With the main pathological features of glomerulosclerosis and interstitial fibrosis， renal fibrosis is a key pathological process causing chronic kidney disease to progress to end-stage disease. As a cellular autophagic process， mitochondrial autophagy plays a crucial role in maintaining mitochondrial mass and functional stability. Mitochondrial dysfunction is considered to be one of the key factors driving the progression of fibrosis. Phosphatase and tension protein homologue （PTEN） induce various signalling pathways such as putative kinase 1/parkin， Nip3-like protein X/Bcl-2 interacting protein 3， and FUN14 structural domain-containing protein 1 to activate mitochondrial autophagy to participate in the regulation of fibrogenic factors， amelioration of oxidative stress， and inhibition of inflammatory response and apoptosis， which in turn effectively slows down the progression of renal fibrosis. Studies have shown that traditional Chinese medicine monomers and compound preparations， including phenolics， terpenoids， ketones， and alkaloids， can regulate mitochondrial autophagy-related signalling pathways and achieve significant clinical efficacy in intervening in the progression of renal fibrosis for the treatment of chronic kidney disease. This paper summarized the mechanism of mitochondrial autophagy and the research progress of traditional Chinese medicine intervention in renal fibrosis to provide new ideas for the study of the mechanism of traditional Chinese medicine in treating renal fibrosis.

With the main pathological features of glomerulosclerosis and interstitial fibrosis， renal fibrosis is a key pathological process causing chronic kidney disease to progress to end-stage disease. As a cellular autophagic process， mitochondrial autophagy plays a crucial role in maintaining mitochondrial mass and functional stability. Mitochondrial dysfunction is considered to be one of the key factors driving the progression of fibrosis. Phosphatase and tension protein homologue （PTEN） induce various signalling pathways such as putative kinase 1/parkin， Nip3-like protein X/Bcl-2 interacting protein 3， and FUN14 structural domain-containing protein 1 to activate mitochondrial autophagy to participate in the regulation of fibrogenic factors， amelioration of oxidative stress， and inhibition of inflammatory response and apoptosis， which in turn effectively slows down the progression of renal fibrosis. Studies have shown that traditional Chinese medicine monomers and compound preparations， including phenolics， terpenoids， ketones， and alkaloids， can regulate mitochondrial autophagy-related signalling pathways and achieve significant clinical efficacy in intervening in the progression of renal fibrosis for the treatment of chronic kidney disease. This paper summarized the mechanism of mitochondrial autophagy and the research progress of traditional Chinese medicine intervention in renal fibrosis to provide new ideas for the study of the mechanism of traditional Chinese medicine in treating renal fibrosis.

Objective To examine the possible factors affecting the attainment of target serum trough concentration of vancomycin in premature newborns for optimization of clinical dosing regimens.Methods The vancomycin trough concentration data were collected retrospectively from preterm newborns who received intravenous infusion of vancomycin from December 2016 to March 2021.According to the Evidence-based Guideline for Therapeutic Drug Monitoring of Vancomycin:2020 Update by the Division of Therapeutic Drug Monitoring,Chinese Pharmacological Society,the patients were assigned to failure(＜5 mg/L)or success(5-15 mg/L)in target attainment,or beyond target group(＞15 mg/L)base on vancomycin trough concentration.Statistical software SPSS was used to analyze differences in clinical characteristics between different groups,and profile various factors that may affect attainment of target serum trough concentration of vancomycin.Results The median(interquartile range)trough concentration of vancomycin was 12.50(7.95-18.05)mg/L in 82 preterm newborns.The target trough concentration of vancomycin was attained in 47 preterm newborns(57.32％),and the corresponding trough concentration of vancomycin was 10.90(7.80-13.30)mg/L.The trough concentration of vancomycin was beyond target in 27 preterm newborns(32.93％).The corresponding median trough concentration of vancomycin was 21.80(18.00-23.80)mg/L.Serum trough concentration of vancomycin failed to achieve the target in only 8 preterm newborns(9.75％).The corresponding median trough concentration was 4.10(2.48-4.60)mg/L.Univariate analysis showed that there were statistically significant differences(P＜0.05)in postmenstrual age and current weight between the patients succeeded in attaining target trough concentration and those who failed to attain the target.Baseline serum creatinine and dosing interval showed statistically significant differences(P＜0.01)between the newborns who attained the target concentration and those with higher trough concentration beyond the target.Multivariate regression analysis showed that baseline serum creatinine(OR=1.063,95％CI 1.024-1.102,P=0.001,cutoff:62 pmol/L)and dosing interval(OR=6.693,95％CI 1.604-27.920,P=0.009)were independent risk factors for excessively high vancomycin trough concentrations.Conclusions The dosing regimens as recommended in the current package insert only enable the attainment of target serum trough concentration of vancomycin in half of the premature newborns.The dosing regimen of vancomycin should be optimized by taking postmenstrual age,current weight,baseline serum creatinine and dosing interval into account.Therapeutic drug monitoring is necessary to ensure safety and effectiveness.

