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Background/aim: Osimertinib is a key drug for treating epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). Genetic differences may be associated to adverse events (AEs) induced by osimertinib. This retrospective observational multicenter study evaluated the association of genotypes, including STAT3 -1697C>G, CYP3A5 6986A>G, and ABCG2 421C>A, with the incidence of osimertinib-induced AEs in patients with EGFR mutation-positive NSCLC., Patients and Methods: A total of 85 patients treated with osimertinib (Institution A: 33 patients, Institution B: 52 patients) were enrolled in the study. Single nucleotide polymorphisms were determined by real-time PCR, and the incidence of AEs was compared for each genotype., Results: Paronychia incidence was 59% for the CC genotype, 19% for the CG genotype, and 19% for the GG genotype at STAT3 -1697C>G. A genotype-related trend was observed (Cochran-Armitage test, p=0.009). Multivariate analysis showed that the CC genotype at STAT3 -1697C>G and female sex were significant independent factors associated with paronychia [odds ratio (OR)=6.41, 95% confidence interval (CI)=1.94-21.20 and OR=3.40, 95%CI=1.03-11.22, respectively]. The incidence of diarrhea was 53% for the CC genotype, 30% for the AC genotype, and 29% for the AA genotype at ABCG2 421C>A, and a genotype-related trend was observed (p=0.048). However, the CC genotype at ABCG2 421C>A was not a significant independent factor associated with diarrhea in multivariate analysis. No significant associations were detected between other polymorphisms and the incidence of AEs., Conclusion: STAT3 -1697C>G may be a novel risk factor for osimertinib-induced paronychia in patients with NSCLC., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: This study evaluated the associations between bone invasion of gingival squamous cell carcinoma (SCC) and clinicopathological manifestations, and aimed to determine whether bone invasion is an independent prognostic factor in gingival SCC., Patients and Methods: The study was a retrospective review of 78 patients with gingival SCC who underwent surgery with curative intent. The level of bone invasion was pathologically categorized as medullary, cortical or no bone invasion., Results: Cortical and medullary bone invasion was present in 29 and 22 patients, respectively. There was a significant association between medullary bone invasion and tumor size (p=0.017), pathological N classification (p<0.001), differentiation (p=0.017) and lymphovascular invasion (p=0.007). Medullary bone invasion and lymphovascular invasion were independent predictors of reduced overall survival (p=0.015, 0.048); medullary bone invasion was also an independent predictor of reduced disease-specific survival (p=0.018)., Conclusion: Pathologically-proven medullary bone invasion and lymphovascular invasion were found to be key prognostic factors in gingival SCC. The results suggest that it is necessary to consider adjuvant therapy in patients with medullary bone invasion., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Sonic hedgehog (SHH) signaling is related to the pathogenesis of oral squamous cell carcinoma (OSCC), but its role in OSCC is not yet well understood. In this study, we analyzed the role of SHH signaling in OSCC., Materials and Methods: We examined the expression pattern of SHH and its signal proteins in clinically resected OSCC samples by immunohistochemistry. We also evaluated the function of SHH signaling using the hedgehog signaling inhibitor cyclopamine in vivo and in vitro by proliferation, migration and angiogenesis analyses., Results: We found that SHH was highly expressed in human tongue OSCC, whereas patched (PTCH1), glioma-associated oncogene 1 (GLI1) and GLI2 proteins were expressed in the microvascular cells in the tumor invasive front. Administration of cyclopamine to mice suppressed the growth and angiogenesis of OSCC xenografts in vivo. Moreover, cyclopamine inhibited endothelial cell proliferation and migration, and reduced aorta vascular length in the rat., Conclusion: These findings suggest that OSCC-derived SHH stimulates angiogenesis at the tumor invasive front., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The neurokinin 3 receptor (NK-3R) is differentially expressed in the central nervous system including cases of human oral squamous cell carcinoma. However, the role of NK-3R signaling in oral squamous cell carcinoma is not well known., Materials and Methods: NK-3R expression in surgically resected oral squamous cell carcinoma was examined immunohistochemically and the strength of the expression was quantified. We evaluated the function of NK-3R signaling using NK-3R antagonist in human oral squamous cell carcinoma bone invasion mouse model., Results: NK-3R was significantly expressed in tumor cells that had invaded the bone matrix compared to the oral side tumor cells. SB222200, a selective antagonist of NK-3R, significantly suppressed the radiographic osteolytic lesion and tumorigenesis., Conclusion: NK-3R signaling is a potential target for the treatment of oral squamous cell carcinoma in cases of bone destruction., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Angiogenin undergoes nuclear translocation and stimulates ribosomal RNA transcription in both endothelial and cancer cells. Consequently, angiogenin has a dual effect on cancer progression by inducing both angiogenesis and cancer cell proliferation. The aim of this study was to assess whether neamine, a blocker of nuclear translocation of angiogenin, possesses antitumor activity toward oral cancer., Materials and Methods: The antitumor effect of neamine on oral cancer cells was examined both in vitro and in vivo., Results: Neamine inhibited the proliferation of HSC-2, but not that of SAS oral cancer cells in vitro. Treatment with neamine effectively inhibited growth of HSC-2 and SAS cell xenografts in athymic mice. Neamine treatment resulted in a significant decrease in tumor angiogenesis, accompanied by a decrease in angiogenin- and proliferating cell nuclear antigen-positive cancer cells, especially of HSC-2 tumors., Conclusion: Neamine effectively inhibits oral cancer progression through inhibition of tumor angiogenesis. Neamine also directly inhibits proliferation of certain types of oral cancer cells. Therefore, neamine has potential as a lead compound for oral cancer therapy.

