Objective To establish a stable and reliable sepsis model of rat after liver transplantation (LT) for clinical translational research and analyze its characteristics. Methods The "two-sleeve method" was used to establish the in situ LT model of SD rats, and the sepsis model was constructed through cecal ligation and puncture (CLP) at 3 d after the operation. SD rats were randomly divided into 3 groups: sham operation group (Sham group), LT group, and LT + CLP group, with 6 rats in each group. The changes in body weight, rectal temperature and survival rate were compared, and the sepsis score was used for evaluation. The levels of blood biochemical indicators [alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea (Urea), creatinine (Cr), creatine kinase (CK), lactate dehydrogenase (LDH)] and inflammatory factors [interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α] in each group were detected, and the pathological changes and cell apoptosis in different organs were observed. Results Compared with the Sham group, the body weight of the LT group and LT + CLP group decreased (all P<0.05). The rectal temperature of the LT + CLP group showed a continuous downward trend after the operation, the sepsis score increased sharply after the operation, and the survival rate dropped to 16.7%, and the differences between the Sham group, LT group and LT + CLP group were statistically significant (all P<0.05). The levels of ALT, AST, Urea, Cr, CK, LDH, and serum IL-1β, IL-6, IL-10 and TNF-α in the LT + CLP group were higher than those in the Sham group and LT group rats within 72 hours after the operation(all P<0.05). The pathological examination of the LT + CLP group showed severe tissue structure destruction, necrosis and infiltration of inflammatory cells in multiple organs, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining showed an increased level of cell apoptosis in multiple organs. Conclusions Using liver transplantation combined with CLP, a stable animal model of liver transplantation infection is successfully established, which exhibits a high mortality rate, significant multi-organ damage and intense inflammatory response, providing an ideal animal model for transplantation infection research.

OBJECTIVE: To investigate the predictive role of the modified Endothelial Activation and Stress Index (mEASIX) in the efficacy of chimeric antigen receptor T-cell (CAR-T) therapy and cytokine release syndrome (CRS). METHODS: The clinical data of 70 relapsed and refractory (R/R) B-cell tumor patients who were treated with CAR-T therapy from September 1, 2018 to February 28, 2023 in the Department of Hematology, Affiliated Hospital of Xuzhou Medical University, were retrospectively analyzed. The value of log-2 mEASIX before conditioning (-7 d) was calculated, and the patients were divided into a low-mEASIX group (42 patients) and a high-mEASIX group (28 patients) based on the cut-off value of 5.443 determined by the receiver operating characteristic (ROC) curve. Eventually, the predictive role of mEASIX before conditioning on the efficacy of CAR-T cell therapy and CRS was analyzed. RESULTS: The high-mEASIX group exhibited significantly worse median overall survival (OS) and median progression-free survival (PFS) in comparison to the low mEASIX group (OS: 3.2 months vs not reached, P < 0.01; PFS: 1.3 months vs 6.0 months, P =0.009). The incidence of grade ≥2 CRS in the high-mEASIX group was substantially higher than that in the low-mEASIX group (57.1% vs 19.0%, P =0.007). The degree of remission after CAR-T therapy (P =0.001), whether CRS occurs or not (P =0.041), the lactate dehydrogenase (LDH) level before conditioning (P =0.046), and the mEASIX score before conditioning (P =0.047) were independent influencing factors for the OS of patients receiving CAR-T cell therapy. CONCLUSION The mEASIX score before conditioning can predict OS and the incidence of grade ≥2 CRS in patients with relapsed and refractory B-cell tumors who receive CAR-T cell therapy.
Cytokine Release Syndrome/therapy* ; Immunotherapy, Adoptive/methods* ; Humans ; Lymphoma, B-Cell/therapy* ; Retrospective Studies ; Hematology ; China ; Receptors, Chimeric Antigen/blood* ; Predictive Value of Tests

