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Importance: Diagnosing solid lesions in the pancreas via endoscopic ultrasonographic (EUS) images is challenging. Artificial intelligence (AI) has the potential to help with such diagnosis, but existing AI models focus solely on a single modality. Objective: To advance the clinical diagnosis of solid lesions in the pancreas through developing a multimodal AI model integrating both clinical information and EUS images. Design, Setting, and Participants: In this randomized crossover trial conducted from January 1 to June 30, 2023, from 4 centers across China, 12 endoscopists of varying levels of expertise were randomly assigned to diagnose solid lesions in the pancreas with or without AI assistance. Endoscopic ultrasonographic images and clinical information of 439 patients from 1 institution who had solid lesions in the pancreas between January 1, 2014, and December 31, 2022, were collected to train and validate the joint-AI model, while 189 patients from 3 external institutions were used to evaluate the robustness and generalizability of the model. Intervention: Conventional or AI-assisted diagnosis of solid lesions in the pancreas. Main Outcomes and Measures: In the retrospective dataset, the performance of the joint-AI model was evaluated internally and externally. In the prospective dataset, diagnostic performance of the endoscopists with or without the AI assistance was compared. Results: The retrospective dataset included 628 patients (400 men [63.7%]; mean [SD] age, 57.7 [27.4] years) who underwent EUS procedures. A total of 130 patients (81 men [62.3%]; mean [SD] age, 58.4 [11.7] years) were prospectively recruited for the crossover trial. The area under the curve of the joint-AI model ranged from 0.996 (95% CI, 0.993-0.998) in the internal test dataset to 0.955 (95% CI, 0.940-0.968), 0.924 (95% CI, 0.888-0.955), and 0.976 (95% CI, 0.942-0.995) in the 3 external test datasets, respectively. The diagnostic accuracy of novice endoscopists was significantly enhanced with AI assistance (0.69 [95% CI, 0.61-0.76] vs 0.90 [95% CI, 0.83-0.94]; P < .001), and the supplementary interpretability information alleviated the skepticism of the experienced endoscopists. Conclusions and Relevance: In this randomized crossover trial of diagnosing solid lesions in the pancreas with or without AI assistance, the joint-AI model demonstrated positive human-AI interaction, which suggested its potential to facilitate a clinical diagnosis. Nevertheless, future randomized clinical trials are warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT05476978.
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Inteligência Artificial , Estudos Cross-Over , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Endossonografia/métodos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/diagnóstico por imagem , Adulto , Pâncreas/diagnóstico por imagem , China , Estudos RetrospectivosRESUMO
Respiratory syncytial virus (RSV) hijacks cholesterol or autophagy pathways to facilitate optimal replication. However, our understanding of the associated molecular mechanisms remains limited. Here, we show that RSV infection blocks cholesterol transport from lysosomes to the endoplasmic reticulum by downregulating the activity of lysosomal acid lipase, activates the SREBP2-LDLR axis, and promotes uptake and accumulation of exogenous cholesterol in lysosomes. High cholesterol levels impair the VAP-A-binding activity of ORP1L and promote the recruitment of dynein-dynactin, PLEKHM1, or HOPS VPS39 to Rab7-RILP, thereby facilitating minus-end transport of autophagosomes and autolysosome formation. Acidification inhibition and dysfunction of cholesterol-rich lysosomes impair autophagy flux by inhibiting autolysosome degradation, which promotes the accumulation of RSV fusion protein. RSV-F storage is nearly abolished after cholesterol depletion or knockdown of LDLR. Most importantly, the knockout of LDLR effectively inhibits RSV infection in vivo. These findings elucidate the molecular mechanism of how RSV co-regulates lysosomal cholesterol reprogramming and autophagy and reveal LDLR as a novel target for anti-RSV drug development.