Objective:To evaluate the effect of autologous hematopoietic stem cell transplantation (ASCT) on the treatment of relapsed/refractory multiple myeloma (RRMM) with chimeric antigen receptor T cell (CAR-T) therapy.Methods:A retrospective cohort study. The clinical data of 168 patients with RRMM who underwent CAR-T therapy at the Department of Hematology, Xuzhou Medical University Hospital from 3 January 2020 to 13 September 2022 were analyzed. Patients were classified into a transplantation group (TG; n=47) and non-transplantation group (NTG; n=121) based on whether or not they had undergone ASCT previously. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and the levels of CD3, CD4, CD8, CD19, CD56 and natural killer (NK) cells before CAR-T infusion were analyzed by χ2 test, Kaplan-Meier method and independent sample t-test. Results:Among 168 patients with RRMM, 98 (58.3%) were male. The median age of onset was 57 (range 30-70) years. After CAR-T therapy, the ORR of patients was 89.3% (92/103) in the NTG and 72.9% (27/73) in the TG. The ORR of the NTG was better than that of the TG ( χ2=5.71, P=0.017). After 1 year of CAR-T therapy, the ORR of the NTG was 78.1% (75/96), and that of the TG was 59.4% (19/32). The ORR of the NTG was better than that of the TG ( χ2=4.32, P=0.038). The median OS and PFS in the NTG were significantly longer than those in the TG (OS, 30 vs. 20 months; PFS, 26 vs. 12 months; both P<0.05). The CD4 level before CAR-T infusion in the TG was significantly lower than that in the NTG (25.65±13.56 vs. 32.64±17.21; t=-2.15, P=0.034), and there were no significant differences in the counts of CD3, CD8, CD19, CD56, and NK cells between the TG and NTG (all P>0.05). Conclusion:Among patients suffering from RRMM who received CAR-T therapy, patients who did not receive ASCT had significantly better outcomes than those who had received ASCT previously, which may have been related to the CD4 level before receiving CAR-T therapy.

BACKGROUND: The switch/sucrose nonfermentable chromatin-remodeling (SWI/SNF) complex is a pivotal chromatin remodeling complex, and the genomic alterations (GAs) of the SWI/SNF complex are observed in several cancer types, correlating with multiple biological features of tumor cells. However, their role in liver metastasis of non-small cell lung cancer (NSCLC) remains unclear. Our study aims to investigate the role and potential mechanisms underlying NSCLC liver metastasis induced by the GAs of SWI/SNF complex. METHODS: The GAs of SWI/SNF complex in NSCLC cell lines (H1299, H23 and H460) were identified by whole-exome sequencing (WES). ARID1A knockout H1299 cell was constructed with the CRISPR/Cas9 technology. The mouse model of liver metastasis from NSCLC was established to simulate lung cancer liver metastasis and observe the metastasis rate under different gene mutation conditions. RNA sequencing and Western blot were conducted for differential gene expression analysis. Immunohistochemistry (IHC) analysis was used to assess protein expression levels of SWI/SNF-regulated target molecules in mouse liver metastases. RESULTS: WES analysis revealed intracellular gene mutations. The animal experiments demonstrated a correlation between the GAs of SWI/SNF complex and a higher liver metastasis rate in immunodeficient mice. Transcriptome sequencing and Western blot analysis showed upregulated expression of ALDH1A1 and APOBEC3B in SWI/SNF-mut cells, particularly in ARID1A-deficient H460 and H1299 sgARID1A cells. IHC staining of mouse liver metastases further demonstrated elevated expression of ALDH1A1 in the H460 and H1299 sgARID1A group. CONCLUSIONS This study underscores the critical role of the GAs of SWI/SNF complex, such as ARID1A and SMARCA4, in promoting liver metastasis of lung cancer cells. The GAs of SWI/SNF complex may promote liver-specific metastasis by upregulating ALDH1A1 and APOBEC3B expression, providing novel insights into the molecular mechanisms underlying lung cancer liver metastasis.
Animals ; Mice ; Carcinoma, Non-Small-Cell Lung/genetics* ; Lung Neoplasms/genetics* ; Mutation ; Liver Neoplasms/genetics*

