BACKGROUND AND AIMS:Focal nodular hyperplasia (FNH) is thought to arise from intrahepatic circulatory disturbances, but its distinction from hepatocellular carcinoma (HCC) and hepatocellular adenoma (HCA) remains challenging, especially in lesions with minimal cytological atypia. CAM5.2 is widely available in routine pathology laboratories, yet its diagnostic significance in hepatic lesions is unclear. We investigated whether CAM5.2 immunostaining visualizes hemodynamic-driven phenotypic changes of hepatocytes and whether its spatial pattern is informative. METHODS:CAM5.2 immunohistochemical staining was analyzed in surgically resected specimens of FNH, HCA (HNF1α-inactivated and inflammatory subtypes), and HCC. The localization, distribution, and spatial regularity of CAM5.2 expression in hepatocytes and bile duct structures were evaluated and correlated with histological features of vascular remodeling. RESULTS:In FNH, CAM5.2 showed a regular staining pattern confined to nodules and aligned along fibrous septa or abnormal vessels, highlighting ductular structures and adjacent hepatocytes. This pattern was absent in background liver parenchyma. In contrast, hepatocellular tumors showed irregular patterns:HNF1α-inactivated HCA exhibited weak focal positivity, inflammatory HCA diffuse staining, and HCC heterogeneous, patchy, or negative staining. CONCLUSIONS:CAM5.2 visualizes hemodynamic-driven, ductular reaction-like phenotypic modulation of hepatocytes. A regular spatial pattern supports circulatory disturbance-related hyperplastic lesions e.g., FNH and aids exclusion of HCC and HCA. J. Med. Invest. 73 : 234-240, February, 2026.

Hepatitis D virus (HDV) is a defective RNA virus requiring hepatitis B virus (HBV) for replication, and co-infection of them significantly accelerates liver inflammation, fibrosis, and hepatocarcinogenesis. Recent studies have reported that the prevalence of HDV infection is extremely high in certain regions, such as Mongolia, exceeding 50% among individuals infected with HBV. To clarify the potential presence of HDV infection in Japan, we retrospectively examined 95 surgically resected cases for HBV-related hepatocellular carcinoma (HCC) at Tokushima University Hospital between 2003 and 2023. Formalin-fixed, paraffin-embedded liver tissues were subjected to immunohistochemistry using an antibody against large and small delta antigens of HDV. Plasma samples from 12 patients were additionally tested by ELISA. As a result, none of the HBV-related HCC cases showed immunoreactivity for HDV antigens in either tumor or non-neoplastic tissues, and all available plasma samples were negative by ELISA. These findings suggest that HDV infection is either absent or extremely rare among patients with HBV-related HCC in this cohort. Our results align with prior seroprevalence estimates and provide histopathological evidence supporting minimal contribution of HDV to liver carcinogenesis in Japan, contrasting sharply with patterns in hyperendemic regions. J. Med. Invest. 73 : 52-54, February, 2026.

OBJECTIVES:The Fat gene family, also known as atypical cadherins, contributes to the formation of planar cell polarity, which determines organ shape, size, and polarity. However, their roles in tooth morphogenesis remain unclear. In this study, the aim was to investigate the spatiotemporal expression patterns of Fat1-Fat4 during murine tooth development. METHODS:Quantitative polymerase chain reaction was performed using total RNA from newborn C57BL/6J murine tissues to determine Fat1-Fat4 expression. In situ hybridization was performed to examine the localization of Fat family transcripts during tooth development from embryonic Day 12.5 to birth. The dental epithelial stem cell line, M3H1, was used as an in vitro differentiation model, and small-interfering-RNA-mediated knockdown of Fat2 was performed to assess its function. Public single-cell RNA-sequence (scRNA-seq) datasets were analyzed to confirm cell-type specificity. RESULTS:All Fat genes were expressed in the teeth, with Fat2 having the highest level among tissues examined. Fat1 was expressed in the epithelial and mesenchymal cells, and Fat2 expression was restricted to the outer enamel epithelium (OEE) and stratum intermedia (SI). Fat3 and Fat4 were expressed in the dental mesenchyme. In M3H1 cells, Fat1 and Fat2 had biphasic expression at undifferentiated and differentiated stages. Fat2 knockdown decreased Sox2 and nephronectin expression, and increased Foxj1 expression. scRNA-seq supported Fat2 specificity in the OEE and SI. CONCLUSION:Fat genes have cell-type-specific and developmentally regulated expression during tooth development. Among them, Fat2 emerges as a novel marker of OEE and SI, and it may contribute to epithelial identity and differentiation during odontogenesis.

