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The tumor suppressor TP53 gene, the most frequently mutated gene in human cancers, produces the product tumor protein p53, which plays an essential role in DNA damage. p53 protein mutations may contribute to tumorigenesis by loss of tumor suppressive functions and malignancy of cancer cells via gain‐of‐oncogenic functions. We previously reported that mutant p53 proteins form aggregates and that cytoplasmic p53 aggregates were associated with poor prognosis in human ovarian cancer. However, the prognostic impact of p53 aggregation in other tumors including lung squamous cell carcinoma (SCC) is poorly understood. Here, we demonstrated that lung SCC cases with cytoplasmic p53 aggregates had a significantly poor clinical prognosis. Analysis via patient‐derived tumor organoids (PDOs) established from lung SCC patients and possessing cytoplasmic p53 aggregates showed that eliminating cytoplasmic p53 aggregates suppressed cell proliferation. RNA sequencing and transcriptome analysis of p53 aggregate‐harboring PDOs indicated multiple candidate pathways involved in p53 aggregate oncogenic functions. With lung SCC‐derived cell lines, we found that cytoplasmic p53 aggregates contributed to cisplatin resistance. This study thus shows that p53 aggregates are a predictor of poor prognosis in lung SCC and suggests that detecting p53 aggregates via p53 conventional immunohistochemical analysis may aid patient selection for platinum‐based therapy. [ABSTRACT FROM AUTHOR]

Background: Photodynamic therapy (PDT) is an antitumor therapy and has traditionally been regarded as a localized therapy in itself. However, recent reports have shown that it not only exerts a direct cytotoxic effect on cancer cells but also enhances body's tumor immunity. We hypothesized that the immunological response induced by PDT could potentially enhance the efficacy of programmed death‐1 (PD‐1) / programmed death‐ligand 1 (PD‐L1) blockade. Methods: The cytotoxic effects of PDT on colon 26 cells were investigated in vitro using the WST assay. We investigated whether the antitumor effect of anti‐PD‐1 antibodies could be amplified by the addition of PDT. We performed combination therapy by randomly allocating tumor‐bearing mice to four treatment groups: control, anti‐PD‐1 antibodies, PDT, and a combination of anti‐PD‐1 antibodies and PDT. To analyze the tumor microenvironment after treatment, the tumors were resected and pathologically evaluated. Results: The viability rate of colon 26 cells decreased proportionally with the laser dose. In vivo experiments for combined PDT and anti‐PD‐1 antibody treatment, combination therapy showed an enhanced antitumor effect compared with the control. Immunohistochemical findings of the tumor microenvironment 10 days after PDT indicated that the number of CD8+ cells, the area of Iba‐1+ cells and the area expressing PD‐L1 were significantly higher in tumors treated with combination therapy than in tumors treated with anti‐PD‐1 antibody alone, PDT alone, or the control. Conclusions: PDT increased immune cell infiltration into the tumor microenvironment. The immunological response induced by PDT may enhance the efficacy of PD‐1/PD‐L1 blockade. [ABSTRACT FROM AUTHOR]

Introduction: As inhibitors of advanced glycation end products (AGEs), such as pyridoxamine, significantly inhibit the development of retinopathy and neuropathy in rats with streptozotocin-induced diabetes, treatment with AGE inhibitors is believed to be a potential strategy for the prevention of aging, age- related diseases, and lifestyle-related diseases, including diabetic complications. In the present study, the MeOH extract of Epimedii Herba (EH; aerial parts of Epimedium spp.) was found to inhibit the formation of NE-(carboxymethyl)lysine (CML) and N"-(carboxymethyl) arginine (CMA) during the incubation of collagen- derived gelatin with ribose. Materials and methods: EH was purchased from Uchida Wakan-yaku Co., and a MeOH extract was prepared. Several steps of column chromatography purified the extract. Each fraction was tested for inhibitory activity by ELISA using monoclonal antibodies for CML and CMA. Results: After activity-guided fractionation and purification by column chromatography, three new prenylflavonoids [named Koreanoside L (1), Koreanoside E1 (2), and Koreanoside E2 (3)] and 40 known compounds (4-43) were isolated from EH, and their inhibitory effects against CML and CMA formation were tested. Among these, epimedokoreanin B (8), epimedonin E (21), epicornunin B (22), and epicornunin F (24) inhibited the formation of both CML and CMA, with epimedokoreanin B (8) having the most potent inhibitory effect among the isolated compounds. To obtain the structure-activity relationships of 8, the phenolic hydroxy groups of 8 were methylated by trimethylsilyl-diazomethane to afford the partially and completely methylated compounds of 8. Prenyl derivatives of propolis (artepillin C, baccharin, and drupanin) were used in the assay. Discussion: As only 8 showed significant activity among these compounds, the catechol group of the B ring and the two prenyl groups attached to the flavanone skeleton were essential for activity. These data suggest that 8 could prevent the clinical complications of diabetes and age-related diseases by inhibiting AGEs. [ABSTRACT FROM AUTHOR]

