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Mitochondrial N‐formylpeptides are released from damaged or dead cells to the extracellular spaces and cause inflammatory responses. The role of mitochondrial N‐formylpeptides in aseptic systemic inflammatory response syndromes induced by trauma or cardiac surgery has been well investigated. However, there are no reports regarding the role of mitochondrial N‐formylpeptides in cancer. In this study, we investigated the role of tumor cell‐derived mitochondrial N‐formylpeptides in anti‐tumor immunity using knockout murine tumor cells of mitochondrial methionyl‐tRNA formyltransferase (MTFMT), which catalyze N‐formylation of mitochondrial DNA‐encoded proteins. There was no apparent difference among the wild‐type and MTFMT‐knockout clones of E.G7‐OVA cells with respect to morphology, mitochondrial dynamics, glycolysis and oxidative phosphorylation, oxygen consumption rate, or in vitro cell growth. In contrast, in vivo tumor growth of MTFMT‐knockout cells was slower than that of wild‐type cells. A reduced number of myeloid‐derived suppressor cells and an increase of cytotoxic T‐lymphocytes in the tumor tissues were observed in the MTFMT‐knockout tumors. These results suggested that tumor cell‐derived mitochondrial N‐formylpeptides had a negative role in the host anti‐tumor immunity through modification of the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Several in vivo, in vitro and structural studies are conducted to explain the mechanisms involved in the myristate exposure taking place in the human immunodeficiency virus type 1 matrix protein. The analyzed exposure is shown to be highly modulated by the pH.

Leishmania were previously shown to undergo photolysis when their transgenic mutants were induced endogenously to accumulate cytoplasmic uroporphyrin or when loaded exogenously with aluminum phthalocyanine chloride. A combinational use of both is reported here, which renders Leishmania far more susceptible to photolysis. Fluorescence microscopy of cells loaded with the two photosensitizers localized them to different subcellular sites. Pre-exposure of Leishmania to both synergistically sensitized them for photolysis as extracellular promastigotes and intracellular amastigotes in infected macrophages in vitro when illuminated at specific wavelengths to excite the respective photosensitizers for production of reactive oxygen species. Both Leishmania stages lost their viability completely when doubly photosensitized optimally and illuminated at low intensity, the host cells being left unscathed. Inoculation of mice with photoinactivated Leishmania produced no lesions, which invariably developed in the control groups during a period of observations for 8 weeks. Pretreatment of Leishmania with both photosensitizers rendered these cells susceptible to clearance from the ear dermis by white light illumination. The results suggest that double photosensitization for synergistic activity enhances the efficacy and safety of photodynamic therapy in general and for Leishmania in particular. [ABSTRACT FROM AUTHOR]

Leishmania were previously shown to undergo photolysis when their transgenic mutants were induced endogenously to accumulate cytoplasmic uroporphyrin or when loaded exogenously with aluminum phthalocyanine chloride. A combinational use of both is reported here, which renders Leishmania far more susceptible to photolysis. Fluorescence microscopy of cells loaded with the two photosensitizers localized them to different subcellular sites. Pre-exposure of Leishmania to both synergistically sensitized them for photolysis as extracellular promastigotes and intracellular amastigotes in infected macrophages in vitro when illuminated at specific wavelengths to excite the respective photosensitizers for production of reactive oxygen species. Both Leishmania stages lost their viability completely when doubly photosensitized optimally and illuminated at low intensity, the host cells being left unscathed. Inoculation of mice with photoinactivated Leishmania produced no lesions, which invariably developed in the control groups during a period of observations for 8 weeks. Pretreatment of Leishmania with both photosensitizers rendered these cells susceptible to clearance from the ear dermis by white light illumination. The results suggest that double photosensitization for synergistic activity enhances the efficacy and safety of photodynamic therapy in general and for Leishmania in particular. [ABSTRACT FROM AUTHOR]

