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

Image 1.

Hepatocellular carcinoma (HCC) expresses abundant glycolytic enzymes and displays comprehensive glucose metabolism reprogramming. Aldolase A (ALDOA) plays a prominent role in glycolysis; however, little is known about its role in HCC development. In the present study, we aim to explore how ALDOA is involved in HCC proliferation. HCC proliferation was markedly suppressed both in vitro and in vivo following ALDOA knockout, which is consistent with ALDOA overexpression encouraging HCC proliferation. Mechanistically, ALDOA knockout partially limits the glycolytic flux in HCC cells. Meanwhile, ALDOA translocated to nuclei and directly interacted with c-Jun to facilitate its Thr93 phosphorylation by P21-activated protein kinase; ALDOA knockout markedly diminished c-Jun Thr93 phosphorylation and then dampened c-Jun transcription function. A crucial site Y364 mutation in ALDOA disrupted its interaction with c-Jun, and Y364S ALDOA expression failed to rescue cell proliferation in ALDOA deletion cells. In HCC patients, the expression level of ALDOA was correlated with the phosphorylation level of c-Jun (Thr93) and poor prognosis. Remarkably, hepatic ALDOA was significantly upregulated in the promotion and progression stages of diethylnitrosamine-induced HCC models, and the knockdown of A ldoa strikingly decreased HCC development in vivo. Our study demonstrated that ALDOA is a vital driver for HCC development by activating c-Jun-mediated oncogene transcription, opening additional avenues for anti-cancer therapies.

Objective To search,evaluate and integrate the best evidence of wound procedural pain management in patients with chronic wounds,and to provide evidence-based references for clinical practice.Methods Following the"6S"evidence model,we systematically searched relevant literature of wound procedural pain management in patients with chronic wounds,including clinical practice guidelines,clinical decisions,expert consensuses,evidence summaries,recommended practice and systematic reviews,with the search period from the datebase establishment to December 2022.The quality evaluation,extraction and integration for evidence were conducted independently by 2 researchers,respectively.Results A total of 17 articles were involved,including 2 guidelines,1 expert consensus,3 clinical decisions,6 evidence summaries,2 recommended practice,3 systematic reviews.34 pieces of best evidence were synthesized into 9 categories,including general principles,pain assessment and documentation,replacement and selection of the wound dressing,wound cleaning,wound debridement,negative pressure wound therapy,drug intervention strategies,non-drug intervention strategies,education and training.Conclusion The best evidence of wound procedural pain management in patients with chronic wounds in this study is scientific and practical.Medical staff can select and apply the best evidence based on clinical situation and patient willingness to reduce wound procedural pain.

Objective To explore the relationship between the use of proton pump inhibitors(PPIs)and the short-term and long-term prognosis of patients with acute exacerbation of chronic obstructive pulmonary disease(AECOPD).Methods Clinical data of AECOPD patients admitted to the intensive care unit(ICU)from January 2008 to December 2019 were extracted from the MIMIC-Ⅳ database.Patients were divided into PPIs group and non PPIs group based on whether PPIs were used during ICU treatment.Compare the general conditions of two groups of patients and plot survival curves using Kaplan-Meier method to compare the differences in survival rates between the two groups at 28 d and 90 d,respectively.Cox proportional hazards regression was used to analyze the association between PPIs usage and 28 d and 90 d mortality risk in two groups of patients.Results A total of 447 patients were included,including 358 in the PPIs group and 89 in the non PPIs group.The 28 d mortality rate and 90 d mortality rate of the PPIs group were 15.64％and 23.46％,respectively,which were lower than those of the non PPIs group(31.46％and 40.45％,respectively)(P＜0.05).The Kaplan-Meier curve analysis showed that the 28 d and 90 d survival rates of the PPIs group were higher than those in the non PPIs group(P＜0.001).The Cox proportional hazards regression analysis showed that after adjusting for all included variables,the hazard ratio(HR)for 28 d and 90 d mortality in the PPIs group were 0.58(95％CI 0.35 to 0.94,P=0.030),0.63(95％CI 0.41 to 0.96,P=0.022),respectively,compared to the non PPIs group.Conclusion In AECOPD patients,the use of PPIs may be reduce the 28 d and 90 d mortality risks.

