Chemotherapy remains a primary treatment option for hepatocellular carcinoma (HCC), yet its clinical benefits are often unsatisfactory. Utilizing arsenic trioxide (ATO) as a model, this study elucidates the role of autophagy inhibition in modulating the cellular response to chemotherapy, shifting cell death from apoptosis to pyroptosis via the caspase-3-GSDME pathway, thereby augmenting the anti-tumor efficacy. Building upon these findings, an ATO nanomedicine delivery system capable of autophagy inhibition to promote pyroptosis for enhanced tumor treatment was developed. Folic acid-modified albumin served as the stabilizer for nano self-assemblies formed through ion pairing between Mn²⁺ and ATO, encapsulating DNAzyme (Dz) targeting Beclin 1, a key autophagy regulator. Characterization studies confirmed efficient encapsulation of ATO and Dz within nanoparticles, designed to disintegrate in the intracellular microenvironment, releasing the all-active components, i.e., ATO, Mn²⁺, and Dz. Mn²⁺ acted as a metal cofactor to activate Dz for Beclin 1 mRNA cleavage, inhibiting autophagy and augmenting ATO-induced cell pyroptosis. Elevated cell pyroptosis levels not only enhance ATO's direct tumor cell killing capacity but also trigger anti-tumor immune responses, synergistically enhancing efficacy. Upon intravenous injection, the nanomedicine accumulated in tumor tissue and targeted liver cancer cells. Compared to free ATO, the nanomedicine exhibited significantly improved in vivo anti-tumor effects, achieving a 100% 45-day survival rate in mice with favorable biosafety profiles. This study offers novel insights into tumor chemotherapy sensitization and presents a promising strategy for ATO nanoformulation development.

Objective:To investigate the expressions of cystathionine-β-synthase(CBS)and cystathionine-γ-lyase(CSE)and their effects on the malignant biological behaviours of breast cancer cells,and to elucidate their mechanisms.Methods:The breast cancer tissue and paracancerous normal tissue from 15 cases of patients were selected,and RT-qPCR and Western blotting methods were used to detect the mRNA and protein expression levels of CBS and CSE in breast cancer tissue,paracancerous normal tissue,MCF-7 cells,and MDA-MB-231 cells.The MCF-7 cells were divided into siNC group(transfected with siNC)and siCBS group(transfected with siCBS),and the MDA-MB-231 cells were divided into ovNC group(transfected with CSE over-expression empty plasmid)and ovCSE group(transfected with CSE over-expression plasmid).CCK8 assay was used to detect the proliferation activities of breast cancer cells in various groups,Transwell assay was used to detect the numbers of migration and invasion cells in various groups,and Western blotting method was used to detect the protein expression levels of E-cadherin,N-cadherin and Vimentin proteins in the breast cancer cells in various groups.Results:Compared with paracancerous normal tissue,the expression levels of CBS and CSE mRNA and proteins in breast cancer tissue were increased(P＜0.05 or P＜0.01).Compared with MDA-MB-231 cells,the CBS mRNA expression level in the MCF-7 cells was increased(P＜0.05);compared with MCF-7 cells,the expression level of CSE protein in the MDA-MB-231 cells was decreased(P＜0.05).Compared with siNC group,the proliferation activity,the numbers of migration and invasion cells,the expression levels of N-cadherin and Vimentin proteins in the MCF-7 cells in siCBS group were significantly decreased(P＜0.05),and the expression level of E-cadherin protein was increased(P＜0.05).Compared with ovNC group,the proliferation activity,the numbers of migratoin and invasion cells,and the expression levels of N-cadherin and Vimentin proteins in the MDA-MB-231 cells in ovCSE group were increased(P＜0.05),while the expression level of E-cadherin protein was significantly decreased(P＜0.05).Conclusion:The expressions of CBS and CSE are upregulated in breast cancer tissue,and high levels of CBS and CSE promote proliferation,migration,invasion and epithelial-mesenchymal transition(EMT)of breast cancer cells.

