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PURPOSE: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a 40% recurrence rate, lacking effective prognostic biomarkers and surveillance methods. This prospective, multicenter, observational study aimed to evaluate circulating tumor DNA (ctDNA) as a biomarker for detecting MCC recurrence. METHODS: Plasma samples, clinical data, and imaging results were collected from 319 patients. A tumor-informed ctDNA assay was used for analysis. Patients were divided into discovery (167 patients) and validation (152 patients) cohorts. Diagnostic performance, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), was assessed. RESULTS: ctDNA showed high sensitivity, 95% (discovery; 95% CI, 87 to 99) and 94% (validation; 95% CI, 85 to 98), for detecting disease at enrollment, with corresponding specificities of 90% (95% CI, 82 to 95) and 86% (95% CI, 77 to 93). A positive ctDNA during surveillance indicated increased recurrence risk, with hazard ratios (HRs) of 6.8 (discovery; 95% CI, 2.9 to 16) and 20 (validation; 95% CI, 8.3 to 50). The PPV for clinical recurrence at 1 year after a positive ctDNA test was 69% (discovery; 95% CI, 32 to 91) and 94% (validation; 95% CI, 71 to 100), respectively. The NPV at 135 days after a negative ctDNA test was 94% (discovery; 95% CI, 90 to 97) and 93% (validation; 95% CI, 89 to 97), respectively. Patients positive for ctDNA within 4 months after treatment had higher rates of recurrence, with 1-year rates of 74% versus 21% (adjusted HR, 7.4 [95% CI, 2.7 to 20]). CONCLUSION: ctDNA testing exhibited high prognostic accuracy in detecting MCC recurrence, suggesting its potential to reduce frequent surveillance imaging. ctDNA also identifies high-risk patients who need more frequent imaging and may be best suited for adjuvant therapy trials.

Abstract Background Despite recent reports, the effectiveness of postoperative oral nutritional supplementation (ONS) on body weight loss and malnutrition after gastrectomy remains controversial. We aimed to elucidate the effectiveness of ONS especially in octogenarian patients undergoing oncological gastrectomy. Methods A total of 286 consecutive patients who underwent gastrectomy for gastric cancer were eligible. Postoperative body weight loss, malnutrition, and sarcopenia were compared between patients with and without postoperative ONS among octogenarian patients aged ≥ 80 years and non-octogenarian patients aged

Abstract Background Understanding the roles and competencies of professions outside of one’s specialty is essential for providing efficient healthcare. However, it is difficult for medical professionals to understand the roles and competencies of other related professions while performing their duties. This study examined the impact of clinical practice-based interprofessional education (IPE) on pharmacy students, who are future medical professionals. Methods Sixty-eight pharmaceutical students undergoing clinical practice were divided into non-IPE or IPE groups, with the IPE group attending an educational program with medical students conducted by doctors, pharmacists, and teachers during the clinical practice period. The effect was evaluated through a group survey using self-administered questionnaires focusing on contributing to multidisciplinary team medicine based on the Readiness for Interprofessional Learning Scale. The survey included specific behavioral objectives (SBOs), the Readiness for Interpersonal Learning Scale (RIPLS), and Kikuchi’s Scale of Social Skills (KiSS-18). Results Regardless of group, SBOs [non-IPE: 3.2, 95% CI (2.6–3.8), p

