Glypican-3-targeted macrophages delivering drug-loaded exosomes offer efficient cytotherapy in mouse models of solid tumours.

Cytotherapy is a strategy to deliver modified cells to a diseased tissue, but targeting solid tumours remains challenging. Here we design macrophages, harbouring a surface glypican-3-targeting peptide and carrying a cargo to combat solid tumours. The anchored targeting peptide facilitates tumour cell recognition by the engineered macrophages, thus enhancing specific targeting and phagocytosis of tumour cells expressing glypican-3. These macrophages carry a cargo of the TLR7/TLR8 agonist R848 and INCB024360, a selective indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, wrapped in C16-ceramide-fused outer membrane vesicles (OMV) of Escherichia coli origin (RILO). The OMVs facilitate internalization through caveolin-mediated endocytosis, and to maintain a suitable nanostructure, C16-ceramide induces membrane invagination and exosome generation, leading to the release of cargo-packed RILOs through exosomes. RILO-loaded macrophages exert therapeutic efficacy in mice bearing H22 hepatocellular carcinomas, which express high levels of glypican-3. Overall, we lay down the proof of principle for a cytotherapeutic strategy to target solid tumours and could complement conventional treatment.

Intelligent optimal control model of selection pressure for rapid culture of aerobic granular sludge based on machine learning and simulated annealing algorithm.

Aerobic Granular Sludge (AGS) has advantages over Activated sludge (AS) but faces challenges with long granulation periods. In this study, a novel grey-box model is devised to optimize the cultivation of AGS to shorten the formation time. This model is based on an existing white-box model. The modeling process starts with the application of four sensitivity analysis methods to assess the 12 model metrics selected. Subsequently, 12 prediction models were constructed by combining the six Machine learning (ML) algorithms and integrated algorithms, with the best performance selected (R2 = 0.98). Finally, an AGS selection pressure planning model was designed in conjunction with a simulated annealing (SA) algorithm to guide AGS training. The results demonstrate that AGS formation could be achieved within four days under the model's optimal control. Therefore, the establishment of this model provides a new technique for the cultivation of AGS.

Computational Insights into the Non-Heme Diiron Alkane Monooxygenase Enzyme AlkB: Electronic Structures, Dioxygen Activation, and Hydroxylation Mechanism of Liquid Alkanes.

Alkane monooxygenase (AlkB) is a membrane-spanning metalloenzyme that catalyzes the terminal hydroxylation of straight-chain alkanes involved in the microbially mediated degradation of liquid alkanes. According to the cryoEM structures, AlkB features a unique multihistidine ligand coordination environment with a long Fe-Fe distance in its active center. Up to now, how AlkB employs the diiron center to activate dioxygen and which species is responsible for triggering the hydroxylation are still elusive. In this work, we constructed computational models and performed quantum mechanics/molecular mechanics (QM/MM) calculations to illuminate the electronic characteristics of the diiron active center and how AlkB carries out the terminal hydroxylation. Our calculations revealed that the spin-spin interaction between two irons is rather weak. The dioxygen may ligate to either the Fe1 or Fe2 atom and prefers to act as a linker to increase the spin-spin interaction of two irons, facilitating the dioxygen cleavage to generate the highly reactive Fe(IV)═O. Thus, AlkB employs Fe(IV)═O to trigger the hydrogen abstraction. In addition, the previously suggested mechanism that AlkB uses both the dioxygen and Fe-coordinated water to perform hydroxylation was calculated to be unlikely. Besides, our results indicate that AlkB cannot use the Fe-coordinated dioxygen to directly trigger hydrogen abstraction.

Spectra of well-differentiated neuroendocrine lesions in the extrahepatic biliary system: a case series.