Clear cell foci (CCF) are frequently observed in metabolic dysfunction-associated steatohepatitis (MASH) and are considered potential precursor lesions of hepatocyte nuclear factor 1α-inactivated hepatocellular adenoma (H-HCA). To clarify their chronological development, we examined 55 male TSOD mice at 24, 32, 40, and 48 weeks of age using histology and immunohistochemistry for glutamine synthetase (GS), liver fatty acid-binding protein (L-FABP), β-Klotho, and fibroblast growth factor 21 (FGF21). CCF first appeared at 24 weeks and increased markedly with age (from 11% to 81%). All CCF were positive for β-Klotho, and a subset showed FGF21 expression, indicating that CCF represent a hepatocellular state associated with metabolic dysregulation. H-HCA, characterized by GS negativity and reduced L-FABP expression, emerged at 40 weeks and reached an incidence of 29% at 48 weeks. Notably, multiple H-HCA were partially or completely surrounded by β-Klotho-positive CCF, suggesting a morphologic continuum from CCF to H-HCA. Raman spectroscopic analysis demonstrated that CCF exhibit prominent autofluorescence and possess spectral characteristics distinct from both background hepatocytes and tumor tissue, supporting the concept that CCF represent a unique hepatocellular state. These findings indicate that metabolic abnormalities in TSOD mice promote the sequential formation of CCF and H-HCA, establishing this model as a useful platform for studying adenoma development in metabolic liver disease.

Combined alterations of TP53 and CDKN2A are frequently observed in head and neck squamous cell carcinoma (HNSCC); however, their cooperative roles in oral carcinogenesis remain unclear. To investigate their interaction under carcinogenic stress, we generated Cdkn2a knock-in (KI) mice harboring a human-relevant R80X truncating mutation, along with Trp53 loss-of-function (LOF) mutants and exposed them to 4-nitroquinoline-1-oxide (4NQO). Partial loss of Cdkn2a combined with Trp53 heterozygosity was associated with increased STING-related inflammatory signaling and enhanced T-cell/NK-cell-associated immune infiltration, coinciding with delayed malignant progression. Enhanced production of proinflammatory cytokines and chemokines further indicated selective activation of the cGAS-STING-NF-κB axis. Analysis of the TCGA-HNSC cohort showed that combined TP53/CDKN2A alterations significantly separated overall survival and were associated with distinct survival patterns. These findings reveal a previously unrecognized mechanism by which imbalanced p53-RB signaling triggers tumor immunity during the early stages of oral carcinogenesis.

Metabolic dysfunction-associated steatohepatitis (MASH) represents a systems-level disorder driven by the interplay of metabolic stress, bile acid dysregulation, gut microbiota remodeling, and immune activation. Because no single experimental platform recapitulates the full spectrum of human disease—from steatosis and fibrosis to spontaneous hepatocellular carcinoma (HCC)—model selection must be guided by the dominant biological mechanism under investigation rather than by phenotypic similarity alone. This review proposes a mechanism-oriented framework for model selection, illustrated by representative experimental systems, including the intensified high-fat/high-cholesterol diet supplemented with cholate (iHFC diet) and Tsumura–Suzuki obese diabetic (TSOD) and non-obese (TSNO) mouse models. The iHFC diet provides a reproducible platform for interrogating the bile acid–microbiota–macrophage axis in fibro-inflammatory progression, whereas TSOD mice represent a valuable system in which spontaneous MASH–HCC development can emerge under chronic metabolic imbalance without engineered oncogenic triggers. TSNO mice serve as a controlled background for dissecting bile acid-dependent susceptibility. We further integrate hepatocyte mitochondrial dysfunction, immune remodeling, and stellate cell activation into this triadic framework and position additional diet-induced, genetic, and in vitro models within a complementary translational landscape. Together, this mechanism-centered framework provides a practical roadmap for rational model selection and enhanced translational precision in MASH and metabolic hepatocarcinogenesis research.

