The purpose of this perspective is to discuss the future development of a potential treatment of glial pathology in Alzheimer's disease(AD) and a new regulatory mechanism, nuclear lipids, which may be involved in ...The purpose of this perspective is to discuss the future development of a potential treatment of glial pathology in Alzheimer's disease(AD) and a new regulatory mechanism, nuclear lipids, which may be involved in the pathogenesis of the disease, based on the work of the authors(Takasugi et al., 2011;Komai et al., 2024).展开更多
Uveal melanoma(UM)is the most common intraocular cancer,with approximately 5.2 individuals per million affected annually in the United States.It represents approximately 3%of the global malignant melanoma cases,accoun...Uveal melanoma(UM)is the most common intraocular cancer,with approximately 5.2 individuals per million affected annually in the United States.It represents approximately 3%of the global malignant melanoma cases,accounting for 80%of the overall noncutaneous melanomas.Clinically,it remains silent in about 30%of the cases;when symptomatic,it generally causes metamorphopsia(painless loss or distortion of vision)and/or photopsia(flashing or flickering of light in the visual field).Discoloration of the iris,astigmatism,glaucoma,and even blindness are other,less common clinical manifestations.Several pathophysiological mechanisms underlie the development of UM.Genetic mutations,involving especially the G protein subunit alpha q(GNAQ),guanine nucleotide-binding protein subunit alpha-11(GNA11),BRCA1 associated deubiquitinase 1(BAP1),splicing factor 3b subunit 1(SF3B1),and eukaryotic translation initiation factor 1A,X-linked(EIF1AX)genes as well as the MAPK/ERK signaling pathway genes,have been largely associated with the development of UM.Chromosomal aberrations,inflammatory and immunological alterations are often concurrent factors for the development and progression of UM.Therapies targeting specific genetic alterations and immunotherapy agents have been recently developed and introduced in clinical practice for the management of advanced-stage UMs.This review aims to present the latest advances in the clinical molecular pathology of UM,along with the resulting targeted,immunological,and other therapies that have been introduced or are currently under investigation.展开更多
Parkinson's disease(PD)is the second most common neurodegenerative disorder.The clinical manifestations of PD include motor symptoms,such as bradykinesia,resting tremor,rigidity,and nonmotor symptoms,which include...Parkinson's disease(PD)is the second most common neurodegenerative disorder.The clinical manifestations of PD include motor symptoms,such as bradykinesia,resting tremor,rigidity,and nonmotor symptoms,which include disturbances in sleep,gastrointestinal function,and olfaction.PD misdiagnosis rates have been reported to reach approximately 30%,partly owing to the heterogeneity of parkinsonism with non-PD pathologies,and the differential diagnosis of PD from neurodegenerative diseases such as multiple systemic atrophy(MSA)and progressive supranuclear palsy poses another unmet need.展开更多
Alzheimer’s disease(AD)remains an incurable neurodegenerative disorder with devastating societal and personal impacts.Despite decades of intensive research,therapeutic efforts targeting the clinical stages of AD have...Alzheimer’s disease(AD)remains an incurable neurodegenerative disorder with devastating societal and personal impacts.Despite decades of intensive research,therapeutic efforts targeting the clinical stages of AD have largely failed to halt or reverse disease progression.This has prompted a critical shift in focus toward the earlier,preclinical stages of AD,where interventions may hold greater promise for altering the disease trajectory.展开更多
AIM: To study the purifying method and characteristics of new gosling viral enteritis virus (NGVEV),the etiological agent of new gosling viral enteritis (NGVE) which was first recognized in China, as well as the patho...AIM: To study the purifying method and characteristics of new gosling viral enteritis virus (NGVEV),the etiological agent of new gosling viral enteritis (NGVE) which was first recognized in China, as well as the pathomorphological development in goslings infected artificially with NGVEV. METHODS: (1)NGVEV virions were purified by the procedure of treatment with chloroform and ammonium sulfate precipitation, dialysis to remove the sulfate radical and ammonium ion and separation by gel filtration chromatography, and SDS-PAGE. (2)Forty-2-day-old White Sichuan goslings were orally administered with NGVEV and 24 hr later 2 birds were randomly selected and killed at 24hr intervals until death occurred. Specimens(duodenum, ileum, liver, heart, kidney, spleen, lung, proventriculus, pancreas, esophagus, and the intestinal embolus) were taken until all birds in this group died and were sectioned and stained with hemotoxylin and eosin and studied by light microscope. RESULTS: NGVEV shared the typical characteristics of Adenovirus and which structural proteins consisted of 15 polypeptides. Necrosis and sloughing of the epithelial cells covering the villus tips of the duodenum were first observed in goslings 2 days postinfection artificially with NGVEV. With the progress of infection, this lesion rapidly occurred in the epithelium at the base of the villus and with infiltration of the inflammatory cells, the jejunum tended to be involved. With the intensification of mucosa necrosis and inflammatory exudation of the small intestine, fibrinonecrotic enteritis was further developed and embolus composed of either intestinal contents wrapped by pseudo-membrane or of the mixture of fibrous exudate and necrotic intestinal mucosa were observed in the middle-lower part of the small intestine. This structure occluded the intestinal tract and made the intestine dilated in appearance. The intestinal glandular cells underwent degeneration, necrosis and might be found sloughed into the lumen. Hemorrhage and hyperemia could be observed on the lung and kidney. Epithelial cells of the renal tubular underwent degeneration. In some cases, granular degeneration and fatty degeneration could be found in the liver and in some cases at a later stage of this disease the epithelial cells of trachea and proventriculus might be found sloughed. In some cases at an early stage of this disease, cardiac hyperemia and hemorrhage could be observed. Esophagus, pancreas and brain were found normal. Analyses and comparisons between the pathologic lesions of NGVE and Gosling Plague (GP) were available in this paper as well. CONCLUSION: (1)NGVEV is adenovirus. (2)Pathological characteristic could be as the data for NGVE diagnosis.展开更多
Experimental evidence indicates that chronic mechanical sub-occlusion of the intestine may damage the enteric nervous system （ENS）, although data in humans are lacking. We here describe the first case of enteric deg...Experimental evidence indicates that chronic mechanical sub-occlusion of the intestine may damage the enteric nervous system （ENS）, although data in humans are lacking. We here describe the first case of enteric degenerative neuropathy related to a congenital obstruction of the gut. A 3-year and 9-mo old girl began to complain of vomiting, abdominal distension, constipation with air-fluid levels at plane abdominal radiology. Her subsequent medical history was characterized by 3 operations： the first showed dilated duodeno-jejunal loops in the absence of occlusive lesions; the second （2 years later） was performed to obtain full-thickness biopsies of the dilated intestinal loops and revealed hyperganglionosis at histopathology; the third （9 years after the hyperganglionosis was identified） disclosed a Ladd＇s band which was removed and the associated gut malrotation was corrected. Repeated intraoperative full-thickness biopsies showed enteric degenerative neuropathy along with reduced interstitial cells of Cajal network in dilated loops above the obstruction and a normal neuromuscular layer below the Ladd＇s band. One year after the latest surgery the patient tolerated oral feeding and did well, suggesting that congenital （partial） mechanical obstruction of the small bowel in humans can evoke progressive adaptive changes of the ENS which are similar to those found in animal models of intestinal mechanical occlusion. Such ENS changes mimic neuronal abnormalities observed in intestinal pseudoobstruction.展开更多
