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The use of strigolactone (SL) analogs as suicidal germination agents to control the seed banks of the parasitic weed Striga hermonthica has gained interest for field applications in recent years. However, concerns about the environmental safety of these SL analogs remain. In this study, we evaluated the mutagenic potential of two selected SL analogs, Methyl Phenlactonoate 3 (MP3) and Nijmegen-1, across concentrations ranging from 1.5 to 5000 μg per plate. We conducted this assessment using five histidine-deficient mutant tester strains of Salmonella typhimurium. After incubating the SL analogs with the tester strains, we observed no significant increase in the number of revertants, with and without the S9 mix, compared to both negative and positive laboratory controls. These results suggest that MP3 and Nijmegen-1 are non-mutagenic according to the bacterial reverse mutation test, supporting their potential as environmentally safe agents for managing Striga populations.

The manifestation of glioblastoma, IDH-wildtype (GB) as intracranial hemorrhage (ICH) presents diagnostic and therapeutic challenges. Molecular characteristics, including TERT promoter mutation, EGFR amplification, and chromosome 7 gain/10 loss, were incorporated to diagnose GB in the fifth edition of the World Health Organization Classification of Tumors of the Central Nervous System. When molecular analyses fail to detect low fractions of these genetic alterations, the integrated diagnosis of GB can be enigmatic. This case report describes a 58-year-old man presenting with ICH, masking an underlying GB. Initial histopathology of the evacuated hematoma revealed a small number of atypical glial cells, but a definitive diagnosis was deferred. Subsequent surgery and molecular analysis, including digital polymerase chain reaction (dPCR), confirmed the presence of a TERT C228T mutation in the promoter area, leading to an integrated diagnosis of GB. The patient experienced a favorable clinical outcome following surgery, radiation, temozolomide, and tumor-treating field therapy, without recurrence after 50 months. This case underscores the importance of meticulous histological examination of ICH and exemplifies the clinical utility of dPCR as a complementary diagnostic tool. The effectiveness of dPCR is particularly noteworthy, even in scenarios with minimal tumor cell content, reinforcing its value in the integrated diagnosis of GB., (© 2025 Japanese Society of Neuropathology.)

Critical limb ischemia (CLI) is the most advanced stage of peripheral arterial disease, posing a high risk of mortality. Sphingomyelin, a sphingolipid synthesized by sphingomyelin synthases (SMSs) 1 and 2, plays an essential role in signal transduction as a component of lipid rafts. However, the role of sphingomyelin in the inflammation of ischemic skeletal muscles remains unclear. In this study, we analyzed the roles of sphingomyelin and SMSs in CLI-induced myopathy using a mouse hindlimb ischemia model. We observed that hypoxia after CLI triggered an increase in SMS2 levels, thereby elevating sphingomyelin concentrations in ischemic skeletal muscles. The expression of SMS2 and sphingomyelin was induced by hypoxia in C2C12 myotubes and regulated by the prolyl hydroxylase domain enzyme. Additionally, SMS2 deficiency suppressed skeletal muscle inflammation after CLI, attenuated the phosphorylation of inhibitor of κBα (IκBα), and reduced the nuclear translocation of nuclear factor κB (NFκB) p65. Meanwhile, the administration of sphingomyelin hampered skeletal muscle inflammation by inhibiting IκBα phosphorylation and NFκB p65 nuclear translocation and extending inflammation post-CLI. Our results suggest that hypoxia-induced enhancement in SMS2 levels and the consequent increase in sphingomyelin expression levels promote inflammation in ischemic muscle tissues via the NFκB pathway and propose sphingomyelin as a potential therapeutic target in patients with CLI and other hypoxia-related inflammatory diseases., (© 2024 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Purpose: The present study investigated the clinical feasibility of replacing a part of conventional physiotherapy (PT) with Nintendo Wii® for the recovery of motor function and activities of daily living (ADL) in patients with glioma., Methods: This study included 10 patients with first-episode gliomas who were admitted to the neurosurgery department of a tertiary hospital. According to the patients' preferences, they were allocated to conventional PT or Wii® rehabilitation groups in which a part of the conventional PT sessions were replaced with Wii® training. The Fugl-Meyer Assessment (FMA), Short Physical Performance Battery (SPPB), Functional Independence Measure (FIM), and Hospital Anxiety and Depression Scale (HAD) measures were compared between the treatment groups using