Objective: To explore the prevalence of elevated blood pressure and overweight/obesity and their comorbidities among Tibetan middle school students in Lhasa, and to analyze their association with lifestyle and other factors, so as to provide a basis for the intervention measures targeting elevated blood pressure, overweight and obesity among middle school students in high altitude area. Methods: Using a stratified cluster random sampling method in September 2021, a total of 1 488 Tibetan junior and high students from Lhasa City were investigated with blood pressure measurement, physical examination and questionnaire survey. The influencing factors of elevated blood pressure, overweight and obesity and their comorbidities association were analyzed by multivariate Logistic regression. Results: The prevalence of elevated blood pressure, overweight/obesity and their comorbidities were 17.8%, 17.4% , 5.0% respectively. Multivariate Logistic regression analysis showed that age( OR =0.81), residence, body mass inex(BMI) and gender were the influencing factors of elevated blood pressure; and the risks of elevated blood pressure in female students were higher than male students ( OR =1.89), suburban students were higher than urban students ( OR =8.06), overweight and obesity groups were higher than normal groups ( OR =2.55, 2.87) ( P <0.05). Adjusting for confounding factors such as gender, residence and school, and BMI (only for elevated blood pressure), daily screen time ≥2 h was positively correlated with elevated blood pressure, overweight/obesity and its comorbidities ( OR =1.56, 1.59 , 2.51) ( P <0.05). Conclusions The prevalence of elevated blood pressure, overweight/obesity are relatively high in Lhasa. Longer screen time is a common factor affecting with elevated blood pressure, overweight/obesity and comorbidities among Tibetan students. Measures should be taken intervene in the lifestyle of Tibetan students, in order to reduce elevated blood pressure and overweight/obesity.

Objective:To investigate the clinical effect of combining medial plantar flap with medial foot flap for repairing weight-bearing area defects of the foot.Methods:A retrospective case series study was used to analyze the clinical data of 12 patients with weight-bearing area defects of the foot, who were admitted to the Affiliated Hospital of Zunyi Medical University from March 2020 to March 2022. There were 9 males and 3 females, with the age of 27-62 years [(39.3±8.7)years]. There were 4 patients with palm defects and 8 with heel defects. The defect area ranged from 10 cm×8 cm to 13 cm×12 cm. The cutting area of skin flap ranged from 11 cm×8 cm to 14 cm×13 cm. A total of 5 patients were treated with free flaps (4 patients with palm and 1 with heel defects) and 7 with pedicled flaps (all with heel defects). The flap donor areas were repaired with skin grafting. The flap survival was observed after surgery. At the last follow-up, the appearance, texture, and two point discrimination of the flap were recorded; the foot function was evaluated by Maryland foot function score; the sensory function of the reconstructed skin flap was evaluated by testing the two-point discrimination using a bipedal gauge.Results:The patients were followed up for 6-24 months [(11.8±5.3)months], and all the flaps survived. At the last follow-up, the flaps were free of any swelling and ulceration, with good texture and no sliding. The Maryland foot function score was (92.8±7.2)points at the last follow-up, which was significantly higher than the preoperative (36.6±6.1)points ( P<0.01), being excellent in 9 patients and good in 3. The two-point discrimination of the reconstructed flap was (17.8±5.7)mm at the last follow-up, and there was no significant difference compared with the contralateral (16.3±5.1)mm ( P>0.05). The sensation of the flap returned to normal. There were residual scars in the flap donor area after skin grafting, but no significant impact on foot movement. Conclusion:The medial plantar flap combined with medial foot flap has a large cutting area and good texture, meets the functional requirements, and achieves good postoperative sense recovery, making it a good choice for the repair of weight-bearing area defects of the foot.

