👤 Kazutaka Shimoda

Pacific salmon (Oncorhynchus spp.) rely on olfactory information learned in their natal rivers to guide their homing migration. Although molecules associated with synaptic plasticity show marked changes in the olfactory system during periods linked to imprinting, the contribution of brain-derived neurotrophic factor (BDNF/Bdnf), a key regulator of neural development and plasticity, has not been fully examined in salmonids. In this study, we isolated the complete coding sequence of masu salmon (O. masou) pro-bdnf and analyzed its expression profile across the olfactory system using wild individuals at multiple developmental stages. The deduced amino acid sequence of masu salmon pro-Bdnf was highly conserved among vertebrates. Pro-bdnf mRNA was strongly expressed in under-yearling parr prior to smoltification, particularly in the olfactory rosette and olfactory bulb at the sensitive period for imprinting. In the telencephalon, a higher olfactory center homologous to the mammalian cerebrum, pro-bdnf expression remained stable across stages, consistent with ongoing neurogenesis in this region. These results provide molecular evidence that pro-bdnf expression mirrors developmental changes in the olfactory system and support the idea that Bdnf contributes to the formation and refinement of olfactory circuits essential for imprinting and homing in Pacific salmon. Show less

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

This study aimed to investigate the anti-atherosclerotic properties of tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist, in comparison with semaglutide, a selective GLP-1 receptor agonist. ApoE knockout mice were divided into early diabetes (dosed from 10 to 22 weeks of age), late diabetes (dosed from 18 to 30 weeks of age), and non-diabetic groups after streptozotocin treatment, and each group received semaglutide, tirzepatide, or saline for 12 weeks. In the early diabetes group, both agents significantly suppressed aortic plaque formation compared with control, while modestly improving glycemia and lipid levels. No significant vascular effects were observed in late diabetes or non-diabetic groups. Tirzepatide markedly reduced inflammatory mediators, including Mcp-1, Il-6, I-cam, and Cd68, whereas semaglutide showed partial overlap. Notably, these anti-inflammatory effects were also detected in non-diabetic mice, suggesting vascular protection may involve arterial actions independently of metabolic control. Taken together, our findings demonstrate that tirzepatide exerts anti-atherosclerotic effects comparable to semaglutide, supporting the concept that GIP and GLP-1 signaling can confer vascular benefits. These results highlight the potential clinical relevance of dual incretin receptor agonism for cardiovascular risk reduction, although further studies are required to clarify the specific role of GIP signaling. Show less

Myeloid and lymphoid neoplasms associated with FGFR1 abnormalities (MLN-FGFR1 abnormalities) are rare hematologic malignancies associated with chromosome 8p11.2 abnormalities. Translocations of 8p11.2 were detected in 10 of 17,039 (0.06%) unique patient cytogenetic studies performed at nine institutions in Japan. No inversions or insertions of 8p11.2 were detected. Among the 10 patients with 8p11.2 translocations, three patients were diagnosed with MLN-FGFR1 abnormalities, which were confirmed by FISH analysis. Peripheral blood eosinophilia was observed in all three patients, and all progressed to AML or T-lymphoblastic lymphoma/leukemia. The prevalence of 8p11.2 translocations in clinical practice and the proportion of MLN-FGFR1 abnormalities in patients with 8p11.2 translocations in Japan were consistent with those in previous reports from Western countries. Show less

Hypertrophic cardiomyopathy (HCM) is an inherited disorder characterized by left ventricular hypertrophy and diastolic dysfunction, and increases the risk of arrhythmias and heart failure. Some patients with HCM develop a dilated phase of hypertrophic cardiomyopathy (D-HCM) and have poor prognosis; however, its pathogenesis is unclear and few pathological models exist. This study established disease-specific human induced pluripotent stem cells (iPSCs) from a patient with D-HCM harboring a mutation in MYBPC3 (c.1377delC), a common causative gene of HCM, and investigated the associated pathophysiological mechanisms using disease-specific iPSC-derived cardiomyocytes (iPSC-CMs). We confirmed the expression of pluripotent markers and the ability to differentiate into three germ layers in D-HCM patient-derived iPSCs (D-HCM iPSCs). D-HCM iPSC-CMs exhibited disrupted myocardial sarcomere structures and an increased number of damaged mitochondria. Ca Show less

Mutually exclusive KIT and PDGFRA mutations are considered to be the earliest events in gastrointestinal stromal tumors (GIST), but insufficient for their malignant progression. Herein, we aimed to identify driver genes and signaling pathways relevant to GIST progression. We investigated genetic profiles of 707 driver genes, including mutations, gene fusions, copy number gain or loss, and gene expression for 65 clinical specimens of surgically dissected GIST, consisting of six metastatic tumors and 59 primary tumors from stomach, small intestine, rectum, and esophagus. Genetic alterations included oncogenic mutations and amplification-dependent expression enhancement for oncogenes (OG), and loss of heterozygosity (LOH) and expression reduction for tumor suppressor genes (TSG). We assigned activated OG and inactivated TSG to 27 signaling pathways, the activation of which was compared between malignant GIST (metastasis and high-risk GIST) and less malignant GIST (low- and very low-risk GIST). Integrative molecular profiling indicated that a greater incidence of genetic alterations of driver genes was detected in malignant GIST (96%, 22 of 23) than in less malignant GIST (73%, 24 of 33). Malignant GIST samples groups showed mutations, LOH, and aberrant expression dominantly in driver genes associated with signaling pathways of PI3K (PIK3CA, AKT1, and PTEN) and the cell cycle (RB1, CDK4, and CDKN1B). Additionally, we identified potential PI3K-related genes, the expression of which was upregulated (SNAI1 and TPX2) or downregulated (BANK1) in malignant GIST. Based on our observations, we propose that inhibition of PI3K pathway signals might potentially be an effective therapeutic strategy against malignant progression of GIST. Show less