To target the pivotal BCR/ABL oncoprotein in chronic myeloid leukemia (CML) cells, tyrosine kinase inhibitors (TKIs) are utilized as landmark achievements in CML therapy. However, TKI resistance and intolerance remain principal obstacles in the treatment of CML patients. In recent years, drug repositioning provided alternative and promising perspectives apart from the classical cancer therapies, and promoted anthelmintic mebendazole (MBZ) as an effective anti-cancer drug in various cancers. Here, we investigated the role of MBZ in CML treatment including imatinib-resistant CML cells. Our results proved that MBZ inhibited the proliferation and induced apoptosis in CML cells. We found that MBZ effectively suppressed BCR/ABL kinase activity and MEK/ERK signaling pathway by reducing p-BCR/ABL and p-ERK levels with ABL1 targeting ability. Meanwhile, MBZ directly targeted the colchicine-binding site of β-tubulin protein, hampered microtubule polymerization and induced mitosis arrest and mitotic catastrophe. In addition, MBZ increased DNA damage levels and hampered the accumulation of ataxia-telangiectasia mutated and DNA-dependent protein kinase into the nucleus. This work discovered that anthelmintic MBZ exerts remarkable anticancer effects in both imatinib-sensitive and imatinib-resistant CML cells in vitro and revealed mechanisms underlying. From the perspective of drug repositioning and multi‐target therapeutic strategy, this study provides a promising option for CML treatment, especially in TKI-resistant or intolerant individuals.

Objective:To investigate gut microbiota differences between individuals with and without colorectal adenoma(CRA)and to identify gut microbes associated with CRA.Methods:This cross-sectional study analyzed the gut microbiota of 100 patients with CRA and 68 individuals without CRA(aged 40-75 years)who underwent colonoscopies between March 2021 and March 2022 at Tianjin Nankai Hospital.Fecal samples were sequenced for the V3-V4 region of the bacterial 16S rRNA gene using the Illumina NovaSeq platform.Results:Compared to the non-CRA group,the CRA group exhibited reduced relative abundances of identified and unidentified Lachnospiraceae,with increased Faecalibacterium and Streptococcus.In the non-CRA group,the relative abundances of Coprococcus,unidentified Clostridiaceae,and Clostridium were higher.LEfSe analysis revealed significant enrichment of Gammaproteobacteria,Proteobacteria,Enterobacteriales,and Faecalibacterium in the CRA group,while the non-CRA group was enriched for Moraxellaceae,Acinetobacter,and Anaerostipes.Conclusions:These findings suggest a discernible disparity in the gut microbiota structure between CRA patients and individuals without adenoma.The enrichment of potential pathogenic taxa,such as Faecalibacterium and Streptococcus,in the CRA group suggests a possible association with adenoma development.

Purpose To investigate the clinicopathological features,molecular subtypes,and prognostic factors of diffuse midline glioma(DMG)with H3K27 alterations.Methods Clinical data from 19 patients from DMG were col-lected.The clinical manifestations,histopathological features,immunophenotypes,and molecular genetic characteris-tics were analyzed.Relevant literature was also reviewed.Results Among the 19 patients,12 cases had tumors loca-ted in the thalamus,while 7 cases had tumors in other midline regions(including 4 cases in the brainstem,1 case in the cerebellum,and 2 cases in the spinal cord).Clinical symptoms primarily included dizziness,gait instability,and blurred vision.Histological features were diverse,with 12 cases classified as high-grade gliomas and 7 cases as low-grade.Immunohistochemistry revealed a loss of H3K27me3 expression in all cases,with 18 cases showing diffuse H3K27M positivity and 1 case expressing EZHIP.Of the 16 cases that underwent next-generation sequencing(NGS),1 case showed EGFR mutation(1/16,6％),while the remaining 15 cases had H3F3A K27M mutations(15/16,94％).Among these,7 cases had ATRX mutations(7/15,46.6％),5 cases had MAPK pathway alterations(5/15,33.3％,including 2 cases FGFR1,2 cases NF1,1 case co-mutated with BRAF and NF1),5 cases had PDGFRA mis-sense mutations(5/15,33.3％),4 cases had p53 missense or frameshift deletions(4/15,26.6％).One case each had a DICER1 missense mutation and an IDH1-S202R frameshift deletion(1/15,6.6％).The prognosis was general-ly poor,with a median survival of 9.5 months.Conclusion DMG exhibits high tumor heterogeneity and an overall poor prognosis.The predominant molecular aleration was the H3F3A K27M mutation.Patients with co-altered MAPK pathway showed relatively better outcomes,providing new insights into the molecular genetic characteristics of DMG.