Objective:To investigate the effect of myopia on retinal vascular geometry in young subjects.Methods:A retrospective cross-sectional study. From June 2018 to December 2018, 235 participants (235 eyes) who took part in routine physical examination in Huadong Sanatorium were included. There were 94 males and 141 females; age was (34.89±6.15) years old; equivalent spherical refraction (SE) was (-3.78±3.25) D. 59 (25.11%, 59/235) were divided into high myopia group (SE≤-6.0 D), along with 131 (55.74%, 131/235) low to moderate myopia group (-0.5 D> SE>-6.0 D), and 45 (19.15%, 45/235) emmetropia group (0.5 D≥SE≥-0.5 D). Retinal vascular geometric measurements, including central retinal arteriolar equivalent (CRAE), central retinal venular equivalent (CRVE), fractal dimension arteriole (FDa), fractal dimension venule (FDv), curvature tortuosity arteriole (CTORTa), curvature tortuosity venule, branch angle arteriole (BAa), branch angle venule, branch coefficient arteriole and branching coefficient venule, were extracted by using a validated computer program. One-way analysis of variance and analysis of covariance were performed to compare the measurements across the high myopia, low to moderate myopia, and emmetropia groups. Linear regression analysis was used to explore the relationship between SE and retinal vascular geometric parameters.Results:The differences in CRAE ( F=65.11), CRVE ( F=61.52), FDa (F=14.26), FDv ( F=8.31), CTORTa ( F=5.07) and BAa (F=6.51) among eys of high myopia group, low to moderate myopia group and emmetropia group remained significant ( P<0.05) after adjusting for age, glycosylated hemoglobin, mean arterial pressure, body mass index, and intraocular pressure. CRAE and CRVE were linearly correlated with the SE ( P<0.05). FDa, FDv, cTORTa and BAa decreased with the decrease of SE in high myopia ( P<0.05). Conclusions:Myopia is associated with the change of the retinal vascular geometric characteristics. With the deepening of myopia, the change of retinal vascular geometric characteristics gradually worsens.

Objective:To investigate the etiological mechanism in single small subcortical infarction (SSSI) with different imaging features.Methods:The patients registered in a database of ischemic stroke in the Department of Neurology of the First Affiliated Hospital of Zhengzhou University from January 2016 to December 2019 were analyzed. According to the lowest slice (LS) and the total number of involved slices (TNS) on diffusion-weighted imaging, the SSSI was divided into 3 types: proximal SSSI (pSSSI; LS≤2), distal and large SSSI (dl-SSSI; LS>2, TNS>2) and distal and small SSSI (ds-SSSI; LS>2, TNS≤2). The clinical and imaging features among 3 different lesion patterns were compared by using χ 2 test, Kruskal-Wallis H test and multiple Logistic regression analysis, etc. Results:In the 3 groups of ds-SSSI ( n=205), dl-SSSI ( n=157) and pSSSI ( n=166), the prevalences of parent artery disease (PAD)[10.7% (22/205) , 19.1% (30/157) , 42.8% (71/166), respectively, χ 2=54.89, P<0.001], coronary artery disease [8.3% (17/205), 14.0% (22/157), 16.9%(28/166), respectively, χ 2=6.44, P=0.040] and severe white matter hyperintensities (sWMHs)[58.0% (119/205), 43.3% (68/157), 41.0% (68/166), respectively, χ 2=12.94, P<0.001], the level of serum homocysteine (Hcy)[18.01 (13.54, 25.56), 16.03 (12.50, 21.09), 14.72 (11.12, 19.14) μmol/L, respectively, H=19.36, P<0.001], and the National Institutes of Health Stroke Scale (NIHSS) score[2(1, 3), 3(1, 4), 3(2, 6), respectively, H=39.53, P<0.001] showed statistically significant differences. Multiple Logistic regression analysis showed that compared with dl-SSSI patients, the lesion pattern of patients with higher proportion of PAD ( OR=3.12, 95% CI 1.86-5.24, P<0.001) was closer to pSSSI; the lesion pattern of patients with higher serum Hcy level ( OR=1.02, 95% CI 1.00-1.04, P=0.046) or higher proportion of sWMHs ( OR=1.79, 95% CI 1.12-2.86, P=0.015) was closer to ds-SSSI, and the lesion pattern of patients with higher proportion of PAD ( OR=0.50, 95% CI 0.27-0.93, P=0.029) or higher NIHSS score ( OR=0.84, 95% CI 0.77-0.92, P<0.001) was closer to dl-SSSI. Conclusions:The pathogenesis of ds-SSSI tends to be cerebral small vessel disease. The pathogenesis of pSSSI is related to atherosclerosis. The patients with dl-SSSI have the intermediate characteristics of pSSSI and ds-SSSI and may be unstable.

