Bruton's tyrosine kinase inhibitors(BTKi)are a class of drugs approved for treating patients with B cell-related hematologic malig-nancies.They function by blocking B cell signaling,thereby affecting the development and proliferation of B cell-related tumors.Research has revealed that Bruton's tyrosine kinase(BTK)is also expressed in other cells,including mast cells,dendritic cells,granulocytes,platelets,and macrophages.Furthermore,BTK's downstream signaling pathways,such as the activation of phospholipase C gamma 2(PLCγ2),Fc re-ceptor signaling path ways,and Toll-like receptor signaling pathways,are associated with various diseases.These mechanisms provide a the-oretical foundation for using BTK in treating diseases other than B cell-related tumors.This article reviews the progress in the application of BTK for non-B-cell malignancies.

Background and purpose:Relapsed or refractory diffuse large B-cell lymphoma(DLBCL)can be treated with chimeric antigen receptor T-cell(CAR-T)therapy.Imaging-based biomarkers may help identify patients likely to achieve clinical response to this immunotherapy.In this study,an 18-f1uoro-2-deoxy-D-glucose positron emission tomography-computed tomography(18F-FDG PET/CT)based model was developed to assess the progression-free survival(PFS)and overall survival(OS)of patients with relapsed or refractory(R/R)DLBCL who received CAR-T therapy.Methods:We retrospectively analyzed clinical and imaging data from patients with DLBCL who underwent CAR-T therapy at the First Affiliated Hospital of Soochow University between March 2017 and January 2022.Inclusion criteria:① age≥18 years old;② pathologically confirmed R/R DLBCL;③ 18F-FDG PET/CT performed before CAR-T cell therapy;④ complete clinicopathologic data;⑤ patients must have measurable lesions.Exclusion criteria:① patients with incomplete clinical or imaging data;② patients with other types of malignant tumors;③ patients who have received granulocyte colony-stimulating factor treatment within 1 month prior to PET/CT scan.This study was reviewed by the Ethics Committee of the First Affiliated Hospital of Soochow University(ID:2025256).Receiver operating characteristic(ROC)curves were used to determine the optimal thresholds for maximum standardized uptake value(SUVmax),tumor metabolic volume(MTV),and total glycolysis(TLG),and the patients were classified into high-risk and low-risk groups.Univariate and multivariate Cox regression analyses were used to identify potential prognostic factors and construct predictive models,which were visualized by drawing nomogram.Area under the ROC curve was used to assess the performance of each model.Results:A total of 61 patients(37 male patients and 24 female patients,aged 26-75 years)with DLBCL who underwent 18F-FDG PET/CT prior to CAR-T infusion were included.The median follow-up was 14 months;36 patients(59.02%)had disease progression and 25 patients(40.98%)died.Multivariate analysis showed that grade of cytokine release syndrome(CRS)[Hazard ratio(HR)=3.671;P=0.003]and MTV(HR=0.171,P=0.004)were independent prognostic factors for OS;Eastern Cooperative Oncology Group(ECOG)score(HR=2.411,P=0.019),grade of CRS(HR=2.499;P=0.027),and MTV(HR=0.338,P=0.007)were independent prognostic factors for PFS.The combined model(MTV,ECOG score,grade of CRS)was better than the clinical model(ECOG score,grade of CRS),and metabolic parameter model(MTV)in predicting PFS and OS.Conclusion:18F-FDG PET/CT metabolic parameter MTV in combination with traditional clinical risk factors(ECOG score,Grade of CRS)could identify patients with ultra-high risk of DLBCL.

Bruton's tyrosine kinase inhibitors(BTKi)are a class of drugs approved for treating patients with B cell-related hematologic malig-nancies.They function by blocking B cell signaling,thereby affecting the development and proliferation of B cell-related tumors.Research has revealed that Bruton's tyrosine kinase(BTK)is also expressed in other cells,including mast cells,dendritic cells,granulocytes,platelets,and macrophages.Furthermore,BTK's downstream signaling pathways,such as the activation of phospholipase C gamma 2(PLCγ2),Fc re-ceptor signaling path ways,and Toll-like receptor signaling pathways,are associated with various diseases.These mechanisms provide a the-oretical foundation for using BTK in treating diseases other than B cell-related tumors.This article reviews the progress in the application of BTK for non-B-cell malignancies.

