Niigata University

Voriconazole (VRCZ) is a widely used antifungal agent, especially for treating invasive aspergillosis and other serious fungal infections.1 However, prolonged use has been associated with photosensitivity and an increased risk of cutaneous squamous cell carcinoma (cSCC).2, 3 Clinically, VRCZ-induced cSCC (VRCZ-cSCC) has been reported to grow more aggressively than typical cSCC.4 However, the mechanisms underlying the accelerated growth of VRCZ-cSCC remain unclear. Cyclooxygenase-2 (COX-2) is a key mediator of inflammation and tumour promotion, contributing to cell proliferation, angiogenesis and immune evasion through prostaglandin E2 (PGE2) signalling.5 COX-2 overexpression has been linked to several malignancies, including colorectal and lung cancers.6, 7 In addition, COX-2 expression is known to be upregulated by ultraviolet (UV) radiation.7, 8 Based on these findings, and considering that VRCZ increases UV sensitivity,2 we hypothesized that VRCZ may exacerbate COX-2–mediated tumour-promoting pathways in the skin. To explore this, we performed immunohistochemistry to detect COX-2 expression on formalin-fixed tissue samples from one case of VRCZ-cSCC, five cases of typical cSCC and two normal skin samples. From each of these eight patient tissue samples, we obtained five high-power fields (400x magnification) for analysis. In total, 40 high-power fields were analysed. The VRCZ-cSCC sample was obtained from the left cheek, while the five typical cSCC samples were derived from other facial areas. The two normal skin samples were collected from abdominal regions. The VRCZ-cSCC sample was derived from a 73-year-old man who had been receiving VRCZ therapy for over 20 years for chronic pulmonary aspergillosis. He presented with a tumour on his left cheek that had rapidly enlarged over a 2-month period (Figure 1a). COX-2-positive areas were quantified using ImageJ (NIH, Bethesda, MD)9 as absolute pixel-based values from these fields, with a greyscale intensity threshold set from 30 to 130 in 8-bit images and directly compared without normalization. Statistical analysis was performed using one-way ANOVA with JMP Pro 17 (SAS Institute Inc., Cary, NC), with p < 0.05 considered significant. We also examined the expression of Ki-67, a well-established marker of cell proliferation, to assess tumour growth dynamics. COX-2 and Ki-67 expression levels were significantly higher in VRCZ-cSCC than in typical cSCC and normal skin. The average COX-2-positive area was 4.18 pixels2/1.0 × 105 in VRCZ-cSCC, compared to 0.95 in typical cSCC and 1.41 in normal skin; Ki-67-positive areas were 2.13, 1.54 and 0.65 pixels2/1.0 × 105, respectively (p < 0.0001 for both) (Figure 1b–d). The analysis using a mixed-effects model demonstrated a trend towards a positive association between COX-2 and Ki-67 expression (β = 0.146, p = 0.069). This relationship is further illustrated in a scatter plot (Figure 1e), which shows the correlation across all cSCC samples while accounting for the nested data structure within individual patients. Voriconazole has been reported to cause chronic photosensitivity. This effect is mediated by its N-oxide metabolites, which absorb UVB and undergo photodegradation, generating reactive oxygen species (ROS) that induce DNA damage and contribute to photocarcinogenesis.2 This UV-dependent mechanism is thought to play a primary role in tumour initiation. In the progression phase, continued voriconazole exposure may sustain high COX-2 expression, thereby promoting tumour growth. In support of this, Ikeya et al. demonstrated that voriconazole upregulates COX-2 expression in keratinocytes through an aryl hydrocarbon receptor-dependent mechanism, even in the absence of UV exposure.9, 10 They demonstrated that this occurs via the classical (genomic) AhR-ARNT-dependent pathway, leading to a robust and sustained transcriptional activation of COX-2. This key finding indicates that while VRCZ metabolites may participate in tumour initiation, voriconazole itself directly promotes tumour development. Collectively, our findings indicate that voriconazole-associated tumour progression in this case may have been mediated, at least in part, by COX-2 overexpression. These findings suggest that VRCZ may influence both the initiation and promotion phases of cSCC development: by enhancing UV sensitivity and DNA damage via its N-oxide metabolites, and by upregulating COX-2 expression to accelerate tumour progression. Although this is a single case study, the observed association between voriconazole exposure and COX-2 overexpression suggests a potential mechanism of tumour progression that warrants further investigation in larger patient cohorts. Targeting COX-2 may represent a potential therapeutic approach in patients with VRCZ-associated cSCC. None. None declared. The patient provided written informed consent for publication of their clinical details and associated images. The data supporting the findings of this study are available from the corresponding author upon reasonable request.