Objective:To explore the expression of long-chain noncoding RNA (lncRNA) and myocardial infarction-associated transcription (MIAT) in Leukocyte differentiation antigen (CD)4+T cells in peripheral blood of gastric cancer patients and its value of clinical application.Methods:Peripheral blood CD4+T cells were collected from 124 patients with gastric cancer, 90 benign gastric diseases patients and 80 healthy controls enrolled in Taizhou People′s Hospital from January 2019 to April 2021. The expression levels of MIAT and N6-methyladenosine(m6A) binding to MIAT promoter in CD4+T cells were detected by real-time fluorescent quantitative polymerase chain reaction (qPCR) and Chromatin immunoprecipitation (ChIP)-qPCR, respectively. Spearman test was used to analyze the correlation between MIAT and clinicopathological features, as well as between MIAT and regulatory T cell levels. The receivor operating characteristic curve (ROC) of the subjects was used to evaluate the MIAT expression level in the auxiliary diagnostic value of gastric cancer.Results:The relative expression levels of MIAT in the gastric cancer patients, the benign gastric diseases patients, and the healthy controls were 2.849 (2.131, 4.062), 1.511 (0.916, 1.855) and 0.963 (0.729, 1.432), respectively. The difference among the three groups was statistically significant ( H=158.25, P<0.001). The relative expression level of MIAT in the gastric cancer patients was significantly higher than the levels in the benign gastric diseases patients and healthy controls. The difference was statistically significant ( Z=100.63, 145.14, P<0.001). The binding activity of m6A to MIAT promoter in patients with early stage (stage Ⅰ and Ⅱ) and end stage (stage Ⅲ and Ⅳ) gastric cancer was 8.590±1.483 and 4.274±0.425, respectively. The difference was statistically significant ( t=6.255, P=0.002). Furthermore, the binding activity of m6A to MIAT promoter in the gastric cancer patients was significantly lower than that in patients with benign gastric diseases (17.267±3.106) and healthy controls (27.637±3.945) ( t=-7.331,-12.832, P<0.001). The relative expression of MIAT in CD4+T cells in peripheral blood of the gastric cancer patients had no significant difference in age(χ2=0.000, P=1.000), gender(χ2=0.000, P=1.000), CEA (χ2=0.648, P=0.421) and CA199(χ2=1.554, P=0.213), but had significant difference with tumor size expression(χ2=9.443, P<0.01), TNM stage(χ2=23.571, P=0.002) and lymph node metastasis (χ2=45.248, P<0.01). In addition, there was a significant positive correlation between the relative expression of MIAT in CD4+T cells and Treg level ( r2=0.76, P<0.001). The diagnostic efficacies of MIAT in CD4+T cells, CEA and CA199 in the gastric cancer patients were analyzed by ROC curve. When compared with patients with benign gastric diseases, the areas under the curve were 0.879, 0.635 and 0.611, respectively. When compared with healthy patients, the areas under the curve were 0.953, 0.784 and 0.598, respectively. Conclusions:The level of MIAT in CD4+T cells in peripheral blood of patients with gastric cancer is significantly higher than the levels in patients with benign gastric diseases and the healthy controls, which may be related with the decreased activity of m6A binding to the promoter of MIAT. The level of MIAT in CD4+T cells may be a relevant biomarker for the diagnosis and prognosis of gastric cancer.

