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Tumor-associated macrophages (TAMs), one of the major components of the tumor microenvironment, contribute to the progression of esophageal squamous cell carcinoma (ESCC). We previously established a direct co-culture system of human ESCC cells and macrophages and reported the promotion of malignant phenotypes, such as survival, growth, and migration, in ESCC cells. These findings suggested that direct interactions between cancer cells and macrophages contribute to the malignancy of ESCC, but its underlying mechanisms remain unclear. In this study, we compared the expression levels of the interferon-induced genes between mono- and co-cultured ESCC cells using a cDNA microarray and found that interferon-inducible protein 16 ( IFI16 ) was most significantly upregulated in co-cultured ESCC cells. IFI16 knockdown suppressed malignant phenotypes and also decreased the secretion of interleukin-1α (IL-1α) from ESCC cells. Additionally, recombinant IL-1α enhanced malignant phenotypes of ESCC cells through the Erk and NF-κB signaling. Immunohistochemistry revealed that high IFI16 expression in human ESCC tissues tended to be associated with disease-free survival and was significantly associated with tumor depth, lymph node metastasis, and macrophage infiltration. The results of this study reveal that IFI16 is involved in ESCC progression via IL-1α and imply the potential of IFI16 as a novel prognostic factor for ESCC.

The involvement of passenger strands of miRNAs in the molecular pathogenesis of human cancers is a recent concept in miRNA research, and it will broaden our understanding of the molecular mechanisms of miRNA-mediated cancer. The analysis of our miRNA signature of LUAD revealed that both strands of pre- miR-486 ( miR-486-5p and miR-486-3p ) were downregulated in LUAD tissues. Ectopic expression of both miRNAs induced cell cycle arrest in LUAD cells, suggesting both strands of miRNAs derived from pre- miR-486 were tumor suppressive. Our in silico analysis showed a total of 99 genes may be under the control of both miRNAs in LUAD cells. Importantly, among these targets, the high expression of seven genes ( MKI67 , GINS4 , RRM2 , HELLS , MELK , TIMELESS , and SAPCD2 ) predicted a poorer prognosis of LUAD patients ( p < 0.05). We focused on GINS4 , a DNA replication complex GINS protein that plays an essential role in the initiation of DNA replication. Our functional assays showed that GINS4 was directly controlled by both strands of pre- miR-486 , and its aberrant expression facilitated the aggressive behavior of LUAD cells. GINS4 is attractive as a therapeutic target for this disease. MiRNA analysis, including passenger strands, will further improve our understanding of the molecular pathogenesis of LUAD.

Tumor-associated macrophages (TAMs) contribute to disease progression in various cancers, including esophageal squamous cell carcinoma (ESCC). We have previously used an indirect co-culture system between ESCC cell lines and macrophages to analyze their interactions. Recently, we established a direct co-culture system to closely simulate actual ESCC cell-TAM contact. We found that matrix metalloproteinase 9 (MMP9) was induced in ESCC cells by direct co-culture with TAMs, not by indirect co-culture. MMP9 was associated with ESCC cell migration and invasion, and its expression was controlled by the Stat3 signaling pathway in vitro. Immunohistochemical analyses revealed that MMP9 expression in cancer cells at the invasive front ("cancer cell MMP9") was related to high infiltration of CD204 positive M2-like TAMs ( p < 0.001) and was associated with worse overall and disease-free survival of patients ( p = 0.036 and p = 0.038, respectively). Furthermore, cancer cell MMP9 was an independent prognostic factor for disease-free survival. Notably, MMP9 expression in cancer stroma was not associated with any clinicopathological factors or patient prognoses. Our results suggest that close interaction with TAMs infiltrating in cancer stroma or cancer nests induces MMP9 expression in ESCC cells, equipping them with more malignant features.

High infiltration of tumor-associated macrophages (TAMs), which contribute to the progression of several cancer types, is correlated with poor prognosis of esophageal squamous cell carcinoma (ESCC). In addition to the previously reported increase in migration and invasion, ESCC cells co-cultured directly with macrophages exhibited enhanced survival and growth. Furthermore, interleukin-related molecules are associated with ESCC; however, the precise mechanism underlying this association is unclear. Therefore, we explored the role of interleukin-related molecules in ESCC progression. A cDNA microarray analysis of monocultured and co-cultured ESCC cells revealed that the interleukin 7 receptor (IL-7R) was upregulated in ESCC cells co-cultured with macrophages. Overexpression of IL-7R promoted the survival and growth of ESCC cells by activating the Akt and Erk1/2 signaling pathways. The IL-7/IL-7R axis also contributed to the promotion of ESCC cell migration via the Akt and Erk1/2 signaling pathways. Furthermore, immunohistochemistry showed that ESCC patients with high IL-7R expression in cancer nests exhibited a trend toward poor prognosis in terms of disease-free survival, and showed significant correlation with increased numbers of infiltrating macrophages and cancer-associated fibroblasts. Therefore, IL-7R, which is upregulated when directly co-cultured with macrophages, may contribute to ESCC progression by promoting the development of various malignant phenotypes in cancer cells.

