Search Results (4,566)

The mammalian intestinal epithelium is a rapid self-renewal tissue in the body, serving as a critical interface between the host and the external environment. Maintaining the intestinal epithelium homeostasis requires precise coordination of cellular processes, including proliferation, migration, differentiation, autophagy, and cell-to-cell interaction. An increasing body of evidence has unveiled circular RNAs (circRNAs) as abundant and stable regulatory molecules that play pivotal roles in the intestinal epithelial biology and are intimately involved in many aspects of gut mucosal pathologies. Unlike linear RNAs, circRNAs form covalently closed loop structures through back-splicing events, conferring remarkable stability and resistance to exonucleolytic degradation. circRNAs regulate the growth of the intestinal mucosa, injury-induced epithelial regeneration, and gut barrier function via diverse mechanisms, including interactions with microRNAs and RNA-binding proteins. Deregulated circRNAs are implicated in the pathogenesis of various gut mucosal disorders such as inflammatory bowel disease and malignancies. In this review, we highlight pathobiological functions and mechanisms of intestinal epithelium-enriched circRNAs, particularly circHIPK3, Cdrlas, and circPABPN1, in the epithelium homeostasis and pathologies and also discuss potential clinical application of circRNAs as diagnostic biomarkers and therapeutic targets in patients with critical diseases. Full article

The olfactory and gustatory systems are essential for survival, enabling organisms to detect and respond to environmental chemical cues. Although canonical signaling pathways in smell and taste have been well defined, growing evidence highlights additional ion channel families as key modulators of sensory responses. Recent studies identify the anoctamin, transmembrane channel-like, and TMEM63 superfamily as a class of non-canonical sensory effectors that regulate signal amplification, excitability, and epithelial homeostasis across chemosensory systems. In the mammalian olfactory epithelium, specific anoctamin channels enhance odor-evoked responses and contribute to tissue homeostasis. In the gustatory system, salt detection is now understood to involve multiple parallel signaling pathways, with TMC4 emerging as a key contributor to high-salt and salt-associated taste sensing. These channel families are evolutionarily conserved across species, including C. elegans, Drosophila, and aquatic organisms, where they mediate chemosensation, mechanosensation, humidity detection, and osmoregulation. This functional versatility is supported by a shared structural architecture that enables selective ion conduction and, in some members, regulated phospholipid scrambling. This review proposes a unifying framework in which anoctamin and transmembrane channel-like proteins act as multimodal regulators of sensory signaling, linking environmental cues to cellular excitability and microenvironmental control and highlighting new principles of chemosensory organization and therapeutic potential. Full article

Background: Corneal organoids derived from pluripotent stem cells have emerged as powerful tools for studying corneal development, disease modeling, and regenerative medicine applications. While previous protocols have successfully generated corneal tissue structures, there remains a need for three-dimensional models that recapitulate the complex cellular architecture and diversity of native human cornea. Methods: We developed a modified spontaneous three-dimensional corneal organoid model using human embryonic stem cells (hESCs) through an adapted Self-formed Ectoderm Autonomous Multi-zone (SEAM) protocol. hESCs were cultured as spheroids in ultra-low-binding plates under normoxic conditions and differentiated over 7–8 weeks. Organoids were characterized using immunofluorescence staining for corneal-specific markers and single-cell RNA sequencing to assess cellular composition and gene expression patterns. Results: Approximately 20% of organoids developed transparent regions characteristic of corneal tissue by day 30 of differentiation. Immunofluorescence analysis revealed spatially organized expression of corneal markers, including ZO-1 and E-cadherin in the outermost epithelial layers, P63α-positive putative limbal stem cells at the epithelial–stromal interface, vimentin-positive stromal cells in the interior, and laminin-1 deposition that suggests Bowman’s membrane formation. The organoids expressed cornea-specific keratins (K3, K12, and K15) and the master regulator PAX6 in appropriate cellular compartments. Single-cell RNA sequencing identified 18 distinct cell clusters, including three corneal epithelium subclusters with differential expression of MUC16, KRT12, and ΔNp63α, two stromal populations with distinct inflammatory profiles, and a corneal endothelium cluster. Transcriptomic analysis confirmed expression of key corneal genes, including AQP3, CDH1, multiple keratins, mucins, and extracellular matrix components (HAS2, CD34, CD44, COL8A1, and KERA). Conclusions: This three-dimensional spheroid-based putative corneal organoid model successfully recapitulates the multilayered architecture and cellular diversity of human cornea, including stratified epithelium, putative limbal stem cells, stroma, and endothelium in spatially appropriate arrangements. The model demonstrates molecular signatures consistent with native corneal tissue and provides a valuable platform for studying corneal development, disease mechanisms, and potential therapeutic applications. Future optimization to improve organoid formation efficiency and functional maturation will enhance the utility of this system for both basic research and translational medicine. Full article

