Objective To construct a targeted drug delivery system, Ang-BEVs@Dox, based on Angiopep-2 peptide-modified bacterial extracellular vesicles （BEVs） loaded with doxorubicin （Dox）, overcome the challenges of blood-brain barrier （BBB） penetration and systemic toxicity in chemotherapy for glioblastoma （GBM）, enhance drug targeting to brain tumors and reduce its toxic side effects. Methods BEVs derived from Escherichia coli were isolated using ultracentrifugation. The targeting ligand Angiopep-2, specific for the LRP-1 receptor, was conjugated onto the surface of BEVs to construct the targeted carrier （Ang-BEVs）. Dox was loaded into Ang-BEVs using low-frequency sonication to form Ang-BEVs@Dox. The physicochemical properties （morphology and size） of the carriers were characterized by transmission electron microscopy （TEM） and dynamic light scattering （DLS）. The BBB-penetrating capability, in vitro/in vivo anti-tumor efficacy, and biosafety of the system were evaluated using cellular uptake assays, 3D tumor spheroid models, and orthotopic tumor-bearing mouse models. Results ① Carrier characterization and in vitro efficacy: Ang-BEVs@Dox exhibited a particle size of approximately 100 nm and maintained structural stability after Dox loading. It significantly enhanced cellular uptake efficiency in U87MG cells and achieved deep penetration within 3D tumor spheroids. Cytotoxicity assays demonstrated synergistic anti-tumor effects between the BEVs and Dox in the Ang-BEVs@Dox system. ② In vivo targeting and anti-tumor efficacy: In orthotopic tumor-bearing mouse models, Ang-BEVs@Dox effectively penetrated the BBB and significantly inhibited tumor growth, extending the median survival time of tumor-bearing mice to 33.5 days （compared to 23.5 days in the blank control group, P<0.001）. Immunohistochemical analysis revealed significant suppression of the tumor cell proliferation marker Ki-67 and enhancement of the apoptosis marker TUNEL staining signals. ③ Biosafety: Major organs from mice in the Ang-BEVs@Dox treatment group showed no observable pathological damage, indicating good biosafety. Conclusion This study successfully constructed an Angiopep-2 peptide-modified engineered BEVs delivery system （Ang-BEVs@Dox）. Through Angiopep-2-mediated BBB penetration and tumor targeting, it significantly enhanced the accumulation and therapeutic efficacy of BEVs at the GBM site. This method combined efficient delivery, low systemic toxicity, and clinical translation potential, which provided an innovative solution to overcome the therapeutic bottleneck in GBM treatment.

Objective     To explore the efficacy of prone positioning ventilation in patients with acute respiratory distress syndrome (ARDS) after acute Stanford type A aortic dissection (STAAD) surgery. Methods     From November 2019 to September 2021, patients with ARDS who was placed prone position after STAAD surgery in the Xiamen Cardiovascular Hospital of Xiamen University were collected. Data such as the changes of blood gas, respiratory mechanics and hemodynamic indexes before and after prone positioning, complications and prognosis were collected for statistical analysis. Results    A total of 264 STAAD patients had surgical treatment, of whom 40 patients with postoperative ARDS were placed prone position. There were 37 males and 3 females with an average age of 49.88±11.46 years. The oxygen partial pressure, oxygenation index and peripheral blood oxygen saturation 4 hours and 12 hours after the prone positioning, and 2 hours and 6 hours after the end of the prone positioning were significantly improved compared with those before prone positioning ventilation (P<0.05). The oxygenation index 2 hours after the end of prone positioning which was less than 131.42 mm Hg, indicated that the patient might need ventilation two or more times of prone position. Conclusion     Prone position ventilation for patients with moderate to severe ARDS after STAAD surgery is a safe and effective way to improve the oxygenation.

