ObjectiveTo observe the efficacy of Huoxue Jiedu Formulas （活血解毒方药， HJF） as an adjunctive treatement for patients with binding of stasis and toxin syndrome during the vulnerable period after acute myocardial infarction （AMI） percutaneous coronary intervention （PCI） surgery， and to explore its potential mechanism from the perspective of serum neutrophil extracellular traps （NETs）. MethodsA total of 129 patients with binding of stasis and toxin syndrome within 6 months after PCI for AMI were enrolled and divided into a treatment group （65 cases） and a control group （64 cases） based on patients' willingness to take Chinese herbal medicine. The control group received standard western medical therapy alone， while the treatment group additionally received HJF， one dose daily. Both groups were treated for four weeks. Before and after treatment， TCM syndrome scores were assessed. Seattle angina questionnaire （SAQ） was used to record angina stability and frequency scores， while the short form-36 health survey （SF-36） was employed to assess quality of life across eight dimensions， including physical functioning， role-physical， bodily pain， general health， vitality， social functioning， role-emotional， and mental health. The Pittsburgh sleep quality index （PSQI） was used to evaluate sleep quality， and the patient health questionnaire-15 （PHQ-15） was used to assess psychosomatic symptoms； Duke activity status index （DASI） was used to measure daily physical activity. Serum levels of neutrophil extracellular traps （NET） markers including myeloperoxidase-DNA （MPO-DNA）， neutrophil elastase-DNA （NE-DNA）， and citrullinated histone H3 （CitH3） were measured in 20 patients from the treatment group. ResultsAfter treatment， TCM syndrome score， PSQI score and PHQ-15 score in both groups significantly decreased， while DASI score， angina stability and frequency scores， and all eight dimensions of the SF-36 scale significantly increased （P＜0.05）. Compared to the control group， the treatment group had significantly lower TCM syndrome scores and significantly higher DASI， angina stability and frequency scores （P＜0.05）， as well as higher scores in the SF-36 dimensions of physical functioning， role-physical， social functioning， bodily pain， and vitality （P＜0.05）. After treatment， serum levels of MPO-DNA， CitH3， and NE-DNA in the treatment group were significantly reduced （P＜0.05）. ConclusionHJF combined with conventional therapy can significantly improve angina symptoms， TCM syndrome scores， and psychosomatic conditions in patients with binding of stasis and toxin syndrome during the vulnerable period after AMI. It also enhances quality of life， sleep quality， and daily physical activity. The underlying mechanism may be associated with the inhibition of serum NETs level.

Objective:To explore the clinical characteristics and prognosis of children with chronic myeloid leukemia in the blast phase (CML-BP) .Methods:The clinical characteristics, treatment measures, and survival outcomes of 28 children with CML-BP were analyzed in our hospital from January 2008 to November 2022.Results:The male to female ratio of the 28 children with CML-BP was 1.15∶1. The median age of diagnosis of CML-BP was 10 years, and the median follow-up time was 79 months. During the diagnosis of CML, four children were in the BP, one was in the accelerated phase (AP) and 23 children were in the chronic phase (CP). Among the 23 children with CML-CP, 75% had progressed directly from CP to BP without experiencing the AP. Among the children diagnosed with CML-BP, 71.4% were classified as chronic myeloid leukemia lymphoid blast phase (CML-LBP), 25.0% belonged to the chronic myeloid leukemia myeloid blast phase (CML-MBP), and 3.6% belonged to the chronic myeloid leukemia mixed phenotype acute leukemia (CML-MPAL). Treatment with hemaopoietic stem cell transplantation (HSCT) after tyosine kinase inhibitor (TKI) combined with chemotherapy was administered to 19 children, two children received HSCT after TKI alone, and seven children received TKI combined with chemotherapy but without HSCT. The 5-year overall survival of the 28 children with CML-BP was 59.3%.Conclusion:The direct progression of BP from CP is greater in children with CML-BP compared with adults, and the overall prognosis of children with CML-BP is poor.