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Autofagia , Colesterol , Lisossomos , Receptores de LDL , Infecções por Vírus Respiratório Sincicial , Proteínas de Transporte Vesicular , Replicação Viral , Proteínas rab de Ligação ao GTP , proteínas de unión al GTP Rab7 , Lisossomos/metabolismo , Colesterol/metabolismo , Humanos , Animais , Receptores de LDL/metabolismo , Receptores de LDL/genética , Infecções por Vírus Respiratório Sincicial/metabolismo , Infecções por Vírus Respiratório Sincicial/virologia , Proteínas de Transporte Vesicular/metabolismo , Proteínas de Transporte Vesicular/genética , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab de Ligação ao GTP/genética , Camundongos , Complexo Dinactina/metabolismo , Retículo Endoplasmático/metabolismo , Dineínas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Vírus Sincicial Respiratório Humano/fisiologia , Autofagossomos/metabolismo , Proteínas Virais de Fusão/metabolismo , Proteínas Virais de Fusão/genética , Células HeLa , Células A549RESUMO
BACKGROUND AND AIM: Helicobacter pylori infection is linked to various gastrointestinal conditions, such as chronic active gastritis, peptic ulcers, and gastric cancer. Traditional treatment options encounter difficulties due to antibiotic resistance and adverse effects. Therefore, the aim of this study was to explore the effectiveness of a new treatment plan that combines vonoprazan (VPZ), amoxicillin, and bismuth for the eradication of H. pylori. METHODS: A total of 600 patients infected with H. pylori were recruited for this multicenter randomized controlled trial. Patients treated for H. pylori elimination were randomly assigned at a 1:1 ratio to receive 14 days of vonoprazan-based triple therapy (vonoprazan + amoxicillin + bismuth, group A) or standard quadruple therapy (esomeprazole + clarithromycin + amoxicillin + bismuth, group B). Compliance and adverse effects were tracked through daily medication and side effect records. All patients underwent a 13C/14C-urea breath test 4 weeks after treatment completion. RESULTS: Intention-to-treat (ITT) and per-protocol (PP) analyses revealed no substantial differences in H. pylori eradication rates between groups A and B (ITT: 83.7% vs 83.2%; PP: 90.9% vs 89.7%). However, significant differences were observed in the assessment of side effects (13.7% vs 28.6%, P < 0.001). Specifically, group A had significantly fewer "bitter mouths" than group B did (3.7% vs 16.2%, P < 0.001). CONCLUSION: Triple therapy comprising vonoprazan (20 mg), amoxicillin (750 mg), and bismuth potassium citrate (220 mg) achieved a PP eradication rate ≥90%, paralleling standard quadruple therapy, and had fewer adverse events and lower costs (¥306.8 vs ¥645.8) for treatment-naive patients.
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Finding new and effective natural products for designing antiepileptic drugs is highly important in the scientific community. The scorpion venom heat-resistant peptide (SVHRP) was purified from Buthus martensii Karsch scorpion venom, and subsequent analysis of the amino acid sequence facilitated the synthesis of a peptide known as scorpion venom heat-resistant synthesis peptide (SVHRSP) using a technique for peptide synthesis. Previous studies have demonstrated that the SVHRSP can inhibit neuroinflammation and provide neuroprotection. This study aimed to investigate the antiepileptic effect of SVHRSP on both acute and chronic kindling seizure models by inducing seizures in male rats through intraperitoneal administration of pentylenetetrazole (PTZ). Additionally, an N-methyl-D-aspartate (NMDA)-induced neuronal injury model was used to observe the anti-excitotoxic effect of SVHRSP in vitro. Our findings showed that treatment with SVHRSP effectively alleviated seizure severity, prolonged latency, and attenuated neuronal loss and glial cell activation. It also demonstrated the prevention of alterations in the expression levels of NMDA receptor subunits and phosphorylated p38 MAPK protein, as well as an improvement in spatial reference memory impairment during Morris water maze (MWM) testing in PTZ-kindled rats. In vitro experiments further revealed that SVHRSP was capable of attenuating neuronal action potential firing, inhibiting NMDA receptor currents and intracellular calcium overload, and reducing neuronal injury. These results suggest that the antiepileptic and neuroprotective effects of SVHRSP may be mediated through the regulation of NMDA receptor function and expression. This study provides new insight into therapeutic strategies for epilepsy.
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Anticonvulsivantes , Fármacos Neuroprotetores , Peptídeos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato , Venenos de Escorpião , Convulsões , Animais , Masculino , Receptores de N-Metil-D-Aspartato/metabolismo , Venenos de Escorpião/farmacologia , Venenos de Escorpião/química , Ratos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Convulsões/tratamento farmacológico , Convulsões/prevenção & controle , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Peptídeos/química , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/química , Pentilenotetrazol , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Temperatura Alta , Epilepsia/tratamento farmacológico , Epilepsia/induzido quimicamente , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Modelos Animais de DoençasRESUMO
Background: Metabolic syndrome (MetS) is a global health concern, and it is particularly harmful to middle-aged and elderly individuals. Life Element Eight (LE8), a measure to improve cardiovascular health, may offer benefits for MetS. Herein, we examined the relationship between LE8 and MetS among middle-aged and elderly individuals, and elucidated the role of biological aging and inflammation in this process. Methods: We obtained the LE8 scores of 2,901 Americans, along with their biological aging indicators (Biological age, Phenotypic age, Serum Klotho), and computed their inflammatory indicators SII, DII. Using logistic regression model, we assessed the association among inflammatory markers, Biological aging, LE8 and MetS. Additionally, we generated restricted cubic spline (RCS) plots to display trends in significant variables in logistic regression. Using parallel mediation analysis, we evaluated the possible mediating role of various factors in the risk relationship between LE8 and MetS. Results: Our examination revealed that higher LE8 scores were associated with a lower incidence of MetS in a fully adjusted model. The high LE8 subgroup had a 79.73% reduction in the risk of MetS compared to the low subgroup with an OR = 0.2027 (95% Cl 0.0871, 0.4714), with similar correlations between health factor scores and MetS risk. Biological aging mediated the associations between LE8, health behaviors and health factor scores and MetS risk. Conclusion: A rise in the LE8 score among middle-aged and elderly individuals is a protective factor for MetS, and this association may be partially mediated by biological aging, suggesting that LE8 may reduce the risk of MetS by ameliorating aging.
