Randomized comparison of single dose of recombinant human IL-12 versus placebo for restoration of hematopoiesis and improved survival in rhesus monkeys exposed to lethal radiation

BACKGROUND: The hematopoietic syndrome of the acute radiation syndrome (HSARS) is a life-threatening condition in humans exposed to total body irradiation (TBI); no drugs are approved for treating this condition. Recombinant human interleukin-12 (rHuIL-12) is being developed for HSARS mitigation under the FDA Animal Rule, where efficacy is proven in an appropriate animal model and safety is demonstrated in humans. METHODS: In this blinded study, rhesus monkeys (9 animals/sex/dose group) were randomized to receive a single subcutaneous injection of placebo (group 1) or rHuIL-12 at doses of 50, 100, 250, or 500 ng/kg (groups 2–5, respectively), without antibiotics, fluids or blood transfusions, 24–25 hours after TBI (700 cGy). RESULTS: Survival rates at Day 60 were 11%, 33%, 39%, 39%, and 50% for groups 1–5, respectively (log rank p < 0.05 for each dose vs. control). rHuIL-12 also significantly reduced the incidences of severe neutropenia, severe thrombocytopenia, and sepsis (positive hemoculture). Additionally, bone marrow regeneration following TBI was significantly greater in monkeys treated with rHuIL-12 than in controls. CONCLUSIONS: Data from this study demonstrate that a single injection of rHuIL-12 delivered one day after TBI can significantly increase survival and reduce radiation-induced hematopoietic toxicity and infections. These data significantly advance development of rHuIL-12 toward approval under the Animal Rule as an effective stand-alone medical countermeasure against the lethal effects of radiation exposure

In silico analysis of hypermethylation of E-cadherin gene promoter in Nasopharyngeal carcinoma

Background: DNA hypermethylation changes in CpG islands of promoter region of E-cadherin (E-cad) gene, one of the tumor suppressor genes, have been described to be involved the formation and progression of human nasopharyngeal carcinoma, which is the most common and highly incident cancer of head and neck cancer in Asian countries, especially in Vietnam. Purpose: In Vietnam, there is still no research about E-cad promoter methylation in NPC, thus, in current report, a systematic literature revision was carried out to summary the current evidences about the frequencies of Ecad gene promoter on NPC for further applied in Vietnamese population. Methods: A systematic literature analysis was conducted based on the comprehensive search of observational studies. Moreover, CpG islands of candidate gene and transcriptional factors were predicted by using many bioinformatics tools, such as Methprimer, TFsearch, etc. Results: Total of 9 previous published studies were identified and accessed for eligibility from the literature research and enrolled into systematic revision. The variants of E-cad hypermethylation frequency ranked from 11.0% to 64.55% were observed. Moreover, the average weight frequencies of methylated and unmethylated E-cad gene promoter were 55.46% and 40.78%, respectively. Moreover, by several bioinformatics tools, we were successful in predicting the CpG islands as well as identifing transcriptional factor binding sites, served as “hot spot” for ideal primer pick up, located in candidate gene promoter. Conclusion: Based on these data, it suggested that the hypermethylation of E-cad gene promoter was a significant characteristic of NPC, in which, it could be further applied in evaluation of E-cad gene promoter status in Vietnamese population

In silico analysis of hypermethylation in CpGislands of UCHL1 gene’s promoter in nasopharyngeal carcinoma

Background and Objective: The methylation of Ubiquitin C-Terminal Hydrolase L1 (UCHL1) gene has been reported in many human cancers including nasopharyngeal carcinoma (NPC). In Vietnam, the methylation of UCHL1 gene’s promoter in NPC has not been demonstrated yet. In this study, a systematic literature revision was carried out to summarize the current evidences about the frequencies of UCHL-1 gene’s promoter methylation in NPC for further application in Vietnamese population. Methods: A systematic literature analysis was conducted based on the comprehensive studies. Moreover, many bioinformatic tools such as Methprimer, TFsearch, IDT OligoAnalyzer 3.1 were used to predict the CpG islands, transcriptional factors, and to pick up the MSP (Methylation-Specific PCR) primers. Results: Total of three previous studies were summarized and accessed for eligibility from literature research. As the results, the average weight methylated frequencies were 72.4% and 13.0% for NPC and non-cancerous samples, respectively. The significant association between UCHL-1 promoter methylation and NPC with the OR of 10.459 (95% CI = 4.915 – 22.254, p < 0.001) and RR of 4.117 (95% CI = 1.958 – 6.645, p < 0.0001) based on the random effects model, was observed. Moreover, we were successful in predicting the CpG islands as well as identifying transcriptional factor binding sites which served as “hot spot” for ideal primer pick up and located in gene promoter. Conclusion: The methylation of UCHL-1 gene promoter was significantly associated and contributed to NPC developmentin which it could be further applied in evaluation of UCHL-1 gene promoter status in Vietnamese population