Purpose: A high-salt extracellular environment promotes fibrosis in multiple organs by inducing oxidative stress, fibroblast activation, and extracellular matrix remodeling. In the lung, sodium accumulation may result from impaired epithelial ion transport. Transforming growth factor-β1 (TGF-β1), a key profibrotic cytokine, downregulates epithelial sodium and chloride channels, promoting sodium retention and fibrotic remodeling. This study investigated whether antifibrotic drugs can prevent TGF-β1-induced suppression of sodium channel expression in the lung epithelium. Methods: Human A549 alveolar epithelial cells and primary alveolar epithelial cells were cultured with or without TGF-β1 in the presence or absence of nintedanib or pirfenidone. Expression of epithelial sodium channel (ENaC) subunits (SCNN1A, SCNN1B, SCNN1G, SCNN1D) and CFTR was analyzed. In vivo, lung tissues from TGF-β1 transgenic mice and wild-type controls were examined following intranasal administration of pirfenidone. Results: TGF-β1 markedly reduced the expression of all ENaC subunits and CFTR in vitro. Nintedanib prevented suppression of SCNN1A, SCNN1D, and SCNN1G, whereas pirfenidone prevented suppression of SCNN1A, SCNN1B, and SCNN1G. In TGF-β1 transgenic mice, Scnn1a, Scnn1b, and Scnn1g expression was significantly decreased compared with wild-type controls. Pirfenidone administration dose-dependently restored expression of these ENaC subunits in vivo. Conclusions: Antifibrotic drugs partially prevent TGF-β1-induced suppression of epithelial sodium channels, preserving epithelial ion homeostasis. Restoration of ENaC expression may represent a novel mechanism by which antifibrotic therapy mitigates sodium-associated lung fibrosis. Full article

The detailed mechanism and sequence by which tick-borne flaviviruses (TBFVs), such as Langat virus (LGTV), infect and disseminate in arthropod hosts remain undefined. To begin characterizing these processes, we used artificial membrane feeding chambers to feed adult Ixodes scapularis ticks with blood containing LGTV. At 24, 48, 72, and 96 hours (h) after attachment, we removed and dissected the partially fed ticks to obtain the midgut and salivary glands. Histology confirmed infection in cells of the digestive epithelium lineage; infection was noted in midgut generative cells and the more differentiated functional digestive cells over the course of feeding. The viral envelope (E) protein, nonstructural protein 3 (NS3), and double-stranded RNA (dsRNA) were readily detected in these cells by 48 h after infection. Parallel analysis indicated that cells in salivary gland acini were also infected by 48 h, where virus target cells appeared to be the granular cells in acini types II and III. Thus, both salivary glands and midgut showed direct evidence of infection by 48 h. Although viral staining was not observed at 24 h, when organs were removed at 24 h and individually cultured ex vivo, the virus was detected. Taken together, our results provide evidence of LGTV infection in both the salivary glands and midgut within the first 24 h of a blood meal. The findings should prompt a reevaluation of the systemic dissemination of TBFV in infected ticks. Full article

Aflatoxin B1 (AFB1) is a prevalent and highly toxic mycotoxin in the food and feed chain and can directly injure the intestinal epithelium. Yet, its upstream determinants linking epithelial stress to cytotoxicity remain insufficiently defined. Here, we used porcine intestinal epithelial IPEC-J2 cells to characterize AFB1-induced cytotoxic and transcriptomic responses and to determine the role of the tight-junction scaffold, Cingulin-like 1 (CGNL1), a candidate gene identified through genome-scale CRISPR knockout library screening. The results showed that AFB1 exposure reduced cell viability in a dose-dependent manner and induced oxidative stress. RNA-seq profiling analysis revealed broad transcriptional remodeling, with activation of inflammatory pathways (including NF-κB and JAK–STAT signaling). Based on our constructed CGNL1-knockout IPEC-J2 cell line (CGNL1-KO IPEC-J2) using CRISPR/Cas9, it was found that CGNL1 deficiency markedly alleviated AFB1-induced cytotoxicity and oxidative stress. Comparative transcriptomics analysis showed that CGNL1 knockout attenuated AFB1-triggered aberrant expression of some CGNL1-dependent AFB1-responsive genes related to immune response under AFB1 challenge. Together, these findings identify CGNL1 as a potential modulator of epithelial susceptibility to AFB1 and support its involvement in the regulation of toxin-induced oxidative response. Full article

