Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, in patients with refractory or relapsed peripheral T-cell lymphoma (JACKPOT8 Part B): a single-arm, multinational, phase 2 study.

BACKGROUND: Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown encouraging anti-tumour activity in heavily pre-treated patients with relapsed or refractory peripheral T-cell lymphoma in a phase 1 study (JACKPOT8 Part A). Here, we report the full analysis of a phase 2 study, in which we assessed the anti-tumour activity of golidocitinib in a large multinational cohort of patients. METHODS: We did a single-arm, multinational, phase 2 trial (JACKPOT8 Part B) in 49 centres in Australia, China, South Korea, and the USA. Eligible patients were adults (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were given oral golidocitinib 150 mg once daily until disease progression or other discontinuation criteria were met. The primary endpoint was the CT-based objective response rate, assessed by an independent review committee (IRC) per Lugano 2014 classification. The activity analysis set included all patients who received at least one dose and whose pathological diagnosis of peripheral T-cell lymphoma had been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at baseline assessed by IRC. The safety analysis set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04105010, and is closed to accrual and follow-up is ongoing. FINDINGS: Between Feb 26, 2021, and Oct 12, 2022, we assessed 161 patients for eligibility, of whom 104 (65%) were enrolled and received at least one dose of study drug; the activity analysis set included 88 (85%) patients (median age 58 years [IQR 51-67], 57 [65%] of 88 were male, 31 [35%] were female, and 83 [94%] were Asian). As of data cutoff (Aug 31, 2023; median follow-up was 13·3 months [IQR 4·9-18·4]), per IRC assessment, the objective response rate was 44·3% (95% CI 33·7-55·3; 39 of 88 patients, p<0·0001), with 21 (24%) patients having a complete response and 18 (20%) having a partial response. In the safety analysis set, 61 (59%) of 104 patients had grade 3-4 drug-related treatment-emergent adverse events. The most common grade 3-4 drug-related treatment-emergent adverse events were neutrophil count decreased (30 [29%]), white blood cell count decreased (27 [26%]), lymphocyte count decreased (22 [21%]), and platelet count decreased (21 [20%]), which were clinically manageable and reversible. 25 (24%) patients had treatment-related serious adverse events. Deaths due to treatment-emergent adverse events occurred in three (3%) patients: two (2%) due to pneumonia (one case with fungal infection [related to golidocitinib] and another one with COVID-19 infection) and one (1%) due to confusional state. INTERPRETATION: In this phase 2 study, golidocitinib showed a favourable benefit-risk profile in treating relapsed or refractory peripheral T-cell lymphoma. The results of this study warrant further randomised clinical studies to confirm activity and assess efficacy in this population. FUNDING: Dizal Pharmaceutical.

The KIR2DL family serves as prognostic biomarkers and correlates with immune infiltrates in acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is a prevalent haematological malignancy in which various immune and stromal cells in the bone marrow microenvironment have instrumental roles and substantially influence its progression. KIR2DL is a member of the immunoglobulin-like receptor family and a natural killer (NK) cell surface-specific receptor. However, its impact on immune infiltration regarding AML has not been addressed. We aimed to explore molecular markers associated with the immune microenvironment and prognosis of AML with a particular focus on KIR2DL family members. Analysis of data from The Cancer Genome Atlas and Genotype-Tissue Expression databases revealed that KIR2DL1, KIR2DL3 and KIR2DL4 expression were significantly upregulated in AML and associated with decreased overall survival (OS). Moreover, univariate Cox analysis implicated KIR2DL genes as independent prognostic markers of OS. Functional enrichment analysis revealed that KIR2DL genes were associated with immune cells, the immune microenvironment and NK cell-mediated cytotoxicity. Additionally, immune infiltration analyses revealed that KIR2DL upregulation was associated with stronger immune infiltration. Finally, we performed drug sensitivity profiling of KIR2DL genes using the Cellminer database. Collectively, our findings suggest that KIR2DL1, KIR2DL3 and KIR2DL4 have critical roles in AML and may represent novel biomarker genes for disease prognosis and immune infiltration.

Mechanism of salidroside regulating autophagy based on network pharmacology and molecular docking.