Cholangiolocarcinoma (CLC) is a primary liver carcinoma that resembles the canals of Hering and that has been reported to be associated with stem cell features. Due to its rarity, the nature of CLC remains unclear, and its pathological classification remains controversial. To clarify the positioning of CLC in primary liver cancers and identify characteristics that could distinguish CLC from other liver cancers, we performed integrated analyses using whole‐exome sequencing (WES), immunohistochemistry, and a retrospective review of clinical information on eight CLC cases and two cases of recurrent CLC. WES demonstrated that CLC includes IDH1 and BAP1 mutations, which are characteristic of intrahepatic cholangiocarcinoma (iCCA). A mutational signature analysis showed a pattern similar to that of iCCA, which was different from that of hepatocellular carcinoma (HCC). CLC cells, including CK7, CK19, and EpCAM, were positive for cholangiocytic differentiation markers. However, the hepatocytic differentiation marker AFP and stem cell marker SALL4 were completely negative. The immunostaining patterns of CLC with CD56 and epithelial membrane antigen were similar to those of the noncancerous bile ductules. In contrast, mutational signature cluster analyses revealed that CLC formed a cluster associated with mismatch‐repair deficiency (dMMR), which was separate from iCCA. Therefore, to evaluate MMR status, we performed immunostaining of four MMR proteins (PMS2, MSH6, MLH1, and MSH2) and detected dMMR in almost all CLCs. In conclusion, CLC had highly similar characteristics to iCCA but not to HCC. CLC can be categorized as a subtype of iCCA. In contrast, CLC has characteristics of dMMR tumors that are not found in iCCA, suggesting that it should be treated distinctly from iCCA. © 2024 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Surface charging caused by the bombardment of samples with positive ion beams is a significant problem in material processing and surface analysis. The charging potential of an electrically isolated sample is commonly believed to increase with the acceleration voltage of a positive ion beam in the absence of charge compensation. Contrary to the common belief, however, this paper reports that the charging potential of an electrically isolated ionic liquid target decreases with increasing acceleration voltage of a positive cluster ion beam. A typical ionic liquid, 1-ethyl-3-methyl imidazolium bis(trifluoromethanesulfonyl)amide (EMI-TFSA), was used as the target. It was placed on a metal plate that was electrically isolated from the ground, and its charging potential during cluster ion bombardment was measured with a high-impedance electrometer. For comparison, an electrically isolated metal plate was used. This study demonstrates that the charging potential varies significantly depending on cluster ion species and target materials. The charging potential of the metal plate increased monotonically with the irradiation time, whereas that of the ionic liquid target saturated at a lower voltage. The charging potential of the ionic liquid target decreased with increasing acceleration voltage of the ion beam even though the beam current increased. Larger cluster ions (m/z 502) caused less charge buildup than lighter cluster ions (m/z 111). The results obtained are explained by considering secondary ion emission from the ionic liquid target, which reduce the incoming net charge into the target, resulting in reduced surface charging. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a complex pulmonary condition characterized by bronchitis, emphysema, and mucus stasis. Due to the variability in symptoms among patients, traditional approaches to treating COPD as a singular disease are limited. This led us to focus on phenotype/endotype classifications. In this study, we explore the potential therapeutic role of thyroid hormone (T3) by using mouse models: emphysema-dominant elastase-induced COPD and airway-dominant C57BL/6-βENaC-Tg to represent different types of the disease. Here, we showed that intratracheal T3 treatment (40, 80 μg/kg, i.t., every other day) resulted in significant improvements regarding emphysema and the enhancement of respiratory function in the elastase-induced COPD model. T3-dependent improvement is likely linked to the up-regulation of Ppargc1a, a master regulator of mitochondrial biogenesis, and Gclm, a factor associated with oxidative stress. Conversely, neither short- nor long-term T3 treatments improved COPD pathology in the C57BL/6-βENaC-Tg mice. Because the up-regulation of extrathyroidal T3-producing enzyme Dio2, which is also considered a marker of T3 requirement, was specifically observed in elastase-induced COPD lungs, these results demonstrate that exogenous T3 supplementation may have therapeutic potential for acute but not chronic COPD exacerbation. Moreover, this study highlights the relevance of considering not only COPD phenotypes but also COPD endotypes (expression levels of Ppargc1a and/or Dio2) in the research and development of better treatment approaches for COPD. [ABSTRACT FROM AUTHOR]

