Objective:To analyze the efficacy and safety of a fully biodegradable occluder for the treatment of ventricular septal defects through percutaneous and transthoracic strategies.Methods:A case series study was conducted.The clinical data of 38 pediatric patients with a ventricular septal defect treated with a fully biodegradable occluder at Central China Fuwai Hospital from January 2023 to July 2024 were retrospectively analyzed.Among these patients, 15 received the percutaneous approach(percutaneous approach group) and the other 23 adopted the transthoracic approach(transthoracic approach group).The diagnosis was confirmed by transthoracic echocardiography before operation in all patients.The percutaneous approach was defined as establishing a venous-arterial track through X-ray and then placing an occluder under the guidance of transthoracic echocardiograph.The transthoracic approach was achieved by establishing a delivery track with a special hollow bougie through a small right subaxillary incision under the real-time guidance of esophageal ultrasound and then delivery and put an occluder.The clinical data of the patients, including general characteristics, electrocardiograms, echocardiograms and the biodegradable occluder system were collected and analyzed.Categorical variables were tested using the chi-square or Fisher′s exact test.Continuous variables were verified using the t-test or Mann-Whitney U test. Results:The patients were aged (5.7±3.9) years on average, with an average weight of 19.5(14.9, 25.9) kg.There were 39.5%(15 cases) of males among the patients included.The average size of the ventricular septal defect was 4.1(4.0, 5.0) mm.A simple perimembrane ventricular septal defect was detected in 29 patients (76.3%), concomitant membranous aneurysm in 4 patients (10.5%), an intracristal ventricular septal defect in 3 patients (7.9%), and a muscular ventricular septal defect in 2 patients (5.3%).Preoperative aortic and tricuspid valve regurgitations accounted for 5.3%(2/38) and 81.6%(31/38), respectively.The average age was (9.0±3.9) years in the percutaneous approach group and (3.6±1.9) years in the transthoracic approach group.In terms of the cardiac structure, the percutaneous approach group had smaller Z values of the left atrial anterior-to-posterior diameter (-0.5±0.6 vs.0.5±1.0, P<0.01) and the left ventricular end-diastolic diameter (-0.5±1.1 vs.0.8±0.8, P<0.01), and a smaller ventricular septal defect [4.0(3.9, 4.2) mm vs.4.5(4.0, 5.5) mm, P=0.01] than the transthoracic approach group.Regarding the operation, the percutaneous approach group had a larger difference between the waist diameter of the selected occluder and the diameter of the ventricular septal defect [2.8(2.0, 3.0) mm vs.2.0(1.5, 2.5) mm, P=0.02], shorter operative time [(61.5±27.3) minutes vs.(91.5±31.4) minutes, P=0.01], and a shorter hospital stay [8(5, 9) days vs.12(9, 15) days, P<0.01] than the transthoracic approach group.Both groups achieved immediate occlusion postoperatively, with no residual shunts and no grade Ⅲ atrioventricular conduction block.Five new cases of bundle branch blocks and 1 case of trivial aortic valve regurgitation occurred in the transthoracic approach group. Conclusions:Both percutaneous and transthoracic approaches are safe and effective in interventional closure of ventricular septal defects, but the former is more applicable to slightly older or heavier patients with a smaller ventricular septal defect, who need a larger occluder.

