Chimeric antigen receptor T (CAR-T) cells have reshaped the treatment landscape of hematological malignancies, offering a potentially curative option for patients. Despite these major milestones in the field of immuno-oncology, growing experience with CAR-T cells has also highlighted several limitations of this strategy. The production process of CAR-T cells is complex, time-consuming, and costly, thus leading to poor drug accessibility. The potential carcinogenic risk of viral transfection systems remains a matter of controversy. Treatment-related side effects, such as cytokine release syndrome, can be life-threatening. And the biggest challenge is the inadequate efficacy related to poor infiltration and retention of CAR-T cells in tumor tissues and impaired T cell activation caused by the immunosuppressive tumor microenvironment (TME). Innovative strategies are urgently needed to address these problems, and nanomedicine offers good solutions to these challenges. In this review, we provide a comprehensive summary of recent advancements in the application of nanomaterials to enhance CAR-T cell therapy. We examine the role of innovative nanoparticle-based delivery systems in the production of CAR-T cells, with a particular focus on polymeric delivery systems and lipid nanoparticles (LNPs). Furthermore, we explore various strategies for delivering immune stimulators, which significantly enhance the efficacy of CAR-T cells by modulating T cell viability and functionality or by reprogramming the immunosuppressive TME. In addition, we discuss several novel therapeutic approaches aimed at mitigating the adverse effects associated with CAR-T therapies. Finally, we offer an integrated perspective on the future challenges and opportunities facing CAR-T therapies.
Humans ; Nanomedicine/methods* ; Receptors, Chimeric Antigen/metabolism* ; Immunotherapy, Adoptive/methods* ; T-Lymphocytes/immunology* ; Nanoparticles/chemistry* ; Animals

Objective To observe the effects of acupuncture at"Jiaji"on angiogenesis in rats with lumbar muscle aging based on AMPK/SIRT1/PGC-1α signaling pathway;To explore its possible mechanism of improving lumbar muscle aging atrophy.Methods Totally 30 SPF male SD rats were randomly divided into model group,acupuncture group and non-acupoint group,with 10 rats in each group.Subcutaneous injection of D-galactose(300 mg/kg)into the neck and back of rats was used to prepare a subacute lumbar muscle aging rat model.Another 10 rats were selected as the blank group,and an equal amount of normal saline was subcutaneously injected into the neck and back.Intervention began in the 9th week of modeling.The acupuncture group received acupuncture at bilateral L3-L5"Jiaji",while the non-acupoint group received bilateral non-meridian and non-acupoint acupuncture,each time for 30 minutes,once a day,6 times a week,for 4 consecutive weeks.β-galactosidase staining was used to observe the morphology of rat lumbar muscle tissue;TUNEL staining was used to detect apoptosis of lumbar muscle tissue cells;ELISA was used to detect the contents of nitric oxide(NO)and endothelin-1(ET-1)in lumbar muscle tissue;immunofluorescence staining was used to detect CD31 expression and microvascular density in lumbar muscle tissue;Western blot was used to detect protein expressions of p-AMP activated protein kinase(AMPK),silencing information regulatory factor 1(SIRT1)and peroxisome proliferator activated receptor gamma co activator factor 1α(PGC-1α)in lumbar muscle tissue.Results Compared with the blank group,the positive cells of β-galactosidase staining in lumbar muscle tissue of the model group increased significantly,the apoptosis rate significantly increased(P<0.001),the NO content in lumbar muscle tissue significantly decreased(P<0.001),the ET-1 content significantly increased(P<0.001),the expression of CD31 and microvascular density significantly decreased(P<0.001),and the protein expressions of p-AMPK,SIRT1 and PGC-1α significantly decreased(P<0.01,P<0.001).Compared with the model group,the positive cells of β-galactosidase staining in lumbar muscle tissue of rats in the acupuncture group was significantly reduced,the apoptosis rate was significantly decreased(P<0.001),NO content significantly increased(P<0.001),ET-1 content was significantly reduced(P<0.01),CD31 expression and microvascular density significantly increased(P<0.01,P<0.001),and the protein expressions of p-AMPK,SIRT1,PGC-1α significantly increased(P<0.05,P<0.01).Conclusion Acupuncture at"Jiaji"can promote angiogenesis in lumbar skeletal muscle,and then improve the aging atrophy of lumbar muscle,and its mechanism may be related to the activation of AMPK/SIRT1/PGC-1α signaling pathway.