Human embryonic carcinoma (hEC) cells are derived from teratocarcinomas, exhibit robust proliferation, have a high differentiation potential, are the malignant counterparts of human embryonic stem cells (hESCs), and are considered hESC-like. The chromosomal passenger complex (CPC), made up of the microtuble binding protein Borealin, the kinase Aurora-B, the CPC-stabilizing inner centromere protein (INCENP), and the inhibitor of apoptosis family member Survivin, regulates cell division and is active exclusively during mitosis in somatic cells. The anaphase-promoting complex/cyclosome and its cofactor Cdh1 (APC/C Cdh1 ) is a ubiquitylating complex that catalyzes the degradation of Aurora-B and Borealin in somatic cells but has low activity during interphase in hESCs. Here, we found that Borealin and Aurora-B exhibited sustained stability throughout the cell cycle of hEC cells due to low APC/C Cdh1 activity. In contrast with somatic cells, CPC activity persisted across the cell cycle of hEC cells because of diminished APC/C Cdh1 activity. Disrupting the CPC complex by depleting its constituents triggered spontaneous differentiation in hEC cells. As hEC cells differentiated, APC/C Cdh1 activation curtailed CPC activity. Inactivating the CPC by pharmacologically inhibiting Aurora-B induced hEC cell differentiation by activating the epithelial-to-mesenchymal transition (EMT) program. Hence, APC/C Cdh1 -mediated termination of CPC activity triggered hEC cell differentiation. Collectively, these findings demonstrate a role for the CPC in governing hESC cell fate.

The high rate of chronic hepatitis, including hepatitis B, C and D, in Mongolia creates a large health burden of advanced liver disease. This includes liver failure and the highest incidence rate of hepatocellular carcinoma (HCC) worldwide. In the present study, we histopathologically examined 69 recent cases of HCC from the Mongolian National Center for Pathology, which collects specimens from across the country. The background liver histology of HCC exhibited a bimodal distribution, with one peak corresponding to advanced liver fibrosis and another to mild liver fibrosis. The fibrosis severity negatively correlated with age. Additionally, the frequency of poorly differentiated tumors was significantly higher in the HCC with early stage of fibrosis. A comparison of the pathological characteristics of HCC in urban and rural areas showed that poorly differentiated tumors were highly prevalent in urban areas. The characteristics of HCC in Mongolia are different from those in other countries, suggesting that the causes of liver disease are not only related to viruses but also other factors that depend on the region. This study will provide insight into what research is needed next for liver cancer control in Mongolia. J. Med. Invest. 72 : 47-53, February, 2025.

