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Overcoming tolerance to tumor-associated antigens remains a hurdle for cancer vaccine-based immunotherapy. A strategy to enhance the anti-tumor immune response is the inclusion of adjuvants to cancer vaccine protocols. In this report, we generated and systematically screened over twenty gene-based molecular adjuvants composed of cytokines, chemokines, and T cell co-stimulators for the ability to increase anti-tumor antigen T cell immunity. We identified several robust adjuvants whose addition to vaccine formulations resulted in enhanced T cell responses targeting the cancer antigens STEAP1 and TERT. We further characterized direct T cell stimulation through CD80-Fc and indirect T cell targeting via the dendritic cell activator Flt3L-Fc. Mechanistically, intramuscular delivery of Flt3L-Fc into mice was associated with a significant increase in infiltration of dendritic cells at the site of administration and trafficking of activated dendritic cells to the draining lymph node. Gene expression analysis of the muscle tissue confirmed a significant up-regulation in genes associated with dendritic cell signaling. Addition of CD80-Fc to STEAP1 vaccine formulation mimicked the engagement provided by DCs and increased T cell responses to STEAP1 by 8-fold, significantly increasing the frequency of antigen-specific cells expressing IFNγ, TNFα, and CD107a for both CD8+ and CD4+ T cells. CD80-Fc enhanced T cell responses to multiple tumor-associated antigens including Survivin and HPV, indicating its potential as a universal adjuvant for cancer vaccines. Together, the results of our study highlight the adjuvanting effect of T cell engagement either directly, CD80-Fc, or indirectly, Flt3L-Fc, for cancer vaccines.

The complexity of liver tumorigenesis is underscored by the recently observed anti-oncogenic effects of oncoproteins, although the mechanisms are unclear. Shp2/Ptpn11 is a proto-oncogene in hematopoietic cells, and antagonizes the effect of tumor suppressor Pten in leukemogenesis. In contrast, we show here cooperative functions of Shp2 and Pten in suppressing hepatocarcinogenesis. Ablating both Shp2 and Pten in hepatocytes induced early-onset non-alcoholic steatohepatitis (NASH), and promoted genesis of liver tumor-initiating cells likely due to augmented cJun expression/activation, and elevated ROS and inflammation in the hepatic microenvironment. Inhibiting cJun partially suppressed NASH-driven liver tumorigenesis without improving NASH. SHP2 and PTEN deficiencies were detected in liver cancer patients with poor prognosis. These data depict a mechanism of hepato-oncogenesis and suggest a potential therapeutic strategy.

patients who fit the height and IGF-I criteria of severe primary IGFD, i.e. both height and IGF-I standard deviation scores (SDS) ≤−3 with normal or elevated concentrations of growth hormone (GH). rhIGF-I is also approved for patients who have GH gene deletions and who have developed GH neutralizing antibodies to GH. In Europe the indication is slightly different, as severe primary IGFD is defined there as a height SDS ≤−3, but with basal IGF-I concentration of

Resume Au cours de l'annee 1977, cinq souches de Pasteurella multocida ont ete isolees a partir de quatre types de prelevements qui correspondent aux principales formes cliniques humaines des pasteurelloses. Cette diversite incite a envisager l'importance en pathologie humaine de cette espece et a comparer avec la frequence d'isolement de ce germe en milieu veterinaire dans la region. Il semble que la mise en evidence de cette pasteurelle soit facilitee par l'emploi de techniques et de milieux favorisant son isolement, augmentant ainsi sa frequence. Pasteurella multocida apparait surtout comme une espece « opportuniste , agent d'infections secondes en raison de facteurs favorisants dus a l'hote. Les animaux, en particulier de basse-cour, jouent un role epidemiologique important.