Objective:To investigate the role of calcium-binding protein S100A9 in acute lung injury induced by hepatic ischemia-reperfusion (HIR) in mice, and to explore its relationship with nuclear factor erythroid 2-related factor 2 (Nrf2).Methods:A total of 12 specific pathogen-free (SPF) male wild-type (WT) and 12 S100A9 knockout (S100A9 KO) C57BL/6J mice aged 6~8 weeks and weighing 20-25 g were randomly divided into four groups using a random number table: WT+Sham group, S100A9 KO+Sham group, WT+HIR group, and S100A9 KO+HIR group ( n=6 per group). The HIR model was established by clamping the portal vein and hepatic artery of the left and median liver lobes for 60 minutes followed by reperfusion. At 6 hours post-reperfusion, mice were anesthetized again, and blood samples were collected from the inferior vena cava. Both lungs were harvested. The lung wet-to-dry (W/D) weight ratio was measured. Hematoxylin and eosin (HE) staining was used to assess histopathological changes and calculate lung injury scores. The levels of inflammatory markers—S100A9, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) —as well as oxidative stress indicators including myeloperoxidase (MPO), reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) in serum and lung tissue were measured. Western blotting was used to assess the expression levels of nuclear and cytoplasmic Nrf2, and cytoplasmic HO-1. Results:Compared with the WT+Sham group, both the WT+HIR and S100A9 KO+HIR groups showed significantly increased lung injury scores, W/D ratio, TNF-α, IL-6, ROS, MPO, and MDA levels (all P<0.05). Compared with the WT+HIR group, the S100A9 KO+HIR group exhibited significantly reduced levels of these indicators (all P<0.05). Moreover, the S100A9 KO+HIR group showed elevated nuclear Nrf2 expression and decreased cytoplasmic Nrf2 expression, accompanied by increased expression of HO-1, Gclm, Gclc, and Nqo1 (all P<0.05). Conclusion:Upregulation of S100A9 is involved in the development of HIR-induced acute lung injury, possibly through inhibition of Nrf2 nuclear translocation.

Purpose To investigate the clinicopathological features,molecular subtypes,and prognostic factors of diffuse midline glioma(DMG)with H3K27 alterations.Methods Clinical data from 19 patients from DMG were col-lected.The clinical manifestations,histopathological features,immunophenotypes,and molecular genetic characteris-tics were analyzed.Relevant literature was also reviewed.Results Among the 19 patients,12 cases had tumors loca-ted in the thalamus,while 7 cases had tumors in other midline regions(including 4 cases in the brainstem,1 case in the cerebellum,and 2 cases in the spinal cord).Clinical symptoms primarily included dizziness,gait instability,and blurred vision.Histological features were diverse,with 12 cases classified as high-grade gliomas and 7 cases as low-grade.Immunohistochemistry revealed a loss of H3K27me3 expression in all cases,with 18 cases showing diffuse H3K27M positivity and 1 case expressing EZHIP.Of the 16 cases that underwent next-generation sequencing(NGS),1 case showed EGFR mutation(1/16,6％),while the remaining 15 cases had H3F3A K27M mutations(15/16,94％).Among these,7 cases had ATRX mutations(7/15,46.6％),5 cases had MAPK pathway alterations(5/15,33.3％,including 2 cases FGFR1,2 cases NF1,1 case co-mutated with BRAF and NF1),5 cases had PDGFRA mis-sense mutations(5/15,33.3％),4 cases had p53 missense or frameshift deletions(4/15,26.6％).One case each had a DICER1 missense mutation and an IDH1-S202R frameshift deletion(1/15,6.6％).The prognosis was general-ly poor,with a median survival of 9.5 months.Conclusion DMG exhibits high tumor heterogeneity and an overall poor prognosis.The predominant molecular aleration was the H3F3A K27M mutation.Patients with co-altered MAPK pathway showed relatively better outcomes,providing new insights into the molecular genetic characteristics of DMG.

