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A phreatic eruption suddenly occurred at Motoshirane (Kusatsu-Shirane volcano, Japan) at 10:02 JST on January 23, 2018. A member of the Japan Self-Defense Force was killed by volcanic blocks during training in Motoshirane, and 11 people were injured by volcanic blocks or fragments of broken glass. According to a field survey, ash fall was confirmed in Minakami, about 40 km east-northeast from Motoshirane. Although the eruption was not captured by a distant camera, the eruption plume/cloud was captured by three of the Japan Meteorological Agency’s operational weather radars. These radars observed the echo propagated to the northeast in the lower troposphere, and to the east in the middle troposphere. This is generally consistent with the observed ash fall distribution. Using the modified probabilistic estimation method, the maximum plume height was estimated to be about 5580 ± 506 m (1σ) above sea level. Estimates of the erupted mass based on the range of plume heights from radar observations and the duration of volcanic tremor during the eruption (about 8 min) do not match that obtained from a field survey (3.0–5.0 × 107 kg). This discrepancy confirms that estimates of erupted mass based on plume heights must account for eruption style parametrically, which can only be constrained by case studies of varied eruption styles.

CD4 ⁺ Treg cells expressing the transcription factor FOXP3 (forkhead box P3) are abundant in tumor tissues and appear to hinder the induction of effective antitumor immunity. A substantial number of T cells, including Treg cells, in tumor tissues and peripheral blood express C-C chemokine receptor 4 (CCR4). Here we show that CCR4 was specifically expressed by a subset of terminally differentiated and most suppressive CD45RA ⁻FOXP3 ʰⁱCD4 ⁺ Treg cells [designated effector Treg (eTreg) cells], but not by CD45RA ⁺FOXP3 ˡᵒCD4 ⁺ naive Treg cells, in peripheral blood of healthy individuals and cancer patients. In melanoma tissues, CCR4 ⁺ eTreg cells were predominant among tumor-infiltrating FOXP3 ⁺ T cells and much higher in frequency compared with those in peripheral blood. With peripheral blood lymphocytes from healthy individuals and melanoma patients, ex vivo depletion of CCR4 ⁺ T cells and subsequent in vitro stimulation of the depleted cell population with the cancer/testis antigen NY-ESO-1 efficiently induced NY-ESO-1–specific CD4 ⁺ T cells. Nondepletion failed in the induction. The magnitude of the responses was comparable with total removal of FOXP3 ⁺ Treg cells by CD25 ⁺ T-cell depletion. CCR4 ⁺ T-cell depletion also augmented in vitro induction of NY-ESO-1–specific CD8 ⁺ T cells in melanoma patients. Furthermore, in vivo administration of anti-CCR4 mAb markedly reduced the eTreg-cell fraction and augmented NY-ESO-1–specific CD8 ⁺ T-cell responses in an adult T-cell leukemia-lymphoma patient whose leukemic cells expressed NY-ESO-1. Collectively, these findings indicate that anti-CCR4 mAb treatment is instrumental for evoking and augmenting antitumor immunity in cancer patients by selectively depleting eTreg cells.

BackgroundTertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates in non-lymphoid tissues, which are associated with improved prognosis in some cancer types. This study aimed to investigate the clinical significance of TLSs in oesophageal cancer (EC).MethodsIn a series of 316 EC surgical specimens from two different institutes, we evaluated the density and maturity of peritumoral TLSs using haematoxylin/eosin, immunohistochemistry, and multiplex immunofluorescence staining. We analysed the association between TLSs and clinicopathological parameters. The clinical significance of TLSs was further evaluated in a different cohort of 34 patients with recurrent EC treated with anti-PD-1 antibody.ResultsTumours with high TLS density predominantly consisted of matured TLSs. High TLS density was significantly associated with less advanced tumour stage, absence of lymphatic/vascular invasion, better serum nutrition parameters (neutrophils count, albumin, neutrophil-to-lymphocyte ratio, and prognostic nutritional index), and prolonged survival. This survival trend was more remarkable in cases with matured TLSs, which represented an increased population of CD138+ plasma cells. In the second EC cohort, TLS density predicted the clinical response to anti-PD-1 antibody and patient survival.ConclusionThe density and maturity of peritumoral TLSs are useful parameters for predicting long-term survival and response to anti-PD-1 antibody treatment in EC patients.