Fucosylation, the enzymatic addition of fucose residues to glycans, modulates receptor signalling and cellular identity in the intestinal epithelium. Its role as an integrative determinant of cancer cell fate in colorectal cancer (CRC) remains undefined. Transcriptomic and clinicopathological data from 976 CRC patients across three independent cohorts (TCGA-CRC, CPTAC2-CRC, Sidra-LUMC) were analysed. A curated fucosylation gene set was used to calculate tumour fucosylation scores. Associations with histogenetic status, genomic features, microenvironmental phenotypes, drug resistance programmes, and survival were evaluated using gene set enrichment analysis, multivariable Cox regression, and integrated molecular subtyping. High-fucosylation tumours exhibited elevated epithelial differentiation, MSI-H/BRAF-mutant enrichment, oxidative phosphorylation dominance, the complete absence of EMT and invasion programmes, and favourable prognosis (HR = 0.633, 95% CI: 0.470–0.853, p = 0.003). Low-fucosylation tumours demonstrated mesenchymal phenotypes, TP53 mutations, chromosomal instability, comprehensive multi-family RTK signalling, immune-excluded microenvironments, and poor outcomes. Distinct multidrug resistance programmes emerged: drug efflux in low-fucosylation tumours versus xenobiotic sensing, target bypass, and drug sequestration in high-fucosylation tumours. Tumour fucosylation status defines two fundamentally distinct CRC cell states with mutually exclusive engagement of invasion programmes, metabolic pathways, immune phenotypes, and resistance mechanisms. Fucosylation represents an independent prognostic biomarker and integrative determinant of cancer cell fate, with significant implications for risk stratification and personalised therapeutic strategies. Full article

The cornea of the dromedary camel is essential for maintaining ocular clarity and protecting the eye in dry, dusty, and thermally stressful environments. Aquaporins are membrane channels that facilitate water transport, and AQP1 has been widely implicated in corneal fluid homeostasis in several species. The present work investigated, for the first time, the regional distribution of AQP1 in the camel cornea. Corneas collected from twelve healthy adult camels after slaughter were divided into nine anatomical regions: central (C), middle dorsal (MD), middle ventral (MV), middle nasal (MN), middle temporal (MT), peripheral dorsal (PD), peripheral ventral (PV), peripheral nasal (PN), and peripheral temporal (PT). Histological examination and immunohistochemistry were combined with digital morphometry to assess corneal layer thickness and AQP1 localization. AQP1 labeling was identified in the corneal epithelium, stromal keratocytes, and endothelium. Epithelial staining differed among regions and was most pronounced in the peripheral nasal region, whereas stromal keratocytes and endothelial cells showed strong and relatively uniform immunoreactivity. These findings indicate that AQP1 is broadly expressed in the camel cornea and likely contributes to regional control of hydration and tissue maintenance in an arid-adapted species. Full article