Recent rapid developments in molecular biological techniques have allowed the use of gene editing,as a means of genome modification,for the establishment of experimental animal models,with high efficiency,accuracy,and flexibility.This article mainly summarizes the construction and application of the latest gene-editing techniques in animal models,including pigs,non-human primates and dogs.It provides a theoretical reference for the application and in-depth study of gene-editing techniques in large experimental animals,which may better simulate human diseases,and for further studies of the potential pathogenesis of biomedical and human complex diseases.

Objective To observe the effects of acupuncture at"Jiaji"on angiogenesis in rats with lumbar muscle aging based on AMPK/SIRT1/PGC-1α signaling pathway;To explore its possible mechanism of improving lumbar muscle aging atrophy.Methods Totally 30 SPF male SD rats were randomly divided into model group,acupuncture group and non-acupoint group,with 10 rats in each group.Subcutaneous injection of D-galactose(300 mg/kg)into the neck and back of rats was used to prepare a subacute lumbar muscle aging rat model.Another 10 rats were selected as the blank group,and an equal amount of normal saline was subcutaneously injected into the neck and back.Intervention began in the 9th week of modeling.The acupuncture group received acupuncture at bilateral L3-L5"Jiaji",while the non-acupoint group received bilateral non-meridian and non-acupoint acupuncture,each time for 30 minutes,once a day,6 times a week,for 4 consecutive weeks.β-galactosidase staining was used to observe the morphology of rat lumbar muscle tissue;TUNEL staining was used to detect apoptosis of lumbar muscle tissue cells;ELISA was used to detect the contents of nitric oxide(NO)and endothelin-1(ET-1)in lumbar muscle tissue;immunofluorescence staining was used to detect CD31 expression and microvascular density in lumbar muscle tissue;Western blot was used to detect protein expressions of p-AMP activated protein kinase(AMPK),silencing information regulatory factor 1(SIRT1)and peroxisome proliferator activated receptor gamma co activator factor 1α(PGC-1α)in lumbar muscle tissue.Results Compared with the blank group,the positive cells of β-galactosidase staining in lumbar muscle tissue of the model group increased significantly,the apoptosis rate significantly increased(P<0.001),the NO content in lumbar muscle tissue significantly decreased(P<0.001),the ET-1 content significantly increased(P<0.001),the expression of CD31 and microvascular density significantly decreased(P<0.001),and the protein expressions of p-AMPK,SIRT1 and PGC-1α significantly decreased(P<0.01,P<0.001).Compared with the model group,the positive cells of β-galactosidase staining in lumbar muscle tissue of rats in the acupuncture group was significantly reduced,the apoptosis rate was significantly decreased(P<0.001),NO content significantly increased(P<0.001),ET-1 content was significantly reduced(P<0.01),CD31 expression and microvascular density significantly increased(P<0.01,P<0.001),and the protein expressions of p-AMPK,SIRT1,PGC-1α significantly increased(P<0.05,P<0.01).Conclusion Acupuncture at"Jiaji"can promote angiogenesis in lumbar skeletal muscle,and then improve the aging atrophy of lumbar muscle,and its mechanism may be related to the activation of AMPK/SIRT1/PGC-1α signaling pathway.

Recent rapid developments in molecular biological techniques have allowed the use of gene editing,as a means of genome modification,for the establishment of experimental animal models,with high efficiency,accuracy,and flexibility.This article mainly summarizes the construction and application of the latest gene-editing techniques in animal models,including pigs,non-human primates and dogs.It provides a theoretical reference for the application and in-depth study of gene-editing techniques in large experimental animals,which may better simulate human diseases,and for further studies of the potential pathogenesis of biomedical and human complex diseases.