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BACKGROUND: Vessels encapsulating tumor clusters (VETC) is a newly described vascular pattern that is distinct from microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC). Despite its importance, the current pathological diagnosis report does not include information on VETC and hepatic plates (HP). We aimed to evaluate the prognostic value of integrating VETC and HP (VETC-HP model) in the assessment of HCC. METHODS: A total of 1255 HCC patients who underwent radical surgery were classified into training (879 patients) and validation (376 patients) cohorts. Additionally, 37 patients treated with lenvatinib were studied, included 31 patients in high-risk group and 6 patients in low-risk group. Least absolute shrinkage and selection operator (LASSO) regression analysis was used to establish a prognostic model for the training set. Harrell's concordance index (C-index), time-dependent receiver operating characteristics curve (tdROC), and decision curve analysis were utilized to evaluate our model's performance by comparing it to traditional tumor node metastasis (TNM) staging for individualized prognosis. RESULTS: A prognostic model, VETC-HP model, based on risk scores for overall survival (OS) was established. The VETC-HP model demonstrated robust performance, with area under the curve (AUC) values of 0.832 and 0.780 for predicting 3- and 5-year OS in the training cohort, and 0.805 and 0.750 in the validation cohort, respectively. The model showed superior prediction accuracy and discrimination power compared to TNM staging, with C-index values of 0.753 and 0.672 for OS and disease-free survival (DFS) in the training cohort, and 0.728 and 0.615 in the validation cohort, respectively, compared to 0.626 and 0.573 for TNM staging in the training cohort, and 0.629 and 0.511 in the validation cohort. Thus, VETC-HP model had higher C-index than TNM stage system(p < 0.01).Furthermore, in the high-risk group, lenvatinib alone appeared to offer less clinical benefit but better disease-free survival time. CONCLUSIONS: The VETC-HP model enhances DFS and OS prediction in HCC compared to traditional TNM staging systems. This model enables personalized temporal survival estimation, potentially improving clinical decision-making in surveillance management and treatment strategies.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Idoso , Análise de Sobrevida , Estimativa de Kaplan-Meier , Reprodutibilidade dos Testes , Quinolinas/uso terapêutico , Compostos de FenilureiaRESUMO
INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have attracted much attention because of their significant hypoglycemic and weight-loss effects. Previous preparations can only be subcutaneously injected. Oral administration of GLP-1RAs semaglutide helps to broaden treatment options, but its safety in the real world still needs to be observed. This study is based on FDA adverse event reporting system (FAERS) database to mine adverse drug events (ADE) of oral semaglutide, and provide references for the clinical safe use of this drug. METHODS: To analyze the signal quality of oral semaglutide, which is a drug used in the FAERS database from the third quarter of 2019 to the third quarter of 2023, we collected ADE data and performed data mining by using disproportionate analysis. Then, we standardized the data and used a variety of signal-quantification techniques, including reported odds ratio (ROR), proportional reporting ratio (PRR), Bayesian belief propagation neural network (BCPNN), and multiple empirical Bayesian gamma Poisson contractions (MGPS), for further analysis. RESULTS: We screened 2398 reports on the use of semaglutide tablets, involving a total of 5653 ADE. These reports were mainly submitted by consumers, and the reporting country was mainly the United States. A total of 23 system organ classes (SOC) and 93 preferred terms (PT) were mined for the signals of semaglutide tablets. The three most common SOC were gastrointestinal disorders, general disorders and administration site conditions, and investigations. At the PT level, metabolism and nutrition disorders exhibit the highest number of signals, with the top three being thyroid cyst, acute cholecystitis, and ketosis. Gastrointestinal disorders rank second, primarily involving eructation, pancreatitis, impaired gastric emptying, and regurgitation. In addition, vith nerve paralysis occurs and the signal intensity is high. CONCLUSIONS: Our study provides a deeper and broader understanding of the safety of oral semaglutide. The results of the ROR, PRR, BCPNN, and MGPS algorithms exhibit high consistency, with metabolism and nutrition-related disorders having the highest number of signals. The conclusions align with the technical specifications of the product. Notably, other unexpected effects are reported, including acute cholecystitis, paralysis of the abducens nerve, and positional vertigo.