OBJECTIVE: To explore the mechanism of crocin, a major active component of Crocus sativus (Zanghonghua), in regulating amyloid beta (Aβ) generation, endoplasmic reticulum (ER) stress, and autophagy in neuronal cells, with potential therapeutic applications in Alzheimer's disease (AD). METHODS: Mouse neuroblastoma Neuron2a (N2a) cells stably transfected with the human amyloid precursor protein (APP) Swedish mutant was used as a cellular model for AD (N2a/APP). Control cells were vector transfected (N2a/vector). The effects of 3 different doses of crocin on reactive oxygen species (ROS) generation, cytosolic calcium, and apoptosis were evaluated by flow cytometry. Aβ levels were determined by enzyme-linked immunosorbent assay. APP processing and ER stress proteins expressions were determined by Western blot. Autophagosome formation was evaluated by autophagy detection kit and confocal microscope. RESULTS: Crocin inhibited APP expression in N2a/APP cells and promoted α-cleavage of APP processing, while modestly reduced beta-secretase 1 (BACE1) and presenilin 1 (PS1, P<0.05 or P<0.01). ER stress markers, including the binding immunoglobulin protein/78-kD glucose-regulated protein (Bip/GRP78) and C/EBP homologous protein (CHOP), were elevated in N2a/APP cells compared to N2a/vector cells (P<0.05). Crocin could effectively reduce the levels of ER stress (P<0.05 or P<0.01). In addition, crocin enhanced autophagy by promoting formation of autophagosome (P<0.05 or P<0.01). CONCLUSION Crocin significantly inhibited Aβ generation by promoting α-cleavage of APP processing, inhibiting ER stress-associated unfolded protein response, and regulating autophagy.
Endoplasmic Reticulum Stress/drug effects* ; Autophagy/drug effects* ; Animals ; Endoplasmic Reticulum Chaperone BiP ; Mice ; Amyloid beta-Peptides/metabolism* ; Amyloid beta-Protein Precursor/metabolism* ; Carotenoids/pharmacology* ; Humans ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism* ; Apoptosis/drug effects* ; Calcium/metabolism*

Probiotics are natural systems bridging synthetic biology, physical biotechnology, and immunology, initiating innate and adaptive anti-tumor immune activity. We previously constructed an all-in-one engineered food-grade probiotic Lactococcus lactis (FOLactis) which could boost the crosstalk among different immune cells such as dendritic cells (DCs), natural killer cells, and T cells. Herein, considering the limited clinical efficacy of naked personalized neoantigen peptide vaccines, we decorate FOLactis with tumor antigens by employing a Plug-and-Display system comprising membrane-inserted peptides. Intranodal injection of FOLactis coated with neoantigen peptides (Ag-FOLactis) induces robust DCs presentation and neoantigen-specific cellular immunity. Notably, Ag-FOLactis not only triggers a 45-fold rise in the quantity of locally reactive neoantigen-specific T cells but also induces epitope spreading in both subcutaneous and metastatic tumor-bearing models, leading to potent inhibition of tumor growth. These findings imply that Ag-FOLactis represents a powerful platform to rapidly and easily display antigens, facilitating the development of a bio-activated platform for personalized therapy.