Background: Viral hepatitis, particularly hepatitis B (HBV) and hepatitis C (HCV), is highly prevalent in Mongolia. Moreover, Mongolia has the highest prevalence of hepatitis delta virus (HDV) globally, with over 60% of HBV-infected individuals also co-infected with HDV. Since HBV/HDV infections accelerate liver disease progression more compared to HBV infection alone, urgent national health measures are required. Method: This study presents a clinicopathological analysis of 49 hepatocellular carcinoma cases surgically resected at the Mongolia–Japan Hospital of the Mongolian National University of Medical Sciences. Results: HBV infection was found in 27 (55.1%) cases of all HCC cases. Immunohistochemical staining of the liver revealed that 14 (28.6%) cases were HDV antigen-positive in the HCC cases. HDV-positive cases exhibited significantly higher inflammatory activity compared to HDV-negative cases, with lymphocytic infiltrates predominantly composed of CD4-positive cells. Furthermore, HDV-positive cells were spatially distinct from HBs antigen-positive cells, suggesting that HDV-infected cells may interfere with HBV replication. No significant differences in fibrosis or in tumor characteristics were observed between the HDV-positive and negative cases. Early diagnosis of HBV/HDV infections is essential for appropriate treatment and to prevent further domestic transmission of the virus. However, routine testing for HDV infection is rarely conducted in Mongolia. Since HDV-positive cells are morphologically indistinguishable from surrounding HDV-negative cells, routine histopathological analysis may not be sufficient enough to detect HDV infection. Conclusions: Based on this clinicopathological study, CD4 and CD8 immunostaining can be considered an adjunctive diagnostic tool in cases with significant lymphocytic infiltration and hepatocellular damage. Additionally, HDV screening using blood and tissue samples may be recommended to ensure accurate diagnosis.

Cholangiolocellular carcinoma, a subtype of peripheral-type intrahepatic cholangiocarcinoma, is a relatively rare primary liver tumor. This case report describes a patient with cholangiolocellular carcinoma that was initially misdiagnosed as hemangioma, and ultimately underwent complete tumor resection after a seven-year follow-up period. A 72-year-old female patient with a history of chronic hepatitis C was followed up regularly at the hospital. Computed tomography (CT) performed seven years prior had detected a small tumor (12 mm) with radiographic characteristics suggestive of hemangioma. The tumor increased in size from 12 to 32 mm over the next seven years. On CT, the tumor showed poor central enhancement, indicating reduced blood flow in the central region. Due to the suspicion of malignancy, partial surgical resection was performed. Pathological examination confirmed a diagnosis of cholangiolocellular carcinoma. The carcinoma exhibited vascular invasion and a broad central fibrous area with hyalinization, lacking epithelial cells, and marked by venous obstruction. This case underscores the challenge of distinguishing cholangiolocellular carcinoma from hemangioma, particularly in small tumors with similar radiological features. The findings highlight the importance of employing additional diagnostic modalities such as ultrasound and magnetic resonance imaging, as well as the necessity of biopsy when suspicion arises. This case also describes the unique finding of a central fibrous area without tumor cells, which may have resulted from localized circulatory disturbances potentially caused by tumor embolism in the portal and hepatic veins. This pathological finding provides valuable insights into the nature of this rare tumor.

BACKGROUND:Poly (A) binding protein interacting protein 1 (PAIP1) has been shown to causally contribute to the development and progression of cancer. However, the mechanisms of the PAIP1 regulation in tumor cells remain poorly understood. RESULTS:Here, we used a recently developed UV cross-linking and RNA immunoprecipitation method (iRIP-seq) to map the direct and indirect interaction sites between PAIP1 and RNA on a transcriptome-wide level in HeLa cells. We found that PAIP1 not only binds to 3'UTRs, but also to pre-mRNAs/mRNAs with a strong bias towards the coding region and intron. PAIP1 binding sites are enriched in splicing enhancer consensus GA-rich motifs. RNA-seq analysis revealed that PAIP1 selectively modulates the alternative splicing of genes in some cancer hallmarks including cell migration, the mTOR signaling pathway and the HIF-1 signaling pathway. PAIP1-regulated alternative splicing events were strongly associated with PAIP1 binding, demonstrating that the binding may promote selection of the nearby splice sites. Deletion of a PAIP1 binding site containing seven repeats of GA motif reduced the PAIP1-mediated suppression of the exon 6 inclusion in a VEGFA mRNA isoform. Proteomic analysis of the PAIP1-interacted proteins revealed the enrichment of the spliceosome components and splicing factors. CONCLUSIONS:These findings suggest that PAIP1 is both a polyadenylation and alternative splicing regulator, that may play a large role in RNA processing via its role in alternative splicing regulation.