AIMS: Neuroendocrine tumours (NETs) occurring in the extrahepatic biliary system are exceedingly rare. While NETs typically manifest as mass lesions, the occurrence of microscopic neuroendocrine cell proliferation without a distinct mass remains undocumented at this location. This study aims to characterise the clinicopathological features of a series of well-differentiated neuroendocrine lesions involving the extrahepatic biliary tree, including mass forming NETs and microscopic non-mass-forming neuroendocrine cell proliferation, designated neuroendocrine cell micronests (NCMs). METHODS AND RESULTS: Surgical resections of NETs/NCMs involving the extrahepatic bile ducts and gallbladder were identified from electronic pathology databases among seven institutions spanning from January 2011 to September 2023. Clinical and histological findings were recorded. Ten patients (four female, six male: age range = 34-75 years) were included in the study. Histopathological examination revealed visible mass-forming lesions in four cases (1.6-14.0 cm in size), identified in the gallbladder (n = two) or extrahepatic bile duct (n = two), all diagnosed as well-differentiated NETs. The remaining six cases revealed incidental non-mass-forming NCMs in either the cystic duct (n = two), common bile duct (n = three) or gallbladder (n = one), ranging from < 0.1 to 0.4 cm; four were associated with biliary lithiasis. No evidence of metastasis or recurrence was seen in the follow-up period (range = 0.1-11.2 years). CONCLUSIONS: This study highlights the spectrum of extrahepatic biliary well-differentiated neuroendocrine lesions, ranging from incidental microscopic NCMs to grossly apparent mass-forming NETs, potentially requiring different clinical management. Noteworthy is the frequent association of incidental microscopic neuroendocrine cell proliferations with biliary lithiasis, indicating a potential neuroendocrine metaplastic pathogenesis that merits further exploration.

Prediction of Two-Dimensional Janus Transition-Metal Chalcogenides: Robust Ferromagnetic Semiconductor with High Curie Temperature.

Two-dimensional (2D) ferromagnetic semiconductors (FM SCs) provide an ideal platform for the development of quantum information technology in nanoscale devices. However, many developed 2D FM materials present a very low Curie temperature (TC), greatly limiting their application in spintronic devices. In this work, we predict two stable 2D transition metal chalcogenides, V3Se3X2 (X = S, Te) monolayers, by using first-principles calculations. Our results show that the V3Se3Te2 monolayer is a robust bipolar magnetic SC with a moderate bandgap of 0.53 eV, while V3Se3S2 is a direct band-gap FM SC with a bandgap of 0.59 eV. Interestingly, the ferromagnetisms of both monolayers are robust due to the V-S/Se/Te-V superexchange interaction, and TCs are about 406 K and 301 K, respectively. Applying biaxial strains, the FM SC to antiferromagnetic (AFM) SC transition is revealed at 5% and 3% of biaxial tensile strain. In addition, their high mechanical, dynamical, and thermal stabilities are further verified by phonon dispersion calculations and ab initio molecular dynamics (AIMD) calculations. Their outstanding attributes render the V3Se3Y2 (Y = S, Te) monolayers promising candidates as 2D FM SCs for a wide range of applications.

Early-Life Sublethal Exposure to Thiacloprid Alters Adult Honeybee Gut Microbiota.

Thiacloprid, a neonicotinoid pesticide, is known to affect the gut microbiome of honeybees, yet studies often focus on immediate alternations during exposure, overlooking long-term microbiological impacts post-exposure. This study investigates the influences of sublethal thiacloprid administered during the larval developmental stage of honeybees on physiological changes and gut microbiota of adult honeybees. We found that thiacloprid exposure increased mortality and sugar intake in emerged honeybees. Using 16S rDNA sequencing, we analyzed intestinal microbial diversity of honeybees at one and six days post-emergence. Our findings reveal a significant but transient disruption in gut microbiota on day 1, with recovery from dysbiosis by day 6. This study emphasizes the importance of evaluating chronic sublethal exposure risks of thiacloprid to protect honeybee health.

Research on a harmless treatment method for oily sludge in coal chemical wastewater and the pollutant transformation mechanism of oily sludge during the treatment process.