Background and purpose:Relapsed or refractory diffuse large B-cell lymphoma(DLBCL)can be treated with chimeric antigen receptor T-cell(CAR-T)therapy.Imaging-based biomarkers may help identify patients likely to achieve clinical response to this immunotherapy.In this study,an 18-f1uoro-2-deoxy-D-glucose positron emission tomography-computed tomography(18F-FDG PET/CT)based model was developed to assess the progression-free survival(PFS)and overall survival(OS)of patients with relapsed or refractory(R/R)DLBCL who received CAR-T therapy.Methods:We retrospectively analyzed clinical and imaging data from patients with DLBCL who underwent CAR-T therapy at the First Affiliated Hospital of Soochow University between March 2017 and January 2022.Inclusion criteria:① age≥18 years old;② pathologically confirmed R/R DLBCL;③ 18F-FDG PET/CT performed before CAR-T cell therapy;④ complete clinicopathologic data;⑤ patients must have measurable lesions.Exclusion criteria:① patients with incomplete clinical or imaging data;② patients with other types of malignant tumors;③ patients who have received granulocyte colony-stimulating factor treatment within 1 month prior to PET/CT scan.This study was reviewed by the Ethics Committee of the First Affiliated Hospital of Soochow University(ID:2025256).Receiver operating characteristic(ROC)curves were used to determine the optimal thresholds for maximum standardized uptake value(SUVmax),tumor metabolic volume(MTV),and total glycolysis(TLG),and the patients were classified into high-risk and low-risk groups.Univariate and multivariate Cox regression analyses were used to identify potential prognostic factors and construct predictive models,which were visualized by drawing nomogram.Area under the ROC curve was used to assess the performance of each model.Results:A total of 61 patients(37 male patients and 24 female patients,aged 26-75 years)with DLBCL who underwent 18F-FDG PET/CT prior to CAR-T infusion were included.The median follow-up was 14 months;36 patients(59.02%)had disease progression and 25 patients(40.98%)died.Multivariate analysis showed that grade of cytokine release syndrome(CRS)[Hazard ratio(HR)=3.671;P=0.003]and MTV(HR=0.171,P=0.004)were independent prognostic factors for OS;Eastern Cooperative Oncology Group(ECOG)score(HR=2.411,P=0.019),grade of CRS(HR=2.499;P=0.027),and MTV(HR=0.338,P=0.007)were independent prognostic factors for PFS.The combined model(MTV,ECOG score,grade of CRS)was better than the clinical model(ECOG score,grade of CRS),and metabolic parameter model(MTV)in predicting PFS and OS.Conclusion:18F-FDG PET/CT metabolic parameter MTV in combination with traditional clinical risk factors(ECOG score,Grade of CRS)could identify patients with ultra-high risk of DLBCL.

Objective:To investigate the value of radiomics signatures based on 18F-FDG PET/CT for predicting molecular classification and Ki-67 expression of breast cancer. Methods:A total of 134 female patients ((55.4±13.3) years) who underwent 18F-FDG PET/CT examination and were diagnosed with breast cancer by pathology in the First Affiliated Hospital of Soochow University from April 2016 to May 2023 were retrospectively enrolled. LIFEx software was used to extract radiomics features and the least absolute shrinkage and selection operator (LASSO) algorithm and independent-sample t test were used to screen potentially meaningful features and calculate the radiomics score, which were considered as radiomics models. Clinical characteristics were selected by supervised logistic regression and clinical models were established. Radiomics features and clinical characteristics were incorporated to logistic regression analysis to establish combined models. ROC curves were drawn and the differences among AUCs were analyzed by Delong test. Results:Among 134 patients, 22 were with triple negative breast cancer (TNBC), 47 were human epidermal growth factor receptor 2 (HER2) over-expression type, 37 were Luminal A type and the rest 28 were Luminal B type. The expression of Ki-67 was high in 85 patients, and was low in the rest 49 patients. The AUCs (95% CI) of the combined models for predicting TNBC, HER2 overexpression type, Luminal A type and Ki-67 expression were 0.843(0.770-0.900), 0.808(0.723-0.876), 0.825(0.711-0.908) and 0.836(0.762-0.894), respectively, which were higher than those of clinical models ( z values: 1.97-3.06, all P<0.05). Conclusion:The predictive model combining radiomics signatures based on 18F-FDG PET/CT and clinical characteristics can well predict the molecular classification and Ki-67 expression level of breast cancer.