In order to study the effect of antimicrobial drug reduction on the resistance of E.coli and diversity of antibiotic resistance genes(ARGs)and mobile genetic elements(MGEs)in the intes-tinal microbiota of dairy cows in dairy farms in Hebei Province,and to evaluate the implementation effect of antimicrobial drug reduction actions,anal swab samples and fecal samples were collected from three qualified dairy farms and two non-standard dairy farms in different regions of Hebei Province,and E.coli was isolated from the anal swab samples and tested for their resistance to 16 antimicrobial drugs,and the differences in the drug resistance rate of E.coli in the two types of dairy farms were analyzed.SYBR fluorescent dye method was used to detect ARGs and MGEs in dairy feces,their relative abundance was calculated,the differences and correlation between the two types of dairy farms were analyzed.The results showed that a total of 192 ARGs and 7 MGEs were detected in 15 samples,and the relative abundance of ARGs was the highest in β-lactam resistance genes,followed by tetracycline resistance genes.The detection of ARGs and MGEs in some stand-ard dairy farms was lower than that in non-standard farms,suggesting that the large use of antimi-crobial drugs may be related to the production and transmission of ARGs,and the number of MG-Es detected was correlated with the number of ARGs detected,and ARGs may be transmitted through horizontal gene transfer.The results showed that there was little difference in the drug re-sistance rate of E.coli from the two types of dairy farms,and multi-drug resistant strains were more likely to occur in non-standard farms.The implementation of antimicrobial reduction had a certain effect on the diversity of antibiotic resistance genes,but had no significant effect on the prevalence of E.coli drug resistance and the diversity of ARGs in dairy farms in the short term,and there was little difference between different regions,which also revealed the prevalence of anti-biotic resistance in dairy farms.

To explore the role of forkhead box protein O1 (FOXO1) in the progression of glioblastoma multiforme (GBM) and related drug resistance, we deciphered the roles of FOXO1 and miR-506 in proliferation, apoptosis, migration, invasion, autophagy, and temozolomide (TMZ) sensitivity in the U251 cell line using in vitro and in vivo experiments. Cell viability was tested by a cell counting kit-8 (CCK8) kit; migration and invasion were checked by the scratching assay; apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and flow cytometry. The construction of plasmids and dual-luciferase reporter experiment were carried out to find the interaction site between FOXO1 and miR-506. Immunohistochemistry was done to check the protein level in tumors after the in vivo experiment. We found that the FOXO1-miR-506 axis suppresses GBM cell invasion and migration and promotes GBM chemosensitivity to TMZ, which was mediated by autophagy. FOXO1 upregulates miR-506 by binding to its promoter to enhance transcriptional activation. MiR-506 could downregulate E26 transformation-specific 1 (ETS1) expression by targeting its 3'-untranslated region (UTR). Interestingly, ETS1 promoted FOXO1 translocation from the nucleus to the cytosol and further suppressed the FOXO1-miR-506 axis in GBM cells. Consistently, both miR-506 inhibition and ETS1 overexpression could rescue FOXO1 overactivation-mediated TMZ chemosensitivity in mouse models. Our study demonstrated a negative feedback loop of FOXO1/miR-506/ETS1/FOXO1 in GBM in regulating invasiveness and chemosensitivity. Thus, the above axis might be a promising therapeutic target for GBM.
Animals ; Mice ; Brain Neoplasms/genetics* ; Cell Line, Tumor ; Cell Proliferation ; Drug Resistance, Neoplasm ; Feedback ; Gene Expression Regulation, Neoplastic ; Glioblastoma/metabolism* ; MicroRNAs/metabolism* ; Temozolomide/therapeutic use* ; Humans ; Forkhead Box Protein O1/metabolism*

Objective:To explore different strategies of central repair first or malperfusion first to treat type A aortic dissection complicated with limb malperfusion.Methods:From January 2020 to December 2021, 302 patients were diagnosed with acute type A aortic dissection, and 17 consecutive patients were diagnosed as type A acute aortic dissection complicated with limb malperfusion and underwent Sun’s procedure. There were 16 males and 1 female with an average of(52.6±4.2)years. Surgical strategies were as follows: immediate central repair-Sun’s procedure in 14 patients, endovascular stenting followed by central repair in 3 patients, endovascular stenting after central repair in 1 patient.Results:The incidence rate of limb malperfusion of acute Stanford A aortic dissection was 5.6%(17/302). Average extracorporeal circulation time was(271.8±38.9)min, average aortic cross-clamp time was (186.3±31.8)min, and the average circulatory arrest time was (48.75±11.3)min. Early mortality rate was 17.6%(3/17). Two patients were left hospital voluntarily because of cerebral infarction. One patient underwent leg incision osteofascial compartment syndrome and discharged unevently. Five patients underwent continuous renal replacement therapy and hemoperfusion. Follow-up results showed that patients with serious limb malperfusion have symptoms of nerve dysfunction including amyosthenia and sensory disturbance, but recovered gradually with rehabilitation.Conclusion:Sun’s procedure is safe and feasible for type A acute aortic dissection complicated with mild limb malperfusion. For serious limb malperfusion, endovascular stent followed by Sun’s procedure is a good choice with CRRT and hemoperfusion.

