Background and Objectives: Heart failure is a potentially fatal event caused by diverse cardiovascular diseases, leading to high morbidity and mortality. Histone deacetylase (HDAC) inhibitors positively influence cardiac hypertrophy, fibrosis, hypertension, myocardial infarction, and heart failure, causing some side effects. We aimed to investigate the effect of the novel HDAC inhibitor YAK577 on the heart failure mouse model and its underlying mechanism. Methods: New hydroxamic acid YAK577 was prepared via methyl-2,3-diphenylpropanoate synthesis using carboxylic acids. We used a micro-osmotic pump, including isoproterenol (ISO; 80 mg/kg/day), to induce a heart failure with reduced ejection fraction. Cardiac hypertrophy was assessed by heart weight to body weight ratio and cross-sectional area.The left ventricular (LV) function was assessed by echocardiography. Fibrosis was evaluated using picrosirius red staining. Overexpression and knockdown experiments were performed to investigate the association between HDAC8 and matrix metalloproteinase 12 (MMP12). Results: YAK577 treatment restored ISO-induced reduction in LV fractional shortening and ejection fraction (n=9–11). YAK577 significantly downregulated cardiac hypertrophy marker genes (natriuretic peptide B, NPPB, and myosin heavy chain 7, MYH7) and cardiomyocyte size in vitro but not in vivo. YAK577 ameliorated cardiac fibrosis and fibrosis-related genes in vivo and in vitro. Additionally, YAK577 reduced elevated HDAC8 and MMP12 mRNA and protein expressions in ISO-infused mice, H9c2 cells, and rat neonatal cardiomyocytes.HDAC8 overexpression stimulated MMP12 and NPPB mRNA levels, while HDAC8 knockdown downregulated these genes. Conclusions YAK577 acts as a novel heart failure drug through the HDAC8/MMP12 pathway.

Background and Objectives: Heart failure is a potentially fatal event caused by diverse cardiovascular diseases, leading to high morbidity and mortality. Histone deacetylase (HDAC) inhibitors positively influence cardiac hypertrophy, fibrosis, hypertension, myocardial infarction, and heart failure, causing some side effects. We aimed to investigate the effect of the novel HDAC inhibitor YAK577 on the heart failure mouse model and its underlying mechanism. Methods: New hydroxamic acid YAK577 was prepared via methyl-2,3-diphenylpropanoate synthesis using carboxylic acids. We used a micro-osmotic pump, including isoproterenol (ISO; 80 mg/kg/day), to induce a heart failure with reduced ejection fraction. Cardiac hypertrophy was assessed by heart weight to body weight ratio and cross-sectional area.The left ventricular (LV) function was assessed by echocardiography. Fibrosis was evaluated using picrosirius red staining. Overexpression and knockdown experiments were performed to investigate the association between HDAC8 and matrix metalloproteinase 12 (MMP12). Results: YAK577 treatment restored ISO-induced reduction in LV fractional shortening and ejection fraction (n=9–11). YAK577 significantly downregulated cardiac hypertrophy marker genes (natriuretic peptide B, NPPB, and myosin heavy chain 7, MYH7) and cardiomyocyte size in vitro but not in vivo. YAK577 ameliorated cardiac fibrosis and fibrosis-related genes in vivo and in vitro. Additionally, YAK577 reduced elevated HDAC8 and MMP12 mRNA and protein expressions in ISO-infused mice, H9c2 cells, and rat neonatal cardiomyocytes.HDAC8 overexpression stimulated MMP12 and NPPB mRNA levels, while HDAC8 knockdown downregulated these genes. Conclusions YAK577 acts as a novel heart failure drug through the HDAC8/MMP12 pathway.