Sinus macrophages in draining lymph nodes (DLNs) are involved in anti‐tumor immune reactions. CD169 (Sialoadhesin, Siglec‐1) is expressed on sinus macrophages and is considered a surrogate marker for the immunostimulatory phenotype of macrophages. In this study, the significance of sinus macrophages in immunotherapy was evaluated using mouse models. Treatment with anti‐programmed death‐ligand 1 (PD‐L1) antibody suppressed the subcutaneous tumor growth of MC38 and E0771 cells but was not effective against MB49 and LLC tumors. Decreased cytotoxic T‐lymphocyte (CTL) infiltration in tumor tissues and CD169 expression in sinus macrophages were observed in MB49 and LLC cells compared to corresponding parameters in MC38 and E0771 cells. The anti‐tumor effects of the anti‐PD‐L1 antibody on MC38 and E0771 cells were abolished when sinus macrophages in DLNs were depleted, suggesting that sinus macrophages are involved in the therapeutic effect of the anti‐PD‐L1 antibody. Naringin activated sinus macrophages. Naringin inhibited tumor growth in MB49‐ and LLC‐bearing mice but did not affect that in MC38‐ and E0771‐bearing mice. The infiltration of CTLs in tumor tissues and their activation were increased by naringin, and this effect was impaired when sinus macrophages were depleted. Combination therapy with naringin and anti‐PD‐L1 antibody suppressed MB49 tumor growth. In conclusion, CD169‐positive sinus macrophages in DLNs are critical for anti‐tumor immune responses, and naringin suppresses tumor growth by activating CD169‐positive sinus macrophages and anti‐tumor CTL responses. The activation status of sinus macrophages has been suggested to differ among tumor models, and this should be investigated in future studies. [ABSTRACT FROM AUTHOR]

Ionic liquid ion sources are expected to be used in a wide range of applications such as space electric propulsion and focused ion beam micromachining. It is known that the backstreaming of secondary charged species generated by ion beam impacts can cause unexpected temperature rise and chemical changes in ionic liquids. This paper reports on results of heating experiments using a sharp needle emitter wetted with an ionic liquid, 1-ethyl-3-methyl imidazolium bis(trifluoromethanesulfonyl)amide, at temperatures in a range from room temperature to 120 °C. Current measurements show that positive and negative electrospray currents from the heated emitter increased as the temperature increased. Time-of-flight (TOF) mass spectrometric measurements reveal that the beam composition changed significantly with increasing temperature, indicating that charged droplets as well as ions were emitted from the heated emitter. The TOF data show that a significant fraction of the current is due to droplets at higher temperatures. On the basis of the results obtained, the size and charge of the emitted droplets are discussed. The beam is roughly estimated to contain charged droplets with a diameter of around 20 nm at 120 °C. [ABSTRACT FROM AUTHOR]