the Mann-Whitney U test., Results: The Wii® rehabilitation and conventional PT groups included four (age 39 [26-53] years, n = 2 each WHO grade III and IV) and six patients (age 72 [59-80] years; all WHO grade IV), respectively. No patient dropouts were observed. The beneficial changes did not differ significantly between the conventional PT and Wii® groups (FMA: 1.0 vs. 1.5, SPPB: - 1.0 vs. - 0.5, FIM: - 2.5 vs. 2.5, HAD: 6 vs. 0). No adverse events such as falls were observed in either treatment group., Conclusion: Wii® rehabilitation had comparable effects with conventional PT for the inpatient rehabilitation of patients with glioma, with no adverse effects. Wii® rehabilitation showed potential as a home-based training modality because no physical assistance was required. Further investigation will be required because of the selection bias as a non-randomized trial., Implications for Cancer Survivors: Exergame Wii® could be an effective rehabilitation tool for brain tumor patients., Competing Interests: Declarations. Ethics approval: The study was designed in accordance with principles of the Declaration of Helsinki, was approved by the Ethics Review Committee of Kyorin University School of Medicine (approval number: 1864) and was conducted as a clinical trial after registration in the UMIN Clinical Trials Registry (registration number: 000053704). Consent to participate: A verbal informed consent was obtained from all the patients at the enrollment, and the consent was recorded in the electric medical record. Consent to publish: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cell competition and fitness comparison between cancer and tumor microenvironment (TME) cells determine oncogenic fate. Our previous study established a role for human Flower isoforms as fitness fingerprints, where the expression of Flower Win isoforms in tumor cells leads to growth advantage over TME cells expressing Lose isoforms. Here we demonstrate that the expression of Flower Lose and reduced microenvironment fitness is not a pre-existing condition but, rather, a cancer-induced phenomenon. Cancer cells actively reduce TME fitness by the exosome-mediated release of a cancer-specific long non-coding RNA, Tu-Stroma, which controls the splicing of the Flower gene in the TME cells and expression of Flower Lose isoform, which leads to reduced fitness status. This mechanism controls cancer growth, metastasis and host survival in ovarian cancer. Targeting Flower protein with humanized monoclonal antibody (mAb) in mice significantly reduces cancer growth and metastasis and improves survival. Pre-treatment with Flower mAb protects intraperitoneal organs from developing lesions despite the presence of aggressive tumor cells., Competing Interests: Competing interests: All authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Angiocentric glioma (AG) is a supratentorial diffuse low-grade glioma characterized by the MYB::QKI fusion gene, showing angiocentric growth of monomorphous spindle cells with astrocytic and ependymal immunophenotypes. We describe a rare case of MYB::QKI fusion-positive diffuse cerebellar glioma in a 54-year-old male. The patient initially presented with a T2/FLAIR hyperintense lesion in the left cerebellar hemisphere and slowly progressive neurological symptoms. Histopathological evaluation revealed a diffuse glioma characterized by spindle-shaped and small epithelioid cells with perivascular infiltration. Immunohistochemistry showed positivity for glial fibrillary acidic protein and only occasionally positive for Olig2. No dot- or ring-like epithelial membrane antigen immunoreactivity was observed. In this case, the proliferative activity was higher than that in typical AG cases, as manifested by multiple mitoses (four mitoses/slide) and a Ki-67 labeling index of 5%. The tumor cells were negative for IDH1 p.R132H and H3 p.K28M mutation-specific antibodies. Fluorescence in situ hybridization showed a MYB break-apart signal, and reverse transcription-polymerase chain reaction analysis confirmed an in-frame MYB (6q23.3, exon 11, NM_001161659.2)::QKI (6q26, exon 5, NM_006775.3) fusion. IDH1 p.R132, IDH2 p.R172, H3-3A p.K28, H3C2 p.K28, and BRAF p.V600 were all wild type. DNA methylome profiling did not match any of the established methylation classes, including the four subtypes of diffuse glioma, MYB- or MYBL1-altered. Considering the results of DNA methylome profiling, the question remains as to whether this case represents a subset of AG (diffuse glioma, MYB/MYBL1-altered) or a distinct subtype. Although the morphological findings and the presence of fusion indicated that the tumor was a cerebellar AG, the DNA methylome profile did not match that of AG. An accumulation of more cases is needed to determine the precise nature of the tumor, which may lead to an expansion of the tumor concept., (© 2024 Japanese Society of Neuropathology.)

