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Background Myocardial infarction (MI) is a cardiovascular disease that seriously threatens human health. Dysangiogenesis of endothelial cells (ECs) primarily inhibits recovery from MI, but the specific mechanism remains to be further elucidated. Methods In this study, the single-cell RNA-sequencing data from both MI and Sham mice were analyzed by the Seurat Package (3.2.2). The number of ECs in MI and Sham groups were compared by PCA and tSNE algorithm. FindMarkers function of Seurat was used to analyze the DEGs between the MI and Sham groups. Then, the ECs was further clustered into 8 sub-clusters for trajectory analysis. The BEAM was used to analyze the branch point 3 and cluster the results. In addition, the DEGs in the microarray data set of MI and Sham mice were cross-linked, and the cross-linked genes were used to construct PPI networks. The key genes with the highest degree were identified and analyzed for functional enrichment. Finally, this study cultured human umbilical vein endothelial cells (HUVECs), established hypoxia models, and interfered with hub gene expression in cells. The impact of hub genes on the migration and tube formation of hypoxic-induced HUVECs were verified by Wound healing assays and tubule formation experiments. Results The number and proportion of ECs in the MI group were significantly lower than those in the Sham group. Meantime, 225 DEGs were found in ECs between the MI and Sham groups. Through trajectory analysis, EC4 was found to play an important role in MI. Then, by using BEAM to analyze the branch point 3, and clustering the results, a total of 495 genes were found to be highly expressed in cell Fate2 (mainly EC4). In addition, a total of 194 DEGs were identified in Micro array dataset containing both MI and Sham mice. The hub genes (Timp1 and Fn1) with the highest degree were identified. Inhibiting Timp1 and Fn1 expression promoted the migration and tube formation of HUVECs. Conclusions Our data highlighted the non-linear dynamics of ECs in MI, and provided a foothold for analyzing cardiac homeostasis and pro-angiogenesis in MI.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematologic malignancies. However, the initial clinical experience with allo-HSCT revealed a concerning prevalence of severe graft-versus-host disease (GVHD) and graft failure. Subsequent randomized studies highlighted the role of anti-thymocyte globulin (ATG) in reducing acute and chronic GVHD and graft failure, although it did not improve overall survival. Pharmacodynamic studies have established an association between ATG concentration and the incidence of GVHD and life-threatening infections. However, ATG concentration at designated timepoints showed no such correlations with non-relapse mortality and overall survival in allo-HSCT. There is a delicate balance between ATG exposure and the outcomes of allo-HSCT. More specifically, insufficient ATG exposure may diminish its function on GVHD prophylaxis, while excessive ATG may delay immune reconstitution and increase risk of disease relapse and infection. Considering the significant inter-individual heterogeneity in ATG pharmacokinetics, individualized ATG dosing could potentially increase the proportion of transplant recipients attaining the optimal ATG exposure. Recent studies have shown that individualized ATG dosing, guided by absolute lymphocyte count or therapeutic drug monitoring, can improve optimal exposure attainment rate. Which indicated a potential approach to achieve superior transplant outcomes. This review summarizes the advances and the challenges of individualized ATG dosing in allo-HSCT.

Background Chronic heart failure (CHF) significantly harms patients and society, causing high mortality and reduced quality of life, straining healthcare systems; early identification and intervention are crucial for improving long-term prognosis. Methods This retrospective cohort study involved 297 CHF patients. After collecting data on demographics, lab results, echocardiography, and comorbidities, ROC analysis was used to determine optimal cut-off values, followed by survival analysis and multivariate Cox regression to identify poor prognosis risk factors. Results ROC analysis set optimal cut-offs for Scr, BUN, and UA at 101.5 µmol/L, 8.61 mmol/L, and 462 µmol/L, with AUCs of 0.602 (Scr, UA) and 0.674 (BUN). Kaplan-Meier analysis showed significant curve separation, while Cox regression identified risk factors for poor prognosis: Scr ≥ 101.5 µmol/L (HR = 2.209, 95% CI 1.372–3.557, P  = 0.001), BUN ≥ 8.61 mmol/L (HR = 3.709, 95% CI 2.270–6.061, P  < 0.001), UA ≥ 462 µmol/L (HR = 2.625, 95% CI 1.631–4.228, P  < 0.001), male sex(HR = 1.764, 95% CI 1.067–2.915, P  = 0.027), hyperlipidemia (HR = 0.567, 95% CI 0.351–0.916, P  = 0.02), and re-hospitalization(HR = 0.480, 95% CI 0.280–0.826, P  = 0.008). Subgroup analysis indicates that male gender is a significant risk factor for females (OR:2.424, P  < 0.001); and age also posed a risk (OR:1.026, P  = 0.036). NYHA class IV had an OR of 0.42 compared to class III ( P  < 0.001), and class III had an OR of 0.307 compared to class II ( P  = 0.016). Patients without CHD had a 1.905-fold increased risk of poor prognosis ( P  = 0.033). Conclusion This study highlights key characteristics, assessment parameters, and risk factors for CHF patients, emphasizing the importance of Scr, BUN, and UA cut-off levels in management and guiding future research.