This study aimed to explore key quality control factors that affected the prognosis of intensive care unit (ICU) patients in Chinese mainland over six years (2015-2020). The data for this study were from 31 provincial and municipal hospitals (3425 hospital ICUs) and included 2 110 685 ICU patients, for a total of 27 607 376 ICU hospitalization days. We found that 15 initially established quality control indicators were good predictors of patient prognosis, including percentage of ICU patients out of all inpatients (%), percentage of ICU bed occupancy of total inpatient bed occupancy (%), percentage of all ICU inpatients with an APACHE II score ⩾15 (%), three-hour (surviving sepsis campaign) SSC bundle compliance (%), six-hour SSC bundle compliance (%), rate of microbe detection before antibiotics (%), percentage of drug deep venous thrombosis (DVT) prophylaxis (%), percentage of unplanned endotracheal extubations (%), percentage of patients reintubated within 48 hours (%), unplanned transfers to the ICU (%), 48-h ICU readmission rate (%), ventilator associated pneumonia (VAP) (per 1000 ventilator days), catheter related blood stream infection (CRBSI) (per 1000 catheter days), catheter-associated urinary tract infections (CAUTI) (per 1000 catheter days), in-hospital mortality (%). When exploratory factor analysis was applied, the 15 indicators were divided into 6 core elements that varied in weight regarding quality evaluation: nosocomial infection management (21.35%), compliance with the Surviving Sepsis Campaign guidelines (17.97%), ICU resources (17.46%), airway management (15.53%), prevention of deep-vein thrombosis (14.07%), and severity of patient condition (13.61%). Based on the different weights of the core elements associated with the 15 indicators, we developed an integrated quality scoring system defined as F score=21.35%xnosocomial infection management + 17.97%xcompliance with SSC guidelines + 17.46%×ICU resources + 15.53%×airway management + 14.07%×DVT prevention + 13.61%×severity of patient condition. This evidence-based quality scoring system will help in assessing the key elements of quality management and establish a foundation for further optimization of the quality control indicator system.
Humans ; China/epidemiology* ; Cross Infection/epidemiology* ; Intensive Care Units/statistics & numerical data* ; Quality Control ; Quality Indicators, Health Care/statistics & numerical data* ; Sepsis/therapy* ; East Asian People/statistics & numerical data*

Objective To explore the protective effect of polypeptide Apelin on podocyte mitochondria in diabetic nephropathy and underling mechanisms.Methods Human renal podocytes were divided into four experimental groups:control group,high glucose(HG)group(glucose 25 mmol/L,48 h),Apelin intervention HG group(Ape-lin-13 1 μmol/L,48 h)and Apelin group(Apelin-13 1 μmol/L,48 h).The podocyte apoptosis was observed by TUNEL staining,the expression of mitochondrial membrane protein FUNDC1 was detected by Western blot,and the binding of mitochondrial fission protein DRP1 to FUNDC1 was examined by immunoprecipitation.The 8-week-old male mice were divided into three experimental groups:control group,diabetes group(intraperito-neal injection of streptozotocin 150 mg/kg,only one time)and Apelin intervention DM group(intraperitoneal injection of Apelin-13 0.3 μmol/kg,daily).The morphology of renal was observed by PAS staining and trans-mission electron microscopy.Plasma creatinine(Cr),urea nitrogen,urinary albumin and creatinine were de-tected by ELISA kit.The level of creatinine clearance rate(Ccr)and urinary albumin/creatinine(ACR)was calculated.Results Compared with the control group,the podocyte apoptosis and expression of FUNDC1 in the HG group increased significantly(P＜0.05),and the combination of mitochondrial fission division protein DRP1 to FUNDC1 raised.Meanwhile,compared with the HG group,the number of apoptosis,the expression of FUNDC1(P＜0.05),and the combination of DRP1 to FUNDC1 all reduced in Apelin intervention HG group.Animal experiments showed that the kidney structure of the control group was intact.In the DM group,the num-ber of podocytes decreased significantly,the foot processes were fused and dropped off.In the Apelin intervention DM group,podocyte lesions were less severe than those in the DM group.Compared with the control group,the level of plasma Cr,BUN and urine ACR in the DM group increased,while the level of Ccr decreased significantly(P＜0.05).However,compared with the DM group,the level of above biomarkers in the Apelin intervention DM group was improved(P＜0.05).Conclusions Apelin keeps mitochondrial homeostasis and reduces podocyte ap-optosis by inhibiting the expression of mitochondrial membrane protein FUNDC1,which may contribute to allevia-tion of diabetic nephropathy.

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is poorly controlled. Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression, and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment. Therefore, this study developed a novel and selective inhibitor of CSF1R and VEGFR, SYHA1813, possessing potent antitumor activity against GBM. SYHA1813 inhibited VEGFR and CSF1R kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo. SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models, including temozolomide (TMZ) insensitive tumors. Notably, SYHA1813 could penetrate the blood-brain barrier (BBB) and prolong the survival time of mice bearing intracranial GBM xenografts. Moreover, SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody. As a clinical proof of concept, SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial. The data of this study support the rationale for an ongoing phase I clinical study (ChiCTR2100045380).

