[Objective] To validate and optimize the platelet transfusion refractoriness (PTR) prediction model for patients with hematological disorders established by our center. [Methods] The data of patients with hematological diseases who received platelet transfusions from December 2021 to December 2022 were used as the training set, and data from January 2023 to December 2023 as the validation set. The validation set data was used to validate the predictive model constructed on the training set. Relevant risk factors for PTR were collected through literature review and preliminary studies。 The patients were divided into effective and ineffective groups according to the corrected count increment (CCI) of platelet counts. Predictive factors were screened using univariate and multivariate logistic regression. The calibration of the model were assessed via calibration curves, while discrimination, accuracy, sensitivity, and specificity were evaluated using receiver operating characteristic (ROC) curves Clinical utility was further analyzed with decision curve analysis (DCA). [Results] The Hosmer-Lemeshow (H-L) goodness-of-fit test for the validation set yielded S: P=0.000, indicating that the original model needs optimization. Baseline comparisons and logistic regression identified the number of red blood cell units (RBCU) and platelet units (PLT-U) transfused as key predictors for the optimized model. The H-L goodness-of-fit test S: P values for the training and validation sets were 0.930 and 0.056, respectively; the ROC areas were 0.793 5 and 0.809 4, specificities 90.95% and 84.21%, sensitivities 59.26% and 70.04%, and accuracies 78.14% and 74.10%, respectively. DCA demonstrated clinical net benefit within a prediction probability threshold range of 0.2-0.8. [Conclusion] Transfusion volumes of RBC-U and PLT-U were inversely associated with PTR in hematological patients. The resulting PTR prediction model exhibits moderate predictive efficacy and clinical benefit.

Objective To investigate the sputum metabolic profiles of patients with occupational coal workers' pneumoconiosis (CWP) by an untargeted metabolomics method, and to identify relevant differential metabolic pathways and potential biomarkers. Methods A total of 12 male patients with stage Ⅰ CWP were selected as the CWP group, and 16 healthy male individuals were selected as the control group, using a judgmental sampling method. Sputum metabolites of individuals in both groups were detected to perform non-targeted metabolomic analysis using the ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Differential metabolites (DMs) and their pathways were screened using principal component analysis, partial least squares discriminant analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Potential biomarkers were analyzed and identified via the receiver operating characteristic curve (ROC). Results There were apparent metabolic alterations observed in sputum of CWP patients compared with healthy controls. In the positive ion mode, a total of 42 DMs were identified in sputum from CWP patients, including 19 downregulated and 23 upregulated metabolites. In the negative ion mode, a total of 25 DMs were identified in sputum from CWP patients, including 16 downregulated and 9 upregulated metabolites. KEGG enrichment analysis of sputum from CWP patients showed that seven DMs pathways were enriched in ABC transporters, histidine metabolism, phenylalanine metabolism, arachidonic acid metabolism, linoleic acid metabolism, purine metabolism, and oxidative phosphorylation, involving 26 DMs. ROC analysis indicated that 16(R)-hydroxyarachidonic acid, pyrophosphate, and 2-hydroxyphenylacetate of these 26 DMs may serve as potential biomarkers for CWP. Conclusion Sputum metabolomic profiles were altered in CWP patients compared with healthy controls. The potential biomarkers of CWP prevention and treatment are 16(R)-hydroxyarachidonic acid, pyrophosphate, and 2-hydroxyphenylacetate.