The annual number of human leukocyte antigen (HLA)-haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HCT) is increasing steadily. Comparative studies about haplo-HCT versus HCT with HLA-matched sibling donors (MSD-HCT) have been tried in acute myeloid leukemia and B-cell acute lymphoblastic leukemia/lymphoma (ALL). Few studies were reported in adult T-cell ALL (T-ALL). In this retrospective study, a total of 88 consecutive patients with T-ALL were enrolled who underwent MSD-HCT (n = 24) and haplo-HCT (n = 64) with antithymocyte globulin (ATG)-based graft versus host disease (GVHD) prophylaxis between 2010 and 2022. Median follow-up for survivors was similar (43.5 [range: 7–88] months for MSD-HCT versus 43.5 (range: 6–144) months in the Haplo-HCT group). The 100-day cumulative incidence of grade II to IV acute GVHD (aGVHD) was similar, 33% (95% confidence interval [CI], 16%–52%) after MSD-HCT versus 44% (95% CI, 31%–55%) after haplo-HCT, P = 0.52. The cumulative incidences of grade III–IV aGVHD were 8% (95% CI, 1%–23%) in the MSD-HCT group and 5% (95% CI, 1%–12%) in the haplo-HCT group (P = 0.50). The 2-year cumulative incidence of chronic GVHD (limited and extensive) in the haplo-HCT, 11% (95% CI, 5%–20%) was significantly lower than that in the MSD-HCT group (42% [95% CI, 21%–62%], P = 0.002). The cumulative incidence of 4-year relapse rates (44% versus 37%, P = 0.56) and non-relapse mortality (7% versus 21%, P = 0.08) did not differ between these two groups. There were also no differences in 4-year overall survival (46% versus 47%, P = 0.44) and progression-free survival (49% versus 42%, P = 0.45) between these two groups. On multivariate analysis, using busulfan/fludarabine (BU/Flu) conditioning regimen was found to be associated with worse clinical outcome. Our results suggested that ATG-based haplo-HCT platform could work as an alternative to MSD-HCT for adult patients with T-ALL. Compared with MSD-HCT, haplo-HCT might carry a low risk for cGVHD.

Background Dysbiosis of intestinal microecology caused by sepsis plays a crucial role in the onset and progression of sepsis-induced acute lung injury (SALI). As a postbiotic type, inactivated probiotic bacteria can regulate the gut microbiome. Pasteurized bacteria are considered safer than live bacteria in immune dysregulation disorders. Weissella cibaria (W. cibaria) is considered a candidate probiotic with certain beneficial functions. However, whether inactivated W. cibaria can alleviate SALI and the underlying mechanisms remain unclear. This study aimed to investigate whether inactivated W. cibaria can regulate intestinal mucosal barrier function and gut microbiota, thereby improving SALI. Methods Following gavage of pasteurized W. cibaria in septic mice, lung tissue damage and inflammation levels were assessed. Circulating LPS levels and inflammatory cytokine concentrations in the blood were measured. Additionally, colonic tissue inflammation, intestinal mucosal barrier integrity, and alterations in the gut microbiota were evaluated. Result Pasteurized W. cibaria increases survival rates in SALI mice and improves pathological damage and cell apoptosis in lung tissue. Pasteurized W. cibaria also reduces the lung inflammatory response in septic mice by lowering pro-inflammatory cytokine levels and increasing anti-inflammatory cytokine levels. Pasteurized W. cibaria appears to exert its effects by improving the intestinal mucosal barrier and reversing gut microbiota dysbiosis caused by sepsis. Specifically, pasteurized W. cibaria alleviates intestinal barrier damage and inflammation in SALI mice, enhancing the integrity of the intestinal mucosal barrier. Additionally, pasteurized W. cibaria increases the abundance of anti-inflammatory bacteria such as Muribaculaceae . Pasteurized W. cibaria also decreases the levels of LPS-producing bacteria, including Escherichia-Shigella and Helicobacter , leading to significant attenuation in metabolic endotoxemia, which in turn alleviates excessive lung inflammation in septic mice. Conclusions Pasteurized W. cibaria has the potential to act as a postbiotic agent, improving sepsis-induced gut microbiota dysbiosis and acute lung injury, and providing a novel strategy for treating SALI.