Background Necrotic enteritis(NE)can cause intestinal barrier dysfunction in broilers,leading to secondary liver injury(SLI).In this process,the gut-liver axis plays a crucial role.Lonicerae flos and turmeric extracts...Background Necrotic enteritis(NE)can cause intestinal barrier dysfunction in broilers,leading to secondary liver injury(SLI).In this process,the gut-liver axis plays a crucial role.Lonicerae flos and turmeric extracts(LTE),containing chlorogenic acid and curcumin,have been reported to possess anti-inflammatory,and antioxidant properties.Based on these potential biological benefits,this study aims to investigate the reparative effects of LTE on the intestinal barrier dysfunction in NE-infected broilers and assess its therapeutic efficacy in alleviating SLI.By elucidating the regulatory mechanisms of LTE on gut-liver axis health,this research provides new insights into the prevention and treatment of NE in broilers.Results LTE improved body weight and average daily gain while reducing intestinal lesion scores,coccidia oocysts,and Clostridium perfringens counts in NE broilers(P<0.05).LTE enhanced intestinal morphology and up-regulated the expression of tight junction protein genes(CLDN1,TJP1)and MUC2,suppressed pro-inflammatory cytokine and myeloperoxidase(MPO)levels,and minimized endotoxin(ET)accumulation in NE broilers(P<0.05).Furthermore,LTE alleviated oxidative stress in ileal cells and protected mitochondrial structure and function in NE broilers.NE infection induced intestinal permeability in broilers,leading to increased serum pro-inflammatory cytokines and intestinal-derived endotoxin levels,which caused liver damage.LTE significantly reduced liver pathologic damage,pro-inflammatory cytokine levels,aspartate transaminase,alanine aminotransferase,and ROS levels in NE broilers(P<0.05).Additionally,16S rRNA sequencing revealed that NE significantly increased the relative abundance of Barnesiella and decreased the relative abundance of Bacteroidota,Desulfobacterota and Bacteroides in the cecum of broilers.LTE enhanced intestinal microbiota diversity and reduced the segregation of intestinal microbiota induced by NE infection.Conclusions In summary,LTE can alleviate NE and SLI by modulating the microbiota,inhibiting inflammation and oxidative stress,and ameliorating mitochondrial dysfunction,thereby enhancing gut-liver axis health and growth performance.展开更多
Background Necrotic enteritis(NE)in broiler chickens leads to significant economic losses in poultry production.This study examined the inhibitory effects of usnic acid and tannic acid on coccidia,sporozoite,and Clost...Background Necrotic enteritis(NE)in broiler chickens leads to significant economic losses in poultry production.This study examined the inhibitory effects of usnic acid and tannic acid on coccidia,sporozoite,and Clostridium perfringens and assessed their influence on growth performance and intestinal health in NE-challenged broilers through in vitro and in vivo experiments.Methods The in vitro experiment included 5 treatment groups:the negative control(NC),2μmol/L diclazuril(DZ),30μmol/L usnic acid(UA),90μmol/L tannic acid(TA),and 15μmol/L usnic acid^(+)45μmol/L tannic acid(UTA)groups.The in vivo experiment involved 320 broilers divided into four groups:PC(NE-challenged),SA(500 mg/kg salinomycin premix^(+)NE-challenged),UA(300 mg/kg usnic acid^(+)NE-challenged),and UTA(300 mg/kg usnic acid^(+)500 mg/kg tannic acid^(+)NE-challenged)groups.Results In the in vitro study,the UA,TA,and UTA treatments significantly increased apoptosis in coccidian oocysts and sporozoites,lowered the mitochondrial membrane potential(P<0.05),and disrupted the oocyst structure compared with those in the NC group.UA and TA had inhibitory effects on C.perfringens,with the strongest inhibition observed in the UTA group.The in vivo results demonstrated that the SA group presented significantly improved growth performance on d 13,21,and 28(P<0.05),whereas the UA and UTA groups presented improvements on d 13 and 21(P<0.05).The SA,UA,and UTA treatments reduced the intestinal lesion scores by d 28 and the fecal coccidian oocyst counts from d 19 to 21(P<0.05).Compared with the PC group,the UA and UTA groups presented lower intestinal sIgA levels and CD8^(+)cell percentages(P<0.05),with a trend toward a reduced CD3^(+)cell percentage(P=0.069).The SA,UA,and UTA treatments significantly reduced the serum diamine oxidase activity,crypt depth,and plateletderived growth factor levels in the intestinal mucosa while increasing the villus height to crypt depth ratio and number of goblet cells(P<0.05).The UTA treatment also significantly increased the acetate and butyrate concentrations in the cecum(P<0.05).With respect to the gut microbiota,significant changes inβdiversity in the ileum and cecum were observed in the SA,UA,and UTA groups,indicating that the microbial community compositions differed among the groups.Romboutsia dominated the SA group,Bacillales dominated the UA group,and Lactobacillales and Lachnospirales dominated the UTA group in the ileal microbiota.In the cecal microbiota,Lactobacillus,Butyricicoccus,and Blautia abundances were significantly elevated in the UTA group(P<0.05).Conclusion Usnic acid and tannic acid induce apoptosis in coccidia and sporozoites by lowering the mitochondrial membrane potential.Both usnic acid alone and in combination with tannic acid alleviate NE-induced adverse effects in broilers by modulating intestinal immunity,altering the microbial composition,and improving intestinal barrier function.Compared with usnic acid alone,the combination of usnic acid and tannic acid had superior effects,providing a promising basis for the development of effective feed additive combinations.展开更多
Alzheimer's disease (AD) is characterized by an imbalance between excitatory and inhibitory brain networks,leading to aberrant homeostatic synaptic plasticity.AD has progressively been recognized as syna ptopathy ...Alzheimer's disease (AD) is characterized by an imbalance between excitatory and inhibitory brain networks,leading to aberrant homeostatic synaptic plasticity.AD has progressively been recognized as syna ptopathy and syna ptic dysfunction has been identified as a key component of its pathogenesis (Schirinzi et al.,2020).Syna ptic dysfunction is believed to precede synapse loss,a primary biological correlate of cognitive decline in AD,inevita bly associated with neuronal death.展开更多
Objective:Neoadjuvant therapy(NAT)has become the standard treatment option for patients with locally advanced breast cancer.How to non-invasively screen out patients with pathological complete response(pCR)after NAT h...Objective:Neoadjuvant therapy(NAT)has become the standard treatment option for patients with locally advanced breast cancer.How to non-invasively screen out patients with pathological complete response(pCR)after NAT has become an urgent world-wide clinical problem.Our work aims to the assessment of neoadjuvant treatment response in breast cancer patients for higher accuracy prediction using innovative artificial intelligence system.Methods:In this study,we retrospectively collected longitudinal(pre-NAT and post-NAT)multi-parametric magnetic resonance imaging(MRI)and clinicopathologic data of a total of 1,315 breast cancer patients(clinical stageⅠ-Ⅲ)who had undergone NAT followed by standard surgery and treated across 5 independent medical centers from January 2010 to January 2023.We used radiomics,3D convolutional neural network technology and clinical data statistical analysis methods to extract and screen multimodal features,and then developed and validated a Clinical-Radiomics-Deep-Learning(CRDL)model to predict patients'pCR outcomes based on multimodal fusion features.Results:We use the area under the receiver operating characteristic curve(AUC)in the primary cohort(PC)and3 external validation cohorts(VC_(1-3))to evaluate the model performance.The results showed that the AUC in the PC composed of 2 medical centers was 0.947[95%confidence interval(95%CI):0.931-0.960],and the AUC values in VC_(1-3)were 0.857(95%CI:0.810-0.901),0.883(95%CI:0.841-0.918)and 0.904(95%CI:0.860-0.941),respectively.Conclusions:The CRDL model demonstrated high accuracy and robustness in predicting pCR to NAT using multimodal fusion data.This study provides a strong foundation for non-invasive assessment of pCR status in breast cancer patients following NAT and offers critical insights to guide clinical decision-making in post-NAT treatment planning.展开更多
In pathological examinations,tissue must first be stained to meet specific diagnostic requirements,a meticulous process demanding significant time and expertise from specialists.With advancements in deep learning,this...In pathological examinations,tissue must first be stained to meet specific diagnostic requirements,a meticulous process demanding significant time and expertise from specialists.With advancements in deep learning,this staining process can now be achieved through computational methods known as virtual staining.This technique replicates the visual effects of traditional histological staining in pathological imaging,enhancing efficiency and reducing costs.Extensive research in virtual staining for pathology has already demonstrated its effectiveness in generating clinically relevant stained images across a variety of diagnostic scenarios.Unlike previous reviews that broadly cover the clinical applications of virtual staining,this paper focuses on the technical methodologies,encompassing current models,datasets,and evaluation methods.It highlights the unique challenges of virtual staining compared to traditional image translation,discusses limitations in existing work,and explores future perspectives.Adopting a macro perspective,we avoid overly intricate technical details to make the content accessible to clinical experts.Additionally,we provide a brief introduction to the purpose of virtual staining from a medical standpoint,which may inspire algorithm-focused researchers.This paper aims to promote a deeper understanding of interdisciplinary knowledge between algorithm developers and clinicians,fostering the integration of technical solutions and medical expertise in the development of virtual staining models.This collaboration seeks to create more efficient,generalized,and versatile virtual staining models for a wide range of clinical applications.展开更多