The initial study of EBNA-2 polymorphisms in nasopharyngeal carcinoma in Vietnam

Epstein-Barr virus (EBV) infection is the main cause of Nasopharyngeal Carcinoma (NPC). EBNA-2, one of the most important genes participating in the formation of NPC, also helps EBV evade an attack on the immune system. EBNA-2 has 4 variants including E2-A, E2-B, E2-C and E-2D, of which E2-A and E2-C are the characterized variants for NPC. This study aimed to evaluate the variations of EBNA-2 in NPC biopsy samples of Vietnamese patients. This initial study used 10 biopsy samples, which were positively confirmed to NPC, collected from Cho Ray Hospital. Nested PCR – nucleotide sequencing was applied to analyze the variants of EBNA-2. The results showed that 8 out of 10 samples, accounting for 80%, were positive to EBNA-2. Additionally, only two variants, E-2A and E-2C were detected in our study, in which, E2-A subtype was identified as the predominant subtype. These findings would provide initial data about potential contribution of EBNA-2 polymorphisms to etiology of NPC in Vietnamese population

Evaluation of EBNA-1 (epstein-barr virus nuclear antigen-1) gene prevalence in nasopharyngeal carcinoma in Vietnamese patients

This study examined the presence of Epstein-Barr virus (EBV) in nasopharyngeal carcinoma (NPC) based on the detection of EBNA-1 (Epstein-Barr virus nuclear antigen-1) by Polymerase Chain Reaction (PCR), in Vietnamese population. Firstly, we systematically analyzed the mean of percentage weighted of the presence of EBNA-1 in previous relevant studies. Experimentally, 31 nasopharyngeal cancer biopsies and 20 healthy samples were enrolled in current to evaluate the frequency of candidate genes. As the results, the frequency of EBNA-1 was 77.42%, whereas, none of any cases of healthy samples were found to positive to target gene. The p value < 0.05 (p = 0.0001) showed that it was significant correlation between the presence of this candidate gene and nasopharyngeal cancer. Moreover, a high odds ratio (OR) and relative risk (RR) of candidate gene, (OR = 68.16, RR = 2.41) were calculated. Therefore, the detection of EBNA-1, which performed by PCR, could serve as a good supplement to early diagnosis and prognosis of NPC in Vietnamese population

Initial study of single nucleotide polymorphism genotyping of Epstein-barr nuclear antigen 1 (EBNA-1) from Vietnamese nasopharyngeal biopsy samples

Background: Epstein-Barr virus nuclear antigen (EBNA1), encoded by EBNA-1 gene, has been shown as one of the most frequently detected protein in Nasopharyngeal carcinoma (NPC), which the most common and highly incident cancer of head and neck cancer in Asian countries. The geographically-associated polymorphisms of EBNA-1 have been observed in East-Southern Asia, including Vietnam. The subtype V-val EBNA-1 has been demonstrated that it may contribute to the oncogenesis of NPC. This current study is initially performed to characterize the variations of EBNA-1 in NPC biopsy samples from Vietnamese patients. Methods: Nested PCR-sequencing was applied to amplify and characterize the C-terminal region of EBNA-1 gene by the designed oligonucleotide primers. Results: 10 NPC biopsy samples were enrolled, as the results, only two patterns of EBNA-1 variations: P-ala and V-val were observed. In addition, of these two subtypes, the frequency of V-val and P-ala were determined counting for 80% (8 of 10 cases) and 20% (2 of 10 cases), respectively. It indicated the V-val subtype preferentially exists in biopsy NPC samples, which collected from Vietnamese patients. Conclusion: We successfully designed the nested PCR-sequencing primer for detection of EBNA-1 variations based on the data collected from previous study. In our initial study, the sub-strain of EBV with V-val subtype of EBNA-1 infects NPC preferentially to those from biopsies of NPC patients. In further study, it is necessary for a larger number of samples and non-cancerous samples in order to confirm the characteristic of EBNA-1 variations, as well as determination of the association V-val subtype with NPC in Vietnamese patients