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OBJECTIVE: To explore the plasma metabolomic characteristics of children with transfusion-dependent thalassemia (TDT), and reveal the changes of metabolic pattern in children with TDT. METHODS: 23 children with TDT who received regular blood transfusion in Ganzhou Women and Children's Health Care Hospital in 2021 were selected, and 11 healthy children who underwent physical examination during the same period were selected as the control group. The routine indexes between children with TDT and the control group were compared, and then the metabolic composition of plasma samples from children with TDT and the control group was detected by liquid chromatography-mass spectrometry. An OPLS-DA model was established to perform differential analysis on the detected metabolites, and the differential metabolic pathways between the two groups were analyzed based on the differential metabolites. RESULTS: The results of routine testing showed that the indexes of ferritin, bilirubin, total bile acid, glucose and triglycerides in children with TDT were significantly higher than those in healthy controls, while hemoglobin and total cholesterol were significantly lower (all P <0.05). However there was no significant difference in lactate dehydrogenase between the two groups (P >0.05). Compared with the control group, 190 differential metabolites (VIP>1) were identified in TDT children. Among them, 168 compounds such as arginine, proline and glycocholic acid were significantly increased, while the other 22 compounds such as myristic acid, eleostearic acid, palmitic acid and linoleic acid were significantly decreased. The metabolic pathway analysis showed that the metabolic impact of TDT on children mainly focused on the upregulation of amino acid metabolism and downregulation of lipid metabolism. CONCLUSION: The amino acid and lipid metabolism in children with TDT were significantly changed compared with the healthy control group. This finding is helpful to optimize the treatment choice for children with TDT, and provides a new idea for clinical treatment.
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Metaboloma , Talassemia , Humanos , Criança , Talassemia/terapia , Talassemia/sangue , Transfusão de Sangue , Estudos de Casos e Controles , Plasma , Metabolômica , Triglicerídeos/sangue , FemininoRESUMO
Background and aims: Most pancreatic insulinomas can be treated by minimally invasive modalities. The aim of this meta-analysis was to assess the clinical outcomes of endoscopic ultrasound (EUS)-guided ablation and minimally invasive surgery (MIS) in the treatment of pancreatic insulinoma. Materials and methods: Online databases were searched for relevant studies. The primary aim was to compare the rates of adverse events (AEs) and the secondary aims were to compare the clinical and technical success rates, length of hospital stays, and symptom recurrence rates between EUS and MIS approaches. Results: Eight studies with 150 patients were identified that reported EUS-guided ablation outcomes, forming the EUS group, and 9 studies with 236 patients reported MIS outcomes, forming the MIS group. The pooled median age of the included patients in the EUS group was greater than that of the MIS group (64.06 vs. 44.98 years old, p < 0.001). Also, the technical success rate was significantly higher in the EUS group (100% vs. 96.6%, p = 0.025), while the clinical success was significantly higher (6%) in the MIS group (94% vs. 98.7%, p = 0.021). The AE rates (18.7% vs. 31.1%, p = 0.012) and severe AE rates (1.3% vs. 7.9%, p = 0.011) were significantly lower in the EUS group. The median length of hospital stay in the EUS group (2.68 days, 95% CI: 1.88-3.48, I2 = 60.3%) was significantly shorter than in the MIS group (7.40 days, 95% CI: 6.22-8.58, I2 = 42.2%, p < 0.001). The recurrence rate was significantly higher in the EUS group (15.3% vs. 1.3%, p < 0.001). Conclusions: EUS-guided ablation is associated with a lower AE rate and a shorter length of hospital stay, but a higher recurrence rate for the treatment of insulinoma compared with MIS. The EUS approach may be an alternative, even first-line, treatment for poor surgery candidates.
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Endossonografia , Insulinoma , Procedimentos Cirúrgicos Minimamente Invasivos , Neoplasias Pancreáticas , Humanos , Insulinoma/cirurgia , Insulinoma/diagnóstico por imagem , Neoplasias Pancreáticas/cirurgia , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Endossonografia/métodos , Resultado do Tratamento , Tempo de Internação/estatística & dados numéricosRESUMO
OBJECTIVE: Currently, there is no cure for chronic pancreatitis (CP). Germline loss-of-function variants in SPINK1 (encoding trypsin inhibitor) are common in patients with CP and are associated with acute attacks and progression of the disease. This preclinical study was conducted to explore the potential of adeno-associated virus type 8 (AAV8)-mediated overexpression of human SPINK1 (hSPINK1) for pancreatitis therapy in mice. DESIGN: A capsid-optimised AAV8-mediated hSPINK1 expression vector (AAV8-hSPINK1) to target the pancreas was constructed. Mice were treated with AAV8-hSPINK1 by intraperitoneal injection. Pancreatic transduction efficiency and safety of AAV8-hSPINK1 were dynamically evaluated in infected mice. The effectiveness of AAV8-hSPINK1 on pancreatitis prevention and treatment was studied in three mouse models (caerulein-induced pancreatitis, pancreatic duct ligation and Spink1 c.194+2T>C mouse models). RESULTS: The constructed AAV8-hSPINK1 vector specifically and safely targeted the pancreas, had low organ tropism for the heart, lungs, spleen, liver and kidneys and had a high transduction efficiency (the optimal expression dose was 2×1011 vg/animal). The expression and efficacy of hSPINK1 peaked at 4 weeks after injection and remained at significant level for up to at least 8 weeks. In all three mouse models, a single dose of AAV8-hSPINK1 before disease onset significantly alleviated the severity of pancreatitis, reduced the progression of fibrosis, decreased the levels of apoptosis and autophagy in the pancreas and accelerated the pancreatitis recovery process. CONCLUSION: One-time injection of AAV8-hSPINK1 safely targets the pancreas with high transduction efficiency and effectively ameliorates pancreatitis phenotypes in mice. This approach is promising for the prevention and treatment of CP.
