Objective To investigate the relationship between the serum FMS-like tyrosine kinase 3 ligand(Flt3L),progranulin(PGRN)levels and the disease risk and disease outcome of patients with acute lympho-blastic leukemia(ALL).Methods A total of 104 patients with ALL admitted to the hospital from September 2019 to September 2021 were selected as the research subjects.ALL patients were divided into the low-risk group(n=34),the medium-risk group(n=39),and the high-risk group(n=31)according to the disease risk.The levels of serum Flt3L and PGRN of the patients at admission were detected by enzyme-linked immu-nosorbent assay.Pearson correlation analysis was used to analyze the relationship between serum Flt3L,PGRN in ALL patients and the risk of ALL disease.According to the follow-up results of ALL patients,they were divided into the good prognosis group(n=81)and the poor prognosis group(n=23).The receiver oper-ating characteristic curve and the area under the curve(AUC)were used to analyze the evaluation value of se-rum Flt3L and PGRN for the prognosis of ALL patients,and multivariate Cox regression was used to analyze the prognostic risk factors of ALL patients.Results The serum Flt3L levels in the low-risk group and the medium-risk group were higher than those in the high-risk group,and the difference was statistically signifi-cant(P＜0.05).The serum PGRN levels in the low-risk group and the medium-risk group were lower than those in the high-risk group,and the difference was statistically significant(P＜0.05).Serum Flt3L in ALL patients was negatively correlated with the risk of ALL disease(r=-0.461,0.593,P＜0.05).Serum PGRN in ALL patients was positively correlated with the risk of ALL disease(r=0.593,P＜0.05).The proportions of white blood cell count ≥50 × 109/L,hemoglobin＜90 g/L,and serum PGRN level in the poor prognosis group were higher than those in the good prognosis group,while the serum Flt3L level was lower than that in the good prognosis group,and the differences were statistically significant(P＜0.05).The AUC of serum Flt3L and PGRN in evaluating the prognosis of ALL patients were 0.762(95％CI:0.717-0.816),0.815(95％CI:0.764-0.863),and 0.915(95％CI:0.866-0.964),respectively.White blood cell count ≥50 × 109/L,hemoglobin＜90 g/L,Flt3L＜92.07 pg/mL,and PGRN≥335.14 pg/mL were risk factors affecting the prognosis of ALL patients(P＜0.05).Conclusion The levels of serum Flt3L and PGRN in ALL patients are related to the disease risk and disease outcome of ALL.The combined detection of the two has a good eval-uation value for the prognosis of adult ALL patients.

Objective To investigate the effect of anti-angiogenic drug Sitravatinib combined with poly(adenosine diphosphate[ADP]-ribose)polymerase inhibitor(PARPi)Niraparib on mucosal melanoma cell lines and its possible mechanism.Methods The CCK8 assay was used to detect the maximal half inhibitory concentration(IC50)of Sitravatinib and Niraparib targeting at mucosal melanoma(MM)cell lines.CompuSyn was used to detect the Combination Index(CI)in different concentrations of the two drugs.Flow cytometry was used to detect the effect of drugs on cell apoptosis.Colony formation assay was used to detect the effect of drugs on cell proliferation.Western blot was used to detect the protein expressions and RT-qPCR was used to detect mRNA expression.Results CI values was respectively 0.19 and 0.15 for Sitravatinib(2 μmol/L)in combination with Niraparib(20 μmol/L)in a human vaginal maligant melanoma cell line(HMVII)and a metastasis inguinal lymph node of vulvar malignant melanoma cell line(GAK).Compared with the control group and single-drug groups,the cell proliferation of the combination group was significantly reduced(P＜0.05 or P＜0.01 or P＜0.001).The cell apoptosis rate was signifi-cantly increased(P＜0.01 or P＜0.001).The protein and mRNA expression of apoptosis-related biomarkers signifi-cantly increased(P＜0.001);In addition,the protein and mRNA expression of cell autophagy biomarkers signifi-cantly increased(P＜0.01 or P＜0.001).The protein expression of DNA damage marker significantly increased.Moreover,compared with the control group,The expression of radiation sensitive protein 51(RAD51)recombinase in the Sitravatinib single-drug group and combination group significantly reduced.As the dose of Sitravatinib gradu-ally increased up to 2 μmol/L,the protein and mRNA expression of RAD51 both significantly reduced(P＜0.05 or P＜0.01),the mRNA expression of BRCA1 and BRCA2 also significantly reduced(P＜0.05 or P＜0.01 or P＜0.001).Conclusions Sitravatinib combined with Niraparib inhibits the proliferation of mucosal melanoma cells,induces cell apoptosis and promotes autophagy.The mechanism is potentially related to the inhibition of ho-mology-dependent recombination repairs(HRR).