Objective:To analyze the efficacy and safety of a fully biodegradable occluder for the treatment of ventricular septal defects through percutaneous and transthoracic strategies.Methods:A case series study was conducted.The clinical data of 38 pediatric patients with a ventricular septal defect treated with a fully biodegradable occluder at Central China Fuwai Hospital from January 2023 to July 2024 were retrospectively analyzed.Among these patients, 15 received the percutaneous approach(percutaneous approach group) and the other 23 adopted the transthoracic approach(transthoracic approach group).The diagnosis was confirmed by transthoracic echocardiography before operation in all patients.The percutaneous approach was defined as establishing a venous-arterial track through X-ray and then placing an occluder under the guidance of transthoracic echocardiograph.The transthoracic approach was achieved by establishing a delivery track with a special hollow bougie through a small right subaxillary incision under the real-time guidance of esophageal ultrasound and then delivery and put an occluder.The clinical data of the patients, including general characteristics, electrocardiograms, echocardiograms and the biodegradable occluder system were collected and analyzed.Categorical variables were tested using the chi-square or Fisher′s exact test.Continuous variables were verified using the t-test or Mann-Whitney U test. Results:The patients were aged (5.7±3.9) years on average, with an average weight of 19.5(14.9, 25.9) kg.There were 39.5%(15 cases) of males among the patients included.The average size of the ventricular septal defect was 4.1(4.0, 5.0) mm.A simple perimembrane ventricular septal defect was detected in 29 patients (76.3%), concomitant membranous aneurysm in 4 patients (10.5%), an intracristal ventricular septal defect in 3 patients (7.9%), and a muscular ventricular septal defect in 2 patients (5.3%).Preoperative aortic and tricuspid valve regurgitations accounted for 5.3%(2/38) and 81.6%(31/38), respectively.The average age was (9.0±3.9) years in the percutaneous approach group and (3.6±1.9) years in the transthoracic approach group.In terms of the cardiac structure, the percutaneous approach group had smaller Z values of the left atrial anterior-to-posterior diameter (-0.5±0.6 vs.0.5±1.0, P<0.01) and the left ventricular end-diastolic diameter (-0.5±1.1 vs.0.8±0.8, P<0.01), and a smaller ventricular septal defect [4.0(3.9, 4.2) mm vs.4.5(4.0, 5.5) mm, P=0.01] than the transthoracic approach group.Regarding the operation, the percutaneous approach group had a larger difference between the waist diameter of the selected occluder and the diameter of the ventricular septal defect [2.8(2.0, 3.0) mm vs.2.0(1.5, 2.5) mm, P=0.02], shorter operative time [(61.5±27.3) minutes vs.(91.5±31.4) minutes, P=0.01], and a shorter hospital stay [8(5, 9) days vs.12(9, 15) days, P<0.01] than the transthoracic approach group.Both groups achieved immediate occlusion postoperatively, with no residual shunts and no grade Ⅲ atrioventricular conduction block.Five new cases of bundle branch blocks and 1 case of trivial aortic valve regurgitation occurred in the transthoracic approach group. Conclusions:Both percutaneous and transthoracic approaches are safe and effective in interventional closure of ventricular septal defects, but the former is more applicable to slightly older or heavier patients with a smaller ventricular septal defect, who need a larger occluder.

Objective:To prepare a 177Lu labeled human epidermal growth factor receptor 2 (HER2) affibody 177Lu-1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid (NOTA)-maleimide (Mal)-cysteine (Cys)-ZHER 2: 342 ( 177Lu-NOTA-MZHER2 for short), and investigate its labeling process and anti-tumor properties. Methods:Two kinds of buffer systems (sodium acetate buffer system and sodium ascorbate buffer system) were investigated. The effects of pH value, precursor mass and reaction temperature on 177Lu labeling NOTA-MZHER2 were compared to obtain optimal labeling conditions. The radiochemical purity of labeled product was determined by instant thin-layer chromatography (ITLC), and its stabilities in PBS and plasma were observed. Human ovarian cancer cell line SKOV-3 was selected for cell internalization and cytotoxicity test to evaluate cell uptake and killing effect of 177Lu-NOTA-MZHER2. SKOV-3 tumor-bearing mice( n=3) were injected with 177Lu-NOTA-MZHER2, and microSPECT/CT imaging was performed. Another 40 tumor-bearing mice were divided into 22.2 MBq group (tail vein injection with probe of 22.2 MBq), control group (tail vein injection with PBS), low-dose group (tumor injection with probe of 3.7 MBq) and high-dose group (tumor injection with probe of 7.4 MBq). Tumor volume and mass of tumor-bearing mice were monitored after injection, and the anti-tumor effect and toxicity of probe were evaluated. Repeated measurement analysis of variance (Bonferroni method) was used to analyze the data. Results:The optimal labeling condition was 70-80 ℃ for 30 min in the system of sodium acetate buffer solution with pH=4 and precursor mass of 50 μg. Under these conditions, the labeling rate of 177Lu-NOTA-MZHER2 was (99.3±0.4)% and radiochemical purity was >99%. After 12 d in PBS and plasma, the radiochemical purities were (95.0±1.5)% and (95.0±2.1)%. Results of cell experiment showed that the internalization of 177Lu-NOTA-MZHER2 accounted for (29.02±3.50)% of the total uptake, and the survival rate of SKOV-3 cells was (48±6)% with the probe concerntration of 6×10 -3 Bq/L. SPECT imaging showed that 177Lu-NOTA-MZHER2 was still concentrated at the tumor site 96 h after injection with a dose of 18.5 MBq. Relative tumor volume (RTV) of tumor-bearing mice in 22.2 MBq group, high-dose group and low-dose group was significantly different from that in control group ( F=21.75, P<0.001). Twenty days after injection, RTV and relative body mass of the tumor-bearing mice in high-dose group were (140±7)% and (80±9)%, respectively. Compared with control group, high-dose group had obvious anti-tumor effect (both P<0.001). Conclusion:177Lu-NOTA-MZHER2 is successfully prepared, which is simple and efficient, and the probe has good anti-tumor effect.

