Efficacy of vaccination strategies against intranasal challenge with Brucella abortus in BALB/c mice

Brucellosis is a zoonotic disease affecting 500,000 people worldwide annually. Inhalation of aerosol containing a pathogen is one of the major routes of disease transmission in humans. Currently there are no licensed human vaccines available. Brucella abortus strain RB51 is a USDA approved live attenuated vaccine against cattle brucellosis. In a mouse model, strain RB51 over-expressing superoxide dismutase (SOD) administered intraperitoneally (IP) has been shown to be more protective than strain RB51 against an IP challenge with B. abortus pathogenic strain 2308. However, there is lack of information on the ability of these vaccine strains to protect against intranasal challenge. With the long-term goal of developing a protective vaccine for animals and people against respiratory challenge of Brucella spp., we tested a number of different vaccination strategies against intranasal infection with strain 2308. We employed strains RB51 and RB51SOD to assess the efficacy of route, dose, and prime-boost strategies against strain 2308 challenge. Despite using multiple protocols to enhance mucosal and systemic protection, neither rough RB51 vaccine strains provided respiratory protection against intranasal pathogenic Brucella infection. However, intranasal (IN) administration of B. abortus vaccine strain 19 induced significant (p ≤ 0.05) pulmonary clearance of strain 2308 upon IN challenge infection compared to saline. Further studies are necessary to address host-pathogen interaction in the lung microenvironment and elucidate immune mechanisms to enhance protection against aerosol infection.     

Retinoblastoma co-repressor 1 (RB) and cyclin-dependent kinase inhibitor (CDKN) as a multi-gene panel for differentiating pulmonary from non-pulmonary origin in metastatic neuroendocrine carcinomas

BackgroundNeuroendocrine carcinomas (NECs) arise from neuroendocrine cells present throughout the body, and often present with metastases even with small and undetectable primary tumors. Additionally, neuroendocrine differentiation can be seen in carcinomas of non-neuroendocrine origin further complicating the landscape of metastatic NECs. Organ specific immunohistochemical markers such as TTF1, CDX2 and PAX8 are often lost in high grade tumors and may be non-contributory in localizing the primary site.Though NECs share a common cellular origin, they exhibit great variability in biologic behavior, prognosis and treatment based on the primary organ of origin.DesignTwenty one cases of metastatic NECs were retrieved from our archives and were classified based on location of the primary tumor derived from clinical and radiological findings. Next generation sequencing data was retrieved and analyzed for recurrent genetic abnormalities in these cases. Statistical analysis was performed using IBM SPSS25 software.ResultsRB1 mutations were exclusive to NECs metastasizing from lung primary and were detected in 5 of 12 (41.6 %) cases (p = 0.04). CDKN gene family (CDKN1B and 2 A) mutations were limited to metatstatic NECs of non-pulmonary origin and were detected in 4 of 9 (44.4 %) cases (p = 0.02).ConclusionThe location of the primary tumor in metastatic NECs appears to have significant prognostic and therapeutic implications. But due to the morphological homogeneity, higher grade of tumor, variable sensitivity of immunohistochemical markers, and small, often undetectable primary tumors, the localization of the primary tumor in cases of metastatic NECs is a challenge. In this study, RB1 and CDKN gene family mutations are identified as possible markers for differentiating pulmonary and non-pulmonary origin in metatstatic NECs.     

Detection of allelic imbalance in the gene expression of <Emphasis Type="Italic">hMSH2</Emphasis> or <Emphasis Type="Italic">RB1</Emphasis> in lymphocytes from pedigrees of hereditary,nonpolyposis, colorectal cancer and retinoblastoma by an RNA difference plot

A number of phenotypes in hereditary disorders or common diseases are associated with specific genotypes. However, little is known about the molecular basis of phenotypic variation among individuals carrying the same mutation or polymorphism. Here, a highly quantitative approach was taken to examine a relative amount of mRNA from two polymorphic alleles with a coefficient of variation of less than 10% using an RNA difference plot (RDP). RDP analysis revealed that most genes examined were expressed in equal amount from the two alleles in normal lymphocytes. In contrast, the relative amounts of hMSH2 or RB1 mRNAs carrying premature termination codons were significantly reduced compared with those of wild-type mRNAs in lymphocytes from carriers of hereditary, nonpolyposis, colorectal cancer and hereditary retinoblastoma. The balance of allelic expression of the RB1 was also significantly impaired in a pedigree of retinoblastoma carrying a missense mutation in codon 661. The relative expression of the mutant to the wild-type RB1 alleles among the carriers varied from 0.40 to 2.39. The analysis of the expression diversity of a disease-associated allele by RDP could provide a novel approach to elucidating the mechanisms underlying phenotypic variation among individuals carrying an identical mutation or polymorphism at a single locus.     

RB1在恶性肿瘤中的研究进展

视网膜母细胞瘤基因1(Retinoblastoma1,RB1)是人类发现的第一个抑癌基因,因为最初在视网膜母细胞瘤中发现该基因所以命名为视网膜母细胞瘤基因1. RB1作为一种负性调控因子在细胞周期中有重要作用,通过与转录因子E2 F结合来调控细胞的增殖. 研究还发现RB1在抗细胞凋亡中也扮演着重要的角色,RB1的敲除可以增强抗肿瘤药物导致细胞死亡的敏感性. RB1的这种双重作用提示其可能是恶性肿瘤的发病原因,并且可能成为肿瘤进展及临床治疗效果的预测指标.