BACKGROUND: T-cell lymphoblastic lymphoma/acute lymphoblastic leukemia (T-LBL/ALL) is an aggressive form of hematological malignancy associated with poor prognosis in adult patients. Histone deacetylases (HDACs) are aberrantly expressed in T-LBL/ALL and are considered potential therapeutic targets. Here, we investigated the antitumor effect of a novel HDAC inhibitor, chidamide, on T-LBL/ALL. METHODS: HDAC1, HDAC2 and HDAC3 levels in T-LBL/ALL cell lines and patient samples were compared with those in normal controls. Flow cytometry, transmission electron microscopy, and lactate dehydrogenase release assays were conducted in Jurkat and MOLT-4 cells to assess apoptosis and pyroptosis. A specific forkhead box O1 (FOXO1) inhibitor was used to rescue pyroptosis and upregulated gasdermin E (GSDME) expression caused by chidamide treatment. The role of the FOXO1 transcription factor was evaluated by dual-luciferase reporter and chromatin immunoprecipitation assays. The efficacy of chidamide in vivo was evaluated in a xenograft mouse. RESULTS: The expression of HDAC1, HDAC2 and HDAC3 was significantly upregulated in T-LBL/ALL. Cell viability was obviously inhibited after chidamide treatment. Pyroptosis, characterized by cell swelling, pore formation on the plasma membrane and lactate dehydrogenase leakage, was identified as a new mechanism of chidamide treatment. Chidamide triggered pyroptosis through caspase 3 activation and GSDME transcriptional upregulation. Chromatin immunoprecipitation assays confirmed that chidamide led to the increased transcription of GSDME through a more relaxed chromatin structure at the promoter and the upregulation of FOXO1 expression. Moreover, we identified the therapeutic effect of chidamide in vivo . CONCLUSIONS This study suggested that chidamide exerts an antitumor effect on T-LBL/ALL and promotes a more inflammatory form of cell death via the FOXO1/GSDME axis, which provides a novel choice of targeted therapy for patients with T-LBL/ALL.
Humans ; Pyroptosis/drug effects* ; Forkhead Box Protein O1/genetics* ; Aminopyridines/pharmacology* ; Animals ; Mice ; Benzamides/pharmacology* ; Cell Line, Tumor ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Phosphate-Binding Proteins/metabolism* ; Histone Deacetylase Inhibitors/pharmacology* ; Jurkat Cells ; Histone Deacetylases/metabolism* ; Apoptosis/drug effects* ; Gasdermins

The identification and optimization of mutations in nanobodies are crucial for enhancing their therapeutic potential in disease prevention and control. However, this process is often complex and time-consuming, which limit its widespread application in practice. In this study, we developed a workflow, named Evolutionary-Nanobody (EvoNB), to predict key mutation sites of nanobodies by combining protein language models (PLMs) and molecular dynamic (MD) simulations. By fine-tuning the ESM2 model on a large-scale nanobody dataset, the ability of EvoNB to capture specific sequence features of nanobodies was significantly enhanced. The fine-tuned EvoNB model demonstrated higher predictive accuracy in the conserved framework and highly variable complementarity-determining regions of nanobodies. Additionally, we selected four widely representative nanobody-antigen complexes to verify the predicted effects of mutations. MD simulations analyzed the energy changes caused by these mutations to predict their impact on binding affinity to the targets. The results showed that multiple mutations screened by EvoNB significantly enhanced the binding affinity between nanobody and its target, further validating the potential of this workflow for designing and optimizing nanobody mutations. Additionally, sequence-based predictions are generally less dependent on structural absence, allowing them to be more easily integrated with tools for structural predictions, such as AlphaFold 3. Through mutation prediction and systematic analysis of key sites, we can quickly predict the most promising variants for experimental validation without relying on traditional evolutionary or selection processes. The EvoNB workflow provides an effective tool for the rapid optimization of nanobodies and facilitates the application of PLMs in the biomedical field.

Objective To explore the status of knowledge graph-based research into breast cancer micro-environment and to predict future research hotspots.Methods The literature related to breast cancer microenvironment in recent 20 years was retrieved from CNKI and Web of Science Core Collection database and analyzed with CiteSpace and VOSviewer.Results A total of 825 Chinese articles and 16,221 English articles were retrieved.Visual analysis showed that research focus has gradually shifted from cellular research to molecular research and drug innovation.Cancer stem cells,PD-1,PD-L1,immune checkpoint inhibitors,and nanoparticles are the main subjects of interest in research on breast cancer microenvironment,and the United States has the largest number of studies on breast cancer microenvironment,followed by China and Italy.Conclusion Current research mainly focuses on tumor stemness,immunotherapy,and nanodeli-very.Owing to deepening research in this field,the targeting of the breast cancer microenvironment for the prevention of tumor development and metastasis and improvement of tumor prognosis has emerged as a new research direction.