Alzheimer'sdisease(AD)isaprogressive neurodegenerative disorder characterized by cognitive impairment and distinct neuropathological features,including amyloid-βplaques,neurofibrillary tangles,and reactive astrog...Alzheimer'sdisease(AD)isaprogressive neurodegenerative disorder characterized by cognitive impairment and distinct neuropathological features,including amyloid-βplaques,neurofibrillary tangles,and reactive astrogliosis.Developing effective diagnostic,preventative,and therapeutic strategies for AD necessitates the establishment of animal models that accurately recapitulate the pathophysiological processes of the disease.Existing transgenic mouse models have significantly contributed to understanding AD pathology but often fail to replicate the complexity of human AD.Additionally,these models are limited in their ability to elucidate the interplay among amyloid-βplaques,neurofibrillary tangles,and reactive astrogliosis due to the absence of spatially and temporally specific genetic manipulation.In this study,we introduce a novel AD mouse model(APP/PS1-TauP301L-Adeno mice)designed to rapidly induce pathological symptoms and enhance understanding of AD mechanisms.Neurofibrillary tangles and severe reactive astrogliosis were induced by injecting AAVDJ-EF1a-hTauP301L-EGFP and Adeno-GFAP-GFP viruses into the hippocampi of 5-month-old APP/PS1 mice.Three months post-injection,these mice exhibited pronounced astrogliosis,substantial amyloid-βplaque accumulation,extensiveneurofibrillarytangles,accelerated neuronal loss,elevated astrocytic GABA levels,and significant spatial memory deficits.Notably,these pathological features were less severe in AAVTauP301L-expressing APP/PS1 mice without augmented reactive astrogliosis.These findings indicate an exacerbating role of severe reactive astrogliosis in amyloid-βplaque and neurofibrillary tangle-associated pathology.The APP/PS1-TauP301L-Adeno mouse model provides a valuable tool for advancing therapeutic research aimed at mitigating the progression of AD.展开更多
Computational pathology,a field at the intersection of computer science and pathology,leverages digital technology to enhance diagnostic accuracy and efficiency.With the digitization of pathology and the development o...Computational pathology,a field at the intersection of computer science and pathology,leverages digital technology to enhance diagnostic accuracy and efficiency.With the digitization of pathology and the development of artificial intelligence,computational pathology has made significant strides in the automatic analysis of pathology images,including pathological structure segmentation,tumor classification,and prognosis analysis.Driven by large-scale datasets and advanced methods,computational pathology is moving toward building foundation models to reach more general applications.Generative methods provide a new perspective on addressing challenges in computational pathology.However,challenges in data security and model reliability,reproducibility,and clinical application remain.This review outlines the evolution of computational pathology from pathology slide digitization to pathology image analysis,consolidates the development of foundation and generative models in computational pathology,and discusses the key challenges that persist.Finally,we introduce some rising techniques for precision pathology.展开更多
Objective:To enhance the reading skills of clinical pathology residents,it is essential to establish a well-structured electronic pathology reading library.Methods:In accordance with the Resident Standardization Train...Objective:To enhance the reading skills of clinical pathology residents,it is essential to establish a well-structured electronic pathology reading library.Methods:In accordance with the Resident Standardization Training Content and Standards(2022 Edition),clinical pathology residents are required to master pathological diagnoses across 11 systems:skin,head and neck,mediastinum and respiratory,digestive,urinary and male reproductive,female reproductive and breast,lymphatic and hematopoietic,bone and soft tissue,cardiovascular,central nervous,and endocrine diseases.Senior pathologists specializing in each subspecialty selected classic pathological slides,which were systematically scanned and compiled into an electronic pathology library.Results:A questionnaire survey was conducted to gather feedback on the electronic pathology reading library.Residents generally found it to be convenient,efficient,and conducive to learning.Conclusion:Training in clinical pathology diagnosis is a core component of standardized resident training.The electronic pathology reading library has been well-received and recognized by resident doctors.However,further efforts are needed to explore diverse teaching methods that align with modern educational approaches,ultimately contributing to the development of highly skilled resident doctors.展开更多
Objective:This study aims to develop a deep multiscale image learning system(DMILS)to differentiate malignant from benign thyroid follicular neoplasms on multiscale whole-slide images(WSIs)of intraoperative frozen pat...Objective:This study aims to develop a deep multiscale image learning system(DMILS)to differentiate malignant from benign thyroid follicular neoplasms on multiscale whole-slide images(WSIs)of intraoperative frozen pathological images.Methods:A total of 1,213 patients were divided into training and validation sets,an internal test set,a pooled external test set,and a pooled prospective test set at three centers.DMILS was constructed using a deep learningbased weakly supervised method based on multiscale WSIs at 10×,20×,and 40×magnifications.The performance of the DMILS was compared with that of a single magnification and validated in two pathologist-unidentified subsets.Results:The DMILS yielded good performance,with areas under the receiver operating characteristic curves(AUCs)of 0.848,0.857,0.810,and 0.787 in the training and validation sets,internal test set,pooled external test set,and pooled prospective test set,respectively.The AUC of the DMILS was higher than that of a single magnification,with 0.788 of 10×,0.824 of 20×,and 0.775 of 40×in the internal test set.Moreover,DMILS yielded satisfactory performance on the two pathologist-unidentified subsets.Furthermore,the most indicative region predicted by DMILS is the follicular epithelium.Conclusions:DMILS has good performance in differentiating thyroid follicular neoplasms on multiscale WSIs of intraoperative frozen pathological images.展开更多
Intestinal drug-resistant pathogens,e.g.,Salmonella enterica subsp.enterica serovar Typhimurium(S.Tm)and enteropathogenic Escherichia coli(E.coli),frequently cause life-threatening infectious enteritis.Probiotic-based...Intestinal drug-resistant pathogens,e.g.,Salmonella enterica subsp.enterica serovar Typhimurium(S.Tm)and enteropathogenic Escherichia coli(E.coli),frequently cause life-threatening infectious enteritis.Probiotic-based therapy is a promising way to eliminate drug-resistant pathogens for treatment of infectious enteritis,but its colonizing and therapeutic efficacy after oral administration are limited.Here,we developed a facile therapeutic agent to treat infectious enteritis by co-assembly of the peptide nanodrug melittin-loaded MSN grafted by polysaccharide-binding protein(MMPB)with the famous probiotic bacteria Lactobacillus plantarum(Lac)and Bifidobacterium animalis subsp.lactis(Bif).The nanodrug was composed of the antimicrobial peptide melittin and mesoporous silica nanoparticles exposing the artificial polysaccharide-binding protein.Owing to presence of the artificial protein on the MMPB surface,the nanodrug strongly bound and cross-linked the probiotic cells,forming the Lac+Bif+MMPB co-assembly.During co-incubation with the kanamycin-resistant E.coli strain(Ecka),the co-assembly strongly reduced the viability of Ecka,leading to the increase in the ratio of probiotic to Ecka from 1.6 to 9.2.After oral administration of the co-assembly to themice pre-colonized by Ecka,Lac+Bif+MMPB almost eliminated the kanamycin-resistant gene in the intestine,and led to 2-3-fold higher levels of the probiotic cells than the nanodrug MMPB or the combined probiotics Lac+Bif.More importantly,in the mice suffering from enteritis caused by drug-resistant S.Tm,the co-assembly remarkably recovered the mouse body weight,reduced intestine colonization of S.Tm cells,and decreased the levels of pro-inflammatory cytokines in both serum and colons.This study realized the synthetic biology technique-mediated abiotic/biotic co-assembly for efficient treating infectious enteritis induced by drug-resistant pathogens.展开更多