Salidroside is a natural product of phenols with a wide range of pharmacological functions, but whether it plays a role in regulating autophagy is unclear. We systematically investigated the regulatory effect and molecular mechanism of salidroside on autophagy through network pharmacology, which provided a theoretical basis for subsequent experimental research. First, the target genes of salidroside were obtained using the Chinese Medicine System Pharmacology Database and Analysis Platform, and the target genes were converted into standardized gene names using the Uniprot website. At the same time, autophagy-related genes were collected from GeneCards, and preliminary handling of data to obtain intersecting genes. Then, the String website was used to construct a protein-protein interaction network, and to perform the Gene Ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway analysis. To observe the specific molecular mechanism by which salidroside regulates autophagy, we constructed a drug component-target genes-autophagy network. Finally, we performed molecular docking to verify the possible binding conformation between salidroside and the candidate target. By searching the database and analyzing the data, we found that 113 target genes in salidroside interact with autophagy. Salidroside regulate autophagy in relation to a number of important oncogenes and signaling pathways. Molecular docking confirmed that salidroside has high affinity with mTOR, SIRT1, and AKT1. Through network pharmacology combined with molecular docking-validated research methods, we revealed the underlying mechanism of salidroside regulation of autophagy. This study not only provides new systematic insights into the underlying mechanism of salidroside in autophagy, but also provides new ideas for network approaches for autophagy-related research.

Efficacy and safety of the B-domain-deleted TQG202 for on-demand treatment in moderate and severe haemophilia A patients: A multicentre, single-arm trial.

INTRODUCTION: On-demand treatment is the most common treatment strategy for haemophilia A in China. AIM: This study aims to evaluate the efficacy and safety of a human-derived B-domain-deleted recombinant factor VIII (TQG202) in the on-demand treatment of bleeding episodes in moderate/severe haemophilia A patients. METHODS: This multicentre, single-arm clinical trial enrolled moderate/severe haemophilia patients previously treated with FVIII concentrates for ≥50 exposure days (EDs) from May 2017 to October 2019. TQG202 was injected intravenously on-demand for bleeding episode management. The primary endpoints were the infusion efficiency at 15 and 60 min after the first administration and haemostatic efficacy of the first bleeding episode. Safety was also monitored. RESULTS: Fifty-six participants were enrolled with a median age of 24.5 (range: 12-64) years old. The median total dose of TQG202 was 29,250 IU per participant (range: 1750-2,02,500), and the median number of administrations was 24.5 (2-116). The median infusion efficiency at 15 and 60 min after the first administration was 155.4% and 145.2%, respectively. Among the 48 first bleeding episodes evaluated, 47 (83.9%, 95% CI: 71.7%-92.4%) had a haemostatic efficacy rating of excellent or good. Eleven (19.6%) participants had treatment-related adverse events (TRAEs), but no ≥grade 3 TRAE was observed. Inhibitor development (0.6BU) was observed in one participant (1.8%) after 22 EDs, but was undetectable after 43 EDs. CONCLUSION: TQG202 for on-demand treatment in moderate/severe haemophilia A shows effective control of the bleeding symptoms, with a low incidence of adverse events and inhibitors development.

Comparison of efficacy and safety of ripertamab (SCT400) versus rituximab (Mabthera® ) in combination with CHOP in patients with previously untreated CD20-positive diffuse large B-cell lymphoma: A randomized, single-blind, phase III clinical trial.