Objective To analyze the risks and related influencing factors of early screening for lung cancer,and to study prognostic factors based on survival conditions,in order to ultimately provide baseline data for the prevention and treatment of lung cancer.Methods A cluster sampling method was used to select 40 to 75 year old registered residence residents in 10 districts and 6 counties of Zhengzhou City in 2020 as screening objects.Through voluntary participation and filling in evaluation questionnaires,high-risk groups of lung cancer were evalu-ated,and then three screening tests(tumor markers,low-dose spiral CT and lung function)were performed on high-risk groups.Finally,we will adopt an active and passive follow-up approach to collect information on diag-nosed lung cancer patients.Statistically describe the screening data and describe the epidemiological results of different characteristic populations;Using multivariate logistic regression method for statistical analysis,compare the differences in various results of different factors.Results 50128 cases of early screening for lung cancer in Zhengzhou City were evaluated in 2020,with a completion rate of 100.26%.The average age of the survey was(59.86±17.67)years old,and the gender ratio was 0.81∶1.The high-risk detection rate is 30.15%.Multivariate logistic regression analysis showed that males(smoking)(OR=5.43,95%CI:5.20～5.67),individuals with a history of tobacco exposure(OR=3.82,95%CI:3.67～3.98),first-degree relatives who had previously suffered from lung cancer(OR=12.06,95%CI:11.02～13.20),and other populations were more susceptible to lung cancer(all P<0.05).Conclusion Male(smoking),exposure to secondhand smoke,cancer in first-degree relatives,previous diagnosis of other tumors,symptoms of lung infection,"chest tightness,shortness of breath,and difficulty breathing in daily life",and"significant psychological trauma in the past 3 years"are independent risk factors for lung cancer,which should be given special attention and effective intervention measures should be taken.

DNMT3A encodes a DNA methyltransferase involved in development, cell differentiation, and gene transcription, which is mutated and aberrant-expressed in cancers. Here, we revealed that loss of DNMT3A promotes malignant phenotypes in lung cancer. Based on the epigenetic inhibitor library synthetic lethal screening, we found that small-molecule HDAC6 inhibitors selectively killed DNMT3A-defective NSCLC cells. Knockdown of HDAC6 by siRNAs reduced cell growth and induced apoptosis in DNMT3A-defective NSCLC cells. However, sensitive cells became resistant when DNMT3A was rescued. Furthermore, the selectivity to HDAC6 inhibition was recapitulated in mice, where an HDAC6 inhibitor retarded tumor growth established from DNMT3A-defective but not DNMT3A parental NSCLC cells. Mechanistically, DNMT3A loss resulted in the upregulation of HDAC6 through decreasing its promoter CpG methylation and enhancing transcription factor RUNX1 binding. Notably, our results indicated that HIF-1 pathway was activated in DNMT3A-defective cells whereas inactivated by HDAC6 inhibition. Knockout of HIF-1 contributed to the elimination of synthetic lethality between DNMT3A and HDAC6. Interestingly, HIF-1 pathway inhibitors could mimic the selective efficacy of HDAC6 inhibition in DNMT3A-defective cells. These results demonstrated HDAC6 as a HIF-1-dependent vulnerability of DNMT3A-defective cancers. Together, our findings identify HDAC6 as a potential HIF-1-dependent therapeutic target for the treatment of DNMT3A-defective cancers like NSCLC.

Treating patients with esophageal squamous cell carcinoma (ESCC) is challenging due to the high chemoresistance. Growth differentiation factor 15 (GDF15) is crucial in the development of various types of tumors and negatively related to the prognosis of ESCC patients according to our previous research. In this study, the link between GDF15 and chemotherapy resistance in ESCC was further explored. The relationship between GDF15 and the chemotherapy response was investigated through in vitro and in vivo studies. ESCC patients with high levels of GDF15 expression showed an inferior chemotherapeutic response. GDF15 improved the tolerance of ESCC cell lines to low-dose cisplatin by regulating AKT phosphorylation via TGFBR2. Through an in vivo study, we further validated that the anti-GDF15 antibody improved the tumor inhibition effect of cisplatin. Metabolomics showed that GDF15 could alter cellular metabolism and enhance the expression of UGT1A. AKT and TGFBR2 inhibition resulted in the reversal of the GDF15-induced expression of UGT1A, indicating that TGFBR2-AKT pathway-dependent metabolic pathways were involved in the resistance of ESCC cells to cisplatin. The present investigation suggests that a high level of GDF15 expression leads to ESCC chemoresistance and that GDF15 can be targeted during chemotherapy, resulting in beneficial therapeutic outcomes.
Humans ; Esophageal Squamous Cell Carcinoma/drug therapy* ; Cisplatin/metabolism* ; Esophageal Neoplasms/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; Carcinoma, Squamous Cell/genetics* ; Growth Differentiation Factor 15/therapeutic use* ; Receptor, Transforming Growth Factor-beta Type II/therapeutic use* ; Cell Line, Tumor ; Cell Proliferation ; Gene Expression Regulation, Neoplastic