Objective:To evaluate the association between postoperative delirium (POD) and preoperative frailty in elderly patients undergoing knee or hip arthroplasty.Methods:This nested case-control study utilized medical records from elderly patients who underwent knee or hip arthroplasty under combined spinal-epidural anesthesia at Qingdao Municipal Hospital between September 2021 and May 2023. Participants were divided into 2 groups based on clinically diagnosed POD: POD group ( n=53) and non-POD group ( n=256). Univariate analysis was conducted on suspected influencing factors, and logistic regression analysis was utilized to identify the risk factors for POD. Receiver operating characteristic and clinical decision curves were plotted to evaluate the predictive performance of these risk factors for POD. Mediation analysis was performed, and a clinically applicable nomogram was constructed to achieve visual prediction of outcomes. Results:There were statistically significant differences in age, preoperative frailty, body mass index, American Society of Anesthesiologists Physical Status classification, Memorial Delirium Assessment Scale scores, and concentrations of Aβ 42, Aβ 40, phosphorylated tau protein (p-tau protein) and tau protein, Aβ 42/tau ratio and Aβ 42/p-tau ratio in cerebrospinal fluid (CSF) between non-POD group and POD group ( P<0.05). Preoperative frailty was a risk factor for POD ( P<0.05). Mediation analysis revealed that the association between preoperative frailty and POD was mediated by CSF tau protein concentrations. The area under the receiver operating characteristic curve of preoperative frailty and CSF biomarker concentrations in predicting POD was 0.974 ( P<0.05). The clinical decision curve demonstrated that the model combining the preoperative frailty and CSF biomarker concentrations predicted a higher net benefit ( P<0.05). The clinical decision curve showed that the model combining preoperative frailty and CSF biomarker concentrations predicted a higher net benefit. Conclusions:Preoperative frailty is a risk factor for POD in elderly patients undergoing knee or hip arthroplasty, and its combination with CSF biomarker concentrations can effectively predict the occurrence of POD. CSF tau concentration mediates the association between preoperative frailty and development of POD.

Objective:To evaluate the association between the preoperative aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio and postoperative delirium (POD) in patients undergoing total knee/hip arthroplasty.Methods:In this nested case-control study, medical records from patients, aged ≥55 yr, of American Society of Anesthesiologists Physical Status classification Ⅰ or Ⅱ, with Mini-Mental State Examination (MMSE) scale score >24 on preoperative day 1, scheduled for elective total knee/hip arthroplasty under combined spinal-epidural anesthesia at Qingdao Municipal Hospital between November 2021 and December 2023, were collected. POD was assessed using the Confusion Assessment Method. Patients were categorized into POD and non-POD groups based on the occurrence of POD. Logistic regression was employed to identify protective and risk factors for POD. The predictive performance of preoperative AST/ALT ratio alone and its combination with cerebrospinal fluid (CSF) biomarker concentrations for POD was evaluated using receiver operating characteristic curves, and the clinical utility of the prediction models was assessed using decision curve analysis. Mediation analysis was conducted to examine the mediation role of CSF biomarkers in the relationship between the preoperative AST/ALT ratio and POD. Restricted cubic splines were used to assess the nonlinear relationship between the preoperative AST/ALT ratio and POD.Results:A total of 460 patients were finally included, with 49 in POD group and 411 in non-POD group. After adjustment for multiple confounding factors including age, sex, educational level, MMSE score, history of hypertension, history of diabetes, history of smoking and history of alcohol use, multivariable logistic regression identified that the higher preoperative AST/ALT ratio, CSF total tau protein (t-tau) and phosphorylated tau protein (p-tau) concentrations were independent risk factors for POD, whereas lower CSF β-amyloid 42 (Aβ 42) concentration, Aβ 42/t-tau ratio and Aβ 42/p-tau ratio served as protective factors ( P<0.05). The area under the receiver operating characteristic curve of the preoperative AST/ALT ratio combined with CSF biomarkers in predicting POD was 0.939 ( P<0.001), demonstrating high clinical efficacy. After adjusting for age, educational level, sex, MMSE score, history of hypertension, history of diabetes, history of smoking, history of alcohol use and body mass index, restricted cubic splines revealed a nonlinear relationship between preoperative AST/ALT levels and the probability of POD, and the probability of POD increased with rising ratios when the preoperative AST/ALT ratio ranged from 1.09 to 1.40 ( Poverall < 0.05, Pnonlinear <0.05). After stratification by sex, the preoperative AST/ALT ratio demonstrated a linear relationship with the probability of POD ( Poverall <0.05, Pnonlinear>0.05). Mediation analysis indicated that the relationship between the preoperative AST/ALT ratio and POD was partially mediated by CSF p-tau concentration (proportion mediated 18.1%), CSF t-tau concentration (proportion mediated 12.0%), and the Aβ 42/t-tau ratio (proportion mediated 15.4%). Conclusions:A higher preoperative AST/ALT ratio is an independent risk factor for POD in total knee/hip arthroplasty patients. The concentrations of CSF t-tau and p-tau and Aβ 42/t-tau ratio have a mediating role in the relationship between the preoperative AST/ALT ratio and POD.