This study compared the efficacy, safety and immunogenicity of ripertamab (SCT400) and rituximab (Mabthera® ) combined with CHOP as the first-line treatment for Chinese patients with CD20-positive diffuse large B cell lymphoma (DLBCL). This is a randomized, patient-blind, multicenter, active-control, non-inferiority study with parallel design. Patients were randomly (2:1) to receive ripertamab combined with CHOP (S-CHOP) or rituximab (Mabthera® ) combined with CHOP (R-CHOP) for up to 6 cycles. The primary endpoint was the Independent Review Committee (IRC) assessed objective response rate (ORR) in full analysis set (FAS) and the per protocol set (PPS). A total of 364 patients (243 in the S-CHOP and 121 in the R-CHOP groups) were enrolled in this study. In FAS, IRC-assessed ORRs were 93.8% (95% confidence interval (CI) 90.0%, 96.5%) and 94.2% (95% CI: 88.4%, 97.6%) in the S-CHOP and R-CHOP groups (p = 0.9633), respectively. The ORR difference between the two groups -0.4% (95% CI: -5.5%, 4.8%) met the pre-specified non-inferiority margin of -12%. There were no significant differences between the S-CHOP and R-CHOP groups in 1-year progression-free survival rates (81.1% vs. 83.2%, p = 0.8283), 1 year event-free survival rates (56.2% vs. 58.1%, p = 0.8005), and 3-year overall survival rates (81.0% vs. 82.8%, p = 0.7183). The results in PPS were consistent with those in FAS. The rates of treatment-emergent adverse events (TEAEs) and ≥ grade 3 TEAEs were 97.9% and 99.2%, 85.2% and 86.0% in the S-CHOP and R-CHOP groups, respectively in safety set. The percentage of anti-drug antibodies positive patients in the S-CHOP group was numerically lower than the R-CHOP group (10.9% vs. 16.0%). This study demonstrated that S-CHOP was not inferior to R-CHOP in the first-line treatment of Chinese patients with CD20-positive DLBCL in efficacy, safety and immunogenecity. S-CHOP could be an alternative first-line standard treatment regimen for this patient population.

Efficacy, safety and bioequivalence of the human-derived B-domain-deleted recombinant factor VIII TQG202 for prophylaxis in severe haemophilia A patients.

INTRODUCTION: Current treatment of severe haemophilia A includes prophylaxis with factor VIII (FVIII) replacement. The supply of plasma-derived FVIII is short in China. PURPOSE: To evaluate the efficacy and safety of a new B-domain deleted (BDD) recombinant FVIII (TQG202) produced by human-derived cells for prophylaxis in severe haemophilia A patients and compare the bioequivalence with Xyntha. METHODS: This multicentre, clinical trial consisted of an open-label, randomized, two-period cross-over trial assessing single-dose pharmacokinetics (PK), and a single-arm clinical trial evaluating the efficacy and safety of 24 weeks of TQG202 prophylaxis, and repeated PK were assessed after prophylaxis phase. The single-dose was 50 IU/kg in PK assessment, and the initial dose was 30 ± 5 IU/kg for prophylaxis. The primary endpoints of prophylaxis were the annualized bleeding rate (ABR) and the incremental recovery rate of the first administration. Adverse events (AEs) were recorded. RESULTS: Twenty-six participants were enrolled in the PK assessment and 81 participants in the prophylaxis phase. Mean age was 25.9 ± 10.8 years and all participants were male. The results of PK assessment showed TQG202 is bioequivalent to Xyntha. The total ABR was 2.0 (95% CI: 1.2-2.9) in prophylaxis phase. The mean incremental recovery rate of the first administration was .027 (95% CI: .026-.028) (IU/ml)/(IU/kg). AEs occurred in 42 participants, with an incidence of 51.9%. One severe AE not related to TQG202 occurred. No participants developed FVIII inhibitors. CONCLUSION: TQG202 shows bioequivalence with Xyntha. The promising efficacy and tolerability in the severe haemophilia A prophylaxis support the use of TQG202in clinical practice.

[Research Progress of NK Cell Therapy in Multiple Myeloma Treatment --Review].

Multiple myeloma (MM) is a hematologic neoplasm characterized by malignant proliferation of monoclonal plasma cells in the bone marrow. NK cells, a class of innate lymphocytes with potent natural killer activity, are capable of recognizing and destroying tumor cells and virally infected cells, and have attracted attention as a potential anticancer therapy. In patients with MM, NK cells are suppressed in number and function, resulting in reduced immune surveillance and clearance of myeloma cells. Restoring or enhancing the killing effect of NK cells on myeloma cells is an important strategy for MM immunotherapy, and some progress has been made in clinical trials targeting NK cellrelated therapies. This article reviews the research progress on the applications prospects of NK cell in MM immunotherapy.

EV-mediated intercellular communication in acute myeloid leukemia: Transport of genetic materials in the bone marrow microenvironment.