ABSTRACT We previously reported that hepatitis C virus (HCV) infection or HCV core protein expression induces HOX gene expression by impairing histone H2A monoubiquitination via a proteasome-dependent reduction in the level of RNF2, a key catalytic component of polycomb repressive complex 1 (H. Kasai, K. Mochizuki, T. Tanaka, A. Yamashita, et al., J Virol 95:e01784-20, 2021, https://doi.org/10.1128/jvi.01784-20). In this study, we aimed to investigate the mechanism by which HCV infection accelerates RNF2 degradation. Yeast two-hybrid screening and an immunoprecipitation assay revealed that RNF2 is a PA28γ-binding protein. The proteasome activator PA28γ destabilized the RNF2 protein in a proteasome-dependent manner, since RNF2 degradation was impaired by PA28γ knockout or MG132 treatment. HCV infection or core protein expression reduced the levels of RNF2 and histone H2A K119 monoubiquitination and induced the expression of HOX genes in the presence of PA28γ, while PA28γ knockout reversed these changes. Treatment with a lysine acetyltransferase inhibitor inhibited the acetylation of PA28γ at K195 and the degradation of the RNF2 protein, while treatment with a lysine deacetylase inhibitor accelerated these events in a PA28γ-dependent manner. RNF2 protein degradation was increased by expression of the acetylation mimetic PA28γ mutant but not by expression of the acetylation-defective mutant or the proteasome activation-defective mutant. Furthermore, HCV infection or core protein expression facilitated the interaction between PA28γ and the lysine acetyltransferase CBP/p300 and then accelerated PA28γ acetylation and heptazmerization to promote RNF2 degradation. These data suggest that HCV infection accelerates the acetylation-dependent heptamerization of PA28γ to increase the proteasomal targeting of RNF2.IMPORTANCEHCV is a causative agent of HCV-related liver diseases, including hepatic steatosis, cirrhosis, and hepatocellular carcinoma. PA28γ, which, in heptameric form, activates the 20S core proteasome for the degradation of PA28γ-binding proteins, is responsible for HCV-related liver diseases. HCV core protein expression or HCV infection accelerates RNF2 degradation, leading to the induction of HOX gene expression via a decrease in the level of H2Aub on HOX gene promoters. However, the mechanism of RNF2 degradation in HCV-infected cells has not been clarified. The data presented in this study suggest that PA28γ acetylation and heptamerization are promoted by HCV infection or by core protein expression to activate the proteasome for the degradation of RNF2 and are responsible for HCV propagation. This study provides novel insights valuable for the development of therapies targeting both HCV propagation and HCV-related diseases.

Abstract Reactive sulfane sulfur species such as persulfides (RSSH) and H2S2 are important redox regulators and closely linked to H2S signaling. However, the study of these species is still challenging due to their instability, high reactivity, and the lack of suitable donors to produce them. Herein we report a unique compound, 2H-thiopyran-2-thione sulfine (TTS), which can specifically convert H2S to HSOH, and then to H2S2 in the presence of excess H2S. Meanwhile, the reaction product 2H-thiopyran-2-thione (TT) can be oxidized to reform TTS by biological oxidants. The reaction mechanism of TTS is studied experimentally and computationally. TTS can be conjugated to proteins to achieve specific delivery, and the combination of TTS and H2S leads to highly efficient protein persulfidation. When TTS is applied in conjunction with established H2S donors, the corresponding donors of H2S2 (or its equivalents) are obtained. Cell-based studies reveal that TTS can effectively increase intracellular sulfane sulfur levels and compensate for certain aspects of sulfide:quinone oxidoreductase (SQR) deficiency. These properties make TTS a conceptually new strategy for the design of donors of reactive sulfane sulfur species.

Abstract.: A brief exposure to hydrogen peroxide (H2O2) induces severe deterioration of primary cultured neurons in vitro. We have investigated a link between the H2O2-induced neuronal death and Ca2+-permeable TRPM2 channels regulated by ADP-ribose (ADPR). In cultured cerebral cortical neurons from fetal rat, TRPM2 proteins were detected at cell bodies and neurite extensions. Application of H2O2 to the cultured neurons elicited an increase in intracellular Ca2+ concentration ([Ca2+]i) caused by Ca2+ influx and the Ca2+-dependent neuronal death in a similar concentration range. Molecular cloning of TRPM2 cDNA from rat brain revealed several differences in amino acid sequences within the Nudix box region as compared with those of human and mouse TRPM2. ADPR-induced current responses, H2O2-induced Ca2+ influx, and H2O2-induced cell death were induced in human embryonic kidney cells heterologously expressing rat TRPM2. Treatment of cultured neurons with small interfering RNA against rat TRPM2, which efficiently suppressed immunoreactive TRPM2 content and the H2O2-induced Ca2+ influx, significantly inhibited H2O2-induced neuronal death. These results suggest that TRPM2 plays a pivotal role in H2O2-induced neuronal death as redox-sensitive Ca2+-permeable channels expressed in neurons. Keywords:: ADP-ribose, cation channel, calcium homeostasis, cerebral cortex, TRP channel

