Augmented interferon regulatory factor 7 axis in whole tumor cell vaccines prevents tumor recurrence by inducing interferon gamma-secreting B cells.

Among cancer immunotherapy, which has received great attention in recent years, cancer vaccines can potentially prevent recurrent tumors by using the exquisite power and specificity of the immune system. Specifically, whole tumor cell vaccines (WTCVs) based on surgically resected tumors have been considered to elicit robust anti-tumor immune responses by exposing various tumor-associated antigens to host immunity. However, most tumors have little immunogenicity because of immunoediting by continuous interactions with host immunity; thus, preparing WTCVs based on patient-derived non-modified tumors cannot prevent tumor onset. Hence, the immunogenicity of tumor cells must be improved for effective WTCVs. In this study, we indicate the importance of the interferon regulatory factor 7 (Irf7) axis, including Irf7 and its downstream factors, within tumor cells in regulating immunogenicity. Indeed, WTCVs that augmented the Irf7 axis have exerted remarkable recurrence-preventive effects when vaccinated after tumor inactivation by radiation. Most notably, vaccination with murine colon cancer cells that enhanced the Irf7 axis prevented the development of challenged tumors in all mice and resulted in a 100% survival rate during the observation period. Furthermore, the mechanism leading to vaccine effectiveness was mediated by interferon-gamma-producing B cells. This study provides novel insights into how to enhance tumor immunogenicity and use WTCVs as recurrence prophylaxis.

Direct protein delivery into intact plant cells using polyhistidine peptides.

Polyhistidine peptides (PHPs), sequences comprising only histidine residues (>His8), are effective cell-penetrating peptides for plant cells. Using PHP-fusion proteins, we aimed to deliver proteins into cultured plant cells from Nicotiana tabacum, Oryza sativa, and Cryptomeria japonica. Co-cultivation of cultured cells with fusion proteins combining maltose-binding protein (MBP), red fluorescent protein (RFP), and various PHPs (MBP-RFP-His8-His20) in one polypeptide showed the cellular uptake of fusion proteins in all plant cell lines. Maximum intracellular fluorescence was shown in MBP-RFP-His20. Further, adenylate cyclase (CyaA), a synthase of cyclic adenosine monophosphate (cAMP) activated by cytosolic calmodulin, was used as a reporter for protein delivery in living cells. A fusion protein combining MBP, RFP, CyaA, and His20 (MBP-RFP-CyaA-His20) was delivered into plant cells and increased intracellular fluorescence and cAMP production in all cell lines. The present study demonstrates that PHPs are effective carriers of proteins into the intracellular space of various cultured plant cells.

Interleukin 34, from pathogenesis to clinical applications.

Interleukin-34 (IL-34) is a hematopoietic cytokine that was described for the first time in 2008 as a second ligand of CSF1R in addition to M-CSF. IL-34 and M-CSF share no sequence homology, but have similar functions, affecting the biology of myeloid cell lineage. In contrast to M-CSF, IL-34 shows unique signaling and expression patterns. Physiologically, IL-34 expression is restricted to epidermis and CNS, acting as a regulator of Langerhans cells and microglia, respectively. However, IL-34 expression can be induced and regulated by NF-κB under pathological conditions. Importantly, growing evidence indicates a correlation between IL-34 and disease severity, chronicity and progression. In addition to its promising roles as a novel diagnostic and prognostic biomarker of disease, IL-34 may also serve as a powerful target for therapeutic intervention. Here, we review the current knowledge regarding the emerging roles of IL-34 in disease, and focus on the clinical applications of IL-34 in medicine.

Effect of manganese on guinea pig ventricle: initial depression and late augmentation of contractile force.

Effects of Mn2+ on isolated guinea pig ventricular myocardia were examined. In isolated papillary muscles, Mn2+ produced a transient decrease in contractile force followed by a late sustained augmentation. Mn2+ markedly increased the amplitude of post-rest contractions; the time course of potentiation was almost the same as that of the late augmentation of contractile force after Mn2+ application. Mn2+ also increased the amplitude of rapid-cooling contractures. The negative inotropic effect of diltiazem and nicardipine was not affected by the presence of Mn2+. Mn2+ shortened the action potential duration under normal condition whereas it prolonged the duration under Ca2+ free conditions. Mn2+, when applied to fura-2-loaded ventricular myocytes, markedly quenched the cytoplasmic fluorescence excited at 360 nm wavelength. We concluded that Mn2+ not only causes a decrease in contractile force by blocking the L-type Ca2+ channel, but also enters the cytoplasm through the channel and produces late augmentation of the contractile force through enhancement of sarcoplasmic reticulum function.