Acute myeloid leukemia (AML) is a common hematological cancer. Cancer cells exchange information with the surrounding microenvironment, which can be transmitted by extracellular vesicles (EVs). In recent years, the genetic materials transported by EVs have attracted attention due to their important roles in different pathological processes. EV-derived ncRNAs (EV-ncRNAs) regulate physiological functions and maintain homeostasis, mainly including microRNAs, long noncoding RNAs, and circular RNAs. However, the mechanism of involvement and potential clinical application of EV-ncRNAs in AML have not been reported. Given the unique importance of the bone marrow microenvironment (BMME) for AML, a greater understanding of the communication between leukemic cells and the BMME is needed to improve the prognosis of patients and reduce the incidence of recurrence. Additionally, studies on leukemic EV-ncRNA transport guide the design of new diagnostic and therapeutic tools for AML. This review systematically describes intercellular communication in the BMME of AML and emphasizes the role of EVs. More importantly, we focus on the information transmission of EV-ncRNAs in the BMME to explore their clinical application as potential biomarkers and therapeutic targets.

[Analysis of Risk Factors for Pulmonary Infection in Patients with Acute Leukemia after Chemotherapy].

OBJECTIVE: To investigate the risk factors of pulmonary infection in patients with acute leukemia (AL) after chemotherapy. METHODS: A total of 294 patients with AL were collected and divided into infection group (n=93) and control group (n=201) according to whether the pulmonary infection occurred after chemotherapy. Analyze the correlation between sociodemographic data (sex, age, BMI), clinical data (disease type, ECOG score, invasive procedure, underlying disease, hormone therapy, empirical use of antibiotics, prognosis stratification, chemotherapy intensity, primitive cell count, white blood cell count, neutrophil count, duration of granulocyte deficiency, platelet count, hemoglobin, and albumin and pulmonary infection after chemotherapy. COX regression method was used to analyze the risk factors of pulmonary infection in AL patients after chemotherapy. RESULTS: Among 294 patients with AL, 11 died within 30 days after pulmonary infection. There were statistically significant differences in age, smoking history, ECOG score, invasive procedure, hormone therapy, empirical use of antibiotics, prognosis stratification, chemotherapy intensity, primitive cell count, neutrophil count, duration of granulocyte deficiency, platelet count, hemoglobin, albumin and fasting blood glucose between the 2 groups (P <0.05). COX regression analysis showed that smoking history, invasive procedure, unexperienced use of antibiotics, poor prognosis, long duration of granulocytopenia, low platelet level and low albumin were high risk factors for pulmonary infection in AL patients after chemotherapy (P <0.05). CONCLUSION: Smoking, invasive procedures, unexperienced use of antibiotics, poor prognosis, long duration of granulodeficiency, low platelet levels and low albumin are risk factors for pulmonary infection in AL patients after chemotherapy.

[Research Progress of Bispecific Antibodies in Treatment of Multiple Myeloma--Review].

Multiple myeloma (MM) is an incurable malignant plasma cell diseases, the incidence of which is increasing year by year. The application of immunomodulators drugs, proteasome inhibitors, anti-CD38 antibodies, CAR-T, and HSCT have significantly improved the prognosis of patients with MM, however new therapeutic tools need to be developed to improve the prognosis of patients with relapsed/refractory after conventional regimens treatment. Bispecific antibodies are a novel immunotherapeutic approach that generates immune synapses by binding to targets on malignant plasma cells and cytotoxic immune effector cells (T cells/natural killer cells), leading to T/NK cells activation and malignant plasma cell lysis. Several preclinical and phase I clinical studies have shown good efficacy, bringing new possibilities for patients with relapsed/refractory MM to improve their prognosis in the future in combination with the rest of the treatment options. This article summarizes the classification of bispecific antibodies developed in recent years, and the results of preclinical and clinical trials, which will provide some reference for treating MM.

Characterization and integrated analysis of extrachromosomal DNA amplification in hematological malignancies.