AIM:To explore the methylation status of MSH6 in retinoblastoma(RB)and its impact on clinicopathological features and diagnosis.METHODS:Differentially expressed genes were identified through bioinformatics screening o...AIM:To explore the methylation status of MSH6 in retinoblastoma(RB)and its impact on clinicopathological features and diagnosis.METHODS:Differentially expressed genes were identified through bioinformatics screening of the GSE24673 and GSE125903 datasets,combined with GeneCards database analysis.A total of 102 RB patients and 62 traumaenucleated controls between January 2018 and December 2023 were enrolled,with their clinicopathological data and retinal tissues collected.The mRNA and methylation levels of MSH6 in retinal tissues were detected using real-time quantitative polymerase chain reaction(PCR)and methylation-specific PCR.Western blot analysis was conducted in one pair of RB and control tissues for preliminary protein-level validation of MSH6 expression.Based on the methylation status of MSH6,RB patients were categorized into two groups:low-methylation and highmethylation.Both univariate and multivariate analyses were conducted to identify independent factors influencing the methylation levels using clinicopathological data.Receiver operating characteristic(ROC)curves were applied to evaluate the diagnostic potential of MSH6 methylation in RB.RESULTS:Bioinformatics analysis of public datasets revealed that MSH6 expression was downregulated across multiple cancers,RB.Consistently,in clinical RB tissues,MSH6 mRNA expression was significantly lower than that in control retinal tissues,whereas the promoter methylation level of MSH6 was markedly higher(both P<0.001),indicating that promoter hypermethylation may contribute to transcriptional silencing of MSH6 in RB.Patients with higher MSH6 methylation levels showed more advanced pathological classification and a higher frequency of metastasis.Multivariate logistic regression confirmed that metastatic status(P=0.008,OR=3.51)and pathological classification(P=0.005,OR=3.7)were independent factors associated with MSH6 methylation.Receiver operating characteristic(ROC)analysis demonstrated that MSH6 methylation could effectively distinguish RB tissues from non-tumorous controls(AUC=0.847,sensitivity=78.43%,specificity=80.65%),suggesting that MSH6 hypermethylation may serve as a potential diagnostic biomarker for RB.CONCLUSION:The methylation level of the MSH6 gene may be a key factor in RB pathogenesis.The methylation status of the MSH6 gene is closely associated with clinicopathological features and shows diagnostic potential.展开更多
Ovarian endometrioid carcinoma(OEC)accounts for~10%of epithelial ovarian cancers and displays broad morphologic diversity that complicates diagnosis and grading.Recent data show that the endometrial cancer molecular t...Ovarian endometrioid carcinoma(OEC)accounts for~10%of epithelial ovarian cancers and displays broad morphologic diversity that complicates diagnosis and grading.Recent data show that the endometrial cancer molecular taxonomy(DNA polymerase epsilon,catalytic subunit[POLE]-ultramutated,mismatch repair-deficient[MMRd],p53-abnormal,no specific molecular profile[NSMP])also applies to OEC,and that OEC is enriched for Lynch syndrome–associated tumors,supporting routine MMR testing.We aimed to synthesize contemporary evidence spanning epidemiology,histopathology and immunophenotype,diagnostic pitfalls and differential diagnosis,and to evaluate the clinical utility of The Cancer Genome Atlas(TCGA)-surrogate molecular classification for risk stratification;we also summarize implications for Lynch screening,genetic counseling,and therapeutic opportunities including immune checkpoint inhibitors and targeted approaches,with practical recommendations for diagnostic workflows.Integrating morphology with molecular classification refines diagnosis and prognostication:POLEmut/MMRd subsets generally have excellent outcomes and are candidates for de-escalation or immunotherapy,whereas p53abn/high-grade tumors carry a poorer prognosis and may warrant intensified management and trials of homologous recombination deficiency(HRD)-directed strategies;routine MMR immunohistochemistry(IHC)with reflex germline testing improves Lynch detection,and future priorities include prospective validation and multi-omics to refine NSMP and identify new targets.展开更多
Background Clostridium perfringens is a pathogen that secretes multiple toxins,impacting humans and animals.It can cause intestinal diseases such as necrotic enteritis.Although tannins inhibit C.perfringens proliferat...Background Clostridium perfringens is a pathogen that secretes multiple toxins,impacting humans and animals.It can cause intestinal diseases such as necrotic enteritis.Although tannins inhibit C.perfringens proliferation,the precise underlying mechanisms are unclear.Objective This study integrated transcriptomics and metabolomics to systematically investigate the mechanism by which tannins,specifically pentagalloylglucose(PGG)and tannic acid(TA),inhibit C.perfringens and potential pathways to alleviate infection in vivo.Results Ion concentration measurements,flow cytometric analysis,and transmission electron microscopy revealed that PGG and TA damaged the cell membrane structure of C.perfringens,triggering cytoplasmic content leakage.Additionally,PGG and TA significantly affected C.perfringens at the transcriptional and metabolic levels.Bioinformatics analysis revealed that PGG and TA induced amino acid restriction,disrupted energy metabolism,and impeded the ability of C.perfringens to sense and respond to the external environment.In an in vitro C.perfringens-infected intestinal cell model,PGG and TA boundαtoxin,significantly reduced the mRNA expression of inflammatory factors,and improved intestinal barrier function and cell viability.Compared to PGG,TA exhibited stronger inhibitory activity against C.perfringens and binding toαtoxin.In vivo,PGG and TA alleviated C.perfringens-induced weight loss in mice,improved intestinal villi morphology,and reduced intestinal inflammation and tight junction gene dysregulation.Conclusion These findings indicate that tannins inhibit C.perfringens,improve gut tissue integrity and reduce inflammation,demonstrating their multi-target effects of resisting intestinal diseases caused by harmful bacteria.This offers new insights for plant polyphenol-based strategies against necrotic enteritis.展开更多
Enteritis,involving inflammation of the small intestine,is often accompanied by immune cell dysfunction during intestinal infections.Immunomodulatory β-glucans(BGs)have recently been shown to support antibacterial im...Enteritis,involving inflammation of the small intestine,is often accompanied by immune cell dysfunction during intestinal infections.Immunomodulatory β-glucans(BGs)have recently been shown to support antibacterial immune responses through the induction of trained immunity.However,little is known about the potential role of BG pretreatment in protecting against infectious enteritis in teleost fish.In this work,by establishing an adult zebrafish enteritis model via infection with the fish pathogen Edwardsiella piscicida and pretreating it with BGs,we demonstrated that such pretreatment confers protection against infectious enteritis,accompanied by reduced production of proinflammatory cytokines.Specifically,we found that BG pretreatment could amplify intestinal lectin pathway-associated complement activation to ameliorate the infectious enteritis.Moreover,through comprehensive RNA-seq analysis of immune cell marker genes in zebrafish,we revealed that the lectin pathway amplification by BG pretreatment modulated the responsiveness of intestinal Th17 cells,which was essential for the protection against infectious enteritis.Collectively,these findings identify the intestinal lectin pathway as a potential mediator of the effects of BG pretreatment and reveal its role in maintaining the function of Th17 cells in zebrafish.This suggests that harnessing BG-induced trained immunity might represent a promising therapeutic strategy against infectious enteritis in teleost.展开更多
基金supported by a grant from the Japan Foundation for applied enzymology (to NT)the Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (26430059, 17K08272, and 20K07014 to NT)+1 种基金the establishment of university fellowships toward the creation of science technology innovation (JPMJFS2128)a Grant-in-Aid for JSPS Fellows (23KJ1603)(to MK)。
文摘The purpose of this perspective is to discuss the future development of a potential treatment of glial pathology in Alzheimer's disease(AD) and a new regulatory mechanism, nuclear lipids, which may be involved in the pathogenesis of the disease, based on the work of the authors(Takasugi et al., 2011;Komai et al., 2024).