Background: Primary central nervous system lymphoma (PCNSL) is a rare lymphoid malignancy. Systemic profiling of the PCNSL tumor microenvironment (TME) was previously conducted through gene expression analysis. We investigated the prognostic impact of TME on survival to establish novel prognostic biomarkers in PCNSL patients., Methods: We analyzed expression levels of 770 neuroinflammation-related (NFR) genes via NanoString nCounter technology in tumor samples from 30 PCNSL patients. Genes related to the "recurrence group (RG)" or "non-recurrence group (NRG)" were identified and validated using whole transcriptomic analysis of an independent PCNSL cohort ( n  = 30)., Results: Forty-five of 770 NFR genes were highly expressed in the RG (3-year overall survival (OS, 22.2%), compared with the NRG group (3-year OS 66.7%). Signatures related to glial cells were enriched in the RG-associated gene set. Multivariate analysis revealed that high expressions of TUBB4A ( p  = 0.028, HR: 3.88), S100B ( p  = 0.046, HR: 3.093), and SLC6A1 ( p  = 0.034, HR: 3.765) were significantly related to death. Expression levels of these three genes were also significantly associated with poor OS in the validation cohort. Immunohistochemical staining against TUBB4A, S100B, and proteins specific to glial cells (GFAP, OLIG2, and CD68) revealed significantly higher positivity in RG glial cells., Conclusion: These data suggest that TME-related genes play a crucial role in the pathogenesis of PCNSL, complementing the well-known involvement of the NF-kB signaling pathway. TME targeting, especially glial cell-specific proteins, may thus open new and complementary avenues of therapy for all stages of PCNSL., Competing Interests: Lecture honoraria: Eiichi Ishikawa (Daiichi Sankyo, Eisai, Otuka Pharma); Yoshitaka Narita (Ono Pharma) Motoo Nagane (Ono Pharma); Research fund: Sakata‐Yanagimoto Mamiko (Eisai, Bristol Myers Squib, Otuska Pharma, Chugai Pharma), Shigeru Chiba (Thyas, Astellas, Kyowa Kirin); Eiichi Ishikawa (Mitsubishi Electric); Ryo Nishikawa (Ono Pharma) Motoo Nagane (Ono Pharma); Koichi Ichimura (Daiichi Sankyo, Riken Genesis, Gold Ribbon Network, Sumitomo Pharma); Scholarship grant: Shigeru Chiba (Bayer, Eisai, Chugai Pharma, Kyowa Kirin); Eiichi Ishikawa (Eisai) Ryo Nishikawa (Chugai Pharma); Yoshitaka Narita (Ono Pharma, Sumitomo Pharma, Eisai, Taiho Pharma, Ohara Pharma); Motoo Nagane (Chugai Pharma, Bayer, Eisai, Daiichi Sankyo); Endowed chair: Koichi Ichimura (Idorsia Pharmaceuticals)., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: This study aimed to investigate what treatment are selected for malignant brain tumors, particularly glioblastoma (GBM) and primary central nervous system lymphoma (PCNSL), in real-world Japan and the costs involved., Methods: We conducted a questionnaire survey regarding treatment selections for newly diagnosed GBM and PCNSL treated between July 2021 and June 2022 among 47 institutions in the Japan Clinical Oncology Group-Brain Tumor Study Group. We calculated the total cost and cost per month of the initial therapy for newly diagnosed GBM or PCNSL., Results: The most used regimen (46.8%) for GBM in patients aged ≤74 years was 'Surgery + radiotherapy concomitant with temozolomide'. This regimen's total cost was 7.50 million JPY (Japanese yen). Adding carmustine wafer implantation (used in 15.0%), TTFields (used in 14.1%), and bevacizumab (BEV) (used in 14.5%) to the standard treatment of GBM increased the cost by 1.24 million JPY for initial treatment, and 1.44 and 0.22 million JPY per month, respectively. Regarding PCNSL, 'Surgery (biopsy) + rituximab, methotrexate, procarbazine, and vincristine (R-MPV) therapy' was the most used regimen (42.5%) for patients of all ages. This regimen incurred 1.07 million JPY per month. The three PCNSL regimens based on R-MPV therapy were in ultra-high-cost medical care (exceeding 1 million JPY per month)., Conclusions: Treatment of malignant brain tumors is generally expensive, and cost-ineffective treatments such as BEV are frequently used. We believe that the results of this study can be used to design future economic health studies examining the cost-effectiveness of malignant brain tumors., (© The Author(s) 2024. Published by Oxford University Press.)

Understanding the tumor redox status is important for efficient cancer treatment. Here, we noninvasively detected changes in the redox environment of tumors before and after cancer treatment in the same individuals using a novel compact and portable electron paramagnetic resonance imaging (EPRI) device and compared the results with glycolytic information obtained through autoradiography using 2-deoxy-2-[ 18 F]fluoro-d-glucose ([ 18 F]FDG). Human colon cancer HCT116 xenografts were used in the mice. We used 3-carbamoyl-PROXYL (3CP) as a paramagnetic and redox status probe for the EPRI of tumors. The first EPRI was followed by the intraperitoneal administration of buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, or X-ray irradiation of the tumor. A second EPRI was performed on the following day. Autoradiography was performed after the second EPRI. After imaging, the tumor sections were evaluated by histological analysis and the amount of reducing substances in the tumor was measured. BSO treatment and X-ray irradiation significantly decreased the rate of 3CP reduction in tumors. Redox maps of tumors obtained from EPRI can be compared with tissue sections of approximately the same cross section. BSO treatment reduced glutathione levels in tumors, whereas X-ray irradiation did not alter the levels of any of the reducing substances. Comparison of the redox map with the autoradiography of [ 18 F]FDG revealed that regions with high reducing power in the tumor were active in glucose metabolism; however, this correlation disappeared after X-ray irradiation. These results suggest that the novel compact and portable EPRI device is suitable for multimodal