Nano-drug delivery strategies have been highlighted in cancer treatment, and much effort has been made in the optimization of bioavailability, biocompatibility, pharmacokinetics profiles, and in vivo distributions of anticancer nano-drug delivery systems. However, problems still exist in the delicate balance between improved anticancer efficacy and reduced toxicity to normal tissues, and opportunities arise along with the development of smart stimuli-responsive delivery strategies. By on-demand responsiveness towards exogenous or endogenous stimulus, these smart delivery systems hold promise for advanced tumor-specificity as well as controllable release behavior in a spatial-temporal manner. Meanwhile, the blossom of nanotechnology, material sciences, and biomedical sciences has shed light on the diverse modern drug delivery systems with smart characteristics, versatile functions, and modification possibilities. This review summarizes the current progress in various strategies for smart drug delivery systems against malignancies and introduces the representative endogenous and exogenous stimuli-responsive smart delivery systems. It may provide references for researchers in the fields of drug delivery, biomaterials, and nanotechnology.

Objective:To investigate the effect of S-phase kinase-associated protein 2 (SKP2) expression level on radiosensitivity of human hepatocellular carcinoma (HCC) cells and the correlation of SKP2 expression with clinical prognosis of patients with HCC.Methods:The expression levels of SKP2 gene in liver cancer tissues and normal tissues were validated and its correlation with clinical prognosis of HCC patients was analyzed based on the TCGA database. Western blot was used to determine the SKP2 protein levels in HCC cell lines before and after radiation. CRISPR/Cas9 technology was employed to delete the promoter and first exon of SKP2 gene in PLC/PRF/5 (PLC) and Hep3B HCC cells for generating the SKP2 knockout cell lines. The difference of radiosensitivity and cell survival rate between normal (SKP2 +/ +) and SKP2 knockout (SKP2 -/ -) HCC cells was determined by using cell clonogenic assay and CCK8 kit. Results:Compared with normal tissues, the expression levels of SKP2 gene in HCC were increased based on the results of TCGA database analysis. K-M analysis showed that the HCC patients with high SKP2 expression had relatively poor prognosis. The 5-year overall survival (OS) was 34.6% in high SKP2 expression HCC patients and 50.6% in low SKP2 expression HCC patients, respectively ( HR=2.18, 95% CI=1.46-3.27, P<0.001). In vitro experiment showed that the expression levels of SKP2 were significantly increased after radiation in HCC cells. Simultaneously, deletion of SKP2 significantly increased the radiosensitivity of HCC cells. Conclusion:The expression level of SKP2 gene is increased in HCC patients, and patients with high SKP2 expression have worse prognosis than those with low expression. Radiation can upregulate the SKP2 expression levels in HCC cells, while the radiosensitivity of the cells is significantly increased after SKP2 deletion.

Objective:To analyze characteristics and trends of histopathological diagnosis of adult renal biopsy in Beijing from 2008 to 2020.Methods:A total of 4 652 cases of adult renal biopsy were collected from three hospitals in Beijing between 2008 and 2020. The patients were divided into three age groups: 18-40 years, 40-65 years and≥ 65 years; and also divided into three period: 2008-2011, 2012-2015, and 2016-2020. The pathological characteristics and changes of renal biopsy were analyzed in three age groups at different periods.Results:Among 4 652 cases primary glomerular disease accounted for 81.8%, the membranous nephropathy (MN, 32.4%, 1 509/4 652), IgA nephropathy (IgAN, 29.2%, 1 356/4 652) and minor glomerular abnormalities (MGA, 11.3%, 526/4 652) were the top three pathological types. The overall proportion of MN and diabetic nephropathy (DN) increased from 20.3% and 2.3% in 2008-2011 to 37.3% and 10.1% in 2016-2020) (χ2=99.9 and 96.1, both P<0.01), respectively. For age group 18-40 years, the MN and DN increased from 11.2% and 1.6% in 2008-2011 to 24.7% and 5.5% in 2016-2020 (χ2=32.7 and 20.7, both P<0.01), respectively. For age group 40-65 years the MN and DN increased from 26.6% and 3.2% in 2008-2011 to 41.5% and 13.1% in 2016-2020 (χ2=39.1 and 57.3, both P<0.01), respectively. For age group≥65 years the MN was the most common pathological type in the three periods, fluctuating between 41.3% and 55.0% (χ2=5.2, P=0.08); and DN increased from 0(0/63) in 2008-2011 to 7.5%(22/292) in 2016-2020 (χ2=8.1, P=0.02). Conclusion:The renal biopsy data show that membranous nephropathy and diabetic nephropathy are the most common primary and secondary adult glomerular diseases in Beijing recently.