The role of sinus macrophages (SMs) in anticancer immune responses has received considerable interest in recent years, but the types of molecules that are expressed in human SMs have not yet been clarified in detail. We therefore sought to identify dendritic cell (DC)– or macrophage‐related molecules in SMs in human lymph nodes (LNs). SMs are strongly positive for Iba‐1, CD163, CD169, and CD209. CD169 (clone SP216) reacted with almost all SMs, mainly in the cell surface membrane, while CD169 (clone HSn 7D2) reacted with a subpopulation of SMs, mainly in the cytoplasm, with a significant increase observed after IFN‐α stimulation. The immunoreactivity of clone HSn 7D2 was markedly reduced after transfection with small interfering RNA against CD169, while that of clone SP216 was slightly reduced. The induction of CCL8 and CXCL10 messenger RNA (mRNA) expression by IFN‐α was confirmed using cultured macrophages and RT‐qPCR, but fluorescence in situ hybridization did not detect CCL8 and CXCL10 mRNA expression in SMs. Single‐cell RNA sequence data of LNs indicated that the highest level of CXCL10 gene expression occurred in monocytes. In conclusion, we found that CD209, also known as DC‐related molecule, was expressed in human SMs. The heterogeneity observed in CD169 reacted with cone HSn 7D2 and SP216 was potentially due to the modification of CD169 protein by IFN stimulation. Further, no expression of CXCL10 mRNA in SMs suggested that SMs might be resident macrophages. [ABSTRACT FROM AUTHOR]

Ionic liquid ion sources (ILISs) are similar to liquid metal ion sources and use ionic liquids (i.e., room temperature molten salts) instead of liquid metals. Aprotic ionic liquids have been used in most cases, whereas protic ion liquids have hardly been used thus far. In this study, propylammonium nitrate (PAN), which is a protic ionic liquid, was tested as the liquid material for an ILIS. Beam generation was investigated in DC operation using a tungsten needle externally wetted with PAN. Experimental results showed that a stable ion beam was generated without special measures and that the ion beam contained cluster ions with m/z values on the order of 103. Additionally, electrochemical experiments were performed in vacuum to investigate electrochemical reactions involved in beam generation. Residual gas analysis revealed that H2O and O2 were electrochemically produced at a tungsten electrode immersed in PAN. These products will probably result from electrochemical reactions of water in PAN because protic ionic liquids contain a small amount of water even in vacuum. The stability of the ion beam can be explained by the effect of water in PAN. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have recently improved the prognosis of various cancers. By contrast, some immune‐related adverse events (irAEs) caused by ICIs are fatal and have become problematic. The pathogenesis of irAEs remains unknown and must be elucidated to establish biomarkers. This study investigated plasma cytokine, chemokine, and anti‐CD74 autoantibody levels in patients with renal cell carcinoma (RCC) and analyzed their association with irAEs. In a discovery cohort of 13 patients, plasma levels of chemokine (C–X–C motif) ligand (CXCL) 1, IL‐17A, IL‐1β, IL‐6, IL‐8, CXCL10, MCP‐1, and TNFα were measured at baseline and post–dose 1. Only CXCL10, at post–dose 1 but not at baseline, was significantly associated with grade 2 or higher irAEs (P = 0.0413). Plasma CXCL10 levels were then measured at baseline and post–dose 1 in an extended cohort of 43 patients with RCC who received ICI‐based treatment. Higher plasma CXCL10 levels both at baseline and post–dose1 were significantly associated with the occurrence of grade 2 or higher irAEs (P = 0.0246 and 0.0137, respectively). Plasma CXCL13 levels, which we measured in a previous study, were significantly higher in patients with grade 2 or higher irAEs at baseline but not at post–dose 1 (P = 0.0037 and 0.052, respectively). No significant association between plasma anti‐CD74 autoantibody level and both irAE pneumonitis and any grade 2 or higher irAE was observed. In conclusion, plasma CXCL10 is significantly associated with the occurrence of irAEs in patients with RCC treated with ICIs. CXCL10 is a potential predictive and on‐treatment biomarker for irAEs. [ABSTRACT FROM AUTHOR]

