👤 Yukihiro Bando

Hepatoid adenocarcinoma (HAD) and adenocarcinoma with enteroblastic differentiation (ACED) are rare gastric cancer types that produce alpha-fetoprotein (AFP) that morphologically resembles the liver or fetal organ. This study investigated the molecular profiling of HAD and ACED compared with common-type gastric adenocarcinoma (CGA). This study enrolled 496 patients with gastric adenocarcinoma who underwent radical gastrectomy. Whole-exome sequencing and gene expression profiling were conducted to compare HAD/ACED and CGA. Immunohistochemistry was performed in 39 patients with HAD/ACED, including 10 who underwent genomic analysis. TP53 (100 %), CSMD3 (30 %), LRP1B, FAT3, TG, APOB, CREBBP, PASK, DROSHA, and STK40 (20 %) were mutated genes with high frequency (>20 %) in HAD/ACED. Gene expression analysis revealed 15 overexpressed genes in HAD/ACED, many of which were associated with hepatocytes and fetal organs. Furthermore, cancer stemness gene overexpression, including LIN28B, IGF2BP1, and HMGA2, which are related to TP53, was observed. Immunohistochemistry revealed positive staining for LIN28B (82 %), IGF2BP1 (94 %), and HMGA2 (72 %), as well as staining for AFP (69 %), GPC3 (75 %), and SALL4 (94 %). Additionally, positive cancer stemness gene staining was observed in CGA mucosa coexisting with HAD/ACED. HAD/ACED demonstrated higher TP53 mutation accumulation and TP53-related cancer stemness gene overexpression, including LIN28B, IGF2BP1, and HMGA2. Therefore, TP53 and these cancer stemness genes might be involved in the occurrence of HAD/ACED. Show less

Vascular calcification represents a significant clinical challenge, leading to cardiovascular disease, though its underlying mechanisms remain incompletely understood. Recent studies indicate that Toll-like receptor 9 (TLR9), a key element of innate immunity, plays a pathogenic role in vascular inflammation and atherogenesis. Therefore, we hypothesized that TLR9 signaling promotes vascular chondrogenesis and calcification. We compared apolipoprotein E-deficient (ApoE Show less

Advanced esophageal squamous cell carcinoma (ESCC) has a poor prognosis, and current treatments provide limited survival benefits. This study aimed to identify prognostic biomarkers and therapeutic targets by genomic profiling of advanced ESCC using circulating tumor DNA (ctDNA). The SCRUM-MONSTAR GOZILA study is a nationwide, plasma-based molecular profiling project using Guardant360, involving 31 core cancer institutions in Japan. We evaluated the genomic landscape of advanced ESCC and investigated associations between specific alterations and overall survival (OS). The correlation between blood tumor mutation burden (bTMB) and clinical outcomes in patients with PD-1 inhibitors was also assessed using multiple cutoff values (2, 4, 6, 8, and 10 mutations/Mb). Among 313 patients, alterations predominantly consisted of single nucleotide variants (SNVs, 68.9%) and copy number alterations (20.7%). ctDNA analysis identified key genomic alterations linked to poor outcomes in advanced ESCC, revealing potential prognostic biomarkers and therapeutic targets. In contrast, bTMB did not show predictive value for the efficacy of PD-1 inhibitors in this study. Show less

Lysophosphatidic acid (LPA) and its receptor LPA1 have been implicated in tissue inflammation and fibrosis; however, their role in mucus overproduction remains unclear. Pulmonary neuroendocrine cells (PNECs), which are rare airway epithelial cells, contribute to mucus overproduction and immune modulation. In this study, we investigated the role of the LPA/LPA1 receptor axis in goblet cell hyperplasia and mucus overproduction, as well as the contribution of PNECs, using a chronic mouse model of bronchial asthma. A chronic mouse model of asthma was established by sensitization and challenge with the house dust mite antigen Dermatophagoides pteronyssinus (Dp), with or without treatment using the LPA1 antagonist AM095. Airway hyperresponsiveness, histopathology, mediator concentrations, and molecular expression in lung homogenate supernatants were evaluated. Lysophospholipid levels and low-molecular-weight metabolites were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Lung LPA 22:5 levels were elevated in Dp-challenged mice. LPA1 receptors were co-localized with PNECs in the lung. Treatment with AM095 reduced goblet cell hyperplasia by inhibiting the production of gamma-aminobutyric acid (GABA) and calcitonin gene-related peptide (CGRP) by PNECs. It also suppressed arginase 1 and polyamine production in CGRP-stimulated M2 macrophages. AM095 did not affect eosinophil extracellular trap (EET) formation in bronchoalveolar lavage fluid, which activates PNECs. The LPA/LPA1 axis promotes goblet cell hyperplasia through PNEC activation and downstream GABA and CGRP signaling in a chronic asthma model. LPA1 antagonism may represent a potential therapeutic strategy for controlling mucus overproduction in asthma. Show less

Statins decrease cholesteryl ester transfer protein (CETP) levels, which have been positively associated with hepatic lipid content as well as serum low density lipoproteins-cholesterol (LDL-C) levels. However, the relationship between the CETP status and statin-induced reductions in LDL-C levels has not yet been elucidated in detail. We herein examined the influence of the CETP status on the lipid-reducing effects of pitavastatin in hypercholesterolemic patients with type 2 diabetes mellitus as well as the molecular mechanism underlying pitavastatin-induced modifications in CETP levels. Fifty-three patients were treated with 2 mg of pitavastatin for 3 months. Serum levels of LDL-C, small dense (sd) LDL-C, and CETP were measured before and after the pitavastatin treatment. The effects of pitavastatin, T0901317, a specific agonist for liver X receptor (LXR) that reflects hepatic cholesterol contents, and LXR silencing on CETP mRNA expression in HepG2 cells were also examined by a real-time PCR assay. The pitavastatin treatment decreased LDL-C, sdLDL-C, and CETP levels by 39, 42, and 23%, respectively. Despite the absence of a significant association between CETP and LDL-C levels at baseline, baseline CETP levels and its percentage change were an independent positive determinant for the changes observed in LDL-C and sdLDL-C levels. The LXR activation with T0901317 (0.5 μM), an in vitro condition analogous to hepatic cholesterol accumulation, increased CETP mRNA levels in HepG2 cells by approximately 220%, while LXR silencing markedly diminished the increased expression of CETP. Pitavastatin (5 μM) decreased basal CETP mRNA levels by 21%, and this was completely reversed by T0901317. Baseline CETP levels may predict the lipid-reducing effects of pitavastatin. Pitavastatin-induced CETP reductions may be partially attributed to decreased LXR activity, predictable by the ensuing decline in hepatic cholesterol synthesis. UMIN Clinical Trials Registry ID UMIN000019020. Show less