imaging, which can be used to study tumor redox status and therapeutic efficacy in cancer, and for combined analysis with other imaging modalities., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The ONO-4059-02 phase 1/2 study showed favorable efficacy and acceptable safety profile of tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, for relapsed/refractory primary central nervous system lymphoma (PCNSL). Here, we report the long-term efficacy and safety after a 3-year follow-up., Methods: Eligible patients were aged ≥ 20 years with histologically diagnosed PCNSL and KPS of ≥ 70. Patients received oral tirabrutinib once daily at 320 or 480 mg, or 480 mg under fasted conditions., Results: Between October 19, 2017, and June 13, 2019, 44 patients were enrolled: 33 and 9 had relapsed and refractory, respectively. The 320, 480, and 480 mg fasted groups included 20, 7, and 17 patients, respectively. The median follow-up was 37.1 months. The overall response rate was 63.6% (95% CI: 47.8-77.6) with complete response (CR), unconfirmed CR, and partial response in 9, 7, and 12 patients, respectively. The median duration of response (DOR) was 9.2 months, with a DOR rate of 19.8%; the median progression-free survival (PFS) and median overall survival (OS) were 2.9 months and not reached, respectively, with PFS and OS rates of 13.9% and 56.7%, respectively. Adverse events occurred in 38 patients (86.4%): grade ≥ 3 in 23 (52.3%) including 1 patient with grade 5 events. KPS and quality of life (QoL) scores were well maintained among patients receiving long-term treatment., Conclusions: The results demonstrated the long-term clinical benefit of tirabrutinib, with deep and durable response in a subset of patients and acceptable safety profile, while KPS and QoL scores were maintained., Competing Interests: All authors received support for developing the manuscript, which includes funding, medical writing, and article processing charge. HY reports honoraria from Ono, Chugai, Fujifilm, and Novocure global. YN reports grants from Chugai, Sumitomo Pharma, Eisai, Otsuka, SBI, AbbVie, Daiichi Sankyo, Stella Pharma, and Meiji Seika; honoraria from Chugai, Sumitomo Pharma, Eisai, Otsuka, SBI, AbbVie, Daiichi Sankyo, Stella Pharma, and Meiji Seika. MN reports grants from Chugai, MSD, Nippon Kayaku, Bristol Myers Squibb, Pfizer, Takeda, Shionogi, Kyowa Kirin, Teijin Pharma, Asahi Kasei Medical, HOYA Technosurgical, AbbVie, Eisai, Daiichi Sankyo, Otsuka, Astellas, Tsumura, Sanofi, Mitsubishi Tanabe Pharma, Sanei, CSF Behring, and Ono; consulting fees from Ono, Nippon Shinyaku, and Novocure; honoraria from Chugai, MSD, Nippon Kayaku, UCB Japan, Sumitomo Pharma, Ono, Ohara, AbbVie, Eisai, Daiichi Sankyo, Novocure, Bristol Myers Squibb, and Kyowa Kirin; support for attending meetings and/or travel from Ono, Eisai, Denka, Kyowa Kirin, and Nippon Kayaku; Participation on a Data Safety Monitoring Board or Advisory Board in Novocure; and medical writing support from Ono and Chugai. KM reports grants from Chugai, Eisai, Gunze Medical, Otsuka, Nihon Medi-Physics, Gunze, Stryker Japan, Kyowa Kirin, MSD, Teijin Pharma, AbbVie, Daiichi Sankyo, Novocure, HOYA Technosurgical, Ohara, and CSL Behring; and honoraria from Ono and Chugai. YA reports grants from Philips, Otsuka, Chugai, Nihon Medi-Physics, Daiichi Sankyo, Stryker, Eisai, Japan Blood Products Organization, Ono, Taiho, Sumitomo Pharma, Astellas, Incyte Biosciences, and Servier; and honoraria for lectures from Nippon Kayaku, Novocure, UCB Japan, Ono, Brainlab, Merck, Chugai, Eisai, Daiichi Sankyo, Carl Zeiss, and Nihon Medi-Physics. KA reports honoraria and support for attending meetings and/or travel from Ono. NF reports grants from Ono, Bayer, Chugai, Celgene, and Genmab and Incyte; honoraria from AstraZeneca, Bristol Myers Squibb, Chugai, CSL Behring, Sumitomo Pharma, Eisai, Janssen, Kyowa Kirin, Nippon Shinyaku, Novartis, Ono, Otsuka, Sanofi, SymBio, Takeda, and Zenyaku; and participation on a data safety monitoring board in Huya Japan and an advisory board in AstraZeneca, AbbVie, Eli Lilly, Genmab, and Novartis. KS reports honoraria from Daiichi Sankyo, Eisai, Meiji Seika Pharma, Bristol Myers Squibb, Novartis, Ono, and Nobel Pharma. AA is employed in Ono and holds stocks of Ono. RN reports grants from MSD, Eisai, AbbVie, and Chugai; and consulting fee from Novocure; honoraria from AbbVie, Chugai, Daiichi Sankyo, Eisai, Novocure, and Ono., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Focal segmental glomerulosclerosis, characterized by decreased numbers of podocytes in glomeruli, is a common cause of refractory nephrotic syndrome. Recently, we showed that enhanced glycosphingolipid GM3 expression after administration of valproic acid, an upregulator of ST3GAL5/St3gal5, was effective in preventing albuminuria and podocyte injury. We also revealed the molecular mechanism for this preventive effect, which involves GM3 directly binding nephrin that then act together in glycolipid-enriched membrane (GEM) fractions under normal conditions and in non-GEM fractions under nephrin injury conditions. Kidney disease is frequently referred to as a "silent killer" because it is often difficult to detect subjective symptoms. Thus, primary treatment for these diseases is initiated after the onset of disease progression. Consequently, the efficacy of enhanced levels of GM3 induced by valproic acid needs to be evaluated after the onset of the disease with severe albuminuria such as focal segmental glomerulosclerosis. Here, we report the therapeutic effect of enhanced GM3 expression induced via administration of valproic acid on albuminuria and podocyte injury after the onset focal segmental glomerulosclerosis in anti-nephrin antibody treated mice. Our findings suggest elevated levels of GM3 following treatment with valproic acid has therapeutic utility for kidney disease associated with severe albuminuria and podocyte injury., (© 2023. The Author(s).)