Tumor‐associated macrophages (TAMs) are the most prominent immune cells in the breast cancer microenvironment, and the protumor functions of TAMs are thought to affect cancer progression and resistance to anticancer therapy. Numerous studies using human breast cancer samples, cell lines, and murine breast cancer models have revealed details of the mechanisms by which the protumor functions of TAMs are activated. Recent advances have highlighted the significant involvement of TAMs in the resistance of breast cancer cells to immunotherapy. Tumor‐associated macrophages express a number of immunosuppressive genes, and single‐cell sequence analyses of human and murine cancer samples have helped elucidate the mechanism of TAM‐induced immunosuppression. As TAMs are considered suitable targets for anticancer therapies, we summarized the protumor functions of TAMs and the potential of anticancer therapies targeting TAMs, with a focus on breast cancer research. [ABSTRACT FROM AUTHOR]

Aims: Mismatch‐repair deficiency and microsatellite instability‐high (dMMR/MSI‐H) colorectal cancer (CRC) is treated with programmed death (PD)‐1 antibody regardless of PD‐ligand (L)1 expression in tumor cells. We previously found that abundant CD169+ macrophages in regional lymph node (RLN) sinuses and CD8+ tumor‐infiltrating lymphocytes (TILs) positively correlated in CRC and were associated with a favorable prognosis. However, associations between dMMR/MSI‐H CRC and CD8+ TILs or prognoses vary among studies. In this study, we attempted to compare the association between MMR status, CD169+ macrophages in RLNs, CD8+ TILs, PD‐L1 scores, and prognoses in CRC. Methods and Results: We immunostained 83 surgically resected CRC tumors that we previously analyzed for MMR proteins, and identified 9 that were dMMR. The number of CD169+ macrophages in RLNs and CD8+ TILs significantly correlated with overall survival, whereas MMR status did not. The number of cells positive for the TIL markers CD3, CD4, CD8, and TIA‐1, and macrophage markers CD68 and CD169 in RLNs did not significantly differ between groups according to MMR status. Furthermore, combined positive scores (CPS) for PD‐L1 expression in five of nine dMMR CRCs were all <1. We found that dMMR in CRC did not correlate with numbers of CD169+ macrophages in RLNs or CD8+ TILs. Conclusions: CRC with CD169+ macrophages in RLNs and abundant CD8+ TILs indicates a better prognosis and it should be immunologically classified as a different antitumor group from dMMR CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Macrophages that infiltrate the cancer microenvironment are referred to as tumor-associated macrophages (TAMs). Phosphoprotein 1 (SPP1), also known as osteopontin, is a multifunctional secreted phosphorylated glycoprotein. In this review, we summarize the significance of TAMs in lung cancers and discuss the importance of SPP1 as a new marker for the protumor subpopulation of TAMs in lung adenocarcinoma. (1) The presence of TAMs is reportedly a poor prognostic factor in lung cancer. (2) We recently revealed that SPP1 expression on TAMs is correlated with poor prognosis and chemoresistance in lung adenocarcinoma. (3) SPP1 is a potentially useful marker for detecting monocyte-derived TAMs. Macrophages are a representative cell type in the tumor microenvironment. Macrophages that infiltrate the cancer microenvironment are referred to as tumor-associated macrophages (TAMs). TAMs exhibit protumor functions related to invasion, metastasis, and immunosuppression, and an increased density of TAMs is associated with a poor clinical course in many cancers. Phosphoprotein 1 (SPP1), also known as osteopontin, is a multifunctional secreted phosphorylated glycoprotein. Although SPP1 is produced in a variety of organs, at the cellular level, it is expressed on only a few cell types, such as osteoblasts, fibroblasts, macrophages, dendritic cells, lymphoid cells, and mononuclear cells. SPP1 is also expressed by cancer cells, and previous studies have demonstrated correlations between levels of circulating SPP1 and/or increased SPP1 expression on tumor cells and poor prognosis in many types of cancer. We recently revealed that SPP1 expression on TAMs is correlated with poor prognosis and chemoresistance in lung adenocarcinoma. In this review, we summarize the significance of TAMs in lung cancers and discuss the importance of SPP1 as a new marker for the protumor subpopulation of monocyte-derived TAMs in lung adenocarcinoma. Several studies have shown that the SPP1/CD44 axis contribute to cancer chemoresistance in solid cancers, so the SPP1/CD44 axis may represent one of the most critical mechanisms for cell-to-cell communication between cancer cells and TAMs. [ABSTRACT FROM AUTHOR]