This study describes the dispersal and grain size characteristics of the May 14, 2018 Shinmoedake eruption deposits of Kirishima Volcano in southern Kyushu, southwestern Japan. We discuss the eruption sequence, including the temporal variations in the behavior of the plume, by combining field and meteorological datasets. Following a magmatic activity in 2011 characterized by a substantial change in the eruption style (from subplinian eruptions to lava effusion) and subsequent vulcanian explosions, the Shinmoedake crater experienced intermittent eruptions in 2018. The May 14, 2018 eruption began at 14:44 with a vulcanian eruption, with the eruption plume rising 4500 m above the crater rim. Thereafter, it transitioned to an ash eruption; the plume height decreased gradually until the eruption ceased at 16:10. The tephra fall deposits were distributed more than 27 km to the southeast of the source crater; the mass of the tephra fall deposit was approximately 2.1 × 107 kg, calculated based on an isomass map. The deposit incidence differed between the east and west sides of the major dispersal axis. The deposits found east of the main dispersal axis were primarily composed of coarse to medium sand-sized particles with no fine fraction (fine sand to silt in size). In contrast, the deposits west of the axis were finer-grained than those east of the axis. We analyzed photographs of the eruption plume, along with the regional meteorological data and the dispersal and grain-size characteristics of the deposits, and reached the following conclusion: during the May 14, 2018 eruption, the wind directions above the Shinmoedake crater fluctuated across altitudes. The westerly winds dispersed the eruption plume that rose to a higher altitude, containing coarser tephra associated with the initial vulcanian eruption, further to the east rather than along the main axis. In contrast, a lower-altitude ash eruption plume that was rich in fine materials was dispersed westward rather than along the main axis, which was influenced by northerly winds. The findings of this study can support the analysis of similar volcanic events.

Triple negative breast cancer (TNBC) is responsible for significant number of breast cancer-associated deaths because of lacking of successful molecular-targeted therapy. To explore a therapeutic target for TNBC, we performed a siRNA-mediated knockdown screening and identified Polo-like kinase 1 (PLK1) as a potential therapeutic target for TNBC. Knockdown of PLK1 as well as a small compound inhibitor for PLK1, BI-2536, induced G2/M arrest and created polyploid cell population, shown by increased DNA content and nuclear size. Inhibition of PLK1 eventually triggered apoptosis in multiple TNBC cell lines. In addition, we confirmed that PLK1 was significantly overexpressed in the tissues from TNBC patients compared with the tissues of normal mammary glands and benign breast tumors. Our data indicated that PLK1 plays a pivotal role in the regulation of mitosis of TNBC cells. Although future in vivo studies are warranted, targeting PLK1 by a selective inhibitor such as BI-2536 can be an attractive molecular-targeted therapy for TNBC.

Background Nivolumab is an immune checkpoint inhibitor specific to the programmed death 1 (PD-1) receptor. Nivolumab has shown clinical responses in many malignancies. Although immune-related adverse events (irAEs) associated with nivolumab are largely tolerable, severe irAEs have occurred in some patients. However, the mechanisms underlying the development of irAEs are not fully clarified. Case presentation We report 2 patients with metastatic melanoma who developed colitis, an irAEs caused by nivolumab. Both patients experienced colitis after nivolumab administration. Pathological examination of the colon showed robust infiltration of CD8 + cells and T-bet expressing CD4 + cells in both cases, indicating helper T cells (Th) 1 to be responsible for the dominant response. Additionally, we observed the serum C-reactive protein level (CRP) as well as interleukin-6 (IL-6) reflected the clinical course of irAEs clearly in the two cases. Conclusion Our two cases suggested that the development of irAEs due to nivolumab is associated with Th1 dominant response. CRP as well as IL-6 was found to be a potential biomarker for irAEs. Our findings may help to understand the mechanisms underlying irAEs caused by nivolumab and manage irAEs in clinical practice.