Ozone gas is widely used in hospitals as well as homes to control COVID-19 infection owing to its cost-effectiveness. Safety standard value and the tolerable value of ozone gas are set at 0.05 ppm and 0.1 ppm, respectively, in developed countries; however, this value was principally determined for healthy individuals, and the risks associated with ozone gas inhalation in patients with pulmonary diseases remains unknown. Recently, we demonstrated that 0.1 ppm ozone gas exposure significantly aggravates the symptoms of acute lung injury in mice. In the present study, we further examined the influence of ≤ 0.1 ppm ozone gas exposure on percutaneous oxygen saturation (SpO 2 ) and pro-inflammatory responses in a mouse model of asthma. Female BALB/c mice were subjected to repetitive intranasal sensitization of Dermatophagoides farinae to generate a mouse model of asthma. Inhalation exposure of ozone gas (0.1, 0.03, 0.01 ppm), generated using an ultraviolet lamp, was performed for five consecutive days immediately before the final sacrifice. There were no abnormal findings in control mice exposed to 0.1 ppm ozone; however, 0.1 ppm ozone exposure significantly reduced the SpO 2 level in asthmatic mice. Histological evaluation and gene expression analysis revealed that pro-inflammatory cytokine levels were significantly increased in mice exposed to 0.1 ppm ozone, indicating that 0.1 ppm ozone exposure affects the development of asthma symptoms. Notably, 0.03 and 0.01 ppm ozone exposure did not have any effects even in asthmatic mice. Our findings indicate that the tolerable level of ozone gas should be adjusted for individuals based on a history of respiratory disorders., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Currently, ozone water is utilized for antibacterial and antiviral purposes without any reported safety concerns. Therefore, ozone water may have clinical applications in treating staphylococcal-specific cutaneous diseases, such as atopic dermatitis (AD) and pyoderma. This study aimed to verify the bactericidal effects of ozone water at different concentrations (3 and 11 mg/L) against staphylococcal species in vitro, as well as evaluate the anti-inflammatory effects of ozone water in a mouse model of AD and pyoderma. Initially, the bactericidal properties of several concentrations of ozone water were confirmed with Staphylococcus aureus and methicillin-resistant S. pseudintermedius. Both 3 and 11 mg/L of ozone water exhibited a significant bactericidal effect against staphylococci at less than 100 times dilution. We next examined the cellular cytotoxicity and cytokine production (Interleukin (IL)-6 and IL-8) induced by S. pseudintermedius pre-treated with ozone water, and our findings indicated that cytotoxicity and cytokine production induced by staphylococci were significantly inhibited after ozone water pre-treatment. In vivo experiments showed that ozone water-pre-treated S. pseudintermedius significantly inhibited the development of pyoderma in mice; however, limited effects were observed in a therapeutic setting. Interestingly, ozone water at concentrations of 3 and 11 mg/L exhibits dual bactericidal and anti-inflammatory effects in mice with AD. This observation was corroborated by the significant inhibition of cytokine production in interferon-γ/tumor necrosis factor-stimulated human epidermal keratinocyte cells exposed to ozone in vitro. These findings indicate that administering ozone can be a novel therapeutic approach for managing allergic skin diseases, such as AD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Contamination with fumonisins produced by Fusarium spp. is rapidly growing in both developing and developed countries. The purpose of this study was to determine whether oral exposure to fumonisin contributed to the development of allergic diseases. We initially examined the immunotoxic potential of short-term, oral administration of fumonisin B1 (FB1, 1 mg/kg) and fumonisin B2 (FB2, 1 mg/kg), both naturally occurring fumonisins, using a BALB/c mouse model of allergic contact dermatitis and Dermatophagoides farina-induced asthma. Using an NC/nga mouse model of atopic dermatitis (AD), we evaluated the adverse effects of subchronic oral exposure to low concentrations of FB2 (2 or 200 μg/kg). Finally, we explored the influence of FB2 on regulatory T cell proliferation and function in mesenteric lymph nodes after 1-week oral exposure to FB2 in BALB/c mice. Oral exposure to FB2 markedly exacerbated the symptoms of allergy, including skin thickness, histological evaluation, immunocyte proliferation, and proinflammatory cytokine production, although no change was observed following exposure to FB1. Furthermore, oral exposure to low concentrations of FB2 considerably exacerbated the AD scores, skin thickness, transepidermal water loss, histological features, and proinflammatory cytokine production. The aggravated allergic symptoms induced by oral exposure to FB2 could be attributed to the direct inhibition of IL-10 production by regulatory T cells in mesenteric lymph nodes. Our findings indicate that the