文摘Uveal melanoma(UM)is the most common intraocular cancer,with approximately 5.2 individuals per million affected annually in the United States.It represents approximately 3%of the global malignant melanoma cases,accounting for 80%of the overall noncutaneous melanomas.Clinically,it remains silent in about 30%of the cases;when symptomatic,it generally causes metamorphopsia(painless loss or distortion of vision)and/or photopsia(flashing or flickering of light in the visual field).Discoloration of the iris,astigmatism,glaucoma,and even blindness are other,less common clinical manifestations.Several pathophysiological mechanisms underlie the development of UM.Genetic mutations,involving especially the G protein subunit alpha q(GNAQ),guanine nucleotide-binding protein subunit alpha-11(GNA11),BRCA1 associated deubiquitinase 1(BAP1),splicing factor 3b subunit 1(SF3B1),and eukaryotic translation initiation factor 1A,X-linked(EIF1AX)genes as well as the MAPK/ERK signaling pathway genes,have been largely associated with the development of UM.Chromosomal aberrations,inflammatory and immunological alterations are often concurrent factors for the development and progression of UM.Therapies targeting specific genetic alterations and immunotherapy agents have been recently developed and introduced in clinical practice for the management of advanced-stage UMs.This review aims to present the latest advances in the clinical molecular pathology of UM,along with the resulting targeted,immunological,and other therapies that have been introduced or are currently under investigation.
基金supported by Swiss Center for Applied Human Toxicology(SCAHT AP22-01)(to RN)。
文摘Parkinson's disease(PD)is the second most common neurodegenerative disorder.The clinical manifestations of PD include motor symptoms,such as bradykinesia,resting tremor,rigidity,and nonmotor symptoms,which include disturbances in sleep,gastrointestinal function,and olfaction.PD misdiagnosis rates have been reported to reach approximately 30%,partly owing to the heterogeneity of parkinsonism with non-PD pathologies,and the differential diagnosis of PD from neurodegenerative diseases such as multiple systemic atrophy(MSA)and progressive supranuclear palsy poses another unmet need.
基金supported by the Canadian Institutes of Health Research Project grant (PJT-169197) to QYsupported by a CGS-M fellowship from the Canadian Institutes of Health Research
文摘Alzheimer’s disease(AD)remains an incurable neurodegenerative disorder with devastating societal and personal impacts.Despite decades of intensive research,therapeutic efforts targeting the clinical stages of AD have largely failed to halt or reverse disease progression.This has prompted a critical shift in focus toward the earlier,preclinical stages of AD,where interventions may hold greater promise for altering the disease trajectory.
基金Supported by the Mational Mature Scientific Foundation of China,No.39970561Funds for the Leeders in Academia of Sichuan Province,No.9900009240018.
文摘AIM: To study the purifying method and characteristics of new gosling viral enteritis virus (NGVEV),the etiological agent of new gosling viral enteritis (NGVE) which was first recognized in China, as well as the pathomorphological development in goslings infected artificially with NGVEV. METHODS: (1)NGVEV virions were purified by the procedure of treatment with chloroform and ammonium sulfate precipitation, dialysis to remove the sulfate radical and ammonium ion and separation by gel filtration chromatography, and SDS-PAGE. (2)Forty-2-day-old White Sichuan goslings were orally administered with NGVEV and 24 hr later 2 birds were randomly selected and killed at 24hr intervals until death occurred. Specimens(duodenum, ileum, liver, heart, kidney, spleen, lung, proventriculus, pancreas, esophagus, and the intestinal embolus) were taken until all birds in this group died and were sectioned and stained with hemotoxylin and eosin and studied by light microscope. RESULTS: NGVEV shared the typical characteristics of Adenovirus and which structural proteins consisted of 15 polypeptides. Necrosis and sloughing of the epithelial cells covering the villus tips of the duodenum were first observed in goslings 2 days postinfection artificially with NGVEV. With the progress of infection, this lesion rapidly occurred in the epithelium at the base of the villus and with infiltration of the inflammatory cells, the jejunum tended to be involved. With the intensification of mucosa necrosis and inflammatory exudation of the small intestine, fibrinonecrotic enteritis was further developed and embolus composed of either intestinal contents wrapped by pseudo-membrane or of the mixture of fibrous exudate and necrotic intestinal mucosa were observed in the middle-lower part of the small intestine. This structure occluded the intestinal tract and made the intestine dilated in appearance. The intestinal glandular cells underwent degeneration, necrosis and might be found sloughed into the lumen. Hemorrhage and hyperemia could be observed on the lung and kidney. Epithelial cells of the renal tubular underwent degeneration. In some cases, granular degeneration and fatty degeneration could be found in the liver and in some cases at a later stage of this disease the epithelial cells of trachea and proventriculus might be found sloughed. In some cases at an early stage of this disease, cardiac hyperemia and hemorrhage could be observed. Esophagus, pancreas and brain were found normal. Analyses and comparisons between the pathologic lesions of NGVE and Gosling Plague (GP) were available in this paper as well. CONCLUSION: (1)NGVEV is adenovirus. (2)Pathological characteristic could be as the data for NGVE diagnosis.
基金Supported by the Italian Ministry of Education, University and Research (CCOFIN Project No. 2004062155 to RDeG,2004055120 to GB and 2003064378 to RDeG, GB and VS)
文摘Experimental evidence indicates that chronic mechanical sub-occlusion of the intestine may damage the enteric nervous system （ENS）, although data in humans are lacking. We here describe the first case of enteric degenerative neuropathy related to a congenital obstruction of the gut. A 3-year and 9-mo old girl began to complain of vomiting, abdominal distension, constipation with air-fluid levels at plane abdominal radiology. Her subsequent medical history was characterized by 3 operations： the first showed dilated duodeno-jejunal loops in the absence of occlusive lesions; the second （2 years later） was performed to obtain full-thickness biopsies of the dilated intestinal loops and revealed hyperganglionosis at histopathology; the third （9 years after the hyperganglionosis was identified） disclosed a Ladd＇s band which was removed and the associated gut malrotation was corrected. Repeated intraoperative full-thickness biopsies showed enteric degenerative neuropathy along with reduced interstitial cells of Cajal network in dilated loops above the obstruction and a normal neuromuscular layer below the Ladd＇s band. One year after the latest surgery the patient tolerated oral feeding and did well, suggesting that congenital （partial） mechanical obstruction of the small bowel in humans can evoke progressive adaptive changes of the ENS which are similar to those found in animal models of intestinal mechanical occlusion. Such ENS changes mimic neuronal abnormalities observed in intestinal pseudoobstruction.
基金provided by the precise assessment of the combined toxic effects of major mycotoxins on monogastric animals(2023YFD1301002).