Background::The role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with high-risk (HR) T-cell acute lymphoblastic leukemia (T-ALL) in first complete remission (CR1) is still under evaluation. Moreover, relapse is the main factor affecting survival. This study aimed to explore the effect of allo-HSCT (especially haploidentical HSCT [haplo-HSCT]) on improving survival and reducing relapse for HR childhood T-ALL in CR1 and the prognostic factors of childhood T-ALL in order to identify who could benefit from HSCT.Methods::A total of 74 newly diagnosed pediatric T-ALL patients between January 1, 2012 and June 30, 2018 were enrolled in this retrospective study. Patients were stratified into the low-risk chemotherapy cohort ( n = 16), HR chemotherapy cohort ( n = 31), and HR transplant cohort ( n = 27). Characteristics, survival outcomes, and prognostic factors of all patients were then analyzed. Results::Patient prognosis in the HR chemotherapy cohort was significantly worse than that in the low-risk chemotherapy cohort (5-year overall survival [OS]: 58.5% vs. 100%, P = 0.003; 5-year event-free survival [EFS]: 54.1% vs. 83.4%, P = 0.010; 5-year cumulative incidence of relapse [CIR]: 45.2% vs. 6.3%, P = 0.011). In HR patients, allo-HSCT improved the 5-year EFS and CIR compared to that of chemotherapy (5-year EFS: 80.1% vs. 54.1%, P = 0.041; 5-year CIR: 11.6% vs. 45.2%, P = 0.006). The 5-year OS was higher in the HR transplant cohort than that in the HR chemotherapy cohort (81.0% vs. 58.5%, P = 0.084). Minimal residual disease re-emergence was an independent risk factor for 5-year OS, EFS, and CIR; age ≥10 years was an independent risk factor for OS and EFS; and high white blood cell count was an independent risk factor for EFS and CIR. Conclusion::Allo-HSCT, especially haplo-HSCT, could effectively reduce relapse of children with HR T-ALL in CR1.

Objective:To prepare a novel tri-specific T cell engager (19TriTE) targeting CD19 antigen, and to investigate its immunotherapeutic effect on CD19-positive hematological malignancies.Methods:19TriTE was constructed by molecular cloning technology and successfully expressed through the eukaryotic expressing system. The effects of 19TriTE on the proliferation and activation of T cells, as well as the specific cytotoxicity against CD19 positive tumor cell lines were verified.Results:①19TriTE expressing plasmid was constructed and successfully expressed through the eukaryotic expressing system. ②19TriTE can specifically bind to T cells and Nalm6 cells, with equilibrium dissociation constants of 19.21 nmol/L and 11.67 nmol/L, respectively. ③The expression rates of CD69 positive T cells and CD25 positive T cells were 35.4% and 49.8% respectively, when 2 nmol/L 19TriTE were added in the co-culture system, which were significantly higher than those in the control group. ④19TriTE can significantly promote the proliferation of T cells. The absolute count of T cells expanded from the initial one million to 74 million with an 74 fold increase at the concentration of 1 nmol/L on day 12. ⑤19TriTE can significantly mediate T cells killing of CD19 positive target cells in a dose-dependent manner. At the concentration of 10 nmol/L, the target cells lysis reached 50%. ⑥Degranulation experiment verified that 19TriTE can activate T cells in the presence of CD19 positive target cells, and the activation of T cells positively correlated with the dose of 19TriTE. ⑦When 19TriTE fusion protein co-cultured with T cells and target cells overexpression RFP and luciferase genes respectively, 19TriTE can notably mediate T cells killing of CD19 positive target cells through fluorescent microscope or bioluminescence imaging technology.Conclusion:In this study, we successfully constructed and expressed 19TriTE fusion protein and verified that it can effectively activate T cells and promote their proliferation in vitro. At the same time, it can bind to CD19 positive target cells and T cells, as well as enhance T cells anti-leukemia effect in vitro, providing the foundation for further clinical research.

Objective:To study the distribution and drug resistance of Carbapenem-Resistant Organism (CRO) and to analysis the risk factors of CRO 30-day mortality.Methods:A total of 181 patients with CRO infection diagnosed in Department of Hematology, Fujian Medical University Union Hospital from January 2018 to June 2020 were retrospectively investigated. The clinical and laboratory data of the patients were collected, the prognosis of patients diagnosed with CRO infection in day 30 was followed up, and the risk factors of prognosis were analyzed. The clinical significance of Carbapenem-Resistant Enterobacteriaceae (CRE) active screening was further evaluated in the CRE subgroup.Results:Among the total of 181 CRO isolates, 47.2% were CRE, 37.0% were Pseudomonas aeruginosa, and 32.6% were Klebsiella pneumoniae, which were highly resistant to carbapenem and had high MIC value, 76.8% (139/181) of CRO were MIC of imipenem resistance≥16 μg/ml. The main sources of isolates were blood and sputum. The 30-day all-cause mortality rates of patients with CRO or CRE infection were (41.4±3.7) % and (44.7±5.4) %, respectively. The COX multivariate regression analysis showed that the level of procalcitonin >0.2 ng/ml and the MIC value of imipenem resistance ≥ 16 μg/ml were independent risk factors for 30-day mortality of CRO infected patients. The CRE subgroup analysis showed that MIC value of imipenem resistance ≥16 μg/ml were independent risk factors for 30-day mortality of CRE infected patients. The 30-day cumulative survival rate of patients with CRE active screening was higher than the patients without CRE active screening [ (68.0±9.3) % vs (50.0±6.5) %, P=0.21]. Conclusion:The high MIC value of imipenem resistance isolates seriously affects the prognosis of patients with CRO infection in the hematology department, and the mortality rate was high. CRE active screening is expected for early prevention, early diagnosis, and early treatment for high-risk patients.