recommended maximum fumonisin level should be reconsidered based on the potential for allergy development., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Pancreatic adenocarcinoma (PAAD) is one of the most fatal human cancers, but effective therapies remain to be established. Cancer stem cells (CSCs) are highly resistant to anti-cancer drugs and a deeper understanding of their microenvironmental niche has been considered important to provide understanding and solutions to cancer eradication. However, as the CSC niche is composed of a wide variety of biological and physicochemical factors, the development of multidisciplinary tools that recapitulate their complex features is indispensable. Synthetic polymers have been studied as attractive biomaterials due to their tunable biofunctionalities, while hydrogelation technique further renders upon them a diversity of physical properties, making them an attractive tool for analysis of the CSC niche., Methods: To develop innovative materials that recapitulate the CSC niche in pancreatic cancers, we performed polymer microarray analysis to identify niche-mimicking scaffolds that preferentially supported the growth of CSCs. The niche-mimicking activity of the identified polymers was further optimized by polyethylene glycol (PEG)-based hydrogelation. To reveal the biological mechanisms behind the activity of the optimized hydrogels towards CSCs, proteins binding onto the hydrogel were analyzed by liquid chromatography with tandem mass spectrometry (LC-MS/MS), and the potential therapeutic targets were validated by looking at gene expression and patients' outcome in the TCGA database., Results: PA531, a heteropolymer composed of 2-methoxyethyl methacrylate (MEMA) and 2-(diethylamino)ethyl methacrylate (DEAEMA) (5.5:4.5) that specifically supports the growth and maintenance of CSCs was identified by polymer microarray screening using the human PAAD cell line KLM1. The polymer PA531 was converted into five hydrogels (PA531-HG1 to HG5) and developed to give an optimized scaffold with the highest CSC niche-mimicking activities. From this polymer that recapitulated CSC binding and control, the proteins fetuin-B and angiotensinogen were identified as candidate target molecules with clinical significance due to the correlation between gene expression levels and prognosis in PAAD patients and the proteins associated with the niche-mimicking polymer., Conclusion: This study screened for biofunctional polymers suitable for recapitulation of the pancreatic CSC niche and one hydrogel with high niche-mimicking abilities was successfully fabricated. Two soluble factors with clinical significance were identified as potential candidates for biomarkers and therapeutic targets in pancreatic cancers. Such a biomaterial-based approach could be a new platform in drug discovery and therapy development against CSCs, via targeting of their niche., (© 2023. The Author(s).)

Background: One of the most significant challenges in patients with medulloblastoma is reducing the dose of craniospinal irradiation (CSI) to minimize neurological sequelae in survivors. Molecular characterization of patients receiving lower than standard dose of CSI therapy is important to facilitate further reduction of treatment burden., Methods: We conducted DNA methylation analysis using an Illumina Methylation EPIC array to investigate molecular prognostic markers in 38 patients with medulloblastoma who were registered in the Japan Pediatric Molecular Neuro-Oncology Group and treated with reduced-dose CSI., Results: Among the patients, 23 were classified as having a standard-risk and 15 as high-risk according to the classic classification based on tumor resection rate and presence of metastasis, respectively. The median follow-up period was 71.5 months (12.0-231.0). The median CSI dose was 18 Gy (15.0-24.0) in both groups, and 5 patients in the high-risk group received a CSI dose of 18.0 Gy. Molecular subgrouping revealed that the standard-risk cohort included 5 WNT, 2 SHH, and 16 Group 3/4 cases; all 15 patients in the high-risk cohort had Group 3/4 medulloblastoma. Among the patients with Group 3/4 medulloblastoma, 9 of the 31 Group 3/4 cases were subclassified as subclass II, III, and V, which were known to an association with poor prognosis according to the novel subtyping among the subgroups. Patients with poor prognostic subtype showed worse prognosis than that of others (5-year progression survival rate 90.4% vs. 22.2%; p < 0.0001). The result was replicated in the multivariate analysis (hazard ratio12.77, 95% confidence interval for hazard ratio 2.38-99.21, p value 0.0026 for progression-free survival, hazard ratio 5.02, 95% confidence interval for hazard ratio 1.03-29.11, p value 0.044 for overall survival)., Conclusion: Although these findings require validation in a larger cohort, the present findings suggest that novel subtyping of Group 3/4 medulloblastoma may be a promising prognostic biomarker even among patients treated with lower-dose CSI than standard treatment., (© 2023. BioMed Central Ltd., part of Springer Nature.)