文摘Background Necrotic enteritis(NE)can cause intestinal barrier dysfunction in broilers,leading to secondary liver injury(SLI).In this process,the gut-liver axis plays a crucial role.Lonicerae flos and turmeric extracts(LTE),containing chlorogenic acid and curcumin,have been reported to possess anti-inflammatory,and antioxidant properties.Based on these potential biological benefits,this study aims to investigate the reparative effects of LTE on the intestinal barrier dysfunction in NE-infected broilers and assess its therapeutic efficacy in alleviating SLI.By elucidating the regulatory mechanisms of LTE on gut-liver axis health,this research provides new insights into the prevention and treatment of NE in broilers.Results LTE improved body weight and average daily gain while reducing intestinal lesion scores,coccidia oocysts,and Clostridium perfringens counts in NE broilers(P<0.05).LTE enhanced intestinal morphology and up-regulated the expression of tight junction protein genes(CLDN1,TJP1)and MUC2,suppressed pro-inflammatory cytokine and myeloperoxidase(MPO)levels,and minimized endotoxin(ET)accumulation in NE broilers(P<0.05).Furthermore,LTE alleviated oxidative stress in ileal cells and protected mitochondrial structure and function in NE broilers.NE infection induced intestinal permeability in broilers,leading to increased serum pro-inflammatory cytokines and intestinal-derived endotoxin levels,which caused liver damage.LTE significantly reduced liver pathologic damage,pro-inflammatory cytokine levels,aspartate transaminase,alanine aminotransferase,and ROS levels in NE broilers(P<0.05).Additionally,16S rRNA sequencing revealed that NE significantly increased the relative abundance of Barnesiella and decreased the relative abundance of Bacteroidota,Desulfobacterota and Bacteroides in the cecum of broilers.LTE enhanced intestinal microbiota diversity and reduced the segregation of intestinal microbiota induced by NE infection.Conclusions In summary,LTE can alleviate NE and SLI by modulating the microbiota,inhibiting inflammation and oxidative stress,and ameliorating mitochondrial dysfunction,thereby enhancing gut-liver axis health and growth performance.
基金supported by China Agriculture Research System Program(Project No.CARS-41-G04)。
文摘Background Necrotic enteritis(NE)in broiler chickens leads to significant economic losses in poultry production.This study examined the inhibitory effects of usnic acid and tannic acid on coccidia,sporozoite,and Clostridium perfringens and assessed their influence on growth performance and intestinal health in NE-challenged broilers through in vitro and in vivo experiments.Methods The in vitro experiment included 5 treatment groups:the negative control(NC),2μmol/L diclazuril(DZ),30μmol/L usnic acid(UA),90μmol/L tannic acid(TA),and 15μmol/L usnic acid^(+)45μmol/L tannic acid(UTA)groups.The in vivo experiment involved 320 broilers divided into four groups:PC(NE-challenged),SA(500 mg/kg salinomycin premix^(+)NE-challenged),UA(300 mg/kg usnic acid^(+)NE-challenged),and UTA(300 mg/kg usnic acid^(+)500 mg/kg tannic acid^(+)NE-challenged)groups.Results In the in vitro study,the UA,TA,and UTA treatments significantly increased apoptosis in coccidian oocysts and sporozoites,lowered the mitochondrial membrane potential(P<0.05),and disrupted the oocyst structure compared with those in the NC group.UA and TA had inhibitory effects on C.perfringens,with the strongest inhibition observed in the UTA group.The in vivo results demonstrated that the SA group presented significantly improved growth performance on d 13,21,and 28(P<0.05),whereas the UA and UTA groups presented improvements on d 13 and 21(P<0.05).The SA,UA,and UTA treatments reduced the intestinal lesion scores by d 28 and the fecal coccidian oocyst counts from d 19 to 21(P<0.05).Compared with the PC group,the UA and UTA groups presented lower intestinal sIgA levels and CD8^(+)cell percentages(P<0.05),with a trend toward a reduced CD3^(+)cell percentage(P=0.069).The SA,UA,and UTA treatments significantly reduced the serum diamine oxidase activity,crypt depth,and plateletderived growth factor levels in the intestinal mucosa while increasing the villus height to crypt depth ratio and number of goblet cells(P<0.05).The UTA treatment also significantly increased the acetate and butyrate concentrations in the cecum(P<0.05).With respect to the gut microbiota,significant changes inβdiversity in the ileum and cecum were observed in the SA,UA,and UTA groups,indicating that the microbial community compositions differed among the groups.Romboutsia dominated the SA group,Bacillales dominated the UA group,and Lactobacillales and Lachnospirales dominated the UTA group in the ileal microbiota.In the cecal microbiota,Lactobacillus,Butyricicoccus,and Blautia abundances were significantly elevated in the UTA group(P<0.05).Conclusion Usnic acid and tannic acid induce apoptosis in coccidia and sporozoites by lowering the mitochondrial membrane potential.Both usnic acid alone and in combination with tannic acid alleviate NE-induced adverse effects in broilers by modulating intestinal immunity,altering the microbial composition,and improving intestinal barrier function.Compared with usnic acid alone,the combination of usnic acid and tannic acid had superior effects,providing a promising basis for the development of effective feed additive combinations.
文摘Alzheimer's disease (AD) is characterized by an imbalance between excitatory and inhibitory brain networks,leading to aberrant homeostatic synaptic plasticity.AD has progressively been recognized as syna ptopathy and syna ptic dysfunction has been identified as a key component of its pathogenesis (Schirinzi et al.,2020).Syna ptic dysfunction is believed to precede synapse loss,a primary biological correlate of cognitive decline in AD,inevita bly associated with neuronal death.
基金supported by the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2023-JKCS-23)the Special Research Fund for Central Universities,Peking Union Medical College[No.2022-I2M-C&T-A-014,CAMS Innovation Fund for Medical Sciences(CIFMS)]。
文摘Objective:Neoadjuvant therapy(NAT)has become the standard treatment option for patients with locally advanced breast cancer.How to non-invasively screen out patients with pathological complete response(pCR)after NAT has become an urgent world-wide clinical problem.Our work aims to the assessment of neoadjuvant treatment response in breast cancer patients for higher accuracy prediction using innovative artificial intelligence system.Methods:In this study,we retrospectively collected longitudinal(pre-NAT and post-NAT)multi-parametric magnetic resonance imaging(MRI)and clinicopathologic data of a total of 1,315 breast cancer patients(clinical stageⅠ-Ⅲ)who had undergone NAT followed by standard surgery and treated across 5 independent medical centers from January 2010 to January 2023.We used radiomics,3D convolutional neural network technology and clinical data statistical analysis methods to extract and screen multimodal features,and then developed and validated a Clinical-Radiomics-Deep-Learning(CRDL)model to predict patients'pCR outcomes based on multimodal fusion features.Results:We use the area under the receiver operating characteristic curve(AUC)in the primary cohort(PC)and3 external validation cohorts(VC_(1-3))to evaluate the model performance.The results showed that the AUC in the PC composed of 2 medical centers was 0.947[95%confidence interval(95%CI):0.931-0.960],and the AUC values in VC_(1-3)were 0.857(95%CI:0.810-0.901),0.883(95%CI:0.841-0.918)and 0.904(95%CI:0.860-0.941),respectively.Conclusions:The CRDL model demonstrated high accuracy and robustness in predicting pCR to NAT using multimodal fusion data.This study provides a strong foundation for non-invasive assessment of pCR status in breast cancer patients following NAT and offers critical insights to guide clinical decision-making in post-NAT treatment planning.
基金supported by the National Natural Science Foundation of China under Grant 62371409Fujian Provincial Natural Science Foundation of China under Grant 2023J01005.