Endometrial cancer is the most prevalent gynecological cancer in developed countries. Although the prognosis of endometrial cancer is better than that of other gynecological cancers, the prognosis of advanced endometrial cancer is still poor and thus new therapeutic modalities, such as immune therapies, are urgently required. For the further development of new modalities, exploration of new biomarkers is important. The present study investigated the circulating cell-free DNA (cfDNA) integrity as a ratio of the necrotic tumor cell-derived long cfDNA fragments to the total dead cell-derived short cfDNA fragments from genomic Alu elements in patients with advanced endometrial cancer during peptide vaccination treatment. The results demonstrated that: i) The plasma cfDNA integrity was decreased during the first cycle of vaccination in patients with endometrial cancer treated with the personalized peptide vaccination, and ii) the post-vaccination cfDNA integrity levels were correlated with good prognosis. Some of these findings have been confirmed in other cancers, and thus cfDNA integrity might be an important marker for future cancer vaccine therapies in general, and might also be applicable for other immune therapies. [ABSTRACT FROM AUTHOR]

Therapeutic cancer vaccines have been dramatically progressing in a variety of their forms for the last two decades. The CTIepitope peptide vaccines are one of them. We proposed the personalized peptide vaccine (PPV) therapy. Our PPV is different from the classical one in that a maximum of four peptides are selected based on the patient's HLA-A types and.their pre-existing immunity (=immunological memory), leading to the more rapid and stronger re- sponses to the vaccinated peptides. Since then, we have been conducting clinical studies for various types of advanced cancers. We summarized the clinical outcomes of the PPV studies and described its prospect for the clinical application.

The present study analyzed polymorphisms of the 5' flanking region (from nt -840 to +151) of the haptoglobin gene in 120 patients with advanced non-small cell lung cancer (NSCLC) receiving personalized peptide vaccinations. In the region, six single nucleotide polymorphisms (SNPs) were confirmed, of which two, rs5472 and rs9927981, were completely linked to each other. The minor allele frequencies of rs5472/rs9927981 and rs4788458 were higher than those of the other three SNPs. The genotype frequencies of rs5472 or rs9927981 were A/A or C/C (42.5%, n=51), A/G or C/T (40.8%, n=49), and G/G or T/T (16.7%, n=20), respectively; and those of rs4788458 were T/T (34.2%, n=41), T/C (40.0%, n=48), and C/C (25.8%, n=31). The association between polymorphism rs5472/rs9927981 and prognosis, or between rs4788458 and prognosis, was analyzed further. However, no correlation was found between these SNPs and overall survival, regardless of subgroup analysis of gender, histology or concurrent therapy. These results suggest that the polymorphisms rs5472/rs9927981 and rs4788458 are not useful prognostic tools for patients with NSCLC treated with personalized peptide vaccination.

The prognosis of non-small cell lung cancer (NSCLC) patients who failed two or more treatment regimens remains very poor. We conducted a phase II study to explore the feasibility of personalized peptide vaccination (PPV), in which peptides are selected and administered based on the pre-existing host immunity before vaccination, as a third or more line treatment in advanced NSCLC patients who failed two or more regimens. Among 57 patients enrolled, 23 or 16 patients received PPV with chemotherapy or targeted therapy, respectively, whereas 18 patients received PPV alone. A maximum of four HLA-matched peptides showing higher peptide-specific IgG responses in pre-vaccination plasma were selected from 31 pooled peptide candidates applicable for patients with HLA-A2, -A24, -A3 supertypes, and/or -A26, followed by subcutaneous administration. No severe adverse events related to PPV were observed. Median survival time was 692, 468, or 226 days in the group of PPV/chemotherapy, PPV/targeted therapy, or PPV alone, respectively. CTL responses to the vaccinated peptides became detectable after vaccination in 58, 50, or 42% of patients in each of these three groups, respectively. In contrast, peptide-specific IgG responses after vaccination augmented in 55, 75, or 62% of patients in each of these groups, respectively. These results suggest the feasibility of PPV for heavily treated advanced NSCLC patients from the view of both immunological responses and safety. Therefore, further evaluation of PPV by prospective randomized trial is warranted for a third or fourth line treatment of advanced NSCLC.