The objective of this study was to investigate the effects of supplemental starter feeding on the development of the ruminal epithelium in suckling yak calves using transcriptomic analysis. Twenty healthy one-month-old male yak calves with similar body weights were selected and randomly assigned to two groups. The pre-feeding adaptation period lasted 14 days, followed by a 120-day experimental feeding period. At the end of the trial, five calves from each group were slaughtered, and samples of abomasum tissue and ruminal contents were collected for subsequent analyses. The results demonstrated that early concentrate supplementation markedly increased the final body weight and ruminal NH₃-N concentration of calves in the RAS group compared with the control (RA) group (p < 0.05). Similarly, dry matter intake and ruminal microbial protein (MCP) content were significantly higher in the RAS group (p < 0.05). In contrast, the concentration of acetic acid in ruminal fluid was significantly higher in the RA group, whereas valeric acid concentration was higher in the RAS group. Furthermore, ruminal TNF-α, TNF-γ, and IL-2 concentrations were significantly elevated in the RAS group (p < 0.05), suggesting enhanced ruminal immune function. Transcriptomic analysis revealed that both up- and down-regulated gene expression contributed to the morphological development and overall health of the ruminal epithelium. Up-regulated genes were enriched in pathways related to chemical carcinogenesis, cytochrome P450 metabolism, steroid hormone biosynthesis, retinol metabolism, ascorbate and aldarate metabolism, drug metabolism-cytochrome P450, pentose and glucuronate interconversions, ovarian steroidogenesis, and porphyrin and chlorophyll metabolism. Conversely, down-regulated genes were mainly associated with cytokine–cytokine receptor interactions, mineral absorption, arachidonic acid metabolism, and viral protein interactions with cytokine receptors. Overall, early supplementation with concentrate feed enhanced the expression of genes associated with ruminal epithelial development, improved immune responses, and promoted better growth performance in suckling yak calves. Full article

Iodoacetic acid (IAA), a highly cytotoxic disinfection byproduct commonly detected in drinking water, poses a potential risk to female reproductive health. The direct molecular mechanisms underlying its effects on the reproductive system epithelium remain unclear. This study demonstrates that IAA induces glycational stress in primary porcine uterine (UECs) and oviduct epithelial cells (OECs), representing an early event contributing to extensive cellular toxicity. IAA exposure inhibited Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) enzymatic activity and promoted the accumulation of advanced glycation end products (AGEs) Nε-(carboxymethyl)lysine (CML), triggering mitochondrial dysfunction, redox imbalance, calcium dyshomeostasis, and endoplasmic reticulum stress. These disturbances activated a dysregulated signaling network involving the p38 MAPK, AKT, and NF-κB pathways, ultimately causing G1/S cell cycle arrest and apoptosis. Notably, pretreatment with the AGE inhibitor pyridoxamine reduced CML accumulation, restored mitochondrial function, and alleviated apoptotic cell death. These findings identify glycational stress as a key initiating mechanism for IAA-induced reproductive epithelial toxicity, providing mechanistic insight into the potential health risks of environmental disinfection byproducts. Full article

Crude glycerin (CG) is an energy-dense ingredient capable of partially or fully replacing corn in high-concentrate diets for ruminants. Its rapid ruminal absorption, favorable fermentative profile, and absence of lactic acid production may support safer adaptation to intensive feeding systems. The aim of this study was to evaluate the effects of replacing corn with CG (300 g/kg DM) on growth performance, feeding behavior, rumen morphometry, and proteomic responses of ruminal papillae in feedlot lambs. Sixty-five Santa Inês × Dorper lambs were assigned to either a control diet or a diet containing CG and were evaluated during pre-adaptation, adaptation, and finishing phases. Replacing corn with CG slightly reduced average daily gain (p = 0.02), without affecting final body weight, dry matter intake, or carcass yield (p > 0.05). Lambs fed CG exhibited lower subcutaneous fat thickness (p = 0.04) and reduced neutral detergent fiber intake during feeding behavior assessments (p < 0.05). Rumen papillae showed higher mitotic index and greater epithelial activity throughout the feedlot period, regardless of treatment. Proteomic analysis revealed upregulation of proteins involved in epithelial integrity (Claudin-1, Occludin) and mitochondrial energy metabolism (ATP synthase β, glycerol kinase) in CG-fed lambs, alongside downregulation of proteins related to oxidative stress and inflammation (HSP70, Annexin A1, SOD1, Peroxiredoxin-6). These findings demonstrate that CG promotes beneficial molecular adaptations in the ruminal epithelium without compromising carcass traits, supporting its use as a safe, functional, and sustainable alternative to corn in lamb finishing systems. Full article

