[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 investigate the correlation between moderate intensity aerobic exercise and cerebral blood flow regulation in patients with mild carotid artery stenosis.Methods:A retrospective study was conducted to select 30 cases of patients with unilateral mild carotid artery stenosis and moderate intensity aerobic exercise for more than 1 year in the Central Hospital of Dalian University of Technology from July 2022 to November 2023 as the exercise group (study group), and 30 cases of patients with unilateral mild carotid artery stenosis without exercise habits matched by age, gender and other factors as the non-exercise group (control group). Transcranial Doppler ultrasound (TCD) examination was performed in both groups, and the recumbent-upright-test, breath holding test and breath exchange test were performed to calculate the occurrence rate of "w" wave in recumbent-upright position, the slope of "w" wave in recubitus position, the change rate of pulse index (PI) before and after breath holding, resistance index (RI), breath holding index (BHI), and cerebral blood flow velocity before and after breath exchange. The blood pressure and heart rate difference in the recumbent-upright position were calculated, and the correlation between moderate intensity aerobic exercise and cerebral blood flow regulation function in patients with mild carotid artery stenosis was evaluated by statistical analysis. The correlation analysis between the exercise years and BHI in the study group was carried out to explore the relationship between the exercise years and cerebrovascular reactivity.Results:The occurrence rate and slope of "w" wave in the study group were higher than those in the control group: 93.3%(28/30) vs. 86.7%(26/30), 2.27 ± 1.14 vs. 1.28 ± 0.23, 2.67 ± 0.63 vs. 1.41 ± 0.69, there were statistically significant ( P<0.05). The change rates of PI and RI before and after breath holding and ventilation in the study group were higher than those in the control group: 21.23 ± 7.67 vs. 13.89 ± 9.67, 14.62 ± 6.63 vs. 11.17 ± 1.78 and 26.26 ± 12.46 vs. 18.36 ± 12.13, 14.91 ± 4.91 vs. 10.83 ± 2.35, and the average cerebral blood flow velocity before and after ventilation was higher than that in the control group: (31.26 ± 4.92) cm/s vs. (24.89 ± 6.34) cm/s, there were statistically significant ( P<0.01). The exercise years of the study group was negatively correlated with the breath holding index. Conclusions:Moderate intensity exercise is associated with cerebral blood flow regulation in patients with mild carotid artery stenosis. Exercise years are negatively correlated with cerebral blood flow regulation. Impaired cerebral blood flow regulation may be one of the potential mechanisms of poor prognosis of stroke in carotid artery stenosis population.

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.

Cerebral hyperperfusion syndrome (CHS) is a rare but serious complication after cerebral revascularization, which may lead to catastrophic consequences. The mechanism of CHS is not fully understood, and it may be related to cerebral autoregulation dysfunction and the increase of blood pressure after operation. Timely detection and treatment of cerebral hyperperfusion can avoid CHS. This article reviews the pathogenesis, diagnosis, clinical manifestations, prevention and treatment of CHS.

