-γ, GATA-3, T-bet, and FOXP-3 as well as the protein expression of INF-γ (Th1), IL-4 (Th2), IL-35 (Treg), IL-17A (Th17), IL-22, TNF-α, IL-6, and IL-2 were evaluated in T cells co-cultured with DCs. RESULTS: A significant increase in CD40, CD86, and CCR7 expression and a reduction in the phagocytosis rate were observed in pp150-stimulated DCs compared with unstimulated DCs. T cells co-cultured with stimulated DCs showed higher expressions of ROR-γ, IL-6, IL-2, IL-17A, IL-22, and TNF-α. CONCLUSION: Despite improvements in maturity status, pp150-stimulated DCs did not seem to be able to induce Th1 or Th2 immunity. In fact, Th17 and its mediators, IL-17A and IL-22, might be the main inflammatory factors involved in pp150-stimulated DC's mechanism of action. However, it is necessary to conduct further investigations to corroborate these observations.

Improved Function and Maturation of Dendritic Cells Stimulated by Recombinant pp65 Protein: An in-vitro Design.

BACKGROUND: Stimulated dendritic cells (DCs) have been shown to be effective in the induction of specific immune cells. Also, the CMV pp65 plays an important role in CMV life cycle and immune recognition. OBJECTIVE: To assess the effect of CMV pp65 on the maturity and function of dendritic cells. METHODS: Splenic DCs were treated with non-cytotoxic concentrations of the pp65 and analyzed for MHC II, CD86, and CD40 expression by flow cytometry. Then, ROR-γ, GATA3, T-bet, and FOXP3 gene expression levels were evaluated in T cells co-cultured with DCs using Real time-PCR. Finally, the effects of pp65 on allogenic T-cell responses in mixed lymphocyte culture (MLR), and the release of cytokines were investigated by ELISA and flow cytometry. RESULTS: The phagocytosis rate was significantly lower in the pp65-treated DCs than the non-stimulated DCs. There were significant differences in the raised level of CD40, CD86, and CCR7 in DCs as maturation markers. Furthermore, ROR-γ, and T-bet overexpression in T cells of the pp65-treated group compared with the non-stimulated group was observed. Significant differences were observed in the levels of IL-2, IL-6, IL-17, IL-22, TNF-α, and IFN-γ in pp65-stimulated groups compared with the non-stimulated DCs. CONCLUSIONS: The pp65-treated DCs can induce differentiation and functional activity of the cellular immune system, including Th17, and Th1, but not other major T-cell subsets such as Tregs, and Th2 population.

Genotype-related variations in proinflammatory and regulatory cytokine levels in treated and treatment-naive HCV-infected patients.

Hepatitis C virus (HCV) modulates immune-related inflammatory responses to induce milder reactions leading to virus persistence. In this regard, the present study aimed to investigate the link between the HCV genotypes and the proinflammatory and regulatory cytokine levels. Ninety patients with hepatitis C infection (68 treatment-naive and 22 treated patients) and 76 healthy blood donors were studied. The serum levels of IFN-γ, IL-10, IL-17A, and IL-21 were measured by ELISA in the patients and healthy controls. IL-10, IL-17A, and IL-21 levels were significantly higher in HCV patients than in the healthy controls. The same cytokines were also higher in genotype 3a-infected patients compared with genotype 1a-infected patients. Interestingly, in treated patients, lower serum levels of IL-17A and IL-21 were detected in G3a-infected individuals, but not in those infected with G1a. G3a viral load displayed a significant correlation with IL-21 and IL-17A levels. In addition, G1a viral load correlated with IL-10 levels. In G3a-infected patients, a significant association was found between IL-17A serum levels and ALT. We found differences in IL-21 and IL-17A serum levels among HCV-infected patients which were genotype dependent. Since Th17-associated cytokines are associated with the progression of liver disease in HCV patients, IL-17A and IL-21 can be used as important biological markers for evaluating the immunopathogenesis of chronic hepatitis. Our results suggest that HCV G3a along with immune responses such as cytokines in HCV patients should be taken into account when interpreting clinical data and IFN-based therapeutic response.