Chemotherapy-induced mucositis (CIM) is a dose-limiting toxicity of cancer therapy that is mainly associated with mitochondrial dysfunction in epithelial cells. We investigated whether GV1001, a mitochondrial protective peptide from human telomerase reverse transcriptase (hTERT), attenuates 5-fluorouracil (5-FU)-induced mucositis in a murine model. 5-FU induced notable mortality, leukopenia, and mucositis in the gastrointestinal (GI) tract, including tongue, esophagus and small intestine. It promoted epithelial–mesenchymal transition (EMT), nuclear factor kappa-B (NF-κB) activation, systemic and mucosal inflammation, DNA damage, impaired cell proliferation, and apoptosis throughout the GI tract. GV1001 blocked 5-FU–associated mortality, significantly attenuated leukopenia, and notably prevented mucositis. GV1001 also suppressed 5-FU-induced DNA damage, EMT, loss of proliferative capacity, apoptosis, and NF-κB activation in mucosal epithelium. In normal human keratinocytes, 5-FU inhibited the cell proliferation, disrupted mitochondrial function, as evidenced by reduced mitochondrial membrane potential, increased reactive oxygen species (ROS) production, impaired electron transport chain (ETC) complex integrity, decreased ATP synthesis, and cytochrome c release into the cytosol. GV1001 markedly mitigated these 5-FU-induced mitochondrial defects. Taken together, GV1001 mitigates CIM by most likely preserving mitochondrial integrity and function, supporting its potential as a strategy to prevent cancer chemotherapy-associated mucosal injury in patients. Full article

Prominin-1 (Prom1/CD133) has long been recognized as a structural determinant of photoreceptor outer segment (OS) morphogenesis, yet rapidly accumulating evidence extends its role to retinal pigment epithelium (RPE) homeostasis, encompassing autophagy–lysosomal flux, outer segment phagocytosis, mitochondrial function, and regulation of inflammatory stress. This review synthesizes mechanistic and transcriptomic insights that position PROM1 as a central regulator of photoreceptor and RPE integrity, reframing Prom1 disease as a multi-compartment retinal disorder relevant to both inherited retinal dystrophies (IRDs) and atrophic age-related macular degeneration (aAMD). We develop a dual-axis conceptual model in which Prom1 dysfunction can initiate pathology in either the photoreceptors (OS morphogenesis failure) or the RPE, including impaired autophagic flux, lysosomal activity, defective phagocytosis, and Epithelial-Mesenchymal Transition (EMT)-like de-differentiation, with secondary cross-compartmental degeneration. Clinically, autosomal-dominant missense variants associate with macular or cone-rod dystrophy, whereas biallelic truncating/splice-site mutations drive early-onset rod–cone disease and panretinal/RPE atrophy, illustrating genotype–phenotype diversity. By integrating recent high-resolution transcriptomic data from Prom1-deficient RPE cells with long-standing insights into photoreceptor biology, we highlight converging pathways of degeneration that challenge a photoreceptor-centric view and unify disparate phenotypes within a single molecular framework. These insights broaden the therapeutic landscape, advancing gene augmentation and pathway-targeted strategies to preserve RPE integrity, sustain photoreceptor function, and modify disease course in PROM1-associated IRDs and atrophic AMD. Full article

Purpose: Neuroinflammation and oxidative stress are increasingly recognized as central, interconnected drivers of neurodegeneration in the visual system. This review examines the pathogenic mechanisms shared across glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and Alzheimer’s disease (AD), and evaluates the therapeutic rationale for targeting both pathways simultaneously. Methods: A narrative review of peer-reviewed literature was conducted using PubMed. Searches included the following MeSH terms: neuroinflammation, oxidative stress, retinal neurodegeneration, microglia, Müller glia, mitochondrial dysfunction, glaucoma, age-related macular degeneration, diabetic retinopathy, and Alzheimer’s disease. Priority was given to original research, systematic reviews, and high-impact publications from 2000 through 2025. However, seminal foundational works were included regardless of publication date. Studies were selected based on relevance to glial activation, mitochondrial dysfunction, reactive oxygen and nitrogen species, and disease-specific neuronal outcomes. Results: Across all four diseases, persistent microglial and Müller glial activation, mitochondrial electron transport chain dysfunction, and excess reactive oxygen species (ROS) and reactive nitrogen species (RNS) production form a self-amplifying feed-forward loop that accelerates neuronal injury. In glaucoma, these mechanisms drive intraocular pressure-independent retinal ganglion cell loss. In AMD and DR, lipid dysregulation, complement activation, and chronic hyperglycemia sustain oxidative-inflammatory injury to the retinal pigment epithelium, photoreceptors, and neurovasculature. In AD, retinal amyloid deposition and oxidative burden mirror cortical pathology, positioning the retina as a noninvasive biomarker site. Conclusions: Neuroinflammation and oxidative stress constitute unifying upstream mechanisms across major vision-threatening neurodegenerative diseases. Combination therapeutic strategies that simultaneously modulate glial activation and restore redox homeostasis may offer superior neuroprotective efficacy compared to approaches targeting isolated downstream mediators. Full article