This study developed an ultrasound synergistic subcritical hydrothermal treatment method (U-SHT) to address the challenges posed by the high oil and water content, complex composition, and hazardous nature of oily sludge (OS) generated during the pretreatment of coal chemical wastewater. The study investigated the efficiency of this method for the harmless disposal and resource recovery of OS, and the migration-transformation mechanism of hazardous organic pollutants in OS. The findings revealed that U-SHT achieved a removal efficiency of chemical oxygen demand in OS of 91.16 %, an oil resource recovery efficiency of 96.60 %, and a residual oil rate of 0.28 %, meeting API emission standards. Further research indicated that the solubilizing effect of the surfactant on the oil enhanced the demulsifying effect of ultrasonic cavitation on the emulsified structure of OS, enabling ultrasound to efficiently release and disperse pollutants within OS. This promoted the decomposition and transformation of pollutants under subcritical hydrothermal conditions, with synergistic removal efficiencies for typical pollutants such as long-chain alkanes, polycyclic aromatic hydrocarbons, and phenols reaching 96.61 %, 97.63 %, and 97.76 %, respectively. Economic evaluation indicated that the cost of OS treatment was $29.66/m3, significantly lower than existing methods, demonstrating promising practical application prospects.

[Zirconium-based metal-organic framework composites for solid phase extraction of brevetoxin-A from seawater].

Red tides are a type of natural marine disaster caused by harmful algae characterized by a high toxicity, wide distribution, and long duration. Since the concentration of algal toxins in seawater increases with the occurrence of red tides, algal toxins detected in seawater could be used to predict the occurrence and evolution of red tides. Brevetoxin-A (BTX-A) is a secondary metabolite produced by the harmful algae Karenia brevis, whose detection in seawater could form the basis of an accurate warning system for incoming red tides. However, due to the inherent complexity of the seawater matrix and the extremely low levels of BTX-A in seawater, the use of instruments for its direct detection is difficult. Therefore, there is an urgent need to develop a sample pretreatment method for the efficient enrichment of BTX-A in seawater. In this study, a metal-organic backbone material (UiO-66) and its composite with silica microspheres (SiO2@UiO-66) were successfully synthesized using the solvothermal method. The prepared SiO2@UiO-66 exhibited good hydrophilicity, water stability, and large specific surface area. Furthermore, it also exhibited hydrogen bonding and electrostatic interactions with BTX-A, had a strong affinity for BTX-A, and was able to efficiently adsorb BTX-A in complex matrices. Therefore, SiO2@UiO-66 showed potential as a novel packing material for the extraction of BTX-A from solid phase extraction columns. Combined with high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), a highly sensitive detection method for the determination of BTX-A in marine water was established. The established analytical method had a low detection limit (3.0 pg/mL), a wide linear range (10.0 -200.0 pg/mL), and a good linear relationship (R=0.9992). Combined with the Fujian Province Red Tide Monitoring and Early Warning Information 2021 issued by the Fujian Provincial Oceanic and Fisheries Bureau, the analytical method established herein was successfully applied to analyze and monitor the content of BTX-A in actual seawater samples. This highlights the proposed system's potential for use as an early warning factor in the monitoring of red tides, representing a simple and fast pretreatment methodology for the detection of BTX-A in seawater.

Machine learning-aided understanding of the structure-activity relationship: a case study of MoS2 supported metal-nonmetal pairs for the hydrogen evolution reaction.