Objective:To radiolabel hyperbranched polymer (HG)-modified liquid metal nanodroplet (LMND)@HG with 177Lu, and explore the radiotherapy sensitization effect on anti-breast cancer therapy. Methods:The ultrasonication method was used to prepare LMND@HG, and then 177LuCl 3 was mixed with LMND@HG to label 177Lu by alloying reactions. The labeling rate, plasma stability and cytotoxicity of 177Lu-LMND@HG were detected. Xenograft mouse model of breast cancer was constructed, and the tumor inhibition test was performed by an intratumoral injection. The tumor progression was monitored by in vivo imaging system. The mechanism of tumor inhibition was verified by immunohistochemistry and immunofluorescence assays. One-way analysis of variance, repeated measures analysis of variance, and the least significant difference t test were used to analyze the data. Results:177Lu was successfully labeled to LMND@HG with a high labeling efficiency >95%. The product did not require further purification and the plasma radiochemical purity was still higher than 95% after 5 d. The cytotoxicity test showed that a dose of 888 kBq (40 mg/L) 177Lu-LMND@HG had obvious toxicity to 4T1 cells, which was significantly lower than 177LuCl 3 (cell viabilities: (16.48±7.81)% vs (85.77±8.87)%; F=77.81, t=11.73, P<0.001) and LMND@HG ((46.53±5.75)%; t=6.20, P<0.001). The biological distribution results showed that 177Lu-LMND@HG was mainly distributed in tumor tissue 5 d after intratumoral injection. The results of the tumor inhibition experiment showed that 1.48 MBq 177Lu-LMND@HG could significantly inhibit the tumor growth compared with the 177LuCl 3 (tumor volume: (222.66±97.70) vs (789.13±245.04) mm 3;F=18.55, t=4.29, P=0.005). In vivo optical imaging of small animals showed that 1.48 MBq and 3.70 MBq 177Lu-LMND@HG both significantly inhibited the tumor growth. Immunofluorescence and immunohistochemical results showed that 177Lu-LMND@HG caused double-stranded DNA break, and suppressed the tumor growth by inhibiting cell proliferation and angiogenesis. Conclusions:A novel 177Lu-liquid metal-based reactive oxygen species (ROS) radiation sensitizer is successfully prepared in this study. The preparation method is efficient and convenient, and the product has high stability. 177Lu-LMND@HG shows an obvious radiotherapy sensitization effect on breast tumor-bearing mice.

Objective:To prepare a novel 68Ga-labeled bicyclic peptide targeting poliovirus receptor related protein 4 (PVRL4, Nectin-4), and evaluate its feasibility for breast cancer imaging via in vitro and in vivo experiments. Methods:A Biotin-modified bicyclic peptide targeting Nectin-4, Biotin-BMIC, was synthesized, and its targeting properties were preliminarily evaluated by in vitro cell staining experiments. BMIC was modified by 1, 4, 7-triazonane-1, 4-diacetic acid (NODA) and the labeling precursor NODA-BMIC was prepared. A potential PET probe targeting Nectin-4, 68Ga-NODA-BMIC was prepared by one-step labeling strategy. The imaging properties of the probe were investigated by in vivo microPET imaging and in vitro experiments in mice bearing breast tumors. Data were analyzed by independent-sample t test and repeated measures analysis of variance. Results:Fluorescence staining of the cells showed that the fluorescently labeled bicyclic peptide, Biotin-BMIC, was highly aggregated in Nectin-4 positive BT474 breast cancer cells compared to those in Nectin-4 negative MDA-MB-231 cells. The uncorrected yield of 68Ga-NODA-BMIC was (71.5±2.2)% and the radiochemical purity was greater than 95%. The specific activity was greater than 3 GBq/μmol. After incubation 10, 30, 60 and 120 min, higher radioactivity uptakes were found in BT474 breast cancer cells compared to those in MDA-MB-231 breast cancer cells respectively ( F=1 302.00, P<0.001). MicroPET imaging showed that the BT474 xenograft tumors were clearly visible with favorable contrast. A significant statistical difference in uptakes between BT474 and MDA-MB-231 xenograft tumor uptake at 10, 30, 60, and 120 min after probe injection respectively was existed ( F=1 826.00, P<0.001). At 60 min postinjection, the uptake value of BT474 tumors was (5.03±0.14) percentage activity of injection dose per gram of tissue (%ID/g), which was significantly higher than that of MDA-MB-231 tumors ((0.19±0.04) %ID/g; t=79.40, P<0.001). Meanwhile, the tumor-to-muscle ratios in the former were also greater than those in the latter ( F=222.00, P<0.001). At 60 min postinjection, the tumor-to-muscle ratio in the former was significantly higher than that in the latter (24.75±3.10 vs 1.30±0.15; t=14.31, P=0.002). The results were consistent with the immunohistochemistry staining. Conclusions:A novel bicyclic peptide PET probe targeting Nectin-4, 68Ga-NODA-BMIC, is easy to be synthesized and owns satisfactory labeling yield and radiological purity. The imaging performance is good and the target tissues could be visualized. It may play a unique role in the diagnosis and treatment of breast cancer.

