31.若年者胃癌の一例(第538回千葉医学会例会・第10回佐藤外科例会)

Additional file 2. ChIL-26/LPS induces cytokine secretion by the CU91 T cell line. The CU91 chicken T cell line was cultured in the presence or absence of 200 ng/mL ChIL-26, with or without 5 Âľg/mL LPS, and cytokine expression was analyzed by qRT-PCR. The results are indicated as fold increases of mRNA expression compared to that in unstimulated control cells. Data are presented as the mean Âą SEM (n = 3) of three independent experiments: * p < 0.05, ** p < 0.01, and *** p < 0.001

Enhanced Immunogenicity of Engineered HER2 Antigens Potentiates Antitumor Immune Responses

For cancer vaccines, the selection of optimal tumor-associated antigens (TAAs) that can maximize the immunogenicity of the vaccine without causing unwanted adverse effects is challenging. In this study, we developed two engineered Human epidermal growth factor receptor 2 (HER2) antigens, K965 and K1117, and compared their immunogenicity to a previously reported truncated HER2 antigen, K684, within a B cell and monocyte-based vaccine (BVAC). We found that BVAC-K965 and BVAC-K1117 induced comparable antigen-specific antibody responses and antigen-specific T cell responses to BVAC-K684. Interestingly, BVAC-K1117 induced more potent antitumor activity than the other vaccines in murine CT26-HER2 tumor models. In addition, BVAC-K1117 showed enhanced antitumor effects against truncated p95HER2-expressing CT26 tumors compared to BVAC-K965 and BVAC-K684 based on the survival analysis by inducing T cell responses against intracellular domain (ICD) epitopes. The increased ICD epitope-specific T cell responses induced by BVAC-K1117 compared to BVAC-K965 and BVAC-K684 were recapitulated in human leukocyte antigen (HLA)-untyped human PBMCs and HLA-A*0201 PBMCs. Furthermore, we also observed synergistic antitumor effects between BVAC-K1117 and anti-PD-L1 antibody treatment against CT26-HER2 tumors. Collectively, our findings demonstrate that inclusion of a sufficient number of ICD epitopes of HER2 in cellular vaccines can improve the antitumor activity of the vaccine and provide a way to optimize the efficacy of anticancer cellular vaccines targeting HER2.Y

Children with COVID-19 after Reopening of Schools, South Korea

PURPOSE: To describe pediatric coronavirus disease 2019 (COVID-19) cases after the reopening of schools in the Republic of Korea and their transmission routes. METHODS: All case report forms and epidemiologic investigation forms for children aged 3–18 years reported as COVID-19 cases to the National Notifiable Disease Surveillance System from May 1 to July 12, 2020, were reviewed. RESULTS: After the schools were reopened in May 2020, a total of 127 pediatric COVID-19 cases were confirmed until July 12. Of these, 59 children (46%) were exposed to severe acute respiratory syndrome coronavirus 2 through family and relatives, followed by 18 children (14%) through cram schools or private lessons, 8 children (6%) through multi-use facilities, and 3 children (2%) through school. CONCLUSIONS: The present data do not suggest an increased risk of COVID-19 transmission in the context of stringent school-based infection prevention measures introduced across the country

Analysis of Differentially Expressed Genes in Necrotic Enteritis-infected Fayoumi Chickens using RNA Sequencing