In the hepatobiliary system, the majority of neoplasms grow within the hepatic parenchyma; however, some arise, grow, and/or spread within the lumen of the intrahepatic large bile ducts and the perihilar/distal bile ducts (collectively referred to as large bile ducts), representing specialized ductal organs associated with unique peribiliary glands and being distinct from the intrahepatic small bile ducts and bile ductules embedded within the hepatic parenchyma. Precursors of cholangiocarcinoma (CCA) arising within the lumen of large bile ducts have recently been proposed. Neoplasms growing and spreading within the lumen of large bile ducts have been categorized into four groups and are discussed here in light of updated pathological findings. (i) Precursor(s) of CCA arising in the large bile ducts (large-duct-type intrahepatic CCA and perihilar/distal CCA): These precursors include high-grade biliary intraepithelial neoplasia (BilIN), intraductal papillary neoplasm of the bile duct (IPNB), and intraductal oncocytic papillary neoplasm (IOPN). High-grade BilIN presents as a flat, microscopic lesion with dysplastic cytoarchitectural alterations and grows along the luminal surface of large bile ducts, whereas the latter two present as grossly visible polypoid or tumorous lesions composed of papillary, villous, or tubular proliferation of neoplastic epithelium with delicate fibrovascular cores. These lesions may eventually progress to invasive CCA. Intraductal tubulopapillary neoplasm of the bile duct (ITPN), previously categorized as another precursor of CCA arising in large bile ducts, appears to represent a heterogeneous group of neoplasms with respect to progression and presumed cell of origin. Some ITPNs are frequently associated with nodular invasive carcinoma resembling small-duct-type intrahepatic CCA (SD-iCCA) and share genetic alterations with SD-iCCA; such cases may arise in association with small bile ducts or bile ductules. In contrast, other ITPNs exhibit cystic changes with tubulopapillary features and may arise in association with peribiliary glands or cysts. (ii) Secondary growth and spread of biliary neoplasms: This category comprises several patterns. First, intraepithelial neoplastic spread directly and continuously from the primary neoplastic lesion is observed in almost all cases of high-grade BilIN, IPNB, and IOPN; it spreads laterally along the luminal surface of the proximal and distal bile ducts and extends vertically into the adjacent peribiliary glands. Intraluminal cast-like spread in the bile ducts adjacent to the primary neoplastic lesion also occurs in some precursor lesions, particularly in ITPN. Implantation of a biliary neoplasm from one part of the biliary tract to another results in discontinuous, multifocal biliary neoplasms, particularly in IPNB, and occurs mainly in the distal bile ducts relative to the main tumor. Multicentric tumorigenesis may contribute to the multifocal development of precursors and CCA in the bile ducts. The accumulation of additional genetic alterations, beyond the common mutations detected in primary tumors, may contribute to metachronous recurrence of CCA after curative resection of the primary biliary tumor. Cancerization of the duct (COD) by CCA may also contribute to secondary growth and spread within the bile duct lumen. Specifically, flat-type cancerization of pre-existing non-neoplastic bile ducts, resembling high-grade BilIN, occurs in approximately one-third of hilar CCA cases. Intraductal polypoid, cast-like cancerization within the lumen of adjacent bile ducts, resembling polypoid precursors of CCA, can also occur in approximately one-tenth of SD-iCCA. (iii) Prominent intraductal polypoid growth of invasive CCA: Invasive CCA rarely presents with predominant intraductal polypoid carcinoma that is continuous with periductal infiltrating CCA; this pattern can be referred to as polypoid invasive CCA. (iv) Nonbiliary neoplasms presenting bile duct tumor thrombus (BDTT): BDTT associated with hepatocellular carcinoma and with extrahepatic malignancies extending into the bile duct lumen can mimic the intraluminal growth and spread patterns of the above-mentioned biliary neoplasms. In conclusion, intraluminally growing biliary neoplasms in the large bile ducts comprise a heterogeneous group that can be reasonably classified into four categories. This categorization may facilitate understanding of these intrabiliary growing neoplasms. Full article