The development of flavivirus vaccines

Mosquito and tick-borne flaviviruses are the causative agents of some of the world’s most important diseases, including dengue fever, yellow fever, Japanese encephalitis, tick-borne encephalitis and West Nile fever. Cumulatively, these viruses cause many millions of infections each year and impose a significant burden on public health resources, particularly in developing and newly developed countries. Vaccine development to eliminate flaviviral infections has been marked by uneven progress and a large number of setbacks. To date, no single approach has proved successful in leading to vaccine development against a wide range of flaviviruses, but the application of modern techniques to the problem is opening up new avenues of approach. This review summarizes some of the developments in vaccine research aimed at inducing protective immunity against flaviviral infections

Spatio-temporal differences in presentation of CD8 T cell epitopes during HBV infection

Distinct populations of hepatocytes infected with HBV or only harboring HBV-DNA integrations coexist within an HBV chronically infected liver. These hepatocytes express HBV antigens at different levels and with different intracellular localizations but it is not known whether this heterogeneity of viral antigen expression could result in an uneven hepatic presentation of distinct HBV epitopes/HLA class-I complexes triggering different level of activation of HBV-specific CD8+ T cells.Using antibodies specific to two distinct HLA-A*02:01/HBV epitope complexes of HBV nucleocapsid and envelope proteins, we mapped their topological distribution in liver biopsies of two anti-HBe+ chronic HBV (CHB) patients. We demonstrated that the core and envelope CD8+T cell epitopes were not uniformly distributed in the liver parenchyma but preferentially located in distinct and sometimes mutually exclusive hepatic zones. The efficiency of HBV epitope presentation was then tested in vitro utilizing HLA-A*02:01/HBV epitope-specific antibodies and the corresponding CD8+ T cells, in primary human hepatocyte and hepatoma cell lines either infected with HBV or harboring HBV-DNA integration. We confirmed the existence of a marked variability in the efficiency of HLA-class I/HBV epitope presentation among the different targets that was influenced by presence of IFN-γ and availability of newly-translated viral antigens. In conclusion, HBV antigen presentation can be heterogeneous within an HBV-infected liver. As a consequence, CD8+ T cells of different HBV specificities might have different antiviral efficacy.Importance The inability of patients with chronic HBV infection to clear HBV is associated with defective HBV-specific CD8+ T cells. Hence, the majority of immunotherapy developments focus on HBV specific T cell function restoration. However, knowledge of whether distinct HBV-specific T cells can equally target all the HBV-infected hepatocytes of a chronically infected liver are lacking. In this work, analysis of CHB patient liver parenchyma and in vitro HBV infection models shows a non-uniform distribution of HBV CD8+ T cells epitopes that is influenced by presence of IFN-γ and availability of newly-translated viral antigens. These results suggest that CD8+ T cells recognizing different HBV epitopes can be necessary for efficient immune therapeutic control of chronic HBV infection

The infection status of Mycobacterium avium paratuberculosis in traditional dairy cattle farms in Moghan region

Mycobacterium avium paratuberculosis is the causative agent of John's disease which is a remedial chronic disease in all ruminants and is important from economical viewpoint. In this study, a total of 86 fecal samples from suspected dairy cattle were obtained from 11 traditional dairy farms in Moghan region. All samples were evaluated by direct microscopic examination. Subsequently, milk sample of the related cattle were tested by PCR technique. Twenty samples from positive and 10 specimens of negative samples in direct microscopic assay were selected randomly for PCR examination. Among the 86 samples, 51 (59%) samples were positive, while, 35 (41%) samples were found as negative by microscopic assay. From 20 positive samples, 19 (95%) samples showed positive result by PCR, however, among negative samples, 3 (30%) samples were positive in PCR assay. Results revealed that there is a direct relation between contamination of fecal and milk samples. Moreover, due to the correlation between the results of microscopic examination of fecal samples and PCR assay of milk specimens, direct microscopic evaluation of feces could be performed prior to PCR-based detection of Mycobacterium avium paratuberculosis in milk samples. According to the results, high contamination rate of Mycobacterium avium paratuberculosis was found in milk samples. On the other hand, duo to possible etiological role of this bacterium in the development of Crohn’s diseases in human, it should be considered as a serious concern indeed

Investigation of the Cut-off Value for Prostate-Specific Antigen in Patients referring to Shahid Beheshti Hospital of Babol

BACKGROUND AND OBJECTIVE: Prostate cancer is the most common form of malignancy among men. Prostate-specific antigen (PSA) is used to screen for prostate cancer and may vary depending on different factors, such as age. This study aimed to investigate the cut-off value for PSA in patients diagnosed with prostate cancer. METHODS: This cross-sectional study was conducted on patients with prostate biopsy diagnosis undergoing transrectal ultrasound during 2011-2014. Data collection was performed using prepared checklists. FINDINGS: In total, 422 patients were enrolled in this study, 180 of whom (42.7%) were diagnosed with adenocarcinoma, and 242 (57.3%) had benign prostatic hyperplasia (BPH). Mean age of the patients was 63.03±9.62 years, and the mean PSA was 27.95±64.44 ng/ml. The mean of PSA in patients over 51 years was 28.66±65.51 ng/ml, which was significantly higher than the values of the patients under 50 years of age (p=0.005). CONCLUSION: According to the results of this study, the risk of prostate cancer was higher in the men within the age range of 60-80 years. In addition, patients with PSA levels of 10-20 ng/mL need to be fully screened for prostate cancer

Spatiotemporal Differences in Presentation of CD8 T Cell Epitopes during Hepatitis B Virus Infection

10.1128/JVI.01457-18JOURNAL OF VIROLOGY93

Construction and Functional Characterization of a Fully Human Anti-mesothelin Chimeric Antigen Receptor (CAR) Expressing T Cell

Chimeric antigen receptor (CAR) T cell therapy is considered as an encouraging approach for the treatment of hematological malignancies. However, its efficacy in solid tumors has not been satisfying, mainly in the immunosuppressive network of the tumor microenvironment and paucity of appropriate target antigens. Mesothelin (MSLN) is a tumor-associated antigen (TAA) expressed in numerous types of solid tumors such as gastrointestinal, ovarian, and pancreatic tumors. Owing to high expression in tumor cells and low expression in normal tissues, MSLN-targeted therapies like monoclonal antibodies have been previously developed. In the present study, a CAR T cell harboring the second-generation of a fully human anti-MSLN-CAR construct containing CD3 zeta and 4-1BB signaling domains was produced and it was functionally evaluated against an MSLN-expressing cell line. The findings showed potent, specific proliferation, cytotoxic activity, and interleukin (IL)-2, Tumor necrosis factor-(TNF) alpha, and Interferon-(IFN) gamma production in an antigen-dependent manner. Cytotoxic activity was shown in effector-to-target ratio from 1:1 to 20:1, but the most adequate efficacy was observed in the ratio of 10:1. Non-specific activity against MSLN negative cell line was not observed. Our data demonstrated that primary human T cells expressing fully human MSLN-CAR construct are effective against MSLN-expressing cell lines in vitro, suggesting this MSLN-CAR construct as a potential therapeutic tool in a clinical setting

Bayesian analysis of cytokines and chemokine identifies immune pathways of HBsAg loss during chronic hepatitis B treatment

10.1038/s41598-021-86836-5Scientific Reports1117455