Objective:To report the preliminary clinical exploration result of spatially fractionated radiation therapy (SFPT) using the pencil-beam-scanning (PBS) technique at a single center for the treatment of patients with bulky tumors.Methods:Data on the clinical characteristics, tumor characteristics, and dosimetric parameters were retrospectively collected from patients with bulky tumors at the Radiation Oncology Department, Ion Medical Center, First Affiliated Hospital of University of Science and Technology of China (i.e., the Hefei Ion Medical Center) from April 2024 to December 2024. Three-dimensional lattice radiotherapy (LRT) was primarily utilized in the SFRT, with multi-field robust optimization performed using pencil beam scanning. SFRT target volumes (STVs) were defined as 1.0 cm-diameter spheres. Primary observation indicators included the remission rate of tumor-associated symptoms, followed by the local tumor control rate.Results:A total of 12 patients were enrolled in this study, with a median age of 61 years (28-85 years). The primary tumors included hepatocellular carcinoma (six patients), sarcomas (three patients), and lung cancer (two patients). Eight patients received concurrent systemic therapy. The SFRT plans showed a median gross tumor volume (GTV) of 429.63 cm 3 (120.60-2 053.30 cm 3), a median STV number of 8 (3-20), a single-fraction dose to STVs of 10 GyE, a median irradiation quantity of 6 (3-8), a median STV of 8 cm 3 (3-20 cm 3), a median STV proportion of 2.09% (0.62%-3.30%), a median GTV corresponding to a single STV of 52.91 cm 3 (30.25-159.82 cm 3), and a median peak-to-valley dose ratio of 3.37 (2.29-7.60). All patients received conventionally fractionated proton therapy (CFPT), with a median prescription dose of 50 GyE (40-60 GyE). Furthermore, these patients showed a median follow-up time of 174 d (133-235 d), a remission rate of tumor-associated symptoms of 75%, and a local control rate of 100%. Four patients experienced grade 1-2 treatment-related adverse events, suggesting high overall tolerability of the patients. Conclusions:SFRT represents a promising technique with high control rates and tolerability for bulky tumors, providing the possibility for quick symptom relief and the control of tumor progression.

Objective:To explore advantages of CT and MRI imaging in clinical assessment of specific indicators (trochlear dysplasia and tibial tubercle lateralization) of acute patellar dislocation in adolescents by comparing CT versus MRI imaging.Methods:A retrospective study was conducted to analyze the CT and MRI imaging data of 73 patients with acute patellar dislocation who had been admitted to Department of Orthopedics, The Second Hospital of Tangshan from January 2014 to September 2024. There were 37 males (21 left knees and 16 right knees) and 36 females (19 left knees and 17 right knees), with a mean age of 15 (13, 16) years. On MRI images, the distance between the patellar tendon-trochlear groove (PT-TG) was measured. On CT images, the distance between the tibial tuberosity-trochlear groove (TT-TG) was measured. Additionally, the distance from the tibial tubercle-Roman arch (TT-RA), the sulcus angle (SA), the trochlear depth (TD), the lateral trochlear inclination (LTI), and the trochlear facet asymmetry (TFA) were measured on both MRI and CT images.Results:The TT-TG measured on CT [(20.47±4.42) mm] was significantly greater than that on MRI [(17.89±4.23) mm] ( t = -4.047, P < 0.001). The TT-RA [(24.28±4.27) mm], TD [2.95 (2.36, 4.08) mm], LTI (15.4°±3.85°), and TFA [0.42 (0.38, 0.49)] measured on CT were all significantly greater than those on MRI [(21.34±3.99) mm, 2.52 (1.64, 2.98) mm, 14.11°±3.58°, 0.38 (0.34, 0.44)] ( P < 0.001). The SA measured on CT (151.30°±6.74°) was significantly less than that measured on MRI (159.06°±5.40°) ( P < 0.001). The intra-observer ICC values for all indicators were greater than 0.9, and the inter-observer ICC values greater than 0.85. Conclusions:There are differences between CT and MRI in each indicator in evaluation of acute patellar dislocation in adolescents. The PT-TG measured on MRI and the TT-RA measured on CT can better evaluate the tibial tubercle lateralization; the indicators for trochlear dysplasia measured on MRI respond better to the severity of trochlea dysplasia than those on CT.