Uveal melanoma (UM) poses a significant lethality, with approximately 50% of those developing metastases surviving less than one year. In the progression of UM, vasculogenic mimicry (VM) induced by hypoxia plays a pivotal role, which also partially explains the resistance of UM to anti-angiogenic therapies. Nevertheless, the crucial molecular mechanisms underlying VM in the progression of UM remain unclear. We identified ubiquitin conjugating enzyme E2 G2 (UBE2G2) as a critical suppressor through transcriptomic sequencing and metastasis correlation screening. In UM, hypoxia-induced VM and metastasis are markedly exacerbated by UBE2G2 knockdown and significantly alleviated by its overexpression. Mechanistically, UBE2G2 directly binds to galectin 3 binding protein (LGALS3BP) and forms a complex with the E3 ubiquitin ligase tripartite motif containing 38 (TRIM38), facilitating ubiquitination-mediated degradation of LGALS3BP at the K104 residue. Furthermore, UBE2G2 inhibits oncogenic phenotypes by inactivating intracellular PI3K/AKT signaling and reprogramming the tumor microenvironment. Therefore, targeting intercellular and intracellular molecular mechanisms of the hypoxia-UBE2G2-LGALS3BP axis may contribute to developing various therapeutic strategies for UM.

Objective:To investigate the influencing factors for the recurrence of TNM(T3~4N0M0)stage Ⅱ colorectal cancer in patients aged 75 years and over after radical resection.Methods:Clinicopathologic data of 161 colorectal cancer patients aged 75 years and over undergone radical resection in our hospital from January 2012 to August 2017 were retrospectively analyzed.They were followed up for 49 months(range: 2-84 months). Survival analysis was conducted by the Kaplan-Meier method and the survival rate was examined using the Log-rank method.Multivariate analysis was conducted by the proportional hazards regression model.Results:Univariate analysis showed that age≥80 years, preoperative comorbidities involving more than 1 system, weight loss≥10%, preoperative intestinal obstruction or perforation, preoperative CEA elevation, preoperative CA199 elevation, depth of primary tumor invasion T4, dissection of lymph nodes<12, vascular invasion, nerve invasion, deficient mismatch repair(dMMR), risk stratification and adjuvant chemotherapy were related factors for the prognosis in patients with TNM stage Ⅱ colorectal cancer aged 75 years and over after radical resection.Multivariate analysis showed that preoperative comorbidities involving more than 1 system, weight loss≥10%, preoperative intestinal obstruction or perforation, preoperative CEA elevation, depth of primary tumor invasion T4, dissection of lymph nodes<12 and vascular invasion were independent risk factors for poor prognosis, and adjuvant chemotherapy was an independent factor for favorable prognosis.The 5-year-disease-free survival(DFS)rate was 41.6% in all patients.The Kaplan-Meier curves indicated that disease-free survival(DFS)between the low-risk, middle-risk and high-risk groups had a statistically significant difference( χ2=14.632, P=0.001). Kaplan-Meier survival analysis showed that high-risk patients receiving Oxaliplatin combined with Capecitabine adjuvant chemotherapy had better DFS than those receiving Capecitabine or non-adjuvant chemotherapy( χ2=11.157, P=0.004). Conclusions:DFS is improved in strictly selected patients with stage Ⅱ colorectal cancer aged 75 years and over and at high risk who receive Oxaliplatin combined with Capecitabine adjuvant chemotherapy.