Dysregulated Epiregulin(EREG)can activate epidermal growth factor receptor(EGFR)and promote tumor progression in head and neck squamous cell carcinoma(HNSCC).However,the mechanisms underlying EREG dysregulation remain largely unknown.Here,we showed that dysregulated EREG was highly associated with enhanced PDL1 in HNSCC tissues.Treatment of HNSCC cells with EREG resulted in upregulated PDL1 via the c-myc pathway.Of note,we found that N-glycosylation of EREG was essential for its stability,membrane location,biological function,and upregulation of its downstream target PDL1 in HNSCC.EREG was glycosylated at N47 via STT3B glycosyltransferases,whereas mutations at N47 site abrogated N-glycosylation and destabilized EREG.Consistently,knockdown of STT3B suppressed glycosylated EREG and inhibited PDL1 in HNSCC cells.Moreover,treatment of HNSCC cells with NGI-1,an inhibitor of STT3B,blocked STT3B-mediated glycosylation of EREG,leading to its degradation and suppression of PDL1.Finally,combination of NGI-1 treatment with anti-PDLl therapy synergistically enhanced the efficacy of immunotherapy of HNSCC in vivo.Taken together,STT3B-mediated N-glycosylation is essential for stabilization of EREG,which mediates PDL1 upregulation and immune evasion in HNSCC.

Dysregulated Epiregulin(EREG)can activate epidermal growth factor receptor(EGFR)and promote tumor progression in head and neck squamous cell carcinoma(HNSCC).However,the mechanisms underlying EREG dysregulation remain largely unknown.Here,we showed that dysregulated EREG was highly associated with enhanced PDL1 in HNSCC tissues.Treatment of HNSCC cells with EREG resulted in upregulated PDL1 via the c-myc pathway.Of note,we found that N-glycosylation of EREG was essential for its stability,membrane location,biological function,and upregulation of its downstream target PDL1 in HNSCC.EREG was glycosylated at N47 via STT3B glycosyltransferases,whereas mutations at N47 site abrogated N-glycosylation and destabilized EREG.Consistently,knockdown of STT3B suppressed glycosylated EREG and inhibited PDL1 in HNSCC cells.Moreover,treatment of HNSCC cells with NGI-1,an inhibitor of STT3B,blocked STT3B-mediated glycosylation of EREG,leading to its degradation and suppression of PDL1.Finally,combination of NGI-1 treatment with anti-PDLl therapy synergistically enhanced the efficacy of immunotherapy of HNSCC in vivo.Taken together,STT3B-mediated N-glycosylation is essential for stabilization of EREG,which mediates PDL1 upregulation and immune evasion in HNSCC.

Objective To investigate the relationship between the expression of ITGAV and the radiosensitivity of NSCLC cells. Methods The expression of ITGAV in NSCLC and its relationship to the prognosis of patients who received radiotherapy were analyzed using bioinformatics methods. Differences in radiosensitivity between radio-resistant cells and parent cells were verified by clone formation experiment, and the protein expression of ITGAV was detected by Western blot. The transfection efficiency of si-ITGAV was determined by Western blot and qRT-PCR analyses. The best ITGAV interference sequence was selected to transfect A549R and H1299R cells. Clone formation experiment and flow cytometry were used to detect clone formation, apoptosis and cell cycle of A549R and H1299R cells. Results The expression of ITGAV in NSCLC tissues was significantly higher than that in normal tissues (P<0.05), and NSCLC patients with high ITGAV expression had poor prognosis. The clonogenic ability of the si-ITGAV group was significantly lower than that of the negative control group at 4, 6, 8Gy irradiation (all P<0.05). After 6 Gy irradiation, the apoptosis of the si-ITGAV group was increased (P_H1299R<0.0001, P_A549R=0.0002), the proportion of G₂/M phase cells to A549-siITGAV and H1299R-siITGAV cells was higher than that in the negative control group (P_H1299R<0.0001, P_A549R=0.0007). Conclusion Interfering with ITGAV expression can increase the radiosensitivity of NSCLC.