Futaba County was the area most affected by the 2011 Fukushima Daiichi nuclear power plant accident. To understand issues around the re-development of the medical system, we investigated the post-accident changes in medical needs and the system's transition. We analyzed reports from Fukushima Prefecture and local municipalities, ambulance transport data from the Futaba Fire Department, and patient data from Futaba Medical Center (FMC). After the accident, all medical institutions were closed, and the number of ambulance use dropped sharply. With the lifting of evacuation orders beginning in 2014, the amount of ambulance use increased at an annual rate of about 10%. Early on, the proportion of trauma caused by occupational and traffic accidents increased rapidly to more than 30%. As residents returned, the proportion related to endogenous diseases (most commonly respiratory) increased. Soon after the FMC opened in 2018, the majority of the patients were in their 60s, and by 2019 the proportion of patients in their 80s markedly increased. The return of the residents as well as ongoing decontamination and reconstruction projects were related to changes in the demographics of patients and the types of injuries and illnesses observed.

Digital tools are increasingly used for health promotion, but their utility during recovery from a nuclear disaster has yet to be established. This study analysed differences in knowledge, attitude, and practice (KAP) toward digital tools for radiation protection and health promotion, and preferences for specific application functions, among cohorts living within and outside areas affected by the Fukushima Daiichi nuclear power station (FDNPS) accident. A needs assessment was conducted by internet survey, and responses from those affected (N = 86) and not affected (N = 253) were compared and quantified by an adjusted odds ratio (aOR), using logistic regression analyses. KAP toward the radiation-related application in the affected group had an aOR of 1.95 (95% confidence interval (CI) = 1.12-3.38) for knowledge, and 5.71 (CI = 2.55-12.8) for practice. Conversely, toward the health-related application, the aOR of the affected group was 0.50 (CI = 0.29-0.86). The preference in the affected group was significantly lower for two application functions related to radiation measurement and two health-related functions (one about the effects of radiation in general and another about personal health advice in general): aOR range 0.43-0.50. Development of specific applications incorporating the findings from this survey was intended to foster a locally appropriate eHealth environment during recovery from the FDNPS accident.

Esophageal cancer has the sixth highest mortality rate worldwide. Cancer-associated fibroblasts (CAFs) are involved in the progression of various cancers. Previously, we demonstrated an association between high expression of the CAF marker, fibroblast activation protein, and poor prognosis of esophageal squamous cell carcinoma (ESCC). We also established CAF-like cells by indirect co-culture of bone marrow-derived mesenchymal stem cells with ESCC cell lines and found metallothionein 2A (MT2A) to be highly expressed in them. Here, to explore the function of MT2A in CAFs, we silenced MT2A in the CAF-like cells and ESCC cell lines using small interfering RNA. MT2A knockdown in the CAF-like cells suppressed expression and secretion of insulin-like growth factor binding protein 2 (IGFBP2); recombinant IGFBP2 promoted migration and invasiveness of ESCC cells via NFκB, Akt, and Erk signaling pathways. Furthermore, MT2A knockdown in the ESCC cell lines inhibited their growth, migration, and invasiveness. Immunohistochemistry demonstrated that high MT2A expression in the cancer stroma and cancer nest of ESCC tissues correlated with poor prognosis of ESCC patients. Hence, we report that MT2A in CAFs and cancer cells contributes to ESCC progression. MT2A and IGFBP2 are potential novel therapeutic targets in ESCC.

The mycobacterial cell wall is composed of large amounts of lipids with varying moieties. Some mycobacteria species hijack host cells and promote lipid droplet accumulation to build the cellular environment essential for their intracellular survival. Thus, lipids are thought to be important for mycobacteria survival as well as for the invasion, parasitization, and proliferation within host cells. However, their physiological roles have not been fully elucidated. Recent studies have revealed that mycobacteria modulate the peroxisome proliferator-activated receptor (PPAR) signaling and utilize host-derived triacylglycerol (TAG) and cholesterol as both nutrient sources and evasion from the host immune system. In this review, we discuss recent findings that describe the activation of PPARs by mycobacterial infections and their role in determining the fate of bacilli by inducing lipid metabolism, anti-inflammatory function, and autophagy.