Understanding the structure-performance relationship is crucial for designing highly active electrocatalysts, yet this remains a challenge. Using MoS2 supported metal-nonmetal atom pairs (XTM@MoS2, TM = Sc-Ni, and X = B, C, N, O, P, Se, Te, and S) for the hydrogen evolution reaction (HER) as an example, we successfully uncovered the structure-activity relationship with the help of density functional theory (DFT) calculations and integrated machine learning (ML) methods. An ML model based on random forest regression was used to predict the activity, and the trained model exhibited excellent performance with minimal error. SHapley Additive exPlanations analysis revealed that the atom mass and covalent radius of the X atom (m_X and R_X) dominate the activity, and their higher values usually lead to better activity. In addition, four promising candidates, i.e., PCr@MoS2, SV@MoS2, SeTi@MoS2, and SeSc@MoS2, with excellent activity are selected. This work provides several promising catalysts for the HER but, more importantly, offers a workflow to explore the structure-activity relationship.

Single cell RNA-sequencing identifies the effect of Normothermic ex vivo liver perfusion on liver-resident T cells.

BACKGROUND: Normothermic ex vivo liver perfusion (NEVLP) is an exciting strategy to preserve livers prior to transplant, however, the effects of NEVLP on the phenotype of tissue-resident immune cells is largely unknown. The presence of tissue-resident memory T cells (TRM) in the liver may protect against acute rejection and decrease allograft dysfunction. Therefore, we investigated the effects of NEVLP on liver TRMs and assessed the ability of anti-inflammatory cytokines to reduce TRM activation during NEVLP. METHODS: Rat livers underwent NEVLP with or without the addition of IL-10 and TGF-ß. Naïve and cold storage livers served as controls. Following preservation, TRM T cell gene expression profiles were assessed through single cell RNA sequencing (scRNA-seq). Differential gene expression analysis was performed with Wilcoxon rank sum test to identify differentially expressed genes (DEGs) associated with a specific treatment group. Using the online Database for Annotation, Visualization and Integrated Discovery (DAVID), gene set enrichment was then conducted with Fisher's exact test on DEGs to highlight differentially regulated pathways and functional terms associated with treatment groups. RESULTS: Through scRNA-seq analysis, an atlas of liver-resident memory T cell subsets was created for all livers. TRM T cells could be identified in all livers, and through scRNA-seq, DEG was identified with Wilcoxon rank sum test at FDR < 0.05. Based on the gene set enrichment analysis of DEGs using Fisher's exact test, NEVLP is associated with downregulation of multiple gene enrichment pathways associated with surface proteins. Furthermore, NEVLP with anti-inflammatory cytokines was associated with down regulation of 52 genes in TRM T cells when compared to NEVLP alone (FDR <0.05), most of which are pro-inflammatory. CONCLUSION: This is the first study to create an atlas of liver TRM T cells in the rat liver undergoing NEVLP and demonstrate the effects of NEVLP on liver TRM T cells at the single cell gene expression level.

Efficient Adsorption of Azo Dye Acid Brilliant Red on Graphite Carbon Nitride in Aqueous Solution.

In this study, two types of graphite carbon nitrides were prepared by directly calcinating urea (U-g-C3N4) and melamine (M-g-C3N4) in a muffle furnace. Their adsorption performances on acid brilliant red (ABR) from aqueous solution were examined and compared. Results showed that, at the optimum calcination temperature of 580 °C, both the adsorption capacity of U-g-C3N4 and that of M-g-C3N4 increased strongly with decreasing solution pH. U-g-C3N4 exhibits higher adsorption capacity than M-g-C3N4 at an initial pH > 2.0. However, at an initial pH of 1.0, M-g-C3N4 displayed a much higher adsorption capacity than U-g-C3N4, where the maximum adsorption capacity of M-g-C3N4 can reach 25 635.64 mg g-1, being the highest reported to date. Adsorptions of both adsorbents followed pseudo-second-order kinetic models and the Langmuir adsorption isothermal models. The adsorption is spontaneous and exothermic and occurs mainly through electrostatic attraction between the protonated g-C3N4 and the negatively charged ABR. In addition, the used U-g-C3N4 can be easily regenerated with ethanol and the renewed U-g-C3N4 possesses comparable adsorption capability of its original form, showing its superior recyclability and broad industrial application prospects.