Objective:To explore the molecular response and prognostic factors of pediatric patients with Ph-positive acute lymphoblastic leukemia (Ph + ALL) treated by tyrosine kinase inhibitors (TKI) with chemotherapy in TKI era. Methods:The clinical data of children newly diagnosed with Ph + ALL admitted at Department of Pediatrics, Peking University People′s Hospital from August 2006 to February 2017 were retrospectively reviewed.The molecular biological characteristics and survival prognosis of the 30 patients who received continuous TKI with chemotherapy from early induction combined and no subsequent transplantation were analyzed. Results:The 30 patients with Ph + ALL had 19 males and 11 females with a median age of 8-year-old (ranging from 2 to 16 years). The complete remission (CR) rate after the first cycle of induction chemotherapy was 96.7% (29/30 cases), with overall CR rate of 100.0%; Before treatment, the mean level of BCR/ ABL mRNA in the 30 patients was 73.2% (0.12%-160.60%) and the level declined significantly with the progression of chemotherapy courses, reaching the plateau stage at the 6 th month of chemotherapy ( Z=-1.922, P>0.05); nine patients had recurrence, with a median recurrence time of 7 months (3.7-58.8 months). Univariate analysis showed that age ( P<0.05), the lever of minimal residual disease (MRD) after induction chemotherapy ( P<0.01) and the MRD level at the 3 th month of induction chemotherapy ( P<0.01) affected the recurrence rate.The median follow-up time of 30 patients was 42.6 months (6.4-96.5 months), and the 3-year overall survival (OS) rate and event-free survival (EFS) rate were (78.6±7.8)% and (72.4±8.4)%, respectively; Cox multivariate analysis showed that the initial white blood cell count ≥34.0×10 9/L ( OR=11.955, 95% CI: 1.075-132.899, P<0.05) and BCR/ ABL mRNA reduction less than 3 log from baseline [major molecular response (MMR)] at the 3 th month of induction chemotherapy ( OR=8.563, 95% CI: 1.254-58.478, P<0.05) were independent risk factors affecting the 3-year EFS rate.In addition, the initial white blood cell count ≥34.0×10 9/L ( OR=14.327, 95% CI: 1.843-243.592, P<0.05) was also an independent risk factor affecting the 3-year OS rate. Conclusions:The application of TKI can significantly deepen the molecular response of Ph + ALL in children.In the TKI era, the initial white blood cell count ≥ 34.0×10 9/L and BCR/ ABL mRNA reduction less than 3 log from baseline (MMR) at the 3 th month of induction chemotherapy are independent risk factors for the long-term survival of pediatric Ph + ALL.

Objective: To analyze the clinical outcome and the prognostic factor in pediatric patients with core binding factor-acute myeloid leukemia (CBF-AML). Methods: A total of 121 newly diagnosed pediatric CBF-AML patients enrolled from Aug. 2005 to Sep. 2017 were retrospectively reviewed. Cumulative incidence of relapse (CIR), event-free survival (EFS) and overall survival (OS) rates were estimated by Kaplan-Meier method and prognostic factors were evaluated by Cox regression with SPSS. Results: Of the 121 patients, 120 patients were assessed for bone marrow remission after induction chemotherapy. 100 cases (83.3%) achieved complete remission (CR) after the first course of chemotherapy. 119 cases (99.2%) achieved CR after the second course of chemotherapy. Of the 121 patients, 13 patients (10.7%) had recurrence with the median interval of recurrence as 13.8 months (3.7 to 58.8 months). 17 patients (14.0%) died. The CIR, EFS and OS at 3 years were 12.7%, 77.5% and 82.8%, respectively. The factors including age at diagnosis, sex, initial WBC count, presence of extramedullary leukemia, C-KIT expression, additional chromosomal abnormalities, and CR after the first course of chemotherapy were analyzed by multivariate regression analysis of Cox. Multivariate analysis identified that additional chromosomal abnormalities was the only independent risk factor affecting OS (HR=4.289, 95%CI 1.070-17.183, P=0.040). Conclusions Pediatric CBF-AML was a unique setting of prognostic subtypes. Chemotherapy produced good responses. Additional chromosomal abnormalities was the only independent risk factor for OS in pediatric CBF-AML.