Older patients with acute myeloid leukemia (AML) respond poorly to standard induction therapy. DNA methyltransferases (DNMTs) and histone-deacetylases (HDACs) are key regulators of gene expression in cells and have been investigated as important therapeutic targets. However, their effects remains unclear as induction therapy for AML. Previously untreated AML patients aged 60 years and over (N=40) were enrolled into this single arm, open-label, phase 2 study to evaluate the clinical efficacy and safety of chidamide combined with CAG and venetoclax-azacitidine (referred to as CACAG-VEN) in elderly AML patients (ClinicalTrials.gov:NCT05659992). All patients received induction treatment with aclarubicin (10 mg/m2/d on days 1, 3, and 5), azacitidine (75 mg/m2 on days 1-7), cytarabine (75 mg/m2 bid on days 1-5), chidamide (30 mg, twice/week for 2 weeks), and venetoclax (100 mg on day 1, 200 mg on day 2, 400 mg on days 3-14). Granulocyte colony-stimulating factor 5 mg/kg/day was administered. Theoverall response rate was 97.5%, with a composite complete response (CRc) rate of 85.0% after one cycle of CACAG-VEN. Patients with adverse risk according to the ELN guidelines had CRc rates of 81.3%. No patients experienced early death within 30 days of therapy initiation. Grade 3 - 4 non-hematological adverse events included febrile neutropenia in 15 (37.5%) of 40 patients, pneumonia in three (7.5%), sepsis in two (5.0%) and blood bilirubin increase in one (2.5%). The 12-month overall survival rate was 73.4% (95% CI: 55.9-84.8%). The median time to recovery was 15.0 (IQR 10.0-19.5) days for platelets ≥ 20000/mL and 13.0 (IQR 10.5-17.0) days for an absolute neutrophil count ≥ 1000 cells/mL after induction therapy. In conclusion, chidamide in combination with CAG and venetoclaxazacitidine was effective and well tolerated in elderly patients with AML. https://www.clinicaltrials.gov/, identifier NCT05659992.

TP53 mutations are associated with poor prognosis in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers a potential cure, but outcomes are suboptimal and risk stratification remains challenging. This multi-center, retrospective study analyzed 66 patients with TP53-mutated AML/MDS who underwent allo-HSCT. The study endpoints included overall survival (OS), progression-free survival (PFS), and cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and Graft-versus-host disease-free, relapse-free survival (GRFS). After median 1054-day follow-up, 3-year rates for OS, PFS, CIR, NRM, and GRFS were 47.2%, 39.7%, 37.3%, 23%, and 37.4%, respectively. Survival did not differ between AML and MDS. Univariate analysis showed that < 2 somatic myeloid co-mutations predicted inferior OS (3-y OS: 32% vs. 65.9%, p  = 0.02) and PFS (27.6% vs. 59.1%, p  = 0.01). Age > 50 years adversely affected PFS, and complex karyotype showed a negative trend. Multivariate analysis found no independent factors, likely due to sample size and collinearity. A combined risk factor analysis revealed that patients with ≥ 1 adverse factor (either co-mutations < 2 or complex karyotype) had significantly worse OS (3-y OS: 72.6% vs. 37.2%, p  = 0.04) and PFS (3-y PFS: 67.7% vs. 28.9%, p  = 0.02) compared to those with neither risk factor. In patients with TP53-mutated AML/MDS undergoing allo-HSCT, a low myeloid co-mutation burden (< 2) is strongly associated with poor outcomes. A composite model integrating co-mutation burden with karyotype may assist in post-transplant risk stratification, offering a practical supplementary parameter when TP53 allelic status is uncertain. This finding requires validation in larger prospective studies.