Objective:To observe the toxic and side effects of TCM syndrome differentiation and treatment combined with abemaciclib and endocrine drugs in the treatment of hormone receptor ( HR ) positive and human epidermal growth factor receptor 2 ( HER2 ) negative advanced breast cancer and the dose of abemaciclib under the influence of toxic and side effects.Methods:Patients with HR+/HER2- advanced breast cancer who received TCM combined with abemaciclib and endocrine therapy in Beijing Hospital of Traditional Chinese Medicine, Capital Medical University from March 2021 to February 2023 were selected, and the relevant data of East Asian population in MONARCH 2 and MONARCH 3 of abemaciclib random phase Ⅲ clinical study were extracted for retrospective cohort study. The TCM exposure cohort was divided into 20 cases of TCM + abemaciclib + fulvestrant group (EXP 1) and 22 cases of TCM + abemaciclib + aromatase inhibitor (AI) group (EXP 2). The East Asian populations in MONARCH 2 and 3 were non-exposed cohorts, which were divided into NEXP 1 group ( 146 cases ) and NEXP 2 group (102 cases). The safety analysis of the 2 cohorts was carried out, and the reduction and termination of abemaciclib taken by patients under the influence of toxic and side effects were counted.Results:①There were significant differences in CTCAE any grade, grade 2 ( χ2 values were 8.11, 4.59, respectively ) between EXP 1 group and NEXP 1 group, as well as in CTCAE any grade ( χ2=18.57) between EXP 2 group and NEXP 2 group compare the incidence rate of diarrhoea ( P<0.05 or P<0.01). There was significant differences in CTCAE ≥ grade 2 EXP 1 group compare the incidence rate of diarrhoea ( χ2=5.56, P=0.02). The incidence of grade ≥ 3 neutropenia in EXP 1 was [ 5 cases (27.78%) ] and in EXP 2 was [ 2 cases (13.33%)]. There were 65 cases (44.52%) in NEXP 1 and 30 cases (29.41%) in NEXP 2, and the exposed cohort were lower than those in the non-exposed cohort. The increase of GPT, GOT and SCr in the exposed cohort were lower than those in the non-exposed cohort. ② Compared with the non-exposed cohort, the first occurrence time of diarrhea and neutropenia was prolonged and the duration was shortened in the exposed cohort. ③ The patients in the exposed cohort were less likely to take abemaciclib reduction and discontinuation due to diarrhea, neutropenia, impaired liver function, and elevated SCr than those in the non-exposed cohort. Conclusion:TCM syndrome differentiation and treatment combined with abemaciclib and endocrine drugs is safe in the treatment of HR+/HER2- advanced breast cancer, which can effectively prevent and treat the toxic and side effects caused by abemaciclib, and reduce the drug reduction and discontinuation.

Objective To explore the changes in serum energy metabolites in patients with peripheral T-cell lymphoma,and investigate serum biomarkers for monitoring peripheral T-cell lymphoma from the perspective of energy metabolism.Methods Multiple/selected reaction monitoring(MRM/SRM)was used to detect the energy-related metabolites in the sera of 16 patients with newly diagnosed peripheral T-cell lymphoma admitted in the Hematology Medical Center of the Second Affiliated Hospital of Army Medical University from November 2020 to December 2021,as well as 10 recruited healthy volunteers.The corresponding clinical data including medical history,laboratory results and image data were collected and retrospectively analyzed.Results Significant differences were seen in the contents and expression profiles of serum energy metabolism-related products between the patients and the healthy volunteers.The patients had significantly reduced serum contents of cyclic AMP,succinate,citrate and cis-aconitate(P＜0.05),and elevated D-glucose 6-phosphate content(P＜0.05).The serum contents of citrate and succinate were negatively correlated with the risk stratification(low-,moderate-and high-risk)and clinical stage of the disease(P＜0.05).Meanwhile,there was a negative correlation between the contents of L-malic acid and citrate and the mid-term efficacy evaluation results,such as complete/partial response(CR/PR)or stable disease(SD)(P＜0.05).For patients with extranodal NK/T cell lymphoma(n=10),there were also significant reductions in the contents of cyclic AMP,succinate,citrate,isocitrate and cis-aconitate in the sera of patients compared with healthy volunteers(P＜0.05),and the contents of citrate and succinate were negatively correlated with the clinical stage(P＜0.05)and were rather correlated with mid-term efficacy evaluation results(CR/PR or SD)(P＜0.05).For patients with angioimmunoblastic T-cell lymphoma(n=6),the serum contents of cyclic AMP,citrate and succinate were significantly lower,while the content of D-glucose 6-phosphate was higher when compared with the healthy volunteers(P＜0.05),and the content of succinate was negatively correlated with both clinical stage and risk grade of the patients(P＜0.05).Conclusion There are 5 serum differential metabolites identified between patients with peripheral T-cell lymphoma and healthy controls,and succinate and citrate are expected to be serum biomarkers of peripheral T-cell lymphoma.

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.