ObjectiveTo explore the mechanism of Gancao Fuzitang （GCFZ）in inhibiting the bone destruction of collagen-induced arthritis （CIA） model in mice. MethodThirty male DBa/1J mice were randomly divided into normal group， CIA group， low-dose GCFZ group （GCFZ-L， 2.4 g·kg^-1）， high-dose GCFZ group （GCFZ-H， 4.8 g·kg^-1）， and methotrexate group （MTX， 1 mg·kg^-1）， with six mice in each group. The CIA model was induced by secondary immunization method. The arthritis index of mice in each group was observed and recorded， and the histopathological changes in ankle joint were observed by hematoxylin-eosin （HE） staining. The damage to ankle cartilage was detected by safranin O-fast green staining. Micro-CT scanning was used to detect the bone destruction of ankle joint， and the expression of nuclear factor-κB p65 （NF-κB p65）， p-NF-κB p65， inhibitory-κB kinase α/β （IKKα/β）， and p-IKKα/β was observed by immunohistochemical staining. ResultCompared with the normal group， the CIA group showed manifest joint swelling and increased arthritis index score （P<0.01）. Compared with the CIA group， the groups with drug intervention could inhibit joint swelling and reduce arthritis index score （P<0.05， P<0.01）. As revealed by HE staining and safranine O-green staining， compared with the CIA group， the groups with drug intervention could inhibit synovial invasion and reduce the destruction of articular cartilage. Micro-CT scanning analysis showed that compared with the CIA group， the GCFZ-H group and the MTX group showed reduced bone destruction scores （P<0.01）. The immunohistochemical results showed that compared with the normal group， the CIA group showed increased optical density values of NF-κB p65， p-NF-κB p65， IKKα/β， and p-IKKα/β（P<0.01）. Compared with the CIA group， the GCFZ-H group and the MTX group showed reduced optical density values of NF-κB p65， p-NF-κB p65， IKKα/β， and p-IKKα/β（P<0.05，P<0.01）. In the GCFZ-L group， only the NF-κB p65 optical density value decreased（P<0.01）. ConclusionGCFZ may inhibit bone destruction in CIA mice by regulating the NF-κB signaling pathway.

Hand, foot and mouth disease (HFMD) is an acute infectious disease induced by enterovirus. More than 30 pathogenic viruses for hand, foot and mouth disease have been discovered, of which enterovirus 71 (EV-A71) and Coxsackievirus A16 (CV-A16) are the most common. Enterovirus 71 (EV-A71) is also the main cause of severe hand, foot and mouth disease. In recent years, it has been discovered that Coxsackievirus A6 (CV-A6) infection has broken out in many regions of the world, and the pathogenicity rate is increasing, which indicatesthat it may rise to become a new major pathogenic agent of hand, foot and mouth disease. Hand, foot and mouth disease has become a global public health problem. Therefore, research on the pathogenic mechanism of multiple enteroviruses that induce hand, foot and mouth disease and analysis of its epidemiology will become the top priority of prevention, control and treatment of the disease.