We identified and evaluated differentially expressed genes (DEGs) by RNA-Sequencing (RNA-Seq) in the intestinal mucosa of two Fayoumi chicken lines, M5.1 and M15.2, that are affected by necrotic enteritis (NE); these chicken lines share the same genetic background but have different major histocompatibility complexes. RNA-Seq generated over 49 and 40 million reads for lines M5.1 and M15.2, respectively. The alignment of these sequences with the Gallus gallus genome database revealed the expression of more than 14,500 genes in two lines, among which 581, 1270, and 1140 DEGs were detected when lines M15.2 and M5.1 were compared with the control and compared between each other. The analysis of all DEGs using the gene ontology database revealed annotations for 111 biological processes, 32 cellular components, and 17 molecular functions, and KEEG pathway mapping indicated that the DEGs were primarily involved in immunity, responses to various stimuli, and signal transduction. In addition, we analyzed 183 innate immune genes that were differentially expressed in NE-induced chicken lines, including 46 CD molecular genes, 89 immune-related genes, and 13 β-defensin genes with 3 lineage-specific duplications. Taken together, the transcriptional profiles showed that line M5.1 was more resistant to NE than line M15.2 and that differential gene expression patterns were associated with host genetic differences in resistance to NE. qRT-PCR and RNA-Seq analyses showed that all the genes examined had similar responses to NE (correlation coefficient R＝0.84 to 0.88, p&lt;0.01) in both lines. To the best of our knowledge, this is the first study that describes NE-induced DEGs using RNA-seq in two lines with different levels of susceptibility to NE. These results will lead to increased insights on NE disease resistance mechanisms and the role of host genes in the control of the host immune response

Tumor-derived osteopontin suppresses antitumor immunity by promoting extramedullary myelopoiesis

Extramedullary myelopoiesis occurs commonly in tumor-bearing animals and is known to lead to accumulation of peripheral myeloid-derived suppressor cells (MDSC), which play an important role in immune escape. However, the cellular and molecular mechanisms by which tumors induce extramedullary myelopoiesis are poorly understood. In this study, we found that osteopontin expressed by tumor cells enhances extramedullary myelopoiesis in a CD44-dependent manner through the Erk1/2-MAPK pathway. Osteopontin-mediated extramedullary myelopoiesis was directly associated with increased MDSCs in tumor-bearing hosts. More importantly, osteopontin silencing in tumor cells delayed both tumor growth and extramedullary myelopoiesis, while the same treatment did not affect tumor growth in vitro. Finally, treatment with an antibody against osteopontin inhibited tumor growth and synergized with cell-based immunotherapeutic vaccines in mediating antitumor immunity. Our findings unveil a novel immunosuppressive role for tumor-derived osteopontin and offer a rationale for its therapeutic targeting in cancer treatment. (C) 2014 AACR.N

Urbanization of scrub typhus disease in South Korea.

BACKGROUND:Scrub typhus is an endemic disease in Asia. It has been a rural disease, but indigenous urban cases have been observed in Seoul, South Korea. Urban scrub typhus may have a significant impact because of the large population. METHODS:Indigenous urban scrub typhus was epidemiologically identified in Seoul, the largest metropolitan city in South Korea, using national notifiable disease data from 2010 to 2013. For detailed analysis of clinical features, patients from one hospital that reported the majority of cases were selected and compared to a historic control group. Chigger mites were prospectively collected in the city using a direct chigger mite-collecting trap, and identified using both phenotypic and 18S rDNA sequencing analyses. Their infection with Orientia tsutsugamushi was confirmed by sequencing the 56-kDa antigen gene. RESULTS:Eighty-eight cases of urban scrub typhus were determined in Seoul. The possible sites of infection were mountainous areas (56.8%), city parks (20.5%), the vicinity of one's own residence (17.0%), and riversides (5.7%). Eighty-seven chigger mites were collected in Gwanak mountain, one of the suspected infection sites in southern Seoul, and seventy-six (87.4%) of them were identified as Helenicula miyagawai and eight (9.2%) as Leptotrombidium scutellare. Pooled DNA extracted from H. miyagawai mites yielded O. tsutsugamushi Boryong strain. Twenty-six patients from one hospital showed low APACHE II score (3.4 ± 2.7), low complication rate (3.8%), and no hypokalemia. CONCLUSIONS:We identified the presence of indigenous urban scrub typhus in Seoul, and a subgroup of them had mild clinical features. The chigger mite H. miyagawai infected with O. tsutsugamushi within the city was found. In endemic area, urban scrub typhus needs to be considered as one of the differential febrile diseases and a target for prevention