Objective: To evaluate the image quality of novel dark-blood computed tomography angiography (CTA) imaging combined with deep learning reconstruction (DLR) compared to delayed-phase CTA images with hybrid iterative reconstruction (HIR), to visualize the cervical artery wall in patients with Takayasu arteritis (TAK). Materials and Methods: This prospective study continuously recruited 53 patients with TAK (mean age: 33.8 ± 10.2 years; 49 females) between January and July 2022 who underwent head-neck CTA scans. The arterial- and delayed-phase images were reconstructed using HIR and DLR. Subtracted images of the arterial-phase from the delayed-phase were then added to the original delayed-phase using a denoising filter to generate the final-dark-blood images. Qualitative image quality scores and quantitative parameters were obtained and compared among the three groups of images: Delayed-HIR, Dark-blood-HIR, and Dark-blood-DLR. Results: Compared to Delayed-HIR, Dark-blood-HIR images demonstrated higher qualitative scores in terms of vascular wall visualization and diagnostic confidence index (all P < 0.001). These qualitative scores further improved after applying DLR (Dark-blood-DLR compared to Dark-blood-HIR, all P < 0.001). Dark-blood DLR also showed higher scores for overall image noise than Dark-blood-HIR (P < 0.001). In the quantitative analysis, the contrast-to-noise ratio (CNR) values between the vessel wall and lumen for the bilateral common carotid arteries and brachiocephalic trunk were significantly higher on Darkblood-HIR images than on Delayed-HIR images (all P < 0.05). The CNR values were significantly higher for Dark-blood-DLR than for Dark-blood-HIR in all cervical arteries (all P < 0.001). Conclusion Compared with Delayed-HIR CTA, the dark-blood method combined with DLR improved CTA image quality and enhanced visualization of the cervical artery wall in patients with TAK.

Objectives:To finely divide the aortic sinus into sections and accurately localize the coronary ostium through CARTO three-dimensional mapping,and to assess the clinical effects of treating aortic sinus cusps premature ventricular contraction(ASC-PVC)and the ablation risk in the corresponding area with zero X-ray radiofrequency ablation. Methods:A total of 66 patients who underwent radiofrequency ablation for ASC-PVC from January 2020 to January 2023 were included in this analysis,patients were divided into experimental group(n=34)and conventional group(n=32).In the conventional group,the CARTO 3 system was used to create an aortic sinus model through the conventional method.The earliest stimulating target was identified by using electrical stimulation mapping(ESM).Radiofrequency ablation treatment was performed after the distance between the target and the coronary ostium was precisely measured by coronary angiography through the hollow tube of the ablation catheter or coronary angiography tube.In the experimental group,the CARTO 3 system was used to build a model of the aortic sinus and the coronary ostium and aortic sinus were divided into sections.The earliest stimulating target was identified by ESM.After localizing coronary ostium through the impedance changing pattern on the ablation catheter tips,catheter ablation was performed with zero X-ray.The data regarding the impedance of the ablation catheter in the aortic sinus were collected.The total operative time,the operative time in the aortic sinus,contrast dosage,X-ray exposure time,immediate and short-term success rates of the operation and complication rates were compared between the two groups.Besides,the distribution of successfully ablated targets and their relationship with the risk of ablation were analyzed in both groups. Results:There was no significant statistical difference in the immediate and short-term success rates between the two groups(93.8%vs.94.1%;90.6%vs.88.2%,both P>0.05).The experimental group did not receive contrast agents during the operation,and the total operation time and intra-aortic sinus operation time in the experimental group were significantly shorter than those in the conventional group([58.76±4.94]min vs.[66.91±5.94]min,P<0.001;[43.12±4.49]min vs.[50.31±5.18]min,P<0.001).During the process of moving the ablation catheter from the intra-aortic sinus to the coronary artery opening and into the coronary artery,the impedance suddenly increased,which was significantly different from the impedance in other parts of the intra-aortic sinus(all P<0.001). Conclusions:Radiofrequency ablation of ASC-PVC with zero X-ray can simplify the procedures and shorten the operative time.The steep increase in impedance at the tip of the ablation catheter can be used as a basis for localizing the coronary ostium.Dividing the aortic sinus into sections allows a detailed assessment of the risk for ablation treatment at the targets.