Objective:To investigate the clinical characteristics and prognostic significance of germline mutations in patients with myelodysplastic neoplasms (MDS) .Methods:Clinical data from 407 patients with MDS [male, 252; female, 155; median age, 64 (range, 19-85) years] diagnosed at the First Affiliated Hospital of Zhejiang University School of Medicine were retrospectively analyzed. The clinical features and prognostic effects of germline mutations were evaluated.Results:The prevalence of germline mutations in patients with MDS was 5.9% (24/407), peaking at 20.0% in the group aged 21-30 years. The spectrum of germline mutations comprised DDX41 (9 cases, 2.2%), TP53 (3 cases, 0.7%), and single cases of RUNX1, TET2, MPL, CBL, ATRX, CEBPA, ETV6, IDH1, KDM5C, SBDS, GNAS, and CTC1. Patients with germline mutations exhibited significantly lower peripheral WBC counts than those without (1.87×10 9/L vs 2.50×10 9/L, P=0.018), but showed comparable median overall survival (21.3 months vs 21.1 months, P=0.97). Patients with DDX41 germline mutations, compared with those with other germline mutations, had a significantly older median age (65 vs 54 years, P=0.010), lower WBC counts (1.51×10 9/L vs 2.31×10 9/L, P=0.040), increased mean corpuscular volume (111.80 fl vs 97.25 fl, P=0.003), and a higher prevalence of normal karyotypes (100.0% vs 53.3%, P=0.022). The most frequently co-occurring somatic mutations in DDX41 germline mutation carriers were ASXL1, TET2, and RUNX1. Conclusion:In this study, the detection rate of germline mutations in MDS patients was 5.9% (24/407), peaking at 20% in the group aged 21-30 years. DDX41 and TP53 were the most prevalent germline mutations. DDX41 mutation carriers displayed distinct clinical characteristics; however, germline mutations overall showed no significant prognostic effect.

Objective:To identify the relevant factors for the first-course remission of acute myeloid leukemia (AML) and to develop a predictive model as well as assess its predictive capability.Methods:Clinical data of 749 patients newly diagnosed with AML admitted to the Department of Hematology, the First Affiliated Hospital, Zhejiang University, School of Medicine from January 1, 2019, to April 30, 2023, were collected and randomly divided into training and validation sets. Multivariate logistic regression analysis was conducted to determine variables associated with complete remission in the first course of induction therapy, and a predictive model was established based on these variables. The receiver operating characteristic (ROC) curve of the predictive model was plotted, and the area under the curve (AUC) was calculated.Results:The indicators predicting the first remission course included peripheral blood white blood cell count during onset, CBF::MYH11 fusion gene, CEBPA bZIP region mutation, myelodysplastic syndrome-related gene mutation, and induction chemotherapy regimen selection as independent factors for the first remission course. The model’s area under the training and validation curves was 0.738 (95% CI: 0.696-0.780) and 0.726 (95% CI: 0.650-0.801), respectively. The Hosmer-Lemeshow test results yielded P-values of 0.993 and 0.335, respectively. Conclusion:In this study, the developed model demonstrates a strong predictive capability for the efficacy of the first course of patients with AML, providing valuable guidance to clinicians in assessing patient prognosis and selecting appropriate treatment strategies.