The condition of patients with severe traumatic brain injury (sTBI) complicated by corona virus 2019 disease (COVID-19) is complex. sTBI can significantly increase the probability of COVID-19 developing into severe or critical stage, while COVID-19 can also increase the surgical risk of sTBI and the severity of postoperative lung lesions. There are many contradictions in the treatment process, which brings difficulties to the clinical treatment of such patients. Up to now, there are few clinical studies and therapeutic norms relevant to sTBI complicated by COVID-19. In order to standardize the clinical treatment of such patients, Critical Care Medicine Branch of China International Exchange and Promotive Association for Medical and Healthcare and Editorial Board of Chinese Journal of Trauma organized relevant experts to formulate the Chinese expert consensus on clinical treatment of adult patients with severe traumatic brain injury complicated by corona virus infection 2019 ( version 2023) based on the joint prevention and control mechanism scheme of the State Council and domestic and foreign literatures on sTBI and COVID-19 in the past 3 years of the international epidemic. Fifteen recommendations focused on emergency treatment, emergency surgery and comprehensive management were put forward to provide a guidance for the diagnosis and treatment of sTBI complicated by COVID-19.

Traumatic intracranial hematoma progresses rapidly and may cause quick increase of intracranial pressure and even brain hernia, ultimately leading to coma or death. Therefore, traumatic intracranial hematoma needs prompt treatment, but the prerequisite of treatment is early examination and diagnosis. Due to the limited transportation and other reasons, the existing large-scale detection devices such as CT and MRI cannot be deployed on the rescue site or during patient transportation. Instead, the portable diagnosis devices have the characteristics of miniaturization and high flexibility, which is conducive to promoting early detection, assisting diagnosis and further guiding the formulation of treatment plans. At present, more and more attention has been paid to the portable diagnosis devices in the diagnosis of intracranial hematoma. The authors summarized the conventional diagnosis methods and application of portable diagnosis devices for traumatic intracranial hematoma, aiming to provide a reference for the diagnosis of traumatic intracranial hematoma.

Objective To investigate the influence of renal failure on the area under curve (AUC) and adverse reactions of docetaxel in breast cancer patients, and provide evidence for the dosage of docetaxel in renal failure patients. Methods A retrospective study was conducted on 24 patients with breast cancer who had undergone radical mastectomy and received AC-T adjuvant chemotherapy in our hospital from January 2019 to November 2021. According to renal function cases, the patients were divided into two groups: renal failure group (n=5) and normal renal function group (n=19). The clinical characteristics such as gender, age, body weight and body surface area of patients in two groups, docetaxel dose, blood concentration, area under the curve, liver and kidney function, white blood cell count and absolute value of neutrophil before chemotherapy were collected. Single factor linear regression was used to analyze the influencing factors of the AUC of docetaxel. Adverse reactions after chemotherapy with docetaxel including nausea and vomiting, bone marrow suppression, constipation and liver function injury were collected. CTCAE 4.0 evaluation standard was used to evaluate adverse reactions. Results The clinical characteristics of creatinine [908.0 (819.0, 1018.0) μmol/L vs 54.8 (52.0, 65.0) μmol/L] and creatinine clearance rate [4.9 (4.3, 5.4) ml /min vs 86.3 (59.3, 92.5) ml/min] of the renal failure group and the normal renal function group have significant difference (P<0.001), while no significant difference (P>0.05) were found in the body surface area [1.4 (1.4, 1.5) m² vs 1. 6 (1.5, 1.6) m²], docetaxel dose [70.4 (69.4, 73.0) mg/m² vs 74.4 (72.3, 91.2) mg/m²], body weight [(51.4±3.8) kg vs (51.5±5.5) kg]. Liver function, white blood cells and neutrophils were within the normal range before chemotherapy with docetaxel. There was no significant difference in AUC value [(1.6±0.6) mg·h/L vs (1.8±0.8) mg·h/L] between the two groups after chemotherapy with docetaxel (P>0.05). Linear univariate regression analysis indicated that the blood concentration at the end of docetaxel infusion was significantly associated with AUC of docetaxel (P<0.001), while the body surface area, dose of docetaxel, body weight, liver and kidney function were not correlated with AUC of docetaxel (P>0.05). After chemotherapy with docetaxel, adverse reactions of patients in the two groups: nausea and vomiting (grade I incidence: 40% vs. 57.9%, grade II incidence: 60% vs. 42.1%), myelosuppression (grade I incidence: 60% vs. 84.2%, grade II incidence: 20% vs 15.8%) and constipation (all mild constipation) had no significant difference (P>0.05). Conclusion Renal failure did not affect the exposure of docetaxel and the adverse reactions after chemotherapy with docetaxel in breast cancer patients.