Objective To retrieve,analyse and integrate the best evidences in perioperative fluid management for elderly patients with hip fracture,therefore to provide references for patient care.Methods Following the 6S evidence model,databases and websites were searched to collect the evidences on perioperative fluid management of elderly patients with hip fracture.The searched databases including BMJ Best Practice,UpToDate,AAOS Clinical Practice Guidelines,ASBMR,ANZHFR,ESTES,NICE,SIGN,JBI,Cochrane Library,CINAHL,Embase,PubMed,Web of Science,CNKI,Wanfang Data,VIP database,CEBM Database,Medive,China Science and Technology Journal Database,SinoMed,and other websites about orthopaedics.The searched literatures included guidelines,clinical decision-making,best practices,expert consensus and systematic reviews.The time span for the published literatures was from the inception of the databases and websites to August 2022.Two researchers independently completed quality evaluations of the retrieved literatures,as well as extraction,assessment and integration of the abstracted evidences.Results A total of 15 articles were included,they were 2 guidelines,3 clinical decision-makings,1 best practice,7 expert consensus,and 2 systematic reviews.Thirty pieces of evidence were summarised from 7 aspects,covering multidisciplinary team collaboration,dynamic assessment and monitoring of fluid status,fluid resuscitation,fluid management before and after the surgery and health education.Conclusions This study summarised the best evidences in perioperative fluid management for elderly patients with hip fracture.The evidences provide an evidence-based solution which will enable the healthcare workers to fully combine the clinical scenarios,evaluate changes in fluid volume status dynamically,develope personalised fluid management strategies and improve patient outcomes.

Objective To explore the effect of Jiawei Liujunzi decoction in improving volume overload and residual renal protection in continuous ambulatory peritoneal dialysis(CAPD)patients with spleen deficiency.Methods A total of 82 patients treated in the Peritoneal Dialysis Center of Dongyang Hospital of Traditional Chinese Medicine of Affiliated to Wenzhou Medical University from July 2022 to April 2023 were selected as study objects.According to random number table method,the patients were divided into control group and treatment group,41 cases in each group.The control group was given basic western medicine treatment,and the treatment group was given supplemented with Jiawei Liujunzi decoction on the basis of control group,and the treatment course was 8 weeks.The percentage of extracellular water to total body water(ECW％),urea clearance index of residual kidney(Kt/V)and brain natriuretic peptide(BNP)of two groups were compared,and safety of the drug was evaluated.Results After treatment,ECW％and BNP in two groups were significantly lower than before treatment(P＜0.05).The urine volume of control group was significantly lower than that before treatment(P＜0.05).After treatment,there were no significant differences in ECW％,BNP,Kt/V and urine volume between two groups(P＞0.05).After treatment,there were no significant differences in alanine aminotransferase,aspartate aminotransferase,albumin,phosphorus,calcium and potassium between two groups(P＞0.05),indicating good safety.After 12 months of follow-up,the survival rate of treatment group was significantly higher than that of control group(P＜0.05).Conclusion Jiawei Liujunzi decoction can improve the volume overload of CAPD patients with spleen deficiency to a certain extent,with good safety,and can improve the long-term survival rate of patients.

Objective:To evaluate the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined with tislelizumab and tyrosine kinase inhibitor (TKI) as a conversion therapy in patients with initially unresectable hepatocellular carcinoma (HCC).Methods:The clinical data of 51 initially unresectable HCC patients admitted to the Department of Hepato-Pancreato-Biliary Surgery, the Eighth Affiliated Hospital of Guangxi Medical University from March 2022 to November 2023 were prospectively collected, including 46 males and 5 females, aged (53±11) years old. All patients received TACE combined with tislelizumab and TKI. For initially unresectable HCC patients who have successfully undergone conversion therapy, surgical resection was performed sequentially. Follow-up was conducted through regular outpatient visits or hospitalization combined with telephone contact, and the surgical conversion, relapse-free survival and adverse reactions of patients were recorded.Results:Among the 51 patients with initial unresectable HCC, there were 12 cases of stage Ib, 14 cases of stage IIa, 10 cases of stage IIb, and 15 cases of stage IIIa in Chinese liver cancer staging. The 51 patients were evaluated according to the modified solid tumor response evaluation criteria, and 15 patients had complete response, 26 had partial response, 5 had stable disease, and 5 had disease progression. The objective response rate was 80.4% (41/51), and the disease control rate was 90.2% (46/51). The conversion success rate was 49.0% (25/51), 2 patients gave up surgery, and the actual conversion rate was 45.1% (23/51). Among the 23 patients who underwent surgical resection, irregular hepatectomy was performed in 11 cases, lobectomy in 8 cases, and hemihepatectomy in 4 cases. Common treatment-related adverse events were hand-foot syndrome, hypertension, gingival bleeding, etc. Most of the drug-related adverse events were grade 1 to grade 2. A total of 10 patients (19.6%, 10/51) had grade 3 drug-related adverse events, and no grade 4 or above adverse events occurred, and no treatment-related deaths occurred. The cumulative recurrence free survival rates of 23 patients with initial unresectable HCC at 6 and 12 months after sequential hepatectomy were 100% and 94.7% respectively.Conclusion:The triple combination therapy of TACE combined with tislelizumab and TKI in the treatment of initial unresectable HCC has good clinical efficacy, and the adverse reactions are safe and controllable.