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Dependovirus , Modelos Animais de Doenças , Terapia Genética , Vetores Genéticos , Animais , Camundongos , Terapia Genética/métodos , Dependovirus/genética , Inibidor da Tripsina Pancreática de Kazal/genética , Pâncreas/patologia , Pâncreas/metabolismo , Humanos , Pancreatite Crônica/genética , Pancreatite Crônica/terapia , Masculino , Pancreatite/terapia , Pancreatite/prevenção & controle , Pancreatite/genéticaRESUMO
INTRODUCTION: The effects of genetic factors on pregnancy outcomes in chronic pancreatitis (CP) patients remain unclear. We evaluated the impacts of clinical features and mutations in main CP-susceptibility genes ( SPINK1 , PRSS1 , CTRC , and CFTR ) on pregnancy outcomes in Chinese CP patients. METHODS: This was a prospective cohort study with 14-year follow-up. The sample comprised female CP patients with documented pregnancy and known genetic backgrounds. Adverse pregnancy outcomes were compared between patients with and without gene mutations. Univariate and multivariate analyses were performed to determine the impact factors for adverse pregnancy outcomes. RESULTS: Totally, 160 female CP patients with a pregnancy history were enrolled; 59.4% of patients carried pathogenic mutations in CP-susceptibility genes. Adverse pregnancy outcomes occurred in 38 patients (23.8%); the prevalence of adverse outcomes was significantly higher in those harboring gene mutations than those without (30.5% vs 13.8%, P = 0.015). Notably, the rates of preterm delivery (12.6% vs 3.1%, P = 0.036) and abortion (17.9% vs 4.6%, P = 0.013) were remarkably higher in patients with gene mutations (especially SPINK1 mutations) than those without. In multivariate analyses, both CP-susceptibility gene mutations (odds ratio, 2.52; P = 0.033) and SPINK1 mutations (odds ratio, 2.60; P = 0.037) significantly increased the risk of adverse pregnancy outcomes. Acute pain attack during pregnancy was another risk factor for adverse pregnancy outcomes. DISCUSSION: Pathogenic mutations in CP-susceptibility genes, especially SPINK1 , were independently related to adverse pregnancy outcomes in CP patients. Significant attention should be paid to pregnant females harboring CP-susceptibility gene mutations (ClinicalTrials.gov: NCT06055595).
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Quimotripsina , Regulador de Condutância Transmembrana em Fibrose Cística , Predisposição Genética para Doença , Mutação , Pancreatite Crônica , Complicações na Gravidez , Resultado da Gravidez , Inibidor da Tripsina Pancreática de Kazal , Tripsina , Humanos , Feminino , Gravidez , Adulto , Inibidor da Tripsina Pancreática de Kazal/genética , Pancreatite Crônica/genética , Pancreatite Crônica/complicações , Estudos Prospectivos , Tripsina/genética , Complicações na Gravidez/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , China/epidemiologia , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/genética , Adulto Jovem , Seguimentos , Fatores de Risco , Aborto Espontâneo/genética , Aborto Espontâneo/epidemiologiaRESUMO
Early metastasis is the primary factor in the very poor prognosis of pancreatic ductal adenocarcinoma (PDAC), with liver metastasis being the most common form of distant metastasis in PDAC. To investigate the mechanism of PDAC liver metastasis, we found that PDAC cells can promote the formation of pre-metastatic niches (PMNs) through exosomes to facilitate liver metastasis in the early stage. In our study, hepatic stellate cells (HSCs) were treated with PDAC-derived exosomes (PDAC-exo), and the activation of HSCs was detected. A novel transfer RNA-derived fragment, the tRF-GluCTC-0005 was obtained by small RNA sequencing from serum exosomes of PDAC patients. Bioinformatics analysis and RNA pull-down assays revealed the interaction between WDR1 and tRF-GluCTC-0005. A KPC transgenic mouse model and an AAV-mediated sh-WDR1 mouse model were used to detect the mechanism of liver metastasis in vivo. Finally, the dual luciferase reporter assay, protein mutation truncation assay, Co-IP assay, and flow cytometry assay were used to explore the molecular mechanism in HSCs activation and PMNs formation. We found that the tRF-GluCTC-0005 in exosomes binds to the 3' untranslated region of the mRNA of the WDRl in HSCs and increases mRNA stability. The N-terminals of WDR1 bind to the YAP protein directly, inhibit YAP phosphorylation, and promote the expression of YAP transcription factors. The tRF-GluCTC-0005 in PDAC-exo significantly recruits myeloid-derived suppressor cells (MDSCs) in the liver, creating a PMNs immunosuppressive microenvironment and further advancing liver metastasis from PDAC. Our results suggest that the key of PDAC liver metastasis is the activation of HSCs through upregulation of WDR1 by tRF-GluCTC-0005 in exosomes, which mediates the infiltration of MDSCs to form PMNs.