We have previously reported that 12p gain may predict the presence of malignant components and poor prognosis for CNS germ cell tumor (GCT). Recently, 3p25.3 gain was identified as an independent predictor of poor prognosis for testicular GCT. Eighty-one CNS GCTs were analyzed. Copy number was calculated using methylation arrays. Five cases (6.2%) showed 3p25.3 gain, but only among the 40 non-germinomatous GCTs (NGGCTs) (5/40, 12.5%; p = 0.03). Among NGGCTs, those with a yolk sac tumor component showed a significantly higher frequency of 3p25.3 gain (18.2%) than those without (1.5%; p = 0.048). NGGCTs with gain showed significantly shorter progression-free survival (PFS) than those without (p = 0.047). The 3p25.3 gain and 12p gain were independent from each other. The combination of 3p25.3 gain and/or 12p gain was more frequent among NGGCTs with malignant components (69%) than among those without (29%; p = 0.02). Germinomas containing a higher number of copy number alterations showed shorter PFS than those with fewer (p = 0.03). Taken together, a finding of 3p25.3 gain may be a copy number alteration specific to NGGCTs and in combination with 12p gain could serve as a marker of negative prognosis or treatment resistance. Germinoma with frequent chromosomal instability may constitute an unfavorable subgroup., (© 2023. Springer Nature Limited.)

Background: Tirabrutinib, a second-generation inhibitor of Bruton's tyrosine kinase, was approved in March 2020 for the treatment of relapsed or refractory primary central nervous system lymphoma (r/r PCNSL) based on phase I/II studies in Japan. We previously reported the overall response rate and safety profile. We describe Karnofsky Performance Status (KPS) and the quality of life (QoL) in patients with r/r PCNSL receiving tirabrutinib based on more than 1-year follow-up data., Methods: Patients with r/r PCNSL, age ≥20 years, and KPS ≥70 were treated with tirabrutinib once daily at a dose of 320, 480, or 480 mg under fasted conditions. QoL was assessed using questionnaires issued by the European Organization for Research and Treatment of Cancer (EORTC), namely EORTC QLQ-C30, EORTC QLQ-BN20, and EuroQol 5 dimensions 3-level (EQ-5D-3L) along with KPS., Results: Forty-four patients (mean age, 60 years [range 29-86]) were enrolled. The median follow-up period was 14.9 months (range, 1.4-27.7). The median KPS of the patients at baseline was 80.0 (range, 70-100), and this remained constant during the treatment. The global health status/QoL in the QLQ-C30 showed significant improvements from baseline through cycles 3-17 and remained relatively constant thereafter until cycle 23. Improvements were also seen in emotional functioning and constipation in the QLQ-C30 segments. Other items of QLQ-C30 and QLQ-BN20, EQ-5D visual analog scales, and EQ-5D index were maintained during the treatment., Conclusions: Tirabrutinib generally maintains KPS and QoL scores with some improvements in specific QoL items in patients with r/r PCNSL., Competing Interests: Y.A. received research grants from Ono Pharmaceutical Co. Ltd., Eisai Co., Ltd., Sanofi, Stryker, Taiho Pharmaceutical Co., Ltd., Daiichi-Sankyo, Japan Blood Products Organization, Philips., Nihon Medi-Physics Co., Ltd., Astellas Pharma Inc., Sumitomo Pharma Co., Ltd., Chugai Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd.; payment honoraria from Nippon Kayaku Co., Ltd., Novocure, Daiichi-Sankyo, Ono Pharmaceutical Co., Ltd., Merck, Eisai Co., Ltd., UCB Japan Co., Ltd., Brainlab, Chugai Pharmaceutical Co., Ltd., Carl Zeiss, Nihon Medi-Physics Co., Ltd.; medical writing and article processing charges fees from Ono Pharmaceutical Co. Ltd. Y.N. received research grants from Ono Pharmaceutical Co. Ltd., Eisai Co., Ltd., Taiho Pharmaceutical Co., Ltd., Daiichi-Sankyo, Sumitomo Pharma Co., Ltd., Ohara Pharmaceutical Co., Ltd.; consulting fees form Sumitomo Pharma Co., Ltd.; payment honoraria from Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co. Ltd., Eisai Co., Ltd., Daiichi-Sankyo, Sumitomo Pharma Co., Ltd., Novocure; medical writing and article processing charges fees from Ono Pharmaceutical Co. Ltd. M.N. received research grants from Ono Pharmaceutical Co. Ltd., AbbVie, Daiichi-Sankyo, Kyowa Kirin, Eisai Co., Ltd., Mitsubishi Tanabe Pharma, Shionogi & Co., Ltd., Chugai Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Bayer, Teijin Pharma, Asahi Kasei Medical Co., Ltd.; consulting fees form Ono Pharmaceutical Co. Ltd., Novocure; meeting support form Ono Pharmaceutical Co. Ltd., Nippon Kayaku Co., Ltd., Ohara Pharmaceutical Co., Ltd., Eisai Co., Ltd., Denka Co., Ltd.; ad board advisory, medical writing and article processing charges form Ono Pharmaceutical Co. Ltd.; payment honoraria from Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co. Ltd., Eisai