Serum amyloid A3 exacerbates cancer by enhancing the suppressive capacity of myeloid-derived suppressor cells via TLR2-dependent STAT3 activation

Myeloid-derived suppressor cells (MDSCs), which suppress diverse innate and adaptive immune responses and thereby provide an evasion mechanism for tumors, are emerging as a key population linking inflammation to cancer. Although many inflammatory factors that induce MDSCs in the tumor microenvironment are known, the crucial components and the underlying mechanisms remain elusive. In this study, we proposed a novel mechanism by which serum amyloid A3 (SAA3), a well-known inflammatory factor, connects MDSCs with cancer progression. We found that SAA3 expression in BALB/c mice increased in monocytic MDSCs (Mo MDSCs) with tumor growth. The induction of SAA3 by apo-SAA treatment in Mo MDSCs enhanced their survival and suppressive activity, while it inhibited GM-CSF-induced differentiation. Endogenous SAA3 itself contributed to the increase in the survival and suppressive activity of Mo MDSCs. We demonstrated that SAA3 induced TLR2 signaling, in turn increasing the autocrine secretion of TNF-, that led to STAT3 activation. In addition, activated STAT3 enhanced the suppressive activity of Mo MDSCs. Furthermore, SAA3 induction in Mo MDSCs contributed to accelerating tumor progression in vivo. Collectively, these data suggest a novel mechanism by which Mo MDSCs mediate inflammation through SAA3-TLR2 signaling and thus exacerbate cancer progression by a STAT3-dependent mechanism.N

Differentiation of c-Kit(+)CD24(+) natural killer cells into myeloid cells in a GATA-2-dependent manner

Myeloid progenitor cells have generally been considered the predominant source of myeloid cells under steady-state conditions. Here we show that NK cells contributed to a myeloid cell lineage pool in naive and tumor-bearing mice. Using fate tracing of NKp46(+) cells, we found that myeloid cells could be derived from NK cells. Notably, among mature CD11b(+)CD27(+) NK cells, c-Kit(+)CD24(+) NK cells were capable of differentiating into a range of myeloid lineages in vitro and produced neutrophils and monocytes in vivo. The differentiation was completely inhibited by NK-stimulating cytokines. In addition to the potential for differentiation into myeloid cells, c-Kit(+)CD24(+) NK cells retained NK cell phenotypes and effector functions. Mechanistically, GATA-2 was necessary for the differentiation of c-Kit(+)CD24(+) NK cells. Therefore, we discovered that GATA-2-dependent differentiation of c-Kit(+)CD24(+) NK cells contributes to myeloid cell development and identified a novel pathway for myeloid lineage commitment under physiological conditions.Y

Monocyte-derived dendritic cells dictate the memory differentiation of CD8+ T cells during acute infection

Monocyte-derived dendritic cells (moDCs) have been shown to robustly expand during infection; however; their roles in anti-infectious immunity remain unclear. Here, we found that moDCs were dramatically increased in the secondary lymphoid organs during acute LCMV infection in an interferon-gamma (IFN-gamma)-dependent manner. We also found that priming by moDCs enhanced the differentiation of memory CD8(+) T cells compared to differentiation primed by conventional dendritic cells (cDCs) through upregulation of Eomesodermin (Eomes) and T cell factor-1 (TCF-1) expression in CD8(+) T cells. Consequently, impaired memory formation of CD8(+) T cells in mice that had reduced numbers of moDCs led to defective clearance of pathogens upon rechallenge. Mechanistically, attenuated interleukin-2 (IL-2) signaling in CD8(+) T cells primed by moDCs was responsible for the enhanced memory programming of CD8(+) T cells. Therefore, our findings unveil a specialization of the antigen-presenting cell subsets in the fate determination of CD8(+) T cells during infection and pave the way for the development of a novel therapeutic intervention on infection.Y