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Carcinoma Ductal Pancreático , Exossomos , Neoplasias Hepáticas , Neoplasias Pancreáticas , Humanos , Animais , Camundongos , Células Estreladas do Fígado/metabolismo , Exossomos/metabolismo , Linhagem Celular Tumoral , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , Neoplasias Hepáticas/patologia , RNA de Transferência/metabolismo , Microambiente TumoralRESUMO
The mutual interaction between bone characteristics and brain had been reported previously, yet whether the cortical structure has any relevance to osteoporosis is questionable. Therefore, we applied a two-sample bidirectional Mendelian randomization analysis to investigate this relationship. We utilized the bone mineral density measurements of femoral neck (n = 32,735) and lumbar spine (n = 28,498) and data on osteoporosis (7300 cases and 358,014 controls). The global surficial area and thickness and 34 specific functional regions of 51,665 patients were screened by magnetic resonance imaging. For the primary estimate, we utilized the inverse-variance weighted method. The Mendelian randomization-Egger intercept test, MR-PRESSO, Cochran's Q test, and "leave-one-out" sensitivity analysis were conducted to assess heterogeneity and pleiotropy. We observed suggestive associations between decreased thickness in the precentral region (OR = 0.034, P = 0.003) and increased chance of having osteoporosis. The results also revealed suggestive causality of decreased bone mineral density in femoral neck to declined total cortical surface area (ß = 1400.230 mm2, P = 0.003), as well as the vulnerability to osteoporosis and reduced thickness in the Parstriangularis region (ß = -0.006 mm, P = 0.002). Our study supports that the brain and skeleton exhibit bidirectional crosstalk, indicating the presence of a mutual brain-bone interaction.
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Análise da Randomização Mendeliana , Osteoporose , Humanos , Osteoporose/diagnóstico por imagem , Osteoporose/genética , Encéfalo , Nonoxinol , Compostos Radiofarmacêuticos , Estudo de Associação Genômica AmplaRESUMO
BACKGROUND: Liquid-liquid phase separation (LLPS) enhances oncogenic signaling pathways and advances cancer progression, and has been proposed as a promising cancer biomarker and intervention target. Nevertheless, doubts remain about the prognostic importance of LLPS-related long non-coding RNAs (lncRNAs) in hepatocellular carcinoma (HCC). METHODS: An LLPS-related lncRNA prognostic signature was generated by drivers and regulators of LLPS, and was validated in external datasets. The underlying genetic changes and functional enrichment of the signature were assessed. The drug sensitivity and response to immunotherapy were predicted in patients categorized as high-risk and low-risk. Clinical samples, phase separation agonist, and dispersant were used to identify lncRNAs with the most significant expression change. Cancer cells with ZNF32-AS2 expression regulation were subjected to colony formation assay, scratch test assay, migration and invasion assay, sorafenib resistance assay, and xenograft tumor model. RESULTS: The signature of LLPS-related hub lncRNAs identified through Weighted Gene Co-Expression Network Analysis showed outstanding performance in training and external validation cohorts consistently, and the molecular characteristics varied between different risk groups. Potential drugs for high-risk individuals were identified, and low-risk individuals demonstrated a more favorable reaction to immunotherapy. ZNF32-AS2 showed the most significant expression change in phase separation agonist and dispersant treatment. ZNF32-AS2 promoted the proliferation, mobility, and sorafenib resistance of liver cancer cells. CONCLUSIONS: The LLPS-related lncRNA signature may help assess prognosis and predict treatment efficacy in clinical settings. LLPS-related ZNF32-AS2 promoted the proliferation, mobility, and sorafenib resistance of liver cancer cells, and may be a novel potential biomarker in hepatocellular carcinoma.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante , Humanos , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/patologia , Fatores de Transcrição Kruppel-Like , Neoplasias Hepáticas/patologia , Separação de Fases , Prognóstico , RNA Longo não Codificante/genética , SorafenibeRESUMO