The study of extrachromosomal DNA (ecDNA), an element existing beyond classical chromosomes, contributes to creating a more comprehensive map of the cancer genome. In hematological malignancies, research on ecDNA has lacked comprehensive investigation into its frequency, structure, function, and mechanisms of formation. We re-analyzed WGS data from 208 hematological cancer samples across 11 types, focusing on ecDNA characteristics. Amplification of ecDNA was observed in 7 of these cancer types, with no instances found in normal blood cells. Patients with leukemia carrying ecDNA showed a low induction therapy remission rate (<30 %), a high relapse rate (75 %) among those who achieved complete remission, and a significantly lower survival rate compared to the general leukemia population, even those with complex chromosomal karyotypes. Among the 55 identified ecDNA amplicons, 268 genes were detected, of which 38 are known cancer-related genes exhibiting significantly increased copy numbers. By integrating RNA-Seq data, we discovered that the increased copy number, resulting in a higher amount of available DNA templates, indeed leads to the elevated expression of genes encoded on ecDNA. Additionally, through the integration of H3K4me3/H3K27ac chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin with sequencing, and high-throughput chromosome conformation capture data, we identified that ecDNA amplifications can also facilitate efficient, copy number-independent amplification of oncogenes. This process is linked to active histone modifications, improved chromatin accessibility, and enhancer hijacking, all of which are effects of ecDNA amplification. Mechanistically, chromothripsis and dysfunction of the DNA repair pathway can, to some extent, explain the origin of ecDNA.

[Research Progress of Cancer-associated Fibroblasts in Hematolo- gic Malignancies --Review].

Cancer-associated fibroblasts （CAF） are a key component of the tumor microenvironment, which can secrete a variety of cytokines, chemokines and growth factors, directly and indirectly support cancer cells, also alter the immune cellular environment by inhibiting the activity of immune effector cells and recruiting immunosuppressive cells, thereby allowing cancer cells to evade immune surveillance. CAF has been proven to be associated with the development, progression, and poor prognosis of solid tumors. However, the role of CAF in hematological malignancies is still unclear. This article reviews the research progress of CAF in hematological malignancies.

[Recent Research Progress of Extramedullary Plasmacytoma --Review].

Extramedullary plasma cell tumor (EMP) is a kind of plasma cell tumor, and its pathogenesis is not completely clear. According to whether it is independent of myeloma disease, it can be divided into primary and secondary EMP, which have different biological and clinical characteristics. Primary EMP has low invasion, fewer cytogenetic and molecular genetic abnormalities and good prognosis, and surgery and / or radiotherapy are the mainly treatments. Secondary EMP, as the extramedullary invasive progression of multiple myeloma (MM), is often accompanied by high-risk cellular and molecular genetic abnormalities and poor prognosis, chemotherapy, immunotherapy and hematopoietic stem cell transplantation are the mainly treatment. This paper reviews the latest research progress of EMP in the pathogenesis, cytogenetics molecular genetics and treatment, so as to provide reference for clinical work.

The non-coding competing endogenous RNAs in acute myeloid leukemia: biological and clinical implications.

Acute myeloid leukemia (AML) is a hematologic carcinoma that has seen a considerable improvement in patient prognosis because of genetic diagnostics and molecularly-targeted therapies. Nevertheless, recurrence and drug resistance remain significant obstacles to leukemia treatment. It is critical to investigate the underlying molecular mechanisms and find solutions. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), circular RNAs, long non-coding RNAs, and pseudogenes, have been found to be crucial components in driving cancer. The competing endogenous RNA (ceRNA) mechanism has expanded the complexity of miRNA-mediated gene regulation. A great deal of literature has shown that ncRNAs are essential to the biological functions of the ceRNA network (ceRNET). NcRNAs can compete for the same miRNA response elements to influence miRNA-target RNA interactions. Recent evidence suggests that ceRNA might be a potential biomarker and therapeutic strategy. So far, however, there have been no comprehensive studies on ceRNET about AML. What is not yet clear is the clinical application of ceRNA in AML. This study attempts to summarize the development of research on the related ceRNAs in AML and the roles of ncRNAs in ceRNET. We also briefly describe the mechanisms of ceRNA and ceRNET. What's more significant is that we explore the clinical value of ceRNAs to provide accurate diagnostic and prognostic biomarkers as well as therapeutic targets. Finally, limitations and prospects are considered.

Mechanism of salidroside in the treatment of chronic myeloid leukemia based on the network pharmacology and molecular docking.