The association between the tumor microenvironment (TME) and treatment response or survival has been a recent focus in several types of cancer. However, most study materials are resected specimens that were completely modified by prior chemotherapy; therefore, the unmodified host immune condition has not yet been clarified. The aim of the present study was to evaluate the relationship between TME assessed in pre–therapeutic biopsy samples and chemoresistance in esophageal cancer (EC). A total of 86 endoscopic biopsy samples from EC patients who received neoadjuvant chemotherapy (NAC) prior to surgery were evaluated for the number of intratumoral CD4+ lymphocytes (with/without Foxp3 expression), CD8+ lymphocytes (with/without PD‐1 expression), monocytes (CD14+) and macrophages (CD86+, CD163+ and CD206+) by multiplex immunohistochemistry (IHC). The number of tumor‐infiltrating CD206+ macrophages I significantly correlated with cT, cM, cStage and neutrophil/lymphocyte ratio (NLR), whereas the number of lymphocytes (including expression of Foxp3 and PD‐1) was not associated with clinico‐pathological features. The high infiltration of CD163+ or CD206+ macrophages was significantly associated with poor pathological response to NAC (P = 0.0057 and 0.0196, respectively). Expression of arginase‐1 in CD163+ macrophages tended to be higher in non–responders (29.4% vs 18.2%, P = 0.17). In addition, patients with high infiltration of M2 macrophages exhibited unfavorable overall survival compared to those without high infiltration of M2 macrophages (5‐year overall survival 57.2% vs 71.0%, P = 0.0498). Thus, a comprehensive analysis of TME using multiplex IHC revealed that M2 macrophage infiltration would be useful in predicting the response to NAC and long‐term survival in EC patients. The present study confirmed that pre–therapeutic M2 macrophage infiltration would be a useful biomarker in predicting the response to NAC and unfavorable survival among a variety of immune cells in EC patients. Our results support the possibility of using immunotherapy, targeting M2 macrophages, alongside conventional neoadjuvant chemotherapy.

We identified a p53 target gene, phosphate-activated mitochondrial glutaminase (GLS2), a key enzyme in conversion of glutamine to glutamate, and thereby a regulator of glutathione (GSH) synthesis and energy production. GLS2 expression is induced in response to DNA damage or oxidative stress in a p53-dependent manner, and p53 associates with the GLS2 promoter. Elevated GLS2 facilitates glutamine metabolism and lowers intracellular reactive oxygen species (ROS) levels, resulting in an overall decrease in DNA oxidation as determined by measurement of 8-OH-dG content in both normal and stressed cells. Further, siRNA down-regulation of either GLS2 or p53 compromises the GSH-dependent antioxidant system and increases intracellular ROS levels. High ROS levels following GLS2 knockdown also coincide with stimulation of p53-induced cell death. We propose that GLS2 control of intracellular ROS levels and the apoptotic response facilitates the ability of p53 to protect cells from accumulation of genomic damage and allows cells to survive after mild and repairable genotoxic stress. Indeed, overexpression of GLS2 reduces the growth of tumor cells and colony formation. Further, compared with normal tissue, GLS2 expression is reduced in liver tumors. Thus, our results provide evidence for a unique metabolic role for p53, linking glutamine metabolism, energy, and ROS homeostasis, which may contribute to p53 tumor suppressor function.

Tumor-infiltrating cytotoxic T lymphocytes (TILs), including CD8 TILs, have been associated with favorable clinical outcomes in multiple tumor types. Tumor-infiltrating CD8 T cells and major histocompatibility complex (MHC) class I expression in urothelial carcinoma (UC) have not been previously reported. Most immune responses are mediated by local cytotoxic lymphocytes (CD8 T cells), which can eradicate tumor cells by recognizing tumor-associated antigens presented by MHC class I molecules. Here we analyzed the presence of intratumoral CD8 T cells, the expression of MHC class I antigen, and the expression of the NY-ESO-1 tumor antigen in UC samples and correlated our findings with clinical outcome. Immunohistochemical staining for intratumoral CD8 T cells in tissue samples from 69 patients with UC showed that patients with advanced UC (pT2, pT3, or pT4) and higher numbers of CD8 TILs within the tumor (>=8) had better disease-free survival (P < 0.001) and overall survival (P = 0.018) than did patients with similar-staged UC and fewer intratumoral CD8 TILs. We conclude that the extent of intratumoral CD8 TILs is an important prognostic indicator in advanced UC.