To target the pivotal BCR/ABL oncoprotein in chronic myeloid leukemia (CML) cells, tyrosine kinase inhibitors (TKIs) are utilized as landmark achievements in CML therapy. However, TKI resistance and intolerance remain principal obstacles in the treatment of CML patients. In recent years, drug repositioning provided alternative and promising perspectives apart from the classical cancer therapies, and promoted anthelmintic mebendazole (MBZ) as an effective anti-cancer drug in various cancers. Here, we investigated the role of MBZ in CML treatment including imatinib-resistant CML cells. Our results proved that MBZ inhibited the proliferation and induced apoptosis in CML cells. We found that MBZ effectively suppressed BCR/ABL kinase activity and MEK/ERK signaling pathway by reducing p-BCR/ABL and p-ERK levels with ABL1 targeting ability. Meanwhile, MBZ directly targeted the colchicine-binding site of β-tubulin protein, hampered microtubule polymerization and induced mitosis arrest and mitotic catastrophe. In addition, MBZ increased DNA damage levels and hampered the accumulation of ataxia-telangiectasia mutated and DNA-dependent protein kinase into the nucleus. This work discovered that anthelmintic MBZ exerts remarkable anticancer effects in both imatinib-sensitive and imatinib-resistant CML cells in vitro and revealed mechanisms underlying. From the perspective of drug repositioning and multi‐target therapeutic strategy, this study provides a promising option for CML treatment, especially in TKI-resistant or intolerant individuals.

Objective:To investigate the predictive value of elevated calprotectin S100A9 (S100A9) concentration during living-donor liver transplantation (LDLT) for early acute lung injury (ALI) in children with biliary atresia.Method:A retrospective analysis was conducted on 280 pediatric patients with biliary atresia who underwent LDLT using hyperreduced left lateral segment grafts at Tianjin First Central Hospital between January 2019 and January 2021. Based on intraoperative serum S100A9 levels at 30 minutes after graft reperfusion, patients were divided into the high S100A9 group (≥9.05 μg/L, 141 cases) and the low S100A9 group (<9.05 μg/L, 139 cases). General clinical characteristics were compared between the two groups. Univariate and multivariate logistic regression analyses were performed to examine the correlation between S100A9 levels and early postoperative ALI. The predictive value of risk factors was assessed using receiver operating characteristic (ROC) curve analysis with calculation of the area under the curve (AUC) .Result:A total of 280 eligible children were included in the study, with 141 in the high S100A9 group and 139 in the low S100A9 group. The incidence of ALI was significantly higher in the high S100A9 group (31.2%) compared to the low S100A9 group (10.8%). Multivariate regression analysis identified elevated preoperative creatinine levels ( OR=1.191, 95% CI: 1.069~1.321, P=0.002), increased intraoperative S100A9 concentrations ( OR=1.426, 95% CI: 1.272~1.599, P=0.021), and higher intraoperative blood transfusion volume ( OR=0.985, 95% CI: 0.973~0.997, P=0.017) as independent risk factors for postoperative ALI in pediatric LDLT. The predictive value of intraoperative S100A9 levels for ALI was significant, with an AUC of 0.816 (95% CI: 0.758~0.874), a sensitivity of 80.5%, a specificity of 73.7%, and an optimal cutoff value of 9.49 μg/L. Furthermore, preoperative albumin and creatinine levels were found to be correlated with increased intraoperative S100A9 levels. Conclusion:Elevated intraoperative S100A9 levels, increased preoperative creatinine levels, and higher intraoperative blood transfusion volumes are independent risk factors for early ALI following pediatric LDLT. S100A9 levels have strong predictive value for ALI occurrence, highlighting the need for perioperative monitoring and intervention strategies to improve postoperative outcomes.