Objective To explore the regulatory effect of methyltransferase-like 3(METTL3)on m6A methylation of Sigma-1 receptor(Sigma-1R)mRNA and mitophagy in cerebral microvascular endothelial cells of sepsis mice.Methods Twelve adult male C57BL/6J mice were randomly divided into the Sham group(without cecal ligation or puncture)and the sepsis group(received cecal ligation and puncture),with 6 mice in each group.m6A methylation levels,and relative expression of METTL3 and Sigma-1R mRNA and protein in cerebral micro-vascular tissues were detected by m6A Dot blot,RT-qPCR,and Western blot,respectively.The bEnd.3 cells were cultured in vitro and divided into the control group(normal culture),model group[lipopolysaccharide(LPS)-induced in vitro sepsis],si-NC group(LPS treat-ment combined with si-NC transfection),and si-METTL3 group(LPS treatment combined with si-METTL3 transfection).m6A Dot blot was used to detect m6A methylation levels of cells in each group;RT-qPCR was used to detect the mRNA expression of METTL3 and Sigma-1R;and Western blot was used to detect the expression of METTL3,Sigma-1R,and autophagy-related proteins of Bnip3,LC3B,and Beclin1.m6A chromatin immunoprecipitation-qPCR was used to detect m6A methylation level of Sigma-1R of cells in each group.JC-1 probe was used to detect the mitochondrial membrane potential,and the ATP assay kit was used to detect the mitochondrial ATP content.Results Compared with the Sham group,the sepsis group showed increased m6A methylation level and METTL3 expression(P<0.05),and decreased Sigma-1R expression in cerebral microvascular tissues(P<0.05).Compared with the control group,m6A methylation level,METTL3 expression and m6A methylation level of Sigma-1R mRNA increased,the expression of Sigma-1R,the normal rate and increase rate of mitochondrial membrane potential,and the ATP content decreased,and the protein expression of Bnip3,LC3B and Beclin1 downregulated in the model group and the si-NC group,with statistically significant differences(P<0.05).Compared with the si-NC group,m6A methylation level,METTL3 expression and m6A methylation level of Sigma-1R mRNA decreased,the expression of Sigma-1R,the normal rate and increase rate of mitochondrial membrane potential elevated,the ATP content increased,and the protein expression of Bnip3,LC3B and Beclin1 upregulated in the si-METTL3 group,with statistically significant differences(P<0.05).Conclusion Silencing METTL3 can inhibit m6A methylation of Sigma-1R mRNA and promote the mitophagy in cerebral microvascular endothelial cells of septic mice.

Aim Mouse model of myocardial hypertro-phy was established via intraperitoneal injection of iso-proterenol(ISO)in mice.This approach allows for an in-depth investigation into the pharmacological effects and mechanisms of action of emodin,offering novel in-sights and directions for the improvement of myocardial hypertrophy.Methods The mice were randomly di-vided into the following groups:control group(CON),emodin group(EMO),MAPK activator control group(EMO+Ani),model group(ISO),treatment group(ISO+EMO),and activator intervention group(ISO+EMO+Ani).After treatment with emodin and inter-vention with MAPK activator,the heart weight ratio and cardiac size of each group were observed.Hematoxy-lin-eosin(HE)staining was used to observe the patho-logical changes in cardiac tissue,and kits were utilized to measure the levels of GSH,LDH,and MDA in the serum.Western blot was employed to detect the protein expression levels of inflammatory and oxidative factors,as well as p-p38,p-ERK,p38,and ERK in cardiac tis-sue.Results Emodin can significantly inhibit the production of myocardial inflammatory and oxidative factors induced by ISO,thereby effectively alleviating the degree of myocardial hypertrophy and fibrosis.Af-ter the p38/ERK signaling pathway was specifically ac-tivated by farnesol,the improvement effect of emodin on myocardial hypertrophy was weakened.Further comparison revealed that,compared with the myocardi-al hypertrophy pathological model group,the pathologi-cal protein expression levels in the farnesol-treated group showed no significant difference,and were even higher in some indicators.Conclusion Emodin can effectively inhibit the release of inflammatory factors and improve the state of oxidative stress by modulating the p38/ERK signaling pathway,thereby exerting an ameliorative effect on myocardial hypertrophy.

Neuromyelitis optica spectrum disorder(NMOSD)is an autoimmune neurological condition characterized by relapsing optic neuritis and longitudinally extensive transverse myelitis.Patients with NMOSD are prone to adverse pregnancy outcomes,intrapartum complications,high relapse rates,and significant disability following pregnancy.This paper analyzes a case of NMOSD experienced exacerbation of symptoms during pregnancy and childbirth,postpartum hemorrhage accompanied by coagulopathy,and ultimately successful resuscitation.We propose that active administration of corticosteroids and intravenous immunoglobulin during labor is an effective and feasible strategy for controlling the disease.Rapid replenishment of coagulation factors and timely correction of coagulation function are essential to prevent adverse outcomes.The paper summarizes the prenatal care and childbirth-related risks for such patients,and provides insights for the optimization of management protocols.

