Escherichia coli (E. coli) K1 causes meningitis and remains an unsolved problem in neonates, despite the application of antibiotics and supportive care. The cross-reactivity of bacterial capsular polysaccharides with human antigens hinders their application as vaccine candidates. Thus, protein antigens could be an alternative strategy for the development of an E. coli K1 vaccine. Outer membrane protein A (OmpA) of E. coli K1 is a potential vaccine candidate because of its predominant contribution to bacterial pathogenesis and sub-cellular localization. However, little progress has been made regarding the use of OmpA for this purpose due to difficulties in OmpA production. In the present study, we first investigated the immunogenicity of the four extracellular loops of OmpA. Using the structure of OmpA, we rationally designed and successfully generated the artificial protein OmpAVac, composed of connected loops from OmpA. Recombinant OmpAVac was successfully produced in E. coli BL21 and behaved as a soluble homogenous monomer in the aqueous phase. Vaccination with OmpAVac induced Th1, Th2, and Th17 immune responses and conferred effective protection in mice. In addition, OmpAVac-specific antibodies were able to mediate opsonophagocytosis and inhibit bacterial invasion, thereby conferring prophylactic protection in E. coli K1-challenged adult mice and neonatal mice. These results suggest that OmpAVac could be a good vaccine candidate for the control of E. coli K1 infection and provide an additional example of structure-based vaccine design.
Inherent and acquired resistance of cancer cells is increasingly recognized as a significant impediment to effective radiation cancer treatment. As important intracellular factors, aberrant tumor transmembrane signal transduction pathways, which include the prosurvival cascades (PI3K ⁄ Akt, MAPK ⁄ ERK and JAK ⁄ STAT) and the proapoptosis pathways (Wnt, p53 and TNF-a ⁄ NF-jB), have been proved to be crucial determinants of the probability of cell sensitivity to radiation in malignant lesions. There is increasing evidence that targeting the abnormal pathways that can regulate the activity of the DNA damage response and further influence the response of tumor cells to radiation may be suitable for improving radiation sensitization. Preclinical and clinical evidence suggest that agents targeting aberrant tumor signals can effectively improve the therapeutic effect of ionizing radiation. Therefore, in this review, we discuss the intricate interplay between tumor responses to radiation with the aberrant signal pathways, and the potential druggable targets within the pathways to sensitize tumors without significant collateral damage to normal tissues. The application of novel targeting compounds to manipulate the aberrant signal of tumor cells in clinical treatments is also addressed. (Cancer Sci 2013; 104: 1401-1410 I onizing radiation (IR) is an inalienable part of modern cancer management given the unique advantages of being noninvasive and devoid of intense systemic toxicity. As an integral component of adjuvant treatment strategies for primary tumors and palliative treatment strategies for advanced and metastatic tumors, more than 50% of diagnosed cancer patients receive radiation therapy (RT; alone or combination with chemotherapy or surgery) worldwide. However, RT offers various degrees of success; there is still an increased recurrence and treatment failure in patients. Retrospective studies show that extracellular factors, such as location, size and hypoxia, play important roles in the lack of response to radiotherapy.(1,2) In recent 15 years, as important intracellular factors, the signaling pathways that can regulate the activity of the DNA damage response, cell growth, differentiation and development have been proved to undergo oncogenic changes far more than other molecule groups.(3-5) The genetic alterations that are activated by the signal cascades in premalignant cells and further characterize neoplasm genomes have also been highlighted. (6)(7)(8) Preclinical and clinical studies have indicated that the aberrant signal pathways in cancer cells are crucial determinants of the probability of the improvement of sensitivity to radiation in malignant lesions (9)(10)(11)(12)(13) ; and a more nuanced understanding of the complex radiobiology mechanisms for the response of tumors to RT has paved the way for exploring novel or combinatorial therapeutic approaches for cancer treatment using IR. Hence, the targeted agents that can specifically inhibit the activity of the signal cascades could abrogate the radiores...
Background Escherichia coli K1 (E. coli K1) caused neonatal meningitis remains a problem, which rises the urgent need for an effective vaccine. Previously, we rationally designed and produced the recombinant protein OmpAVac (Vo), which elicited protective immunity against E. coli K1 infection. However, Vo has limited stability, which hinders its future industrial application. Method Chitosan-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles were prepared and used as carried for the recombinant Vo. And the safety, stability and immunogenicity of Vo delivered by chitosan-modified PLGA nanoparticles were tested in vitro and in a mouse model of bacteremia. Results We successfully generated chitosan-modified PLGA nanoparticles for the delivery of recombinant Vo (VoNP). In addition, we found that a freeze-drying procedure increases the stability of the VoNPs without changing the shape, size distribution and encapsulation of the Vo protein. Unlike aluminum adjuvant, the nanoparticles that delivered Vo were immunoprotective in mice even after storage for as long as 180 days. Conclusions We identified an effective strategy to improve the stability of Vo to maintain its immunogenicity, which will contribute to the future development of vaccines against E. coli K1.
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