文摘In pathological examinations,tissue must first be stained to meet specific diagnostic requirements,a meticulous process demanding significant time and expertise from specialists.With advancements in deep learning,this staining process can now be achieved through computational methods known as virtual staining.This technique replicates the visual effects of traditional histological staining in pathological imaging,enhancing efficiency and reducing costs.Extensive research in virtual staining for pathology has already demonstrated its effectiveness in generating clinically relevant stained images across a variety of diagnostic scenarios.Unlike previous reviews that broadly cover the clinical applications of virtual staining,this paper focuses on the technical methodologies,encompassing current models,datasets,and evaluation methods.It highlights the unique challenges of virtual staining compared to traditional image translation,discusses limitations in existing work,and explores future perspectives.Adopting a macro perspective,we avoid overly intricate technical details to make the content accessible to clinical experts.Additionally,we provide a brief introduction to the purpose of virtual staining from a medical standpoint,which may inspire algorithm-focused researchers.This paper aims to promote a deeper understanding of interdisciplinary knowledge between algorithm developers and clinicians,fostering the integration of technical solutions and medical expertise in the development of virtual staining models.This collaboration seeks to create more efficient,generalized,and versatile virtual staining models for a wide range of clinical applications.
基金supported by the National Research Foundation of Korea (NRF)funded by the Ministry of Science,ICT&Future Planning (2022R1A2C2006229,2022R1A6A3A01086868)Korea Dementia Research Project through the Korea Dementia Research Center (KDRC)funded by the Ministry of Health&Welfare and Ministry of Science and ICT,Republic of Korea (RS-2024-00345328)KIST Institutional Grant (2E32851)。
文摘Alzheimer'sdisease(AD)isaprogressive neurodegenerative disorder characterized by cognitive impairment and distinct neuropathological features,including amyloid-βplaques,neurofibrillary tangles,and reactive astrogliosis.Developing effective diagnostic,preventative,and therapeutic strategies for AD necessitates the establishment of animal models that accurately recapitulate the pathophysiological processes of the disease.Existing transgenic mouse models have significantly contributed to understanding AD pathology but often fail to replicate the complexity of human AD.Additionally,these models are limited in their ability to elucidate the interplay among amyloid-βplaques,neurofibrillary tangles,and reactive astrogliosis due to the absence of spatially and temporally specific genetic manipulation.In this study,we introduce a novel AD mouse model(APP/PS1-TauP301L-Adeno mice)designed to rapidly induce pathological symptoms and enhance understanding of AD mechanisms.Neurofibrillary tangles and severe reactive astrogliosis were induced by injecting AAVDJ-EF1a-hTauP301L-EGFP and Adeno-GFAP-GFP viruses into the hippocampi of 5-month-old APP/PS1 mice.Three months post-injection,these mice exhibited pronounced astrogliosis,substantial amyloid-βplaque accumulation,extensiveneurofibrillarytangles,accelerated neuronal loss,elevated astrocytic GABA levels,and significant spatial memory deficits.Notably,these pathological features were less severe in AAVTauP301L-expressing APP/PS1 mice without augmented reactive astrogliosis.These findings indicate an exacerbating role of severe reactive astrogliosis in amyloid-βplaque and neurofibrillary tangle-associated pathology.The APP/PS1-TauP301L-Adeno mouse model provides a valuable tool for advancing therapeutic research aimed at mitigating the progression of AD.
基金supported in part by the Shenzhen Natural Science Fund(the Stable Support Plan Program 20220810144949003)the Key Technology Development Program of Shenzhen(JSGG20210713091811036)+2 种基金the Key-Area Research and Development Program of Guangdong Province(2021B0101420005)the Shenzhen Key Laboratory Foundation(ZDSYS20200811143757022)the Guangdong Provincial Key Laboratory of Mathematical and Neural Dynamical Systems(2024B1212010004).
文摘Computational pathology,a field at the intersection of computer science and pathology,leverages digital technology to enhance diagnostic accuracy and efficiency.With the digitization of pathology and the development of artificial intelligence,computational pathology has made significant strides in the automatic analysis of pathology images,including pathological structure segmentation,tumor classification,and prognosis analysis.Driven by large-scale datasets and advanced methods,computational pathology is moving toward building foundation models to reach more general applications.Generative methods provide a new perspective on addressing challenges in computational pathology.However,challenges in data security and model reliability,reproducibility,and clinical application remain.This review outlines the evolution of computational pathology from pathology slide digitization to pathology image analysis,consolidates the development of foundation and generative models in computational pathology,and discusses the key challenges that persist.Finally,we introduce some rising techniques for precision pathology.
文摘Objective:To enhance the reading skills of clinical pathology residents,it is essential to establish a well-structured electronic pathology reading library.Methods:In accordance with the Resident Standardization Training Content and Standards(2022 Edition),clinical pathology residents are required to master pathological diagnoses across 11 systems:skin,head and neck,mediastinum and respiratory,digestive,urinary and male reproductive,female reproductive and breast,lymphatic and hematopoietic,bone and soft tissue,cardiovascular,central nervous,and endocrine diseases.Senior pathologists specializing in each subspecialty selected classic pathological slides,which were systematically scanned and compiled into an electronic pathology library.Results:A questionnaire survey was conducted to gather feedback on the electronic pathology reading library.Residents generally found it to be convenient,efficient,and conducive to learning.Conclusion:Training in clinical pathology diagnosis is a core component of standardized resident training.The electronic pathology reading library has been well-received and recognized by resident doctors.However,further efforts are needed to explore diverse teaching methods that align with modern educational approaches,ultimately contributing to the development of highly skilled resident doctors.
基金supported by the Taishan Scholar Project(No.ts20190991,tsqn202211378)the Key R&D Project of Shandong Province(No.2022CXPT023)the General Program of National Natural Science Foundation of China(No.82371933)。
文摘Objective:This study aims to develop a deep multiscale image learning system(DMILS)to differentiate malignant from benign thyroid follicular neoplasms on multiscale whole-slide images(WSIs)of intraoperative frozen pathological images.Methods:A total of 1,213 patients were divided into training and validation sets,an internal test set,a pooled external test set,and a pooled prospective test set at three centers.DMILS was constructed using a deep learningbased weakly supervised method based on multiscale WSIs at 10×,20×,and 40×magnifications.The performance of the DMILS was compared with that of a single magnification and validated in two pathologist-unidentified subsets.Results:The DMILS yielded good performance,with areas under the receiver operating characteristic curves(AUCs)of 0.848,0.857,0.810,and 0.787 in the training and validation sets,internal test set,pooled external test set,and pooled prospective test set,respectively.The AUC of the DMILS was higher than that of a single magnification,with 0.788 of 10×,0.824 of 20×,and 0.775 of 40×in the internal test set.Moreover,DMILS yielded satisfactory performance on the two pathologist-unidentified subsets.Furthermore,the most indicative region predicted by DMILS is the follicular epithelium.Conclusions:DMILS has good performance in differentiating thyroid follicular neoplasms on multiscale WSIs of intraoperative frozen pathological images.
基金supported by National Natural Science Foundation of China(32170102)Natural Science Foundation of Tianjin(25JCLMJC00400)the Fundamental Research Funds for the Central Universities(63253191).
文摘Intestinal drug-resistant pathogens,e.g.,Salmonella enterica subsp.enterica serovar Typhimurium(S.Tm)and enteropathogenic Escherichia coli(E.coli),frequently cause life-threatening infectious enteritis.Probiotic-based therapy is a promising way to eliminate drug-resistant pathogens for treatment of infectious enteritis,but its colonizing and therapeutic efficacy after oral administration are limited.Here,we developed a facile therapeutic agent to treat infectious enteritis by co-assembly of the peptide nanodrug melittin-loaded MSN grafted by polysaccharide-binding protein(MMPB)with the famous probiotic bacteria Lactobacillus plantarum(Lac)and Bifidobacterium animalis subsp.lactis(Bif).The nanodrug was composed of the antimicrobial peptide melittin and mesoporous silica nanoparticles exposing the artificial polysaccharide-binding protein.Owing to presence of the artificial protein on the MMPB surface,the nanodrug strongly bound and cross-linked the probiotic cells,forming the Lac+Bif+MMPB co-assembly.During co-incubation with the kanamycin-resistant E.coli strain(Ecka),the co-assembly strongly reduced the viability of Ecka,leading to the increase in the ratio of probiotic to Ecka from 1.6 to 9.2.After oral administration of the co-assembly to themice pre-colonized by Ecka,Lac+Bif+MMPB almost eliminated the kanamycin-resistant gene in the intestine,and led to 2-3-fold higher levels of the probiotic cells than the nanodrug MMPB or the combined probiotics Lac+Bif.More importantly,in the mice suffering from enteritis caused by drug-resistant S.Tm,the co-assembly remarkably recovered the mouse body weight,reduced intestine colonization of S.Tm cells,and decreased the levels of pro-inflammatory cytokines in both serum and colons.This study realized the synthetic biology technique-mediated abiotic/biotic co-assembly for efficient treating infectious enteritis induced by drug-resistant pathogens.