Few advances have been made in the treatment of T-cell acute lymphoblastic leukemia (T-ALL). Approaches targeting histone deacetylases (HDAC) have not been thoroughly investigated in T-ALL. However, the underlying molecular mechanism of HDAC inhibition remains to be fully elucidated. The study aimed to evaluate the clinical outcome of chidamide (an oral selective HDAC inhibitor for HDAC1, HDAC2, HDAC3, and HDAC10) in combination with chemotherapy in relapsed or refractory T-ALL and explore the underlying molecular mechanism of HDAC inhibition in T-ALL. The clinical outcomes of 28 patients with relapsed or refractory T-ALL, who received chidamide in combination with chemotherapy were first evaluated. Chidamide (30mg per dose) was orally administered twice a week for a total of four doses (120mg in total per patient) during the first 2 weeks of the combined salvage chemotherapy. Transcriptomic analysis was used to identify pivotal signaling pathways of histone deacetylase inhibition in T-ALL cell lines. Short hairpin RNA-mediated inhibition, co-immunoprecipitation, and a series of functional assays were performed to verify the putative signaling pathways involved in cell lines, primary patient samples, and mouse models. Of the 28 patients, 16 achieved a complete response and three achieved a partial response. As an inhibitor of histone deacetylases, chidamide significantly suppressed the proliferation of T-ALL cells and induced apoptosis and cell cycle arrest . Chidamide treatment significantly inhibited the protein level of HDAC3, but not HDAC1, HDAC2, or HDAC10, in T-ALL cell lines and primary human T-ALL cells. Moreover, the TYK2-STAT1-BCL2 signaling pathway was also substantially inhibited upon chidamide administration. Finally, overexpression of HDAC3 and TYK2 rescued the inhibitory effects of chidamide on T-ALL cells. HDAC3 was found to associate with TYK2 and contributed to activation of the TYK2-STAT1-BCL2 signaling pathway in T-ALL cells. Our results highlight the effectiveness of the combination of chidamide and chemotherapy in the treatment of T-ALL patients and suggest that HDAC3 can act as a potential novel therapeutic target to inhibit the TYK2-STAT1-BCL2 signaling pathway in T-ALL.

Persistent thrombocytopenia (PT) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with an increased risk of bleeding and poor survival. The exact pathogenesis underlying PT remains unclear, and its management is difficult. Here we conducted a retrospective study to evaluate the efficacy and safety of eltrombopag (EPAG) in 34 patients with PT after allo-HSCT. Seven patients suffered from prolonged isolated thrombocytopenia (PIT), and 27 had secondary failure of platelet recovery (SFPR). For most patients, the initial dose was 25 mg or 50 mg daily, then adjusted to the maximum dose of 50–100 mg per day according to the response of platelet recovery and toleration of patients. The cumulative incidence (CI) of platelet recovery to at least 20 × 109/L and 50 × 109/L without transfusion support for at least 7 days was 72.1% and 60.7%, respectively. Nineteen (86.4%) of 22 responders were able to taper off the medication; furthermore, the platelet counts remained stable 1 month after withdrawal of EPAG. Although two patients discontinued EPAG during treatment due to headache and nausea, no patients developed grade 3 or 4 toxicities. Hypoplasia of bone marrow and decreased megakaryocytes (MKs) were found to be risk factors for overall response (OR) and complete response (CR) in multivariate analysis, respectively. Overall, our results indicated that EPAG can be used in the treatment of PT and that continuous exposure to EPAG may not be necessary.

Relapse remains the leading cause of treatment failure in high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome-IB (MDS-IB) patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Ruxolitinib has demonstrated antileukemic activity , and decitabine has been found to be tolerable when combined with modified busulfan-cyclophosphamide (mBu/Cy) conditioning regimen. Here, we investigated the efficacy of ruxolitinib and decitabine plus a mBu/Cy conditioning regimen (Rux-Dec-mBu/Cy) in reducing relapse in high-risk AML/MDS patients ( ). This prospective investigational study enrolled 58 patients between May 2020 and July 2023. These patients had either a relapsed/refractory status, remission status with adverse genetic abnormalities or positive measurable residual disease (MRD+) prior to conditioning. Ruxolitinib (days -15 to -1) and decitabine (days -15 to -10) were administered, followed by mBu/Cy conditioning. The outcomes of a historical cohort of 58 patients (matched 1:1) who received mBu/Cy are described for reference. All 58 patients achieved engraftment. With a median follow-up of 967 (464-1597) days, the 2-year cumulative incidence of relapse was 19.0%. The probabilities of 2-year overall survival (OS), disease-free survival (DFS) and graft-versus-host disease-free, relapse-free survival (GRFS) were 70.3%, 70.6% and 65.2%, respectively. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 44.1%. The most common grade ≥3 adverse event was oropharyngeal mucositis (8.6%, n=5). Within 6 months post-transplantation, the cumulative incidence of cytomegalovirus (CMV) reactivation was 34.5%, and that of Epstein-Barr virus (EBV) reactivation was 62.1%. This investigational study revealed that the Rux-Dec-mBu/Cy conditioning was tolerable and reduced relapse in high-risk AML/MDS patients.