Delivery Strategy to Enhance the Therapeutic Efficacy of Liver Fibrosis via Nanoparticle Drug Delivery Systems.

Liver fibrosis (LF) is a pathological repair reaction caused by a chronic liver injury that affects the health of millions of people worldwide, progressing to life-threatening cirrhosis and liver cancer without timely intervention. Due to the complexity of LF pathology, multiple etiological characteristics, and the deposited extracellular matrix, traditional drugs cannot reach appropriate targets in a time-space matching way, thus decreasing the therapeutic effect. Nanoparticle drug delivery systems (NDDS) enable multidrug co-therapy and develop multifactor delivery strategies targeting pathological processes, showing great potential in LF therapy. Based on the pathogenesis and the current clinical treatment status of LF, we systematically elucidate the targeting mechanism of NDDS used in the treatment of LF. Subsequently, we focus on the progress of drug delivery applications for LF, including combined delivery for the liver fibrotic pathological environment, overcoming biological barriers, precise intracellular regulation, and intelligent responsive delivery for the liver fibrotic microenvironment. We hope that this review will inspire the rational design of NDDS for LF in the future in order to provide ideas and methods for promoting LF regression and cure.

The RNA helicase DHX35 functions as a co-sensor for RIG-I-mediated innate immunity.

RNA helicases are involved in the innate immune response against pathogens, including bacteria and viruses; however, their mechanism in the human airway epithelial cells is still not fully understood. Here, we demonstrated that DEAH (Asp-Glu-Ala-His) box polypeptide 35 (DHX35), a member of the DExD/H (Asp-Glu-x-Asp/His)-box helicase family, boosts antiviral innate immunity in human airway epithelial cells. DHX35 knockdown attenuated the production of interferon-ß (IFN-ß), IL6, and CXCL10, whereas DHX35 overexpression increased their production. Upon stimulation, DHX35 was constitutively expressed, but it translocated from the nucleus into the cytosol, where it recognized cytosolic poly(I:C) and poly(dA:dT) via its HELICc domain. Mitochondrial antiviral signaling protein (MAVS) acted as an adaptor for DHX35 and interacted with the HELICc domain of DHX35 using amino acids 360-510. Interestingly, DHX35 interacted with retinoic acid-inducible gene 1 (RIG-I), enhanced the binding affinity of RIG-I with poly(I:C) and poly(dA:dT), and formed a signalsome with MAVS to activate interferon regulatory factor 3 (IRF3), NF-κB-p65, and MAPK signaling pathways. These results indicate that DHX35 not only acted as a cytosolic nucleic acid sensor but also synergized with RIG-I to enhance antiviral immunity in human airway epithelial cells. Our results demonstrate a novel molecular mechanism for DHX35 in RIG-I-mediated innate immunity and provide a novel candidate for drug and vaccine design to control viral infections in the human airway.

Concentration, correlation, and health risk assessment of rare earth elements in different edible parts of the swimming crab (Portunus trituberculatus) in Shandong Province, China.

This study is the first work investigating the distribution of rare earth elements (REEs) in three different edible tissues of the swimming crab (Portunus trituberculatus) collected from seven cities of Shandong Province, China. The total concentrations of REEs ranged from 26.1 to 139 ng/g with an average of 63.0 ng/g. The ratio of light REEs to heavy REEs ranged from 9.78 to 16.6 ng/g with an average of 11.5 ng/g. There was no significant differences in REE levels between the edible tissues of male and female crabs. The content of REEs across different tissues followed a consistent pattern: gonads > body muscle > legs muscle, except for Eu. A significant correlation was observed between REEs in P. trituberculatus and marine sediments in the corresponding sea area, following the principle of "abundance law". A health risk assessment revealed a low health risk of REEs for local adults and children consuming Portunus trituberculatus.

Chemoenzymatic Synthesis of Fluorinated Mycocyclosin Enabled by the Engineered Cytochrome P450-Catalyzed Biaryl Coupling Reaction.