UNC-51-like kinase 1(ULK1)is an important factor involved in regulating the initiation of autophagy.ULK1 regu-lates inflammatory cytokines through autophagy and mitochondrial oxidative stress,and is involved in the pathological processes of var-ious diseases.ULK1 and its complexes are regulated by rapamycin(mTOR)and AMP-activated protein kinase(AMPK)to initiate au-tophagy,thereby exerting differential effects on a variety of inflammatory diseases.In inflammatory diseases,mitochondrial oxidative stress can induce ULK1 into the nucleus to accelerate apoptosis.Therefore,ULK1 plays different important roles in inflammatory dis-eases.For example,ULK1 initiates airway epithelial mitochondrial autophagy in asthma,participates in mitochondrial oxidative stress in acute liver failure,affects related inflammatory factors in atherosclerosis,and modulates beneficial effects of autophagy in diabetes.This article reviews the biological function of ULK1,its impact on inflammatory diseases and the research progress of targeted drugs.

Pure-tone audiometry can be performed to evaluate the type and degree of hearing loss， whose results can be divided into four types including low-frequency descending， high-frequency descending， flat descending and total deafness. The low-frequency descending type of sudden hearing loss （SHL） is more likely to be spleen deficiency and dampness exuberance， the high-frequency descending type is often due to yin deficiency of liver and kidney， the flat descending type is commonly associated with qi and blood depletion， and the type of total deafness is often linked to blood stasis. Our team has further developed a comprehensive diagnostic and therapeutic approach for SHL， emphasizing "the integration of disease and syndrome， the combination of acupuncture and herbal medicine， and dynamically administering treatment". Firstly， it advocates integrating disease diagnosis with syndrome differentiation. Secondly， it recommends combining acupuncture and herbal medicine， with local acupoints such as Ermen （TE 21）， Tinggong （SI 19）， Tinghui （GB 2）， and Yifeng （TE 17） used to unblock the auditory orifice， and herbal prescriptions tailored to the hearing curve patterns. For the low-frequency descending type， it is recommended to fortify the spleen and percolate dampness by taking distal points of spleen channel and stomach channel and using Shenling Baizhu Powder （参苓白术散）. For the high-frequency descending type， the method of nourishing kidney and calming liver is recommended， using distal points of kidney and liver channels and taking Erlong Zuoci Pills （耳聋左慈丸）. Regarding the flat descending type， tonifying qi and nourishing blood is advised， for which acupoints of Conception Vessel， spleen， stomach and large intestine channels can be needled， and Yiqi Congming Decoction （益气聪明汤） can be administered. For the total deafness type， it is recommended to activate blood and dissipate stasis， often with Xuehai （SP 10） and Geshu （BL 17） needled and Tongqiao Huoxue Decoction （通窍活血汤） administered. All these are conducted to treat the root and branch simultaneously. At the same time， it emphasizes the need to consider complex syndrome presentations and disease progression， dynamically analyze the disease causes and mechanisms， and adjust treatment according to the changing syndromes. In conclusion， this article is expected to inspire clinical diagnosis and treatment of SHL.