Moist wound healing is known to heal wounds faster than dry wound healing. Hydrogel wound dressings are suitable for moist wound healing because of their hyperhydrous structure. Chitosan, a natural polymer, promotes wound healing by stimulating inflammatory cells and releasing bioactive compounds. Therefore, chitosan hydrogel has great potential as a wound dressing. In our previous study, physically crosslinked chitosan hydrogels were successfully prepared solely by freeze-thawing of chitosan-gluconic acid conjugate (CG) aqueous solution without using any toxic additives. Furthermore, the CG hydrogels could be sterilized by autoclaving (steam sterilization). In this study, we showed that autoclaving (121 °C, 20 min) of a CG aqueous solution simultaneously achieved gelation of the solution and sterilization of the hydrogel. Hydrogelation of CG aqueous solution by autoclaving is also physically crosslinking without any toxic additives. Further, we showed that the CG hydrogels retained favorable biological properties of the CG hydrogels prepared by freeze-thawing and subsequent autoclaving. These results indicated that CG hydrogels prepared by autoclaving were promising as wound dressings. [ABSTRACT FROM AUTHOR]

Ionic liquid ion sources generate ion beams from ionic liquids by vacuum electrospray. Electrospray characteristics generally depend on the physical properties of the liquids used. A key factor affecting physical properties is temperature. In this study, ion beam production was investigated using a protic ionic liquid, propylammonium nitrate (PAN), at temperatures ranging from 22 to 60 °C. An ion beam was produced using a needle emitter equipped with a cartridge heater, thermocouple, and sharpened glass rod externally wetted with PAN. The experimental results showed that the heating of the emitter increased the ion beam current. This will be due to an increase in the conductivity and a decrease in the viscosity of PAN with increasing temperature. Furthermore, the abundance of larger cluster ions increased, whereas that of smaller cluster ions decreased with increasing temperature. It turned out, however, that higher heating of the emitter stopped ion beam production. Two hypotheses for the beam stop are proposed and discussed. [ABSTRACT FROM AUTHOR]

Although pituitary neuroendocrine tumors (PitNETs) are usually benign, some are highly invasive and recurrent. Recurrent PitNETs are often treatment‐resistant and there is currently no effective evidence‐based treatment. Tumor‐associated macrophages (TAMs) promote tumor growth in many cancers, but the effect of TAMs on PitNETs remains unclear. This study investigated the role of TAMs in the incidence of recurrent PitNETs. Immunohistochemical analysis revealed that the densities of CD163‐ and CD204‐positive TAMs tended to increase in recurrent PitNETs. Compared with TAMs in primary lesions, those in recurrent lesions were enlarged. To clarify the cell–cell interactions between TAMs and PitNETs, in vitro experiments were performed using a mouse PitNET cell line AtT20 and the mouse macrophage cell line J774. Several cytokines related to macrophage chemotaxis and differentiation, such as M‐CSF, were elevated significantly by stimulation with macrophage conditioned medium. When M‐CSF immunohistochemistry analysis was performed using human PitNET samples, M‐CSF expression increased significantly in recurrent lesions compared with primary lesions. Although no M‐CSF receptor (M‐CSFR) expression was observed in tumor cells of primary and recurrent PitNETs, flow cytometric analysis revealed that the mouse PitNET cell line expressed M‐CSFR. Cellular proliferation in mouse PitNETs was inhibited by high concentrations of M‐CSFR inhibitors, suggesting that cell‐to‐cell communication between PitNETs and macrophages induces M‐CSF expression, which in turn enhances TAM chemotaxis and maturation in the tumor microenvironment. Blocking the M‐CSFR signaling pathway might be a novel therapeutic adjuvant in treating recurrent PitNETs. [ABSTRACT FROM AUTHOR]