BACKGROUND: Salidroside is a phenolic natural product, which is a kind of Rhodiola rosea. It has been confirmed that it has inhibitory effects on chronic myeloid leukemia, but the specific performance of its molecular effects is still unclear. OBJECTIVE: To systematically study the pharmacological mechanism of salidroside on chronic myeloid leukemia by means of network pharmacology. METHODS: First, the possible target genes of salidroside were predicted through the Traditional Chinese Medicine Pharmacology Database and Analysis Platform, the target gene names were converted into standardized gene names using the Uniprot website. At the same time, the related target genes of chronic myeloid leukemia were collected from GeneCards and DisGenet; Collect summary data and screen for commonly targeted genes. Then, the above-mentioned intersected genes were imported into the String website to construct the protein-protein interaction (PPI) network, and the Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were further analyzed. To investigate the overall pharmacological effects of salidroside on chronic myeloid leukemia, we constructed a drug component-target gene-disease (CTD) network. Finally, molecular docking was performed to verify the possible binding conformation between salidroside and the candidate target. RESULTS: A total of 126 salidroside target genes were retrieved, and 106 of them had interactions with chronic myeloid leukemia. The pharmacological effects of salidroside on chronic myeloid leukemia are related to some important oncogenes and signaling pathways. Molecular docking studies confirmed that the main role of salidroside binding to the target genes is hydrogen bonding. CONCLUSIONS: We revealed the potential mechanism of action of salidroside against chronic myeloid leukemia, verified by network pharmacology combined with molecular docking. However, salidroside is a promising drug for the prevention and treatment of chronic myeloid leukemia, and further research is needed to prove it.

Identifying a prognostic model and screening of potential natural compounds for acute myeloid leukemia.

Background: Acute myeloid leukemia (AML) is one of the most common hematologic malignancies with a poor prognosis and high recurrence rate. The discovery of new predictive models and therapeutic agents plays a crucial role. Methods: The differentially expressed gene that was explicitly highly expressed in The Cancer Genome Atlas (TCGA) and GSE9476 transcriptome databases were screened and included in the least absolute shrinkage and selection operator (LASSO) regression model to derive risk coefficients and build a risk score model. Functional enrichment analysis was conducted on the screened hub genes to explore the potential mechanisms. Subsequently, critical genes were incorporated into a nomogram model based on risk scores to analyze prognostic value. Finally, this study combined network pharmacology to find potential natural compounds for hub genes and used molecular docking to verify the binding ability of molecular structures to natural compounds to explore drug development for possible efficacy in AML. Results: A total of 33 highly expressed genes may be associated with poor prognosis of AML patients. After LASSO and multivariate Cox regression analysis of 33 critical genes, Rho-related BTB domain containing 2 (RHOBTB2), phospholipase A2 (PLA2G4A), interleukin-2 receptor-α (IL2RA), cysteine and glycine-rich protein 1 (CSRP1), and olfactomedin-like 2A (OLFML2A) were found to played a significant role in the prognosis of AML patients. CSRP1 and OLFML2A were independent prognostic factors of AML. The predictive power of these 5 hub genes in combination with clinical features was better than clinical data alone in predicting AML in the column line graphs and had better predictive value at 1, 3, and 5 years. Finally, through network pharmacology and molecular docking, this study found that diosgenin in Guadi docked well with PLA2G4A, beta-sitosterol in Fangji docked well with IL2RA, and OLFML2A docked well with 3,4-di-O-caffeoylquinic acid in Beiliujinu. Conclusions: The predictive model of RHOBTB2, PLA2G4A, IL2RA, CSRP1, and OLFML2A combined with clinical features can better guide the prognosis of AML. In addition, the stable docking of PLA2G4A, IL2RA, and OLFML2A with natural compounds may provide new options for treating AML.

Mechanism of Procyanidin B2 in the Treatment of Chronic Myeloid Leukemia Based on Integrating Network Pharmacology and Molecular Docking.