Small cell lung cancer (SCLC) is a highly aggressive cancer, and patients who become refractory to first-line treatment have a poor prognosis. The development of effective treatment regimens is urgently needed. In this study, we identified a gene expression signature of SCLC after treatment failure using SCLC clinical specimens (GEO accession number: GSE162102). A total of 1,136 genes were significantly upregulated in SCLC tissues. These upregulated genes were subjected to KEGG pathway analysis, and "cell cycle", "Fanconi anemia", "alcoholism", "systemic lupus erythematosus", "oocyte meiosis", "homologous recombination", "DNA replication", and "p53 signaling" were identified as the enriched pathways among the genes. We focused on the cell cycle pathway and investigated the clinical significance of four genes associated with this pathway: minichromosome maintenance ( MCM ) 2, MCM4 , MCM6 , and MCM7 . The overexpression of these MCM genes was confirmed in SCLC clinical specimens. Knockdown assays using siRNAs targeting each of these four MCM genes showed significant attenuation of cancer cell proliferation. Moreover, siRNA-mediated knockdown of each MCM gene enhanced the cisplatin sensitivity of SCLC cells. Our SCLC molecular signature based on SCLC clinical specimens after treatment failure will provide useful information to identify novel molecular targets for this disease.

Lung adenocarcinoma (LUAD) is the most aggressive cancer and the prognosis of these patients is unfavorable. We revealed that the expression levels of both strands of miR-99a ( miR-99a-5p and miR-99a-3p ) were significantly suppressed in several cancer tissues. Analyses of large The Cancer Genome Atlas (TCGA) datasets showed that reduced miR-99a-5p or miR-99a-3p expression is associated with worse prognoses in LUAD patients (disease-free survival (DFS): p = 0.1264 and 0.0316; overall survival (OS): p = 0.0176 and 0.0756, respectively). Ectopic expression of these miRNAs attenuated LUAD cell proliferation, suggesting their tumor-suppressive roles. Our in silico analysis revealed 23 putative target genes of pre- miR-99a in LUAD cells. Among these targets, high expressions of 19 genes were associated with worse prognoses in LUAD patients (OS: p < 0.05). Notably, FAM64A was regulated by both miR-99a-5p and miR-99a-3p in LUAD cells, and its aberrant expression was significantly associated with poor prognosis in LUAD patients (OS: p = 0.0175; DFS: p = 0.0276). FAM64A knockdown using siRNAs suggested that elevated FAM64A expression contributes to cancer progression. Aberrant FAM64A expression was detected in LUAD tissues by immunostaining. Taken together, our miRNA-based analysis might be effective for identifying prognostic and therapeutic molecules in LUAD.

Acyl-CoA:glycerol- sn -3-phosphate acyltransferase (GPAT) is an enzyme responsible for the rate-limiting step in the synthesis of glycerophospholipids and triacylglycerol (TAG). The enzymes of mammalian species are classified into four isoforms; GPAT1 and GPAT2 are localized in the mitochondrial outer membrane, whereas GPAT3 and GPAT4 are localized in the endoplasmic reticulum membrane. The activity of each enzyme expressed is associated with physiological and pathological functions. The transcriptional regulation is well known, particularly in GPAT1. GPAT1 mRNA expression is mainly regulated by the binding of the transcriptional factor SREBP-1c to the specific element (the sterol regulatory element) flanking the GPAT1 promoter. The TAG level is controlled by the insulin-induced transcriptional expression of GPAT1, which occupies most of the GPAT activity in the liver. The transcriptional regulation of the other three GPAT isoforms remains undetermined in detail. It is predicted that retinoic acid serves as a transcription factor in the GPAT2 promoter. PPARγ (peroxisome proliferator-activated receptor γ) increases the mRNA expression of GPAT3, which is associated with TAG synthesis in adipose tissues. Although GPAT has been considered to be a key enzyme in the production of TAG, unexpected functions have recently been reported, particularly in GPAT2. It is likely that GPAT2 is associated with tumorigenesis and normal spermatogenesis. In this review, the physiological and pathophysiological roles of the four GPAT isoforms are described, alongside the transcriptional regulation of these enzymes.

After the Fukushima Daiichi Nuclear Power Station accident in 2011, concerns about radiation exposure and decline in subjective well-being have been reported. To tackle these problems, various countermeasures in relation to radiation have been implemented. In this study, we comprehensively evaluated the effects of radiological countermeasures on subjective well-being (e.g., satisfaction with life (SWL) and emotional well-being) and radiation anxiety, through a questionnaire survey targeting Fukushima residents ( N = 1023). Propensity scores matching was applied to evaluate significant effects of radiological countermeasures on subjective well-being and radiation anxiety. Among the radiological countermeasures, thyroid examination, whole body counter, and air dose monitoring showed the highest proportions of participation, utilization, and useful evaluation, suggesting a high degree of public attention focused on these countermeasures. The basic survey was associated with significant increases in SWL and self-rated health (SH). Thyroid examination was significantly associated with not only a reduction in radiation anxiety but also an increase of emotional stress, suggesting the importance of careful design of system and detailed communication. Food inspection was associated with deterioration in SH. Those who utilized explanatory meetings showed increases in sadness, worry, and radiation anxiety, indicating that additional attention is required of the experts and authorities involved in explanatory meetings., Competing Interests: The authors declare no conflict of interest.