Recently, there has been interest in the tertiary functions of food, those that maintain human health. Moreover, lipopolysaccharides (LPS), which are components of Gram-negative bacteria, have been found to be highly effective in activating innate immunity and have been rediscovered as new functional food materials. In this review, we discuss the significance of LPS as a food component with reference to these tertiary functions based on recent findings. There is special emphasis on the plasticity of responses to LPS by intestinal macrophages. According to the macrophage-network theory, local macrophages cooperate with other tissue macrophages. For this reason, this review also discusses the possibility that information is transferred throughout the body from intestinal macrophages.

Every organism possesses a mechanism for maintaining homeostasis. We have focused on the immune system as a system that helps maintain homeostasis of the body, and particularly on the intestine as the largest organ of immunity in the body. We have also focused our research on the mechanism that responds to foreign substances in the intestine, especially the toll-like receptors (TLR). The activation of myeloid differentiation primary response gene 88 (MyD88) signal transduction as a response to TLR in the intestine is believed to contribute to the maintenance of homeostasis of the body through the homeostasis of the intestine. Furthermore, significant findings were reported in which signal transduction from TLR4 was essential for the maintenance and regulation of the intestine. These results strongly suggest the possibility that homeostasis in the intestine is maintained by TLR4, and signaling by TLR4 after exposure to lipopolysaccharide (LPS) probably has a role in regulating homeostasis. It is expected that the prevention and treatment of various diseases using TLR4 will continue to develop. As LPS is a substance that enhances the activity of TLR4, it will also attract attention as a valuable substance in its own right.

The immune system is part of the homeostasis system. Our research is focused on ways to maintain health, with an emphasis on the role of macrophages. We have hypothesized that tissue macrophages form a systemic network which we believe contributes to the homeostasis system, and have named it the 'macrophage network.' This network creates a dynamic equilibrium situation where macrophages control homeostasis. Our research is based on this macrophage network theory as we believe that the innate immune system provides the foundation for the homeostasis system. As part of our research, we have demonstrated that macrophage activation can provide protection and therapeutic effects for various diseases. Therefore, we have also focused on lipopolysaccharide (LPS). We proved that the LPS of Pantoea agglomerans (which we have named IP-PA1) was useful in preventing various health disorders and in restoring health when administered via the oral or transdermal route. We also developed a 'fermented flour extract', which consists largely of IP-PA1. For LPS to become a valuable commodity, it is very important to provide assurance about safety (when administered orally or transdermally) to build confidence. For this reason, we tested fermented flour extract (in which the major component was IP-PA1) to confirm that it was safe. The results of these safety trials confirmed that oral and transdermal administration of fermented flour extract was very safe. Thus, we believe that fermented flour extract is a new substance that will have applications in health food, cosmetics, animal feeds, fisheries feeds and drugs industries.

Background: Our research is focused on intestinal macrophages, which are believed to contribute to the maintenance of intestinal homeostasis. In addition, intestinal macrophages are unique in that there is an impairment of expression of tumor necrosis factor (TNF) from lipopolysaccharide (LPS). This characteristic can be attributed to the lack or poor level of expression of toll-like receptor 4 (TLR4) or CD14 on the membrane of intestinal macrophages. We therefore decided to identify where CD14 was localized in intestinal macrophages., Materials and Methods: The endoplasmic reticulum and Golgi apparatus were double stained and the intracellular localization in the intestinal macrophages was observed using a confocal laser microscope., Results: CD14 of peritoneal macrophages was expressed both in the endoplasmic reticulum and Golgi apparatus. By contrast, intestinal macrophages expressed very little CD14 on the cellular membrane. CD14 was present in the endoplasmic reticulum of intestinal macrophages, but was rare in the Golgi apparatus., Conclusion: The lack of expression of CD14 on the cell membrane of intestinal macrophages may be caused by transport interference from the endoplasmic reticulum to the Golgi apparatus.

Background: The lipopolysaccharide of Pantoea agglomerans (IP-PA ) has been shown to be effective and safe in the prevention of various diseases, such as bacterial or viral infection, lifestyle-related diseases, when administered transdermally or orally. To clarify the mechanisms of the preventive or therapeutic effect induced by IP-PA1, we tried to establish a monoclonal antibody to detect IP-PA1. The enzyme-linked immunosorbent assay (ELISA) was used to measure the amount of IP-PA1., Materials and Methods: Antibodies were raised by immunization using heat-killed Pantoea agglomerans and screening was conducted to isolate monoclonal antibodies specific to IP-PA1., Results: Six kinds of IP-PA1 specific monoclonal antibodies with different epitopes were established. An ELISA using the monoclonal antibodies was successfully established which could specifically detect IP-PA1., Conclusion: By use of this ELISA, the staple food content and pharmacodynamic analysis of IP-PA1 could be conveniently estimated.

Macrophages are thought to be the cells that initially respond to environmental information and transmit this information to other immune cells. We hypothesize that there is a "network system" consisting of various tissue macrophages; the macrophages respond to stimulation and transmit secondary information to neighboring cells, which is important for the maintenance of homeostasis. Macrophages exist in all animal organs as tissue macrophages, and their cellular characteristics may change as an adaption to tissue-specific environments. It is believed that mucosal macrophages are particularly important in the macrophage network system because mucosa exist where there is regular exposure to foreign substances. However, the molecular mechanism by which intestinal mucosal macrophages respond to the external environment is not yet clear. In this review the biological characteristics of mucosal macrophages are introduced and how they recognize and eradicate various foreign substances is discussed.