Objective:To explore the clinical application and long-term safety of hydroxychloroquine sulfate (HCQ) in the treatment of rheumatic diseases.Methods:A multi-center cross-sectional study was conducted between August 2017 and August 2018 in a random sample of eleven medical institutions of rheumatology and immunology in China. Patients who took HCQ for more than 3 months were enrolled into this study. The cumulative dose and long-term side effects of HCQ were recorded. The changes of laboratory indexes before and after treatment with HCQ were analyzed. Categorical variables were presented with counts and proportions, and evaluated by Chi-square test. Continuous parametric data were presented as Mean±standard deviation, and evaluated by Student's t test or Mann-Whitney U test. P-values less than 0.05 were considered statistically significant. Results:A total of 886 patients with rheumatic diseases were enrolled into this study, including 505 cases with systemic lupus erythematosus (57.0%), 210 cases with rheumatoid arthritis (23.7%), 80 cases with Sj?gren's syndrome (9.0%), 57 cases with undifferentiated connective tissue disease (6.4%), 12 cases of systemic vasculitis (1.4%), 10 cases of mixed connective tissue disease (1.1%), 7 cases of myositis (0.8%) and 5 cases with systemic sclerosis (0.6%). The most common long-term side effects of HCQ was skin or mucous lesions (12.4%) and vision problems (8.0%). Other adverse reactions included problems of digestive system (3.0%), nervous system (2.1%), musculoskeletal system (1.1%) and cardiovascular system (0.9%). 140 cases (15.8%) had stopped taking HCQ during the treatment. More than half of them decided to stop taking medicine by themselves. Fifty-four patients (6.1%) stopped using HCQ due to side effects while 24 of them took it again, and another 12 patients (1.4%) stopped the drug due to remission of illness. Patients were divided into three groups according to the cumulative dose of HCQ: less than 500 g, 500-1 000 g and more than 1 000 g respectively. There was significant difference in the incidence of long-term side effects among the three groups ( χ2=6.382, P=0.041). The last group (more than 1 000 g) suffered the highest incidence of long-term adverse reactions (37.1%). No severe adverse drug reactions were observed in this study. Conclusion:Hydroxychloroquine is widely used in the treatment of rheumatic diseases. The incidence of long-term side effects is 20.4%, is 6.1% lead to drug withdrawal, which are especially related to the cumulative doses. It should be adjusted properly according to the clinical application.

Objective To evaluate whether arm equilibrium pressure (Parm) is helpful to predict the effect of fluid load in improving oliguria in intensive care unit(ICU) patients.Methods Hemodynamically stable patients [mean artery pressure (MAP)＞65 mmHg (1 mmHg=0.133 kPa),heart rate (HR)＜120 beats/min,lactic acid＜2 mmol/L] with urine output (UO)＜0.5 ml· kg-1· h-1 for 3 consecutive hours were enrolled.The fluid loading was performed by infusion of ringer's lactate 500 ml within 30 minute after baseline hemodynamic data were recorded.The positive renal response was defined as UO increased more than 0.5 ml· kg-1 · h-1 1 hour after fluid challenge,otherwise was negative.Results A total of 30 oliguric ICU patients were enrolled including 17 males and 13 females with median age (54.2±16.3) years.After fluid load,patients' HR decreased[(84± 13)beat/min vs.(80± 10) beat/min,P＜0.01],central venous pressure (CVP) increased[(7.0±2.4)mmHg vs.(8.8±2.6) mmHg,P＜0.01],30s Parm [(33.4±5.3) mmHg vs.(35.4±5.8) mmHg,P＜0.01] and 60s Parm [(26.9±4.5) mmHg vs.(28.7±5.0) mmHg,P＜0.01] increased,and UO [(18.5±8.8)ml/h vs.(64.1±38.3)ml/h,P＜0.01] increased significantly,while MAP and lactic acid did not change (P＞0.05).There were eighteen renal responders and 12 patients did not response.In responding group,MAP[(78.1 ±10.7) mmHg vs.(91.2±11.7) mmHg,P＜0.01],30s Parm[(30.4±3.8) mmHg vs.(38.0±3.7) mmHg,P＜0.01]and 60s Parm [(24.3±2.5) mmHg vs.(30.8±4.0) mmHg,P＜0.01] before fluid load were lower than those in negative group.HR,CVP,lactic acid,age and body weight were comparable between two groups (P＞0.05).After volume loading,MAP,30s and 60s Parrn in positive group were still lower than those in negative group (P＜0.05),while HR,CVP and lactic acid were similar (P＞0.05).Correlation analysis showed that baseline 30s Parm (r=-0.75,P＜0.01),60s Parm (r=-0.69,P＜0.01),and MAP (r=-0.46,P＜0.05) were negatively correlated with 1 h UO after fluid load,but HR and CVP were not (P＞0.05).The receiver operating curve (ROC) showed that 30s Parm had the largest area under curve (AUC) of 0.94 (95％ CI 0.84-1.05,P＜0.01),which 35.5 mmHg was the best threshold with sensitivity 94.4％ and specificity 91.7％(likelihood ratio 11.37).Conclusion In hemodynamically stable oliguric ICU patients,if Parm is lower than normal reference value,volume expansion is more likely to increase UO.Thus Parm can be used to predict the effect of fluid loadon UO.