Objective:To investigate the effect of a tankyrase inhibitor NVP-TNKS656 on the growth of hepatocellular carcinoma(HCC)cell lines and the involved molecular mechanisms.Methods:Five HCC cell lines were treated with 0, 2.5, 5.0, 10.0 μmol/L of NVP-TNKS656.The cell lines of HLE and HLF were selected and divided into four groups: 0.0 μmol/L(control or DMSO), 2.5 μmol/L, 5.0 μmol/L, 10.0 μmol/L of NVP-TNKS656 groups.Cells were cultured for 48 h for subsequent experiments.Crystal violet staining was used to count the number of the newly formed cell clones.Western blotting was used to detect the protein expression levels of Yes-associated protein(YAP), angiomotin-like 1(AMOTL1)and AMOTL2.The real-time qRT-PCR was used to detect the mRNA expression of YAP and its downstream connective tissue growth factor(CTGF)and cysteine-rich 61(Cyr61). Dual luciferase reporter gene was used to detect the luciferase activity of transcriptional enhancer activator domain(TEAD)family.Results:NVP-TNKS656 inhibited the growth of 5 HCC cell lines in a dose-dependent manner in HLE, HLF, Huh7, MHCC97-H, and MHCC97-L cell lines.There were significant differences in the newly formed cell clone numbers between control(0 μM of NVP-TNKS656)and each of 2.5 μmol/L, 5.0 μmol/L, 10.0 μmol/L of NVP-TNKS656 groups in a dose-dependent manner( F=90.46, 68.58, 191.8, 114.6 and 201.4, all P<0.05). In HLE and HLF cell lines, NVP-TNKS656 significantly reduced the protein level of YAP in a dose-dependent manner and decreased the YAP target gene CTGF(HLE cells: 1.02±0.02, 0.90±0.03, 0.57±0.02, 0.38±0.03, HLF cells: 0.98±0.03, 0.86±0.02, 0.66±0.02, 0.43±0.01)and Cyr61(HLE cells: 1.00±0.01, 0.86±0.02, 0.74±0.03, 0.44±0.03 and HLF cells: 0.99± 0.02, 0.87±0.01, 0.72±0.02, 0.54±0.01)( P<0.05), and inhibited the activity of YAP/TEAD luciferase.At the same time, NVP-TNKS656 up-regulated two major negative regulators of YAP, namely AMOTL1 and AMOTL2 proteins, and promoted the apoptosis of HLE and HLF cells in a dose-dependent manner. Conclusion:NVP-TNKS656 can inhibit the proliferation of HCC by stabilizing AMOTL1/ AMOTL2 and down-regulating the YAP target gene.This study indicates that NVP-TNKS656 can be used as a potential drug for treating HCC.

Objective To investigate the clinical characteristics,prognosis,and influencing factors of digestive system tumors in elderly patients complicated with acute pulmonary thromboembolism(PTE).Methods In this retrospective cohort study,we analyzed data from 86 elderly patients with digestive system tumors from the Oncology Department of Beijing Hospital from January 2007 to January 2017.Forty-one elderly patients who had digestive system tumors with PTE were assigned into an observation group and forty five without PTE into a control group.We analyzed the clinical characteristics of the two groups.Kaplan-Meier survival analysis was used to assess the median survival time;and Cox regression analysis was used to evaluate the influencing factors for prognosis.Results Eighty-six elderly patients with a mean age of(75.8 ± 13.7)years ranging from 60 to 92 years were enrolled.There was a statistically significant difference in the D-dimer level between the groups at baseline (P ＜ 0.05).In the observation group,the primary symptom was dyspnea(78.0％,n=67).Of all primary tumors complicated with PTE,colorectal cancers had the highest prevalence,accounting for 56.1％ (n =23),followed by gastric cancers,representing 31.7％ (n=13).Twenty-three patients in the observation group were complicated with deep venous thrombosis(56.1％,n-23),which mostly located in the lower limbs (56.5 ％,n =23).Meanwhile,90.2 ％ of PTE(n =37) occurred during chemotherapy or follow-up.Sixty-seven patients (77.9 ％) died during the follow-up,and the difference in mortality between the two groups was statistically significant(P ＜ 0.05).Kaplan Meier survival analysis showed a significant difference in median survival time between the two groups (3.7 vs.8.5 months,P ＜ 0.05).Cox regression analysis indicated that age,PTE,and metastasis were risk factors for median survival time(all P ＜0.05) Conclusions Elderly patients with digestive system tumors complicated with acute pulmonary thromboembolism show no typical characteristics and poor prognosis.Therefore,preventive measures and care should be taken to improve the prognosis,especially for patients at high risk of PTE.