Installing fluorine atoms onto natural products holds great promise for the generation of fluorinated molecules with improved or novel pharmacological properties. The enzymatic oxidative carbon-carbon coupling reaction represents a straightforward strategy for synthesizing biaryl architectures, but the exploration of this method for producing fluorine-substituted derivatives of natural products remains elusive. Here, in this study, we report the protein engineering of cytochrome P450 from Mycobacterium tuberculosis (MtCYP121) for the construction of a series of new-to-nature fluorine-substituted Mycocyclosin derivatives. This protocol takes advantage of a "hybrid" chemoenzymatic procedure consisting of tyrosine phenol lyase-catalyzed fluorotyrosine preparation from commercially available fluorophenols, intermolecular chemical condensation to give cyclodityrosines, and an engineered MtCYP121-catalyzed intramolecular biphenol coupling reaction to complete the strained macrocyclic structure. Computational mechanistic studies reveal that MtCYP121 employs Cpd I to abstract a hydrogen atom from the proximal phenolic hydroxyl group of the substrate to trigger the reaction. Then, conformational change makes the two phenolic hydroxyl groups close enough to undergo intramolecular hydrogen atom transfer with the assistance of a pocket water molecule. The final diradical coupling process completes the intramolecular C-C bond formation. The efficiency of the biaryl coupling reaction was found to be influenced by various fluorine substitutions, primarily due to the presence of distinct binding conformations.

Neuroprotection of Human Umbilical Cord-Derived Mesenchymal Stem Cells (hUC-MSCs) in Alleviating Ischemic Stroke-Induced Brain Injury by Regulating Inflammation and Oxidative Stress.

Brain injury caused by stroke has a high rate of mortality and remains a major medical challenge worldwide. In recent years, there has been significant attention given to the use of human Umbilical cord-derived Mesenchymal Stem Cells (hUC-MSCs) for the treatment of stroke in different adult and neonate animal models of stroke. However, using hUC-MSCs by systemic administration to treat ischemic stroke has not been investigated sufficiently. In this study, we conducted various experiments to explore the neuroprotection of hUC-MSCs in rats. Our findings demonstrate that an intravenous injection of a high dose of hUC-MSCs at 2 × 10^7 cells/kg markedly ameliorated brain injury resulting from ischemic stroke. This improvement was observed one day after inducing transient middle cerebral artery occlusion (MCAO) and subsequent reperfusion in rats. Notably, the efficacy of this single administration of hUC-MSCs surpassed that of edaravone, even when the latter was used continuously over three days. Mechanistically, secretory factors derived from hUC-MSCs, such as HGF, BDNF, and TNFR1, ameliorated the levels of MDA and T-SOD to regulate oxidative stress. In particular, TNFR1 also improved the expression of NQO-1 and HO-1, important proteins associated with oxidative stress. More importantly, TNFR1 played a significant role in reducing inflammation by modulating IL-6 levels in the blood. Furthermore, TNFR1 was observed to influence the permeability of the blood-brain barrier (BBB) as demonstrated in the evan's blue experiment and protein expression of ZO-1. This study represented a breakthrough in traditional methods and provided a novel strategy for clinical medication and trials.

Integrating muti-omics data to identify tissue-specific DNA methylation biomarkers for cancer risk.

The relationship between tissue-specific DNA methylation and cancer risk remains inadequately elucidated. Leveraging resources from the Genotype-Tissue Expression consortium, here we develop genetic models to predict DNA methylation at CpG sites across the genome for seven tissues and apply these models to genome-wide association study data of corresponding cancers, namely breast, colorectal, renal cell, lung, ovarian, prostate, and testicular germ cell cancers. At Bonferroni-corrected P < 0.05, we identify 4248 CpGs that are significantly associated with cancer risk, of which 95.4% (4052) are specific to a particular cancer type. Notably, 92 CpGs within 55 putative novel loci retain significant associations with cancer risk after conditioning on proximal signals identified by genome-wide association studies. Integrative multi-omics analyses reveal 854 CpG-gene-cancer trios, suggesting that DNA methylation at 309 distinct CpGs might influence cancer risk through regulating the expression of 205 unique cis-genes. These findings substantially advance our understanding of the interplay between genetics, epigenetics, and gene expression in cancer etiology.