Background and Objectives: Heart failure is a potentially fatal event caused by diverse cardiovascular diseases, leading to high morbidity and mortality. Histone deacetylase (HDAC) inhibitors positively influence cardiac hypertrophy, fibrosis, hypertension, myocardial infarction, and heart failure, causing some side effects. We aimed to investigate the effect of the novel HDAC inhibitor YAK577 on the heart failure mouse model and its underlying mechanism. Methods: New hydroxamic acid YAK577 was prepared via methyl-2,3-diphenylpropanoate synthesis using carboxylic acids. We used a micro-osmotic pump, including isoproterenol (ISO; 80 mg/kg/day), to induce a heart failure with reduced ejection fraction. Cardiac hypertrophy was assessed by heart weight to body weight ratio and cross-sectional area.The left ventricular (LV) function was assessed by echocardiography. Fibrosis was evaluated using picrosirius red staining. Overexpression and knockdown experiments were performed to investigate the association between HDAC8 and matrix metalloproteinase 12 (MMP12). Results: YAK577 treatment restored ISO-induced reduction in LV fractional shortening and ejection fraction (n=9–11). YAK577 significantly downregulated cardiac hypertrophy marker genes (natriuretic peptide B, NPPB, and myosin heavy chain 7, MYH7) and cardiomyocyte size in vitro but not in vivo. YAK577 ameliorated cardiac fibrosis and fibrosis-related genes in vivo and in vitro. Additionally, YAK577 reduced elevated HDAC8 and MMP12 mRNA and protein expressions in ISO-infused mice, H9c2 cells, and rat neonatal cardiomyocytes.HDAC8 overexpression stimulated MMP12 and NPPB mRNA levels, while HDAC8 knockdown downregulated these genes. Conclusions YAK577 acts as a novel heart failure drug through the HDAC8/MMP12 pathway.

Objective To explore the application of serum signal transducer and activator of transcription 3(STAT3),histone deacetylase 2(HDAC2),and developmental endothelial locus-1(Del-1)levels in the evaluation of disease severity and prognosis of children with respiratory syncytial virus pneumonia(RSVP).Methods A total of 109 children with RSVP admitted to Jiamusi Central Hospital from November 2023 to March 2025 were enrolled as the RSVP group.Based on disease severity,RSVP patients were categorized into a low-risk group(n=31),a medium-risk group(n=42),and a high-risk group(n=36).According to the prognosis after 7 days of treatment,they were divided into a favorable prognosis group(n=78)and a poor prognosis group(n=31).Additionally,109 healthy children undergoing physical examination at the same hospital during the same period were selected as the normal control group(NC group).ELISA method was used to detect serum levels of STAT3,HDAC2,and Del-1.Pearson correlation analysis was used to explore the correlations between serum STAT3,HDAC2,Del-1 levels and pulmonary function indices.Multivariate logistic regression analysis was used to explore the factors affecting the prognosis of children with RSVP.Moreover,ROC curve was used to explore the predictive value of serum STAT3,HDAC2,and Del-1 levels for the prognosis of children with RSV.Results Compared with the NC group,the RSVP group had higher serum STAT3 and HDAC2 levels,and lower serum Del-1 levels(P<0.05).Serum STAT3 and HDAC2 levels progressively increased from the low-risk group,medium risk group,to high-risk group,while the time to peak ratio(time to peak tidal expiratory flow to total expiratory time ratio,TPTEF/TE),peak volume ratio(volume to peak expiratory flow to total expired volume ratio,VPEF/VE),and serum Del-1 levels progressively decreased(P<0.05).TPTEF/TE and VPEF/VE were prominently negatively correlated with serum STAT3 and HDAC2 levels,and prominently positively correlated with Del-1 levels(P<0.05).Compared with the favorable prognosis group,the poor prognosis group had significantly lower initial blood oxygen saturation,serum Del-1 levels,and significantly higher serum STAT3 and HDAC2 levels(P<0.05).High expression levels of STAT3 and HDAC2 were independent risk factors affecting the prognosis of children with RSVP,while high expression of Del-1 was an independent protective factor(P<0.05).The AUC values of serum STAT3,HDAC2,and Del-1 levels alone in predicting the prognosis of children with RSV were 0.824,0.818,and 0.842,respectively.The combined prediction AUC was 0.947,which was superior to individual predictions(ZSTAT3-joint=2.436,ZHDAC2-joint=2.570,ZDel-1-joint=2.611,all P<0.05).Conclusion Serum expression of STAT3 and HDAC2 is upregulated,while the expression of Del-1 is down-regulated in children with RSVP.The three markers are closely related to the disease severity and pulmonary function indices,and are important factors affecting the prognosis of children with RSVP.Combined detection of these markers demonstrates high efficacy for prognosis evaluation.