Objective To construct a nomogram model for predicting pulmonary hemorrhage associated with the positioning of pulmonary nodules with the new four-hook positioning needle based on clinical-CT imaging features and evaluate its predictive efficacy.Methods We made a retrospective analysis of the clinical,imaging and pathological data of 449 patients with pulmonary nodules positioned by the new four-hook positioning needle.According to the random number table method(7∶3),they were divided into a training set of 314 cases and a validation set of 135 cases.Each data set was further divided into positive group and negative group for pulmonary hemorrhage according to the presence or absence of pulmonary hemorrhage.We evaluated the CT imaging features of pulmonary nodules,including nodule nature(pure ground-glass density,mixed ground-glass density,solid nodule),nodule diameter,distance from the nodule to the pleural surface(hereinafter referred to as length),nodule positioning time,and association with pulmonary hemorrhage.Independent sample t-test,Mann-Whitney U test and x2 test were used to compare the correlations of clinical and CT features of pulmonary nodules with pulmonary hemorrhage.LASSO regression and multivariate Logistic regression were employed to screen the independent risk factors related to pulmonary hemorrhage and construct a nomogram model.The receiver operating characteristic(ROC)curve was used to evaluate the predictive efficacy of the model,and the calibration curve and decision curve were respectively used for the verification of the nomogram model and evaluation of the clinical net benefit.Results The results of LASSO regression showed that the nature of pulmonary nodules,underlying diseases,smoking and length were the characteristic variables related to pulmonary hemorrhage.Based on the minimum akaike information criterion(AIC),the screened characteristic variables were included in the multivariate Logistic backward stepwise regression analysis.The results showed that the nature of pulmonary nodules,underlying diseases,smoking and length were all independent risk factors related to pulmonary hemorrhage.A nomogram was established according to the above independent risk factors and the ROC curve was drawn.The AUC of the training set was 0.86(95％CI:0.80-0.91),and the AUC of the validation set was 0.88(95％CI:0.80-0.96),with no statistically significant difference(P＞0.05).The calibration curve suggested that the predicted values of the nomogram were close to the actual values,and the decision curve analysis showed that the net benefit of the model was good.Conclusion The nomogram model established by combining clinical-CT features such as the nature of pulmonary nodules,underlying diseases,smoking and length can effectively predict pulmonary hemorrhage associated with the positioning of pulmonary nodules with the new four-hook positioning needle.

To target the pivotal BCR/ABL oncoprotein in chronic myeloid leukemia (CML) cells, tyrosine kinase inhibitors (TKIs) are utilized as landmark achievements in CML therapy. However, TKI resistance and intolerance remain principal obstacles in the treatment of CML patients. In recent years, drug repositioning provided alternative and promising perspectives apart from the classical cancer therapies, and promoted anthelmintic mebendazole (MBZ) as an effective anti-cancer drug in various cancers. Here, we investigated the role of MBZ in CML treatment including imatinib-resistant CML cells. Our results proved that MBZ inhibited the proliferation and induced apoptosis in CML cells. We found that MBZ effectively suppressed BCR/ABL kinase activity and MEK/ERK signaling pathway by reducing p-BCR/ABL and p-ERK levels with ABL1 targeting ability. Meanwhile, MBZ directly targeted the colchicine-binding site of β-tubulin protein, hampered microtubule polymerization and induced mitosis arrest and mitotic catastrophe. In addition, MBZ increased DNA damage levels and hampered the accumulation of ataxia-telangiectasia mutated and DNA-dependent protein kinase into the nucleus. This work discovered that anthelmintic MBZ exerts remarkable anticancer effects in both imatinib-sensitive and imatinib-resistant CML cells in vitro and revealed mechanisms underlying. From the perspective of drug repositioning and multi‐target therapeutic strategy, this study provides a promising option for CML treatment, especially in TKI-resistant or intolerant individuals.

To target the pivotal BCR/ABL oncoprotein in chronic myeloid leukemia (CML) cells, tyrosine kinase inhibitors (TKIs) are utilized as landmark achievements in CML therapy. However, TKI resistance and intolerance remain principal obstacles in the treatment of CML patients. In recent years, drug repositioning provided alternative and promising perspectives apart from the classical cancer therapies, and promoted anthelmintic mebendazole (MBZ) as an effective anti-cancer drug in various cancers. Here, we investigated the role of MBZ in CML treatment including imatinib-resistant CML cells. Our results proved that MBZ inhibited the proliferation and induced apoptosis in CML cells. We found that MBZ effectively suppressed BCR/ABL kinase activity and MEK/ERK signaling pathway by reducing p-BCR/ABL and p-ERK levels with ABL1 targeting ability. Meanwhile, MBZ directly targeted the colchicine-binding site of β-tubulin protein, hampered microtubule polymerization and induced mitosis arrest and mitotic catastrophe. In addition, MBZ increased DNA damage levels and hampered the accumulation of ataxia-telangiectasia mutated and DNA-dependent protein kinase into the nucleus. This work discovered that anthelmintic MBZ exerts remarkable anticancer effects in both imatinib-sensitive and imatinib-resistant CML cells in vitro and revealed mechanisms underlying. From the perspective of drug repositioning and multi‐target therapeutic strategy, this study provides a promising option for CML treatment, especially in TKI-resistant or intolerant individuals.