本研究では，ケミカルルーピング水素製造（CLHP）プロセスにおける鉄系酸素キャリア（OC）である酸化鉄の酸化・還元反応を評価し，適切な反応条件を検討した．さらに，カーボンニュートラルな水素製造技術の確立を目指し，バイオマスを用いたOCの直接還元反応についても検討した．予備酸化処理は酸素キャリアの表面構造と酸化還元反応性の改善に効果的であることが明らかになった．天然酸化鉄鉱物は，純粋な酸化鉄試薬と比較してガス還元反応における反応性が低いものの，高耐熱性成分を複数種類含むため，高温条件下での粒子凝集が生じにくく，水蒸気酸化反応では優れた反応性を示した．バイオマスによる直接還元では，木質バイオマスを流動床反応器に直接導入し，OCの還元反応が進行することを確認した．バイオマスとOCの供給比やバイオマスの焙焼処理はOCの還元転化率に影響を与えた．また，反応器内に蓄積するバイオマスチャーが層内粒子の流動化状態と反応の進行に影響をおよぼすことも確認された．良好な流動化状態が維持された条件では，還元されたOCの水蒸気酸化反応により単一水素ガスが安定して生成されることが確認された．これらの結果は，CLHPプロセスにおけるバイオマス利用の有効性を示し，高純度水素製造技術としての実現可能性を検証した．

X-inactivation is the process of dosage compensation to balance X-linked gene expression levels between females (XX) and males (XY). One of the 2 X-chromosomes is randomly selected for inactivation in each cell during embryogenesis and remains inactive throughout life. Therefore, females have 2 types of cells: those with paternal X-chromosome activation and those with maternal X-chromosome activation. However, it remains unclear how X-inactivation is involved in palate and tooth development. Ofd1 is located on the X-chromosome. We found cleft palate in all heterozygous Ofd1 mutant mice (Ofd1fl/WT;Wnt1Cre[HET]), even though some cells should activate the normal X-chromosome due to random X-inactivation. Cells with Ofd1 mutant X chromosome activation (Ofd1 mutant cells) accumulated at the tip of the palatal shelves due to cell segregation caused by a lack of EFNB1 expression, resulting in a cleft palate in all Ofd1fl/WT;Wnt1Cre(HET) mice. Unlike the palate, Ofd1fl/WT;Wnt1Cre(HET) mice showed multiple tooth phenotypes, including extra and absent incisors, while a normal number of incisors was also found. Accumulation of Ofd1 mutant cells also occurred in the tooth mesenchyme, and these clusters of Ofd1 mutant cells failed to initiate incisor tooth formation due to a lack of Wnt signaling. In contrast to palate development, the location of Ofd1 mutant cell clusters differed between Ofd1fl/WT;Wnt1Cre(HET) mice, likely leading to diversity of tooth phenotypes. Thus, X-inactivation exhibits different involvement between palate and tooth development.

Autoimmune cerebellar ataxia (ACA) is a potentially treatable cause of cerebellar dysfunction, but remains underrecognized because of diagnostic challenges, including limited access to autoantibody testing and heterogeneous clinical presentations. We aimed to describe the clinical and laboratory characteristics of patients with clinically diagnosed ACA (cdACA) in Japan, based on expert diagnoses, and evaluate associations between clinical factors and response to immunotherapy. This study was a retrospective, multi-center, descriptive study based on a two-step nationwide survey. We inquired at facilities accredited by the Japanese Society of Neurology about the number of patients with cdACA. Furthermore, we asked the facilities with cdACA experience for clinical information. Of 92 cdACA patients, 96.7% had isolated/predominant cerebellar symptoms. Autoantibodies associated with ACA were detected in 47 (51.1%) patients, with glutamic acid decarboxylase (GAD) antibodies being most frequent. 25 (27.2%) patients had concomitant cancer. Among 80 patients who received immunotherapy, 53 (66.2%) responded positively. Responders were more often female (p = 0.006), and had shorter median time to treatment (71 vs 344days, p = 0.010) and lower CSF protein (40.65 vs 71.05mg/dL, p = 0.003). Patients without malignancy responded more frequently (p = 0.006). This nationwide study provides the first real-world insights into the clinical characteristics and management of cdACA in Japan. Although these findings should be interpreted with caution due to diagnostic heterogeneity and the retrospective study design, some patients with concomitant cancer may also show functional improvement following immunotherapy. In the future, there should be further accumulation of ACA cases and the establishment of diagnostic criteria for ACA.