Establishing slash pine plantations is the primary method for restoring sandification land in the Houtian area of South China. However, the microbial variation pattern with increasing stand age remains unclear. In this study, we investigated microbial community structure and function in bare sandy land and four stand age gradients, exploring ecological processes that determine their assembly. We did not observe a significant increase in the absolute abundance of bacteria or fungi with stand age. Bacterial communities were dominated by Chloroflexi, Actinobacteria, Proteobacteria, and Acidobacteria; the relative abundance of Chloroflexi significantly declined while Proteobacteria and Acidobacteria significantly increased with stand age. Fungal communities showed succession at the genus level, with Pisolithus most abundant in soils of younger stands (1- and 6-year-old). Turnover of fungal communities was primarily driven by stochastic processes; both deterministic and stochastic processes influenced the assembly of bacterial communities, with the relative importance of stochastic processes gradually increasing with stand age. Bacterial and fungal communities showed the strongest correlation with the diameter at breast height, followed by soil available phosphorus and water content. Notably, there was a significant increase in the relative abundance of functional groups involved in nitrogen fixation and uptake as stand age increased. Overall, this study highlights the important effects of slash pine stand age on microbial communities in sandy lands and suggests attention to the nitrogen and phosphorus requirements of slash pine plantations in the later stages of sandy management.
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Microbiota , Pinus , Pinus/microbiologia , Areia , Microbiologia do Solo , Solo/química , Bactérias , China , FósforoRESUMO
IMPORTANCE: Respiratory syncytial virus (RSV) is the leading etiological agent of lower respiratory tract illness. However, efficacious vaccines or antiviral drugs for treating RSV infections are currently not available. Indeed, RSV depends on host cells to provide energy needed to produce progeny virions. Glycolysis is a series of oxidative reactions used to metabolize glucose and provide energy to host cells. Therefore, glycolysis may be helpful for RSV infection. In this study, we show that RSV increases glycolysis by inducing the stabilization, transcription, translation, and activation of hypoxia-inducible factor (HIF)-1α in infected cells, which is important for the production of progeny RSV virions. This study contributes to understanding the molecular mechanism by which HIF-1α-mediated glycolysis controls RSV infection and reveals an effective target for the development of highly efficient anti-RSV drugs.
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Doenças Transmissíveis , Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Vírus Sincicial Respiratório Humano/genética , GlicóliseRESUMO
Tumor burden, considered a common chronic stressor, can cause widespread anxiety. Evidence suggests that cancer-induced anxiety can promote tumor progression, but the underlying neural mechanism remains unclear. Here, we used neuroscience and cancer tools to investigate how the brain contributes to tumor progression via nerve-tumor crosstalk in a mouse model of breast cancer. We show that tumor-bearing mice exhibited significant anxiety-like behaviors and that corticotropin-releasing hormone (CRH) neurons in the central medial amygdala (CeM) were activated. Moreover, we detected newly formed sympathetic nerves in tumors, which established a polysynaptic connection to the brain. Pharmacogenetic or optogenetic inhibition of CeMCRH neurons and the CeMCRHâlateral paragigantocellular nucleus (LPGi) circuit significantly alleviated anxiety-like behaviors and slowed tumor growth. Conversely, artificial activation of CeMCRH neurons and the CeMCRHâLPGi circuit increased anxiety and tumor growth. Importantly, we found alprazolam, an antianxiety drug, to be a promising agent for slowing tumor progression. Furthermore, we show that manipulation of the CeMCRHâLPGi circuit directly regulated the activity of the intratumoral sympathetic nerves and peripheral nerve-derived norepinephrine, which affected tumor progression by modulating antitumor immunity. Together, these findings reveal a brain-tumor neural circuit that contributes to breast cancer progression and provide therapeutic insights for breast cancer.