Objective:To provide more options for preoperative localization diagnosis in patients with primary hyperparathyroidism (PHPT), the diagnostic efficacy of parathyroid 4-dimensional computed tomography (4D-CT) in patients with PHPT was evaluated.Methods:This was a single-center retrospective study including 57 patients with surgical proved PHPT. All of the patients underwent 4D-CT, 99Tc m -sestamibi parathyroid imaging (MIBI), and ultrasonography (US) preoperatively. The reference standard for correct localization was based on operation reports and pathology confirmation. The patients were grouped according to the preoperative serum calcium levels, tumor diameter, or ectopic lesions (yes/no), respectively. The sensitivity, specificity, positive predictive value, negative predictive value and area under the curve (AUC) of 4D-CT, MIBI and US, alone or in combination, were analyzed in total and each subgroup patients. Results:Fifty-seven patients (39 women, 18 men; mean age of 56.5 years) were evaluated, including four cases with multi-gland disease and thirteen cases with ectopic parathyroid lesions. In all the patients, similar diagnostic efficacy was found in 4D-CT (AUC: 0.943) and MIBI (AUC: 0.927), both of which were higher than that of US (AUC: 0.847) ( P = 0.01 for 4D-CT vs. US; P = 0.04 for MIBI vs. US). In a subset analysis for ectopic quadrants, the diagnostic efficacy of 4D-CT was significantly higher than that of MIBI ( P = 0.04) or US ( P = 0.01), with the sensitivity of 100%, 69.2%, and 61.5%, and AUC of 0.989, 0.846, and 0.808 for 4D-CT, MIBI and US, respectively. Conclusions:4D-CT has similar diagnostic efficacy for preoperative localization to MIBI in patients with PHPT, and it is superior to MIBI and US in identifying the ectopic parathyroid gland. 4D-CT can be recommended as an alternative preoperative localization method, especially when parathyroid lesions could not be precisely located by US and MIBI.

Objective: To investigate the clinical significance of combined examinations for neutrophil-lymphocyte ratio (NLR), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and fecal occult blood (OB) in the differential diagnosis of Crohn′s disease and irritable bowel syndrome. Methods: A total of 129 patients with Crohn′s disease and 120 patients with irritable bowel syndrome from October 2014 to October 2017 in Changhai Hospital were enrolled in this study. The results of NLR, CRP, ESR and OB were recorded. Logistic regression was used to study the association of the four indicators. The combined impact of the four indicators was explored with multivariable regression. ROC curve was used to compare the diagnostic value of the combined examinations with the four indicators for Crohn′s disease. The diagnosis was performed by substituting the data of individual patient into regression model. Results: The levels of NLR, CRP, ESR and OB in Crohn′s disease group were higher than those in irritable bowel syndrome group (Z=-7.067--4.148, P＜0.01). The area under the curve of combined diagnostic indicator was 0.881, which was higher than that of single NLR, CRP, ESR or OB (0.759, 0.695, 0.652, 0.643) respectively (Z=3.19-5.60, P＜0.01). When the cutoff value was 0.498, the sensitivity was 79.1%, the specificity was 83.3% and the diagnostic accuracy was 81.1%. A patient who was not included within the statistical range of this experimental study was randomly assigned to the model and 0.831 of P value was obtained, which was higher than the cutoff value of 0.498, indicating that the patient suffered from Crohn′s disease with accuracy of 81.1%. Conclusion The logistic regression model established with the combined diagnostic indicators, which was formulated by examinations of NLR, CRP, ESR and OB, exhibited higher diagnostic value than any single indicator in the differential diagnosis of Crohn′s disease and irritable bowel syndrome.

Objective To evaluate the clinical efficacy of portal venous thrombolysis by way of TIPS.Methods The clinical data of 40 patients with portal venous system thrombosis treated by TIPS at our department from May 2012 to May 2018 were retrospectively analyzed.There were 34 cases of via catheterdirected thrombolysis(7 cases by catheter-directed thrombolysis alone and 27 cases by way of TIPS before catheter-directed thrombolysis),and 6 cases via pharmaco mechanical thrombectomy (AngioJet);the postoperative complications of the two methods were followed up.Results The portal vein was opened in all 40 patients,and there were no major complications during the operation.One patient in the catheter-directed thrombolysis group developed acute liver failure after surgery.In the mechanical thrombolysis group,1 patient was discharged after small intestinal necrosis resection and intestinal fistula reconstruction.After 6-24 months of postoperative follow-up,6 patients in the group of thrombolysis suffered from shunt canal stricture.Conclusions It is a safe and minimally invasive method to treat portal venous system thrombosis through TIPS.Mechanical thrombolysis is more direct and rapid than catheter thrombolysis.