Objective To analyze the medication rules of traditional Chinese medicine in treating breast cancer based on real-world data mining.Methods Inpatients with breast cancer who received traditional Chinese medicine treatment at the Affiliated Hospital of Chengdu University of Traditional Chinese Medicine from January 2017 to December 2021 were selected.Python 3.10 software was used to mine traditional Chinese medicine prescription data;SPSS 23.0 software was applied for descriptive analysis,and systematic cluster analysis was performed on high-frequency drugs.Results A total of 3026 consultation records of inpatients with breast cancer were collected.The main traditional Chinese medicine syndrome diagnosis of"predominantly liver depression and Qi stagnation"accounted for 60.94％of the total consultations.A total of 240 kinds of traditional Chinese medicine were used,with a cumulative frequency of 35 462 times.Among them,29 kinds of traditional Chinese medicine such as Danggui,Fuling,Baizhu,Chaihu had a cumulative usage frequency exceeding 300 times.Regarding the four natures of drugs,cold-natured(43.55％),warm-natured(30.05％),and neutral-natured(23.34％)drugs were predominant;In terms of five flavors,sweet(46.12％),bitter(30.91％),and pungent(20.02％)were the main ones.The most frequently used drugs were tonifying herbs(32.77％),followed by heat-clearing herbs(15.96％)and phlegm-resolving herbs(14.71％).Systematic cluster analysis yielded 7 groups of drug combinations.Conclusion In real-world clinical practice,traditional Chinese medicine for breast cancer mainly uses tonifying herbs,reflecting the traditional Chinese medicine principle of"strengthening healthy Qi and cultivating the root"in treating tumors.The four natures and five flavors of drugs follow syndrome differentiation and the combination of cold and heat.The clustered drug combinations have extensive therapeutic effects,covering various syndromes of breast cancer at different stages,which can provide a reference for clinical medication.

Objective To observe the early changes of vault after implantation of posterior chamber phakic intraocular lens implantable collamer lens(ICL),and investigate the effect of different implantation axes on the early vault changes.Methods A prospective,parallel cohort study was performed,enrolling a total of 124 eyes of who underwent ICL(V4c)implantation in the refractive clinic.The changes of vault were observed by scheimpflug tomography(Pentacam)and anterior segment optical coherence tomography(CASIA2)at 1 day,1 week and 1 month after surgery.Results The ICL vault declined significantly by approximately(108.2±82.4)μm 1 week after surgery with the proportion of 16.6%±12.1%compared with the values 1 day after surgery(P<0.001),and then remained stable.Within 1 month after surgery,excluding the difference in vault baseline at 1 day after surgery,the proportion of vault decline in the middle vault group(250-749 μm)and the high vault group(≥750 μm)was similar,and there was no statistically significant difference.We analyzed the relationship between ICL axial directions and vault and found that the vault decline of the horizontal ICL group stabilized quickly at 1 week after surgery,and the vault decline of the vertical ICL group was more significant within 1 month after surgery(P<0.05).Conclusion The vault of the ICL shows a downward trend in the early stage after implantation.The middle vault group and ICL in the horizontal position stabilizes faster,and the downward trend of the high vault group or ICL in the vertical position is more obvious.

Laparoscopic subtotal cholecystectomy (LSC) has been a safe and viable alternative to conversion to laparotomy in cases of severe cholecystitis. The objective of this study is to determine the utility of intraoperative choledochoscopy in LSC for the exploration of the gallbladder, cyst duct, and subsequent stone clearance of the cystic duct in cases of severe cholecystitis. A total of 72 patients diagnosed with severe cholecystitis received choledochoscopy-assisted laparoscopic subtotal cholecystectomy (CALSC). A choledochoscopy was performed to explore the gallbladder cavity and/or cystic duct, and to extract stones using a range of techniques. The clinical records, including the operative records and outcomes, were subjected to analysis. No LSC was converted to open surgery, and no bile duct or vascular injuries were sustained. All stones within the cystic duct were removed by a combination of techniques, including high-frequency needle knife electrotomy, basket, and electrohydraulic lithotripsy. A follow-up examination revealed the absence of residual bile duct stones, with the exception of one common bile duct stone, which was extracted via endoscopic retrograde cholangiopancreatography. In certain special cases, CALSC may prove to be an efficacious treatment for the management of severe cholecystitis. This technique allows for optimal comprehension of the situation within the gallbladder cavity and cystic duct, facilitating the removal of stones from the cystic duct and reducing the residue of the non-functional gallbladder remnant.