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Hormônio Liberador da Corticotropina , Neoplasias , Camundongos , Animais , Hormônio Liberador da Corticotropina/metabolismo , Neurônios/metabolismo , Ansiedade , Encéfalo/metabolismoRESUMO
Evidence comparing ultrasound endoscopy-guided fine-needle biopsy (EUS-FNB) with EUS-guided fine-needle aspiration (EUS-FNA) in deep-seated lymphoma tissue sampling is insufficient. This study aims to evaluate the diagnostic efficacy of immunohistochemistry (IHC) or flow cytometry (FCM) on specimens obtained from EUS-FNB and EUS-FNA in the diagnosis and staging of deep-seated lymphomas. This real-world, dual-center study prospectively evaluated all eligible specimens from patients who underwent EUS-FNB/FNA over an 8-year period. 53 patients were enrolled, with 23 patients in the EUS-FNB group and 30 patients in the EUS-FNA group. FNB yielded specimens with longer core tissues (0.80 mm [0.55, 1.00] vs. 0.45 mm [0.30, 0.50], p = 0.009) and higher scores of specimen adequacy [4 (3.75, 4.00) vs. 3 (1.00, 4.00), p = 0.025]. Overall analysis revealed that the diagnostic accuracy of IHC based on specimens acquired from EUS-FNB was significantly higher than that of EUS-FNA (91.30% vs. 60.00%, p = 0.013). After controlling confounding factors including lesion size and endoscopists, EUS-FNB with IHC maintained a higher-level diagnostic accuracy compared to EUS-FNA (OR = 1.292 [1.037-1.609], p = 0.023). When FCM was additionally used to analyze the specimen acquired from EUS-FNA, the diagnostic yield was significantly improved (ROC AUC: 0.733 vs. 0.550, p = 0.015), and the AUC of FNB alone or combined with FCM was 0.739 and 0.761. Conclusions: FNB needles generate higher histopathological diagnostic accuracy and specimen quality than FNA for the deep-seated lymphoma. Though the application of FCM significantly improves the diagnostic efficacy of EUS-FNA, FNB was still the preferred diagnostic modality with a shorter procedure time, comparable diagnostic accuracy, and better cost-effectiveness.
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BACKGROUND: Uterine tumors resembling ovarian sex cord tumor (UTROSCT) is a rare neoplasm of unknown etiology and has undetermined malignant potential. The emergence of recurrent UTROSCT case reports has led to its initial identification as a tumor of low malignancy potential. Owing to its low incidence, we currently lack any in-depth studies regarding the subset of UTROSCTs that may be aggressive in nature. Here, we sought to identify unique characteristics in aggressive UTROSCT. METHODS: 19 cases of UTROSCT were collected. Their histologic and tumor immune microenvironment were evaluated by three gynecologic pathologists. The gene alteration was also detected by RNA sequencing. For later analyses regarding differences between benign and malignant tumors, we supplemented our 19 included cases with additional reports from the literature. RESULTS: Interestingly, we found PD-L1 expression in stromal tumor-infiltrating immune cells (stromal PD-L1) was markedly higher in aggressive UTROSCT. Patients with high stromal PD-L1 (≥ 22.5 cells/mm2) had worse prognosis. When our cases were added with previous cases identified in the literature, we discovered that aggressive UTROSCT was more likely to have significant mitotic activity and NCOA2 gene alterations than benign UTROSCT. Consistence with those results, patients with significant mitotic activity and gene alteration of NCOA2 had worse prognoses. CONCLUSIONS: Collectively, high expression of stromal PD-L1, significant mitotic activity, and gene alteration of NCOA2 may be useful markers to predict aggressive UTROSCT.
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Tumores do Estroma Gonadal e dos Cordões Sexuais , Neoplasias Uterinas , Humanos , Feminino , Antígeno B7-H1 , Recidiva Local de Neoplasia , Útero , Microambiente TumoralRESUMO
BACKGROUND: Cancer-associated fibroblasts (CAFs), an important component of the tumor microenvironment (TME), play crucial roles in tumor stemness. It has been shown in various cancer studies that stanniocalcin-1 (STC1) is secreted by CAFs, however, its function in HCC is still not clear. METHODS: The serum concentration and intracellular expression level of STC1 were quantified by ELISA and western blotting, respectively. The role of CAF-derived STC1 in HCC stemness was investigated by sphere formation, sorafenib resistance, colony formation, and transwell migration and invasion assays in vitro and in an orthotopic liver xenograft model in vivo. An HCC tissue microarray containing 72 samples was used to evaluate the expression of STC1 and Notch1 in HCC tissues. Coimmunoprecipitation (CoIP) and dual-luciferase reporter assays were performed to further explore the underlying mechanisms. ELISAs were used to measure the serum concentration of STC1 in HCC patients. RESULTS: We demonstrated that CAFs were the main source of STC1 in HCC and that CAF-derived STC1 promoted HCC stemness through activation of the Notch signaling pathway. In HCC patients, the expression of STC1 was positively correlated with Notch1 expression and poor prognosis. The co-IP assay showed that STC1 directly bound to Notch1 receptors to activate the Notch signaling pathway, thereby promoting the stemness of HCC cells. Our data further demonstrated that STC1 was a direct transcriptional target of CSL in HCC cells. Furthermore, ELISA revealed that the serum STC1 concentration was higher in patients with advanced liver cancer than in patients with early liver cancer. CONCLUSIONS: CAF-derived STC1 promoted HCC stemness via the Notch1 signaling pathway. STC1 might serve as a potential biomarker for the prognostic assessment of HCC, and the stromal-tumor amplifying STC1-Notch1 feedforward signal could constitute an effective therapeutic target for HCC patients.