Leigh syndrome is the most common inherited mitochondrial disease in children and is often fatal within the first few years of life. In 2020, mutations in the gene encoding sulfide:quinone oxidoreductase (SQOR), a mitochondrial protein, were identified as a cause of Leigh syndrome. Here, we report that mice with a mutation in the gene encoding SQOR ([Sqor.sup.[DELTA]N/[DELTA]N] mice), which prevented SQOR from entering mitochondria, had clinical and pathological manifestations of Leigh syndrome. [Sqor.sup.[DELTA]N/[DELTA]N] mice had increased blood lactate levels that were associated with markedly decreased complex IV activity and increased hydrogen sulfide ([H.sub.2]S) levels. Because [H.sub.2]S is produced by both gut microbiota and host tissue, we tested whether metronidazole (a broad-spectrum antibiotic) or a sulfur-restricted diet rescues [Sqor.sup.[DELTA]N/[DELTA]N] mice from developing Leigh syndrome. Daily treatment with metronidazole alleviated increased [H.sub.2]S levels, normalized complex IV activity and blood lactate levels, and prolonged the survival of [Sqor.sup.[DELTA]N/[DELTA]N] mice. Similarly, a sulfur-restricted diet normalized blood lactate levels and inhibited the development of Leigh syndrome. Taken together, these observations suggest that mitochondrial SQOR is essential to prevent systemic accumulation of [H.sub.2]S. Metronidazole administration and a sulfur-restricted diet may be therapeutic approaches to treatment of patients with Leigh syndrome caused by mutations in SQOR., Introduction Leigh syndrome is an inherited metabolic disorder that affects the central nervous system and is the most common mitochondrial disease in children. The genetic abnormalities in Leigh syndrome are [...]

Abstract Objectives Disruption of the oxidative stress defense system is involved in developing various diseases. Sulfur compounds such as glutathione (GSH) and cysteine (CysSH) are representative antioxidants in the body. Recently, supersulfides, including reactive persulfide and polysulfide species, have gained attention as potent antioxidants regulating oxidative stress and redox signaling. However, their involvement in the pathogenesis of chronic rhinosinusitis (CRS) remains unclear. Methods To clarify the changes in sulfur compounds within the sinus mucosa of each CRS subtype, we measured sulfur compound levels in the sinus mucosa of control individuals (n = 9), patients with eosinophilic CRS (ECRS) (n = 13), and those with non‐ECRS (nECRS) (n = 11) who underwent sinus surgery using mass spectrometry. Results GSH and CysSH levels were significantly reduced, and the glutathione disulfide (GSSG)/GSH ratio, an oxidative stress indicator, was increased in patients with ECRS. Despite the absence of notable variations in supersulfides, patients with ECRS and nECRS exhibited a significant reduction in glutathione trisulfide (GSSSG), which serves as the precursor for supersulfides. Conclusions This study is the first quantitative assessment of supersulfides in normal and inflamed sinus mucosa, suggesting that sulfur compounds contribute to the pathogenesis of CRS. Level of Evidence N/A.

Abstract Acute exacerbation of idiopathic interstitial pneumonias (AE‐IIPs) is a disease associated with a poor prognosis in patients with IIPs. However, the specific characteristics of fluorine‐18 2‐fluoro‐2‐deoxy‐d‐glucose (18F‐FDG) positron emission tomography/computed tomography (PET/CT) imaging for AE‐IIPs remain unclear. Herein, we present the case of a patient with lung cancer combined with IIPs who underwent 18F‐FDG PET/CT at the early onset of AE‐IIPs. The scan, conducted 18 days post‐bronchoscopy for lung cancer evaluation, revealed AE‐IIPs before the onset of respiratory failure. New ground‐glass opacities appeared, accompanied by significant 18F‐FDG accumulation extending beyond these regions. To the best of our knowledge, this report represents the first assessment of 18F‐FDG PET/CT images at the early onset of AE‐IIPs before respiratory failure in humans. The observed features in this PET image could potentially contribute to our understanding of the pathophysiology of AE‐IIPs.

Merkel cell carcinoma (MCC) incidence has risen to approximately 3,000 cases annually in the USA. Although anti-programmed cell death (ligand) 1 (PD-(L)1) agents are now the first-line treatment for advanced MCC, approximately 50% of such patients do not persistently benefit. In PD-(L)1-refractory cases, ipilimumab (anti-cytotoxic T lymphocyte antigen-4) is often added; however, the extent of the clinical benefit of this combination is controversial. We identified one prospective study, three retrospective studies, and three case reports regarding this combination in refractory MCC. The aggregate response rate from retrospective studies was 32% (13 of 41 patients) with 4 complete responses (CR) and 9 partial responses (PR). In the prospective study, the response rate was very similar at 31% (8 of 26 patients; 4 CR, 4 PR). Response durability was highly variable (range 2 to >43 months), with patients achieving CR having greater durability. Immune-related adverse events (irAEs) were ≥grade III in 29% (retrospective cohort, N=41) and 36% (prospective cohort, N=50). While these aggregate data indicate adding ipilimumab should be considered in this setting, many patients with refractory MCC are ineligible due to comorbidities/irAEs, and approximately 70% will not benefit from this regimen. There is thus a significant unmet need in PD-(L)1-refractory MCC and clinical trials in this setting should be encouraged.