OBJECTIVE: To study the pharmacological mechanism of procyanidin B2 (PCB2) on chronic myeloid leukemia (CML) by integrating network pharmacological methods systematically. METHODS: Firstly, the potential target genes of PCB2 were predicted by the pharmacological database and analysis platform (TCMSP and Pharmmapper). Meanwhile, the relevant target genes of CML were collected from GeneCards and DisGene. Pooled data were collected to screen for common target genes. Furthermore, the above intersection genes were imported into the String website to construct a protein-protein interaction (PPI) network, and the Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were further analyzed. Besides, molecular docking was performed to verify the possible binding conformation between PCB2 and candidate targets. Finally, MTT and RT-PCR experiments of K562 cells were performed to verify the above results of network pharmacology. RESULTS: A total of 229 PCB2 target genes were retrieved, among which 186 target genes had interaction with CML. The pharmacological effects of PCB2 on CML were related to some important oncogenes and signaling pathways. The top ten core targets predicted by Network Analysis were as follows: AKT1, EGFR, ESR1, CASP3, SRC, VEGFA, HIF1A, ERBB2, MTOR, and IGF1. Molecular docking studies confirmed that hydrogen bonding was the main interaction force of PCB2 binding targets. According to the molecular docking score, the following three target proteins were most likely to bind to PCB2: VEGFA (-5.5 kcal/mol), SRC (-5.1 kcal/mol), and EGFR (-4.6 kcal/mol). After treatment of PCB2 for 24h, mRNA expression levels of VEGFA and HIF1A decreased significantly in K562 cells. CONCLUSION: Through integrating network pharmacology combined with molecular docking, the study revealed the potential mechanism of PCB2 anti-chronic myeloid leukemia.

[Mechanism Underlying the Inhibitory Effect of MiR-532-3p on the Cells Proliferation of Diffuse Large B-Cell Lymphoma].

OBJECTIVE: To investigate the effects and underlying mechanism of miR-532-3p and resibufogenin (RES) by regulating Wnt/ß-catenin signaling on diffuse Large B-cell lymphoma (DLBCL) cells proliferation. METHODS: DLBCL tissues and adjacent normal tissues were collected from patients had been diagnosed with DLBCL at the First Hospital of Lanzhou University from October 2019 to October 2021. Four groups including mimics-NC, miR-532-3p mimics, RES control and RES treatment in SU-DHL-4 cells were designed. The expression level of miR-532-3p was detected by RT-qPCR. The protein content of ß-catenin was detected by Western blot. MTT assay was used to detect the proliferation activity of SU-DHL-4 cells. RESULTS: miR-532-3p expression was significantly decreased in DLBCL tissues compared with adjacent normal tissues (P<0.001). The miR-532-3p content in lymphoma cells was significantly lower than that in normal lymphocytes (P<0.001). After overexpression of miR-532-3p, the viability of SU-DHL 4 cells was significantly decreased (P<0.001), with a reduced expression of ß-catenin (P<0.05). RES treatment inhibited the proliferation of SU-DHL-4 cells and decreased ß-catenin expression in SU-DHL-4 cells compared with the control group. CONCLUSION: Overexpression of miR-532-3p reduced Wnt/ß-catenin signaling and inhibited the proliferation of lymphoma cells. Moreover, RES treatment inhibited lymphoma cells growth partially through Wnt/ß-catenin signaling suppression.

Associations between morphokinetic parameters of temporary-arrest embryos and the clinical prognosis in FET cycles.

Infertility is a major health concern worldwide. This retrospective study aimed to assess the predictive value of the morphokinetic parameters of temporary-arrest embryos for the pregnancy outcomes of women undergoing frozen embryo transfer (FET) cycles. In this study, we evaluated 244 FET cycles with 431 day-4 temporary-arrest embryos. They were categorized into two groups (pregnancy and non-pregnancy) according to the pregnancy outcomes of the women after embryo transfer on day 5, and their fundamental characteristics were compared. The morphokinetic parameters from the time-lapse monitoring system were assessed according to different pregnancy outcomes. The mean number of embryo blastomeres thawed on day 3 in the pregnancy group was 7.47, which was significantly higher than the number in the non-pregnancy group (p < 0.01). Besides, embryos in the non-pregnancy group contained more embryo fragments and lower grades than those in the pregnancy group (p < 0.001). Furthermore, morphokinetic parameters: tPNa, t2, t5, and t5_tPNf showed a statistical difference between the pregnancy and non-pregnancy groups (p < 0.05). Receiver-operating characteristic analysis revealed that the time from pronuclear fading to the 5-cell stage (t5_PNF) predicted the clinical prognosis outcomes (area under the curve = 0.64; 95% confidence interval [CI], 0.58-0.70; p < 0.001). The morphokinetic parameter t5_PNF could be regarded as a potential implantation predictor in our study.