Co., Ltd., Kyowa Kirin, Daiichi-Sankyo, Sumitomo Pharma Co., Ltd., Novocure, Nippon Kayaku Co., Ltd., Ohara Pharmaceutical Co., Ltd., UCB Japan Co., Ltd.; medical writing fees from Chugai Pharmaceutical Co., Ltd. K.M. received research grants from Ono Pharmaceutical Co. Ltd., MSD, Eisai Co., Ltd., Teijin, Daiichi-Sankyo, Nihon Medi-Physics, Chugai Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., AbbVie, Medical U and A; payment honoraria from Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd.; medical writing and article processing charges fees from Ono Pharmaceutical Co. Ltd. Y.T. received research grants Ono Pharmaceutical Co. Ltd.; payment honoraria from Eisai Co., Ltd., Celgene Corp., Ono Pharmaceutical Co. Ltd., Janssen, Chugai Pharmaceutical Co., Ltd., Abbvie, Symbio; medical writing and article processing charges fees from Ono Pharmaceutical Co. Ltd. N.F. received research grants Ono Pharmaceutical Co. Ltd.; Bayer, Chugai Pharmaceutical Co., Ltd., Celgene Corp., Genmab, Incyte; payment honoraria from AstraZeneca, BMS, Chugai Pharmaceutical Co., Ltd., CSL Behring, Dainippon Sumitomo, Eisai Co., Ltd., Janssen, Kyowa Kirin, Nippon Shinyaku, Novartis, Ono Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Sanofi, Symbio, Takeda, Zenyaku; Board member for HUYA Japan, AstraZeneca, Abbvie, Eli Lilly, Genmab, Novartis; medical writing and article processing charges fees from Ono Pharmaceutical Co. Ltd. R.N. received research grants, medical writing and article processing charges fees from Ono Pharmaceutical Co. Ltd.; payment honoraria from Eisai Co., Ltd., Varian Medical Systems; consulting fees form Novocure. H.Y., K.A., K.S., and N.S. received research grants, medical writing, and article processing charges fees from Ono Pharmaceutical Co. Ltd. A.A. is an employee of Ono Pharmaceutical Co. Ltd., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Mast cells are a significant source of cytokines and chemokines that play a role in pathological processes. Gangliosides, which are complex lipids with a sugar chain, are present in all eukaryotic cell membranes and comprise lipid rafts. Ganglioside GM3, the first ganglioside in the synthetic pathway, is a common precursor of the specifying derivatives and is well known for its various functions in biosystems. Mast cells contain high levels of gangliosides; however, the involvement of GM3 in mast cell sensitivity is unclear. Therefore, in this study, we elucidated the role of ganglioside GM3 in mast cells and skin inflammation. GM3 synthase (GM3S)-deficient mast cells showed cytosolic granule topological changes and hyperactivation upon IgE-DNP stimulation without affecting proliferation and differentiation. Additionally, inflammatory cytokine levels increased in GM3S-deficient bone marrow-derived mast cells (BMMC). Furthermore, GM3S-KO mice and GM3S-KO BMMC transplantation showed increased skin allergic reactions. Besides mast cell hypersensitivity caused by GM3S deficiency, membrane integrity decreased and GM3 supplementation rescued this loss of membrane integrity. Additionally, GM3S deficiency increased the phosphorylation of p38 mitogen-activated protein kinase. These results suggest that GM3 increases membrane integrity, leading to the suppression of the p38 signalling pathway in BMMC and contributing to skin allergic reaction., (© 2023 Federation of European Biochemical Societies.)

Obesity is a global health problem caused by genetic, environmental, and psychological factors and is associated with various health disorders. As such, there is a growing focus on the prevention of obesity and related diseases. The gut microbiota plays a crucial role in these diseases and has become a therapeutic target. Prebiotics, such as poly-d-3-hydroxybutyric acid (PHB), have gained attention for their potential to alter the gut microbiota, promote beneficial bacterial growth, and alleviate obesity. In this study, we examined the prebiotic effects of PHB in obese mice. We found that, in C57BL/6N mice, PHB reduced blood lipid levels. Analysis of the intestinal microflora also revealed an increase in short-chain fatty acid-producing bacteria. When PHB was administered to obese mice, subcutaneous fat and dyslipidemia were reduced, and the number of beneficial bacteria in the intestinal microflora increased. Furthermore, fatty degradation and oxidative stress were suppressed in the liver. PHB regulates gut bacterial changes related to obesity and effectively inhibits dyslipidemia, suggesting that it could be a prebiotic agent for curing various obesity-related diseases. In summary, PHB increases the beneficial gut microbiota, leading to an alleviation of obesity-associated dyslipidemia., (© 2023 Federation of American Societies for Experimental Biology.)