Sick sinus syndrome(SSS)refers to damage to the sinoatrial node and its surrounding tissues,which leads to excitation and conduction dysfunction of the sinoatrial node,Resultsing in arrhythmia diseases.A better understanding of the pathogenesis of SSS is required to provide a basis for its treatment,including establishing an animal model that can simulate human sinus node dysfunction.In this paper,we review the animal selection,the principles and method of modeling,and the evaluation method and detection indicators of the models,to provide a basis for further studies of the pathogenesis of SSS.

Objective:To analyze the role of dandelion and mulberry leaf in the progression of acute myeloid leukemia(AML)by network pharmacology,and to clarify the active components and their mechanisms in treating AML.Methods:The active components of dandelion and mulberry leaf were screened by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP).The targets were predicted by SwissTargetPrediction Database.The AML-related genes and protein targets were retrieved from the SymMap Database,the GeneCards Human Gene Database,the DisGeNET Database,and the Online Mendelian Inheritance in Man(OMIM)Database.The AML-related genes and target genes of dandelion and mulberry leaf were compared by comparative analysis and were identify by the enrichment genes,followed by Gene Ontology(GO)functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)signaling pathway enrichment analysis.The drug-active component-target network and protein-protein interaction(PPI)network were constructed by Cytoscape 3.8.0 software,and the core genes were selected by CytoNCA plugin;the molecular docking was conducted by AutoDock software.Results:After filtering by databases,39 active components were identified,and 148 common targets between dandelion-mulberry leaf and AML were collected.The GO functional enrichment analysis mainly involved cytokine-mediated signaling pathways,positive regulation of kinase activity,and oxidative stress responses.The KEGG signaling pathway enrichment analysis focused on the phosphatidylinositol 3 kinase/protein kinase B(PI3K-AKT)signaling pathway,the tumor necrosis factor(TNF)signaling pathway,and the Janus kinase/signal transducer and activator of transcription(JAK-STAT)signaling pathway.The key targets were identified by topological analysis including signal transducer and activator of transcription 3(STAT3),epidermal growth factor receptor(EGFR),protein kinase B1(AKT1),recombinant human epidermal growth factor(EGF),vascular endothelial growth factor A(VEGFA),oncogene MYC,tumor protein P53(TP53),mitogen-activated protein kinase 3(MAPK3),cysteiny asparate specific protease-3(CASP3),oncogene SRC,heat shock protein 90 alpha family class A member 1(HSP90AA1),tenascin XB1(CTNNB1),phosphoinositide kinase-3 catalytic subunit alpha(PIK3CA),interleukin 6(IL-6),TNF,mitogen-activated protein kinase 1(MAPK1),and phosphatidylinositide kinase-3 regulatory subunit 1(PIK3R1).The molecular docking results showed the highest affinity pairing to be taraxerol with MYC(-8.74 kcal·mol-1),and quercetin,kaempferol,luteolin,and artemetin demonstrated good binding affinities with various targets.Conclusion:The main active components of dandelion-mulberry leaf,such as quercetin,taraxerol,kaempferol,luteolin,and artemetin,may exert the anti-AML effect by regulating AKT1,STAT3,HSP90AA1,IL-6,and MAPK1;regulation the PI3K-AKT signaling pathway may be the critical mechanism of anti-AML effect by dandelion-mulberry leaf.