OBJECTIVE: The purpose of this study was to prospectively investigate the value of the myocardial extracellular volume fraction (ECV) in predicting myocardial functional outcome after revascularization of coronary chronic total occlusion (CTO). MATERIALS AND METHODS: Thirty patients with CTO underwent cardiovascular magnetic resonance (CMR) before and 6 months after revascularization. Three baseline markers of functional outcome were evaluated in the dysfunctional segments assigned to the CTO vessels: ECV, transmural extent of infarction (TEI), and unenhanced rim thickness (RIM). At the global level, the ECV values of the whole myocardium with and without a hyperenhanced region (global and remote ECV) were respectively measured. RESULTS: In per-segment analysis, ECV was superior to TEI and RIM in predicting functional recovery (area under receiver operating characteristic curve [AUC]: 0.86 vs. 0.75 and 0.73, all p values < 0.010), and it emerged as the only independent predictor of regional functional outcome (odds ratio [OR] = 0.83, 95% confidence interval [CI]: 0.77–0.89; p < 0.001) independent of collateral circulation. In per-patient analysis, global baseline ECV was indicative of ejection fraction (EF) at the follow-up examination (β = −0.61, p < 0.001) and changes in EF (β = −0.57, p = 0.001) in multivariate regression analysis. A patient with global baseline ECV less than 30.0% (AUC, 0.93; sensitivity 94%, specificity 80%) was more likely to demonstrate significant EF improvement (OR: 0.38; 95% CI: 0.17–0.85; p = 0.019). CONCLUSION: Extracellular volume fraction obtained by CMR may provide incremental value for the prediction of functional recovery both at the segmental and global levels in CTO patients, and may facilitate the identification of patients who can benefit from revascularization.
Collateral Circulation ; Coronary Vessels* ; Follow-Up Studies ; Humans ; Infarction ; Magnetic Resonance Imaging* ; Myocardial Infarction ; Myocardial Ischemia ; Myocardium ; Prospective Studies ; ROC Curve ; Sensitivity and Specificity

Objective To explore the effects of graphene oxide (GO)-polyethylene glycol (PEG)-folic acid (FA)-pyrenemethylamine hydrochloride (PyNH2)-mediated RNA interference (RNAi) of hypoxia-inducible factor-1α (HIF-1α) on the biological behaviors of human pancreatic cancer Patu8988 cells.Methods GO-PEG-FA-PyNH2 and RNAi targeting HIF-1α gene (GO-PEG-FA-PyNH2-HIF-1α-RNAi)was constructed.The expressions of HIF-1α and glucose transporter 1 (Glut-l) in Patu8988 cells were determined after knockdown of HIF-1α by RNAi.The invasive ability,the proliferation and the cell cycle of Patu8988 cells were investigated.The effect of HIF-1α knockdown on the uptake of 18F-fluorodeoxyglucose (FDG) in Patu8988 cells was also detected.Comparison of data was conducted by one-way analysis of variance and least significant difference t test.Results The GO-PEG-FA-PyNH2 was successfully constructed,and no cytotoxicity was found.Under the hypoxia or normoxia state,the mRNA and protein levels of HIF-1α and mRNA level of Glut-1 in cells transfected with GO-PEG-FA-PyNH2-HIF-1α-RNAi (study group) were lower than those in cells transfected with GO-PEG-FA-PyNH2 (negative group) and cells transfected with Opti-minimal essential medium (Opti-MEM,control group;F=30.25-32.58,t=3.66-5.81,all P＜0.05);the numbers of migrated cells in the study group were much lower than those in the negative group and the control group (F=38.63 and 41.35,t=20.51-35.25,all P＜0.01);the cell proliferation in the study group was significantly lower than that in the negative group and the control group (F=35.19 and 38.11,t =15.11-22.19,all P＜0.05).The proportions of G0/G1 cells in the study group were higher than those in the negative group and the control group (F=34.60 and 34.83,t=11.55-34.56,all P＜0.05);the 18 F-FDG uptake in the study group was lower than that in the negative group and control group (F=29.85 and 31.69,t =3.35-4.35,all P＜0.05).Conclusion GO-PEG-FA-PyNH2-mediated HIF-1α RNAi inhibits the expression of HIF-1α in pancreatic cancer cells,leading to changes in related biological behaviors.