Hemophagocytic syndrome (HPS), which is currently named as hemophagocytic lymphohistiocytosis (HLH), is a hyperinflammatory syndrome characterized by persistent fever, hepatosplenomegaly, pancytopenia and hemophagocytosis found in bone marrow, liver, spleen and lymph nodes due to excessive activation of macrophages and cytotoxic T cells. Macrophage activation syndrome (MAS) is a specific form of HLH induced by autoinflammatory/autoimmune disorders which can be life-threatening and requires multiple disciplines. In order to improve clinicians′ understanding of MAS and standardize the clinical diagnosis and treatment practice of MAS, the rheumatology branch of Chinese Rheumatology Association organized domestic experts to formulate the diagnosis and treatment standard, in order to improve the diagnosis and treatment level of MAS and improve the prognosis of patients.

The aim of this study was to investigate the effect of activating transcription factor 3 (ATF3) on the differentiation of intramuscular preadipocytes in goat, and to elucidate its possible action pathway at the molecular level. In this study, the recombinant plasmid of goat pEGFP-N1-ATF3 was constructed, and the intramuscular preadipocytes were transfected with liposomes. The relative expression levels of adipocyte differentiation marker genes were detected by quantitative real-time PCR (qRT-PCR). After transfection of goat intramuscular preadipocytes with the goat pEGFP-N1-ATF3 overexpression vector, it was found that the accumulation of lipid droplets was inhibited, and the adipocyte differentiation markers PPARγ, C/EBPα and SREBP1 were extremely significantly down-regulated (P < 0.01), while C/EBPβ and AP2 were significantly down-regulated (P < 0.05). The ATF3 binding sites were predicted to exist in the promoter regions of PPARγ, C/EBPα and AP2 by the ALGGEN PROMO program. The overexpression of goat ATF3 inhibits the accumulation of lipid droplets in intramuscular preadipocytes, and this effect may be achieved by down-regulating PPARγ, C/EBPα and AP2. These results may facilitate elucidation of the regulatory mechanism of ATF3 in regulating the differentiation of goat intramuscular preadipocytes.
3T3-L1 Cells ; Activating Transcription Factor 3/pharmacology* ; Adipocytes ; Adipogenesis/genetics* ; Animals ; CCAAT-Enhancer-Binding Protein-alpha/pharmacology* ; Cell Differentiation ; Goats ; Mice ; PPAR gamma/metabolism*

AIM: To explore the effect of Huatanjiangqi capsule medicated serum (HTJQ) on the resistance of human bronchial epithelial cells (16HBE) to glucocorticoid (GC) stimulated by cigarette smoke extract (CSE). METHODS: After 16HBE cells were treated with HTJQ, the effects of different concentrations of HTJQ on the viability of 16HBE cells were determined by CCK-8 method. 16HBE cells were pretreated with HTJQ, and then cultured with dexamethasone (DEX) and lipopolysaccharide (LPS) for 24 hours, the effect of HTJQ on glucocorticoid (GC) resistance of 16HBE cells was determined by Enzyme-linked immunosorbent assay (ELISA). The effects of HTJQ, sulforaphane (SFN) and glutathione (GSH) on the expression of NF-E2-related factors 2 (Nrf2), Heme oxygenase-1 (HO-1) and histone deacetylase 2 (HDAC2) in 16HBE cells stimulated by CSE were measured by Western blot, and the effects of HTJQ, SFN and GSH on interleukin-8 (IL-8) in 16HBE cells were measured by ELISA. RESULTS: HTJQ promoted the proliferation of 16HBE cells at 1 h, 2 h and 4 h, the results of ELISA and Western blot showed that CSE induced GC resistance and decreased the expression of Nrf2, HO-1 and HDAC2 in 16HBE cells, HTJQ significantly decreased IL-8 and improved GC sensitivity of 16HBE cells (P<0.01), and up-regulated the expression of Nrf2, HO-1 and HDAC2 (P<0.01). In addition, HTJQ significantly up-regulated the level of GSH in 16HBE cells (P<0.01). Nrf2 agonists SFN and GSH significantly improved the glucocorticoid sensitivity of 16HBE cells (P<0.01), and up-regulated the expression of Nrf2, HO-1 and HDAC2 (P<0.01). CONCLUSION: HTJQ improves the GC resistance of 16HBE cells by up-regulating the expression of Nrf2/HDAC2 protein and the level of intracellular GSH.