Objective: To describe the current status of the prevalence of co-morbid myopia and obesity among 7-18 years students in the Inner Mongolia Autonomous Region in 2021 and to analyze the moderating effect of lifestyle in this association ，so as to provide scientific basis for the establishment of the mechanism of Co-morbidity，Shared Etiology，and Shared Prevention of common diseases in children and adolescents. Methods: A total of 139 630 primary and secondary school students aged 7-18 years from Inner Mongolia Autonomous Region were selected by stratified random cluster sampling method in September,2021. Myopia was determined using distance visual acuity examination and refractive error examination, and obesity was determined according to the BMI classification criteria for overweight, obesity screening of Chinese school age children and adolescents. Used a questionnaire, healthy lifestyles were determined according to the American Heart Association s Healthy Lifestyle Score by totaling the six scores for smoking, alcohol consumption, diet, exercise, screen time, and sleep duration.The χ 2 test was used to compare the association between group differences in the co-morbidity rate of myopia and obesity. The multivariable Logistic regression model was used to explore the influencing factors of the co-morbidity of myopia and obesity, and the stratified analysis was used to analyze the moderating effect of lifestyles on the prevalence of the co-morbidity. Results: The prevalence of myopia and obesity co-morbidity among students aged 7-18 years old in the Inner Mongolia Autonmous Region in 2021 was 13.7%, higher among boys than girls ( 15.5 % vs. 11.8%), higher among those aged 10-12 years old than 7-9,13-15,and 16-18 years old (14.7%,13.7%, 13.3%, 12.0%), higher among other ethnic minorities than Han Chinese and Mongolians (15.3%, 14.0%, 12.5%), higher in urban areas than that in suburban areas(15.3%, 13.0%), and middle economic level tracts were higher than poor and good tracts (14.8%, 12.9 %, 12.6%) ( χ 2=392.37，115.73，62.80，119.02，121.60, P <0.05). Multivariable Logistic regression modeling showed that unhealthy lifestyles ( OR=1.24, 95%CI=1.19-1.29 ) and middle level of lifestyle score ( OR=1.15, 95%CI=1.10-1.19 ) students had higher prevalence of co-morbidity, and the results were statistically significant among both boys and girls, the age groups of 10- 12, 13-15, and 16-18 years old, as well as the Han and Mongolian ethnic groups (all P <0.05). Conclusion In 2021, the current situation of myopia and obesity co-morbidity and unhealthy lifestyles among primary and secondary school students in the Inner Mongolia Autonomous Region are not optimistic.

Objective: To analyze the prevalence of overweight, obesity and depression among students in the Inner Mongolia Autonomous Region in 2019-2022 and explore the relevant factors affecting the co-morbidity of overweight,obesity and depression among students, so as to provide scientific basis for the prevention of co-morbidity. Methods: From September 2019 to 2022, used stratified random cluster sampling, 90 519,71 560,90 079,91 089 students were selected from all 12 leagues in Inner Mongolia Autonomous Region for questionnaire survey and physical examination. The χ 2 test was used for demographic characteristics and univariate analysis, and a binary Logistic regression model was used to explore the association between lifestyle behaviors and co-morbidity. Results: The detection rate of overweight,obesity among students from 2019-2022 was 29.21%,34.38%,35.20%,34.61%, the detection rate of depression was 18.35%，17.53%，16.43%，16.00%, and the co-morbidity detection rate of the two was 5.52%，5.93%，5.76%，5.46%. The number of overweight,obesity and depression co-morbidity students in 2022 was 4 978 students, and the co-morbidity detection rates of the students were significantly different in terms of the school segments and the family structures ( χ 2=103.51, 99.90, P <0.01). Multivariate Logistic regression analysis showed that consuming sugar sweetened beverages or fried food ≥1 time/d, sometimes or never eat breakfast, watching computer or TV ≥2 h/d, and less than 1 h of moderate-to-vigorous physical activity on weekends were positively correlated with the occurrence of the co-morbidity of overweight,obesity and depression, with the value of OR ranging from 1.17 to 1.59 ( P <0.05). Eated fresh fruits or drinking milk and soy milk ≥1 time/d, outdoor activities ≥1 h/d, sleep ≥8 h/d, not smoking and not drinking alcohol were negatively correlated with the occurrence of comorbid overweight,obesity and depression, with the value of OR ranging from 0.47 to 0.92 ( P < 0.05). Conclusion The occurrence of overweight,obesity and depressive symptoms co-morbidity in students is associated with dietary, exercise and lifestyle behavior. Targeted measures should be taken to maintain students healthy weight and prevent the occurrence of depression from the aspects of diet, exercise and life habits.

OBJECTIVE: To explore the prenatal ultrasonographic features and genetic basis for an abortus suspected for type II Cornelia de Lange syndrome (CdLS2). METHODS: A fetus diagnosed with CdLS2 at the Shengjing Hospital Affiliated to China Medical University on September 3, 2019 was selected as the study subject. Clinical data of the fetus and family history was collected. Following induced labor, whole exome sequencing was carried out on the abortus. Candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: Prenatal ultrasonography (33 weeks of pregnancy) has revealed multiple anomalies in the fetus, which included slightly widened cavity of septum pellucidum, blurred corpus callosum, slightly reduced frontal lobe volume, thin cortex, fusion of lateral ventricles, polyhydramnios, small stomach bubble, and digestive tract atresia. Whole exome sequencing has revealed a heterozygous c.2076delA (p.Lys692Asnfs*27) frameshifting variant in the SMC1A gene, which was found in neither parent and was rated as pathogenic based on the guidelines of American College of Medical Genetics and Genomics (ACMG). CONCLUSION The CdLS2 in this fetus may be attributed to the c.2076delA variant of the SMC1A gene. Above finding has provided a basis for genetic counseling and assessment of reproductive risk for this family.
Pregnancy ; Female ; Humans ; Cell Cycle Proteins/genetics* ; De Lange Syndrome/diagnosis* ; Phenotype ; Ultrasonography, Prenatal ; Fetus/diagnostic imaging* ; Mutation