Pilot study of humanized glypican-3-targeted zirconium-89 immuno-positron emission tomography for hepatocellular carcinoma.

Purpose: Glypican-3 (GPC3)-targeted radioisotope immuno-positron emission tomography (immunoPET) may lead to earlier and more accurate diagnosis of hepatocellular carcinoma (HCC), thus facilitating curative treatment, decreasing early recurrence, and enhancing patient survival. We previously demonstrated reliable HCC detection using a zirconium-89-labeled murine anti-GPC3 antibody (89Zr-αGPC3M) for immunoPET. This study evaluated the efficacy of the humanized antibody successor (αGPC3H) to further clinical translation of a GPC3-based theranostic for HCC. Methods: In vitro αGPC3 binding to HepG2 cells was assessed by flow cytometry. In vivo 89Zr-αGPC3H and 89Zr-αGPC3M tumor uptake was evaluated by PET/CT and biodistribution studies in an orthotopic xenograft mouse model of HCC. Results: αGPC3H maintained binding to GPC3 in vitro and 89Zr-αGPC3H immunoPET identified liver tumors in vivo. PET/CT and biodistribution analyses demonstrated high 89Zr-αGPC3H tumor uptake and tumor-to-liver ratios, with no difference between groups. Conclusion: Humanized αGPC3 successfully targeted GPC3 in vitro and in vivo. 89Zr-αGPC3H immunoPET had comparable tumor detection to 89Zr-αGPC3M, with highly specific tumor uptake, making it a promising strategy to improve HCC detection.

Clinicopathologic Features of Gastrointestinal Tract Langerhans Cell Histiocytosis.

Gastrointestinal (GI) tract involvement by Langerhans cell histiocytosis (LCH) is rare and its clinicopathologic characteristics have only been described in case reports and small series. We reviewed hematoxylin and eosin and CD1a, S100, and Langerin immunohistochemical-stained slides from 47 patients with well-documented demographic and clinical findings. Our cases included 8 children and 39 adults, with a mean follow-up of 63 months. All pediatric patients had concurrent multisystem LCH, presented with GI symptoms, and showed nonpolypoid lesions. Seven (88%) showed multifocal GI disease, including 5 with multiple GI organ involvement. All sampled lesions from children exhibited infiltrative growth. More than half had died of the disease or manifested persistent LCH at last follow-up. Twenty-five of 39 (64%) adults had LCH involving only the GI tract (single system), with the remaining 14 (36%) exhibiting multisystem disease. Adult single-system GI LCH was typically encountered incidentally on screening/surveillance endoscopy (72%). Most exhibited isolated colorectal involvement (88%) as a solitary polyp (92%), with a well-demarcated/noninfiltrative growth pattern (70%), and excellent prognosis (100%). In comparison, adult patients with multisystem LCH more frequently presented with GI symptoms (92%, P < .001), noncolorectal GI site involvement (50%, P = .02), multifocal GI lesions (43%, P = .005), nonpolypoid lesions (71%, P < .001), infiltrative histologic growth pattern (78%, P = .04), and persistent disease (57%, P < .001). Adult patients with multisystem LCH appear to exhibit similar clinicopathologic features to those of pediatric patients. These results demonstrated that adults with single-system LCH involving the GI tract have an excellent prognosis, whereas multisystem LCH occurring at any age carries an unfavorable prognosis. High-risk features of GI LCH include pediatric age, GI symptomatology, noncolorectal GI involvement, multifocal GI disease, nonpolypoid lesions, and infiltrative growth pattern.