文摘AIM:To explore the methylation status of MSH6 in retinoblastoma(RB)and its impact on clinicopathological features and diagnosis.METHODS:Differentially expressed genes were identified through bioinformatics screening of the GSE24673 and GSE125903 datasets,combined with GeneCards database analysis.A total of 102 RB patients and 62 traumaenucleated controls between January 2018 and December 2023 were enrolled,with their clinicopathological data and retinal tissues collected.The mRNA and methylation levels of MSH6 in retinal tissues were detected using real-time quantitative polymerase chain reaction(PCR)and methylation-specific PCR.Western blot analysis was conducted in one pair of RB and control tissues for preliminary protein-level validation of MSH6 expression.Based on the methylation status of MSH6,RB patients were categorized into two groups:low-methylation and highmethylation.Both univariate and multivariate analyses were conducted to identify independent factors influencing the methylation levels using clinicopathological data.Receiver operating characteristic(ROC)curves were applied to evaluate the diagnostic potential of MSH6 methylation in RB.RESULTS:Bioinformatics analysis of public datasets revealed that MSH6 expression was downregulated across multiple cancers,RB.Consistently,in clinical RB tissues,MSH6 mRNA expression was significantly lower than that in control retinal tissues,whereas the promoter methylation level of MSH6 was markedly higher(both P<0.001),indicating that promoter hypermethylation may contribute to transcriptional silencing of MSH6 in RB.Patients with higher MSH6 methylation levels showed more advanced pathological classification and a higher frequency of metastasis.Multivariate logistic regression confirmed that metastatic status(P=0.008,OR=3.51)and pathological classification(P=0.005,OR=3.7)were independent factors associated with MSH6 methylation.Receiver operating characteristic(ROC)analysis demonstrated that MSH6 methylation could effectively distinguish RB tissues from non-tumorous controls(AUC=0.847,sensitivity=78.43%,specificity=80.65%),suggesting that MSH6 hypermethylation may serve as a potential diagnostic biomarker for RB.CONCLUSION:The methylation level of the MSH6 gene may be a key factor in RB pathogenesis.The methylation status of the MSH6 gene is closely associated with clinicopathological features and shows diagnostic potential.
基金supported by the Japan Society for the Promotion of Science(JSPS KAKENHI Grant Number 24K12615).
文摘Ovarian endometrioid carcinoma(OEC)accounts for~10%of epithelial ovarian cancers and displays broad morphologic diversity that complicates diagnosis and grading.Recent data show that the endometrial cancer molecular taxonomy(DNA polymerase epsilon,catalytic subunit[POLE]-ultramutated,mismatch repair-deficient[MMRd],p53-abnormal,no specific molecular profile[NSMP])also applies to OEC,and that OEC is enriched for Lynch syndrome–associated tumors,supporting routine MMR testing.We aimed to synthesize contemporary evidence spanning epidemiology,histopathology and immunophenotype,diagnostic pitfalls and differential diagnosis,and to evaluate the clinical utility of The Cancer Genome Atlas(TCGA)-surrogate molecular classification for risk stratification;we also summarize implications for Lynch screening,genetic counseling,and therapeutic opportunities including immune checkpoint inhibitors and targeted approaches,with practical recommendations for diagnostic workflows.Integrating morphology with molecular classification refines diagnosis and prognostication:POLEmut/MMRd subsets generally have excellent outcomes and are candidates for de-escalation or immunotherapy,whereas p53abn/high-grade tumors carry a poorer prognosis and may warrant intensified management and trials of homologous recombination deficiency(HRD)-directed strategies;routine MMR immunohistochemistry(IHC)with reflex germline testing improves Lynch detection,and future priorities include prospective validation and multi-omics to refine NSMP and identify new targets.
基金The China Agriculture Research System Program(Project No.CARS-41-G04)Shenyang Governmental Science and Technology Program(Project No.22316-2-02)supported this work.
文摘Background Clostridium perfringens is a pathogen that secretes multiple toxins,impacting humans and animals.It can cause intestinal diseases such as necrotic enteritis.Although tannins inhibit C.perfringens proliferation,the precise underlying mechanisms are unclear.Objective This study integrated transcriptomics and metabolomics to systematically investigate the mechanism by which tannins,specifically pentagalloylglucose(PGG)and tannic acid(TA),inhibit C.perfringens and potential pathways to alleviate infection in vivo.Results Ion concentration measurements,flow cytometric analysis,and transmission electron microscopy revealed that PGG and TA damaged the cell membrane structure of C.perfringens,triggering cytoplasmic content leakage.Additionally,PGG and TA significantly affected C.perfringens at the transcriptional and metabolic levels.Bioinformatics analysis revealed that PGG and TA induced amino acid restriction,disrupted energy metabolism,and impeded the ability of C.perfringens to sense and respond to the external environment.In an in vitro C.perfringens-infected intestinal cell model,PGG and TA boundαtoxin,significantly reduced the mRNA expression of inflammatory factors,and improved intestinal barrier function and cell viability.Compared to PGG,TA exhibited stronger inhibitory activity against C.perfringens and binding toαtoxin.In vivo,PGG and TA alleviated C.perfringens-induced weight loss in mice,improved intestinal villi morphology,and reduced intestinal inflammation and tight junction gene dysregulation.Conclusion These findings indicate that tannins inhibit C.perfringens,improve gut tissue integrity and reduce inflammation,demonstrating their multi-target effects of resisting intestinal diseases caused by harmful bacteria.This offers new insights for plant polyphenol-based strategies against necrotic enteritis.
基金supported by the National Key Research and Development Program of China (2022YFC2804300)Key Program of National Natural Science of China (32430110)+1 种基金Shuguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission (24SG31)Fundamental Research Funds for the Central Universities (222201241733)。
文摘Enteritis,involving inflammation of the small intestine,is often accompanied by immune cell dysfunction during intestinal infections.Immunomodulatory β-glucans(BGs)have recently been shown to support antibacterial immune responses through the induction of trained immunity.However,little is known about the potential role of BG pretreatment in protecting against infectious enteritis in teleost fish.In this work,by establishing an adult zebrafish enteritis model via infection with the fish pathogen Edwardsiella piscicida and pretreating it with BGs,we demonstrated that such pretreatment confers protection against infectious enteritis,accompanied by reduced production of proinflammatory cytokines.Specifically,we found that BG pretreatment could amplify intestinal lectin pathway-associated complement activation to ameliorate the infectious enteritis.Moreover,through comprehensive RNA-seq analysis of immune cell marker genes in zebrafish,we revealed that the lectin pathway amplification by BG pretreatment modulated the responsiveness of intestinal Th17 cells,which was essential for the protection against infectious enteritis.Collectively,these findings identify the intestinal lectin pathway as a potential mediator of the effects of BG pretreatment and reveal its role in maintaining the function of Th17 cells in zebrafish.This suggests that harnessing BG-induced trained immunity might represent a promising therapeutic strategy against infectious enteritis in teleost.