Key Clinical Message Rare but severe, immune‐related adverse events such as myositis and sclerosing cholangitis can occur with immune checkpoint inhibitors in lung cancer treatment. This case report highlights their co‐occurrence after pembrolizumab treatment, indicating the need for vigilance and management strategies in immune checkpoint inhibitors therapy. Abstract Immune checkpoint inhibitors (ICI) are used in advanced treatment of lung cancer but can lead to immune‐related adverse events. ICI‐related myositis and cholangitis are rare, and their combination has not been previously reported. Here, we report the first case of ICI‐related myositis and sclerosing cholangitis. A patient with stage IV lung adenocarcinoma who received one cycle of pembrolizumab with cisplatin and pemetrexed developed myositis. Treatment with prednisolone improved the myositis, but the patient subsequently developed cholangitis. The patient did not respond to a regimen of prednisolone, mycophenolate mofetil, and azathioprine, and eventually died due to worsening lung cancer. An autopsy confirmed the presence of ICI‐related myositis and sclerosing cholangitis.

Background: Cystathionine β-synthase (CBS)-deficient homocystinuria (HCU) is an inherited disorder of sulfur amino acid metabolism with varying severity and organ complications, and a limited knowledge about underlying pathophysiological processes. Here we aimed at getting an in-depth insight into disease mechanisms using a transgenic mouse model of HCU (I278T). Methods: We assessed metabolic, proteomic and sphingolipidomic changes, and mitochondrial function in tissues and body fluids of I278T mice and WT controls. Furthermore, we evaluated the efficacy of methionine-restricted diet (MRD) in I278T mice. Results: In WT mice, we observed a distinct tissue/body fluid compartmentalization of metabolites with up to six-orders of magnitude differences in concentrations among various organs. The I278T mice exhibited the anticipated metabolic imbalance with signs of an increased production of hydrogen sulfide and disturbed persulfidation of free aminothiols. HCU resulted in a significant dysregulation of liver proteome affecting biological oxidations, conjugation of compounds, and metabolism of amino acids, vitamins, cofactors and lipids. Liver sphingolipidomics indicated upregulation of the pro-proliferative sphingosine-1-phosphate signaling pathway. Liver mitochondrial function of HCU mice did not seem to be impaired compared to controls. MRD in I278T mice improved metabolic balance in all tissues and substantially reduced dysregulation of liver proteome. Conclusion: The study highlights distinct tissue compartmentalization of sulfur-related metabolites in normal mice, extensive metabolome, proteome and sphingolipidome disruptions in I278T mice, and the efficacy of MRD to alleviate some of the HCU-related biochemical abnormalities.

Purpose: This case report details the diagnostic process for a patient with an initial diagnosis of scleritis who was unresponsive to typical treatment modalities, culminating in the identification of a cavernous sinus dural arteriovenous fistula (CS-DAVF). The case highlights the role of anterior segment optical coherence tomography angiography (OCTA) in the diagnosis of this vascular anomaly and in monitoring the response to treatment. Observations: A 45-year-old man with persistently elevated intraocular pressure (IOP) and ocular congestion in the left eye was unresponsive to treatment for scleritis. The persistent ocular symptoms and new-onset tinnitus prompted further investigation. Anterior segment OCTA revealed vascular anomalies, and magnetic resonance imaging confirmed a CS-DAVF. The patient underwent endovascular treatment for the CS-DAVF. This intervention led to a significant reduction in IOP in the left eye and the resolution of ocular congestion. Conclusions and importance: This case highlights the diagnostic complexities of ophthalmic symptoms that mimic those of other conditions. Furthermore, it demonstrates the essential role of anterior segment OCTA in the accurate diagnosis and effective management of CS-DAVF and highlights the need for comprehensive diagnostic approaches in ophthalmology.