Objective:To investigate the changes of plasma prothrombin fragment 1+ 2 (F 1+2), tissue factor positive microparticle (TF+ MP) and thrombin antithrombin complex (TAT) level before and after the treatment of low molecular weight heparin combined with reteplase in patients with malignant tumor and lower extremity venous thrombosis. Methods:From July 2016 to October 2019, 64 patients with malignant tumors and lower extremity venous thrombosis in the Third Hospital of Changsha were selected, they were divided into observation group ( n=32) and control group ( n=32) by simple randomization. The control group was treated with low molecular heparin, and the observation group was treated with low molecular heparin combined with reteplase. The efficacy, clinical symptom improvement time, incidence of adverse reactions, difference in lower limb circumference, blood flow velocity, activated partial thromboplastin time (APTT), prothrombin time (PT), plasma F 1+2, TF+ MP, TAT level before and after treatment were compared between the two groups; the correlations of plasma F 1+2, TF+ MP, and TAT level with clinical symptom improvement time, peripheral diameter difference of lower extremity, blood flow velocity, APTT, and PT were analyzed. Results:The total effective rate of the observation group (87.50%) was higher than that of the control group (65.63%) ( P<0.05); The improvement time of clinical symptoms in the observation group was shorter than that in the control group ( P<0.05); After treatment, the peripheral limb diameter difference of the observation group was lower than that of the control group, and the blood flow velocity was higher than that of the control group ( P<0.05); The APTT and PT in the observation group were higher than those in the control group after treatment ( P<0.05); The plasma F 1+2, TF+ MP, and TAT level in the observation group were lower than those in the control group after treatment ( P<0.05); The levels of plasma F 1+2, TF+ MP, and TAT were positively correlated with symptom improvement time and lower limb circumference difference, and negatively correlated with blood flow velocity, APTT, and PT ( P<0.05); There was no significant difference in the incidence of adverse reactions (18.75%) between the observation group and the control group (12.50%) during the treatment period ( P>0.05). Conclusions:Plasma F 1+2, TF+ MP, and TAT expression in patients with malignant tumors and venous thrombosis of the lower extremity can be used as biological indicators to evaluate the patient's condition and treatment effect. Low molecular weight heparin combined with reteplase can significantly reduce the plasma F 1+2, TF+ MP and TAT level, promote the improvement of symptoms, effectively reduce the peripheral diameter difference of lower extremity, improve blood flow velocity and coagulation function, and has a significant effect.

Objective:To discuss the relationships between the expressions of silence information regulator 6 (SIRT6) and survivin and clinicopathological features of gastric cancer, and to investigate their effects in gastric cancer.Methods:The tumor tissues of 110 gastric cancer patients admitted to the First Affiliated Hospital of Xi′an Jiaotong University from March 2013 to October 2014, as well as 40 adjacent tissues and 20 normal tissues, were selected to detect the expressions of SIRT6 and survivin by immunohistochemistry. The correlations between the expression levels of SIRT6 and survivin and the clinicopathological features and prognosis of gastric cancer patients were analyzed.Results:The positive rates of SIRT6 were 41.8% (46/110), 77.5% (31/40) and 85.0% (17/20) in gastric cancer, adjacent tissues and normal gastric tissues, respectively, and the difference among the three groups was statistically significant ( χ2=23.200, P<0.001). The positive rate of SIRT6 in gastric cancer tissue was lower than that in adjacent and normal tissues ( χ2=14.949, P<0.001; χ2=12.634, P<0.001). The expression of SIRT6 was correlated with tumor differentiation ( χ2=19.654, P<0.001). The positive rates of survivin were 58.2% (64/110), 15.0% (6/40) and 0 (0/20) in gastric cancer, adjacent tissues and normal gastric tissues, respectively, and the difference among the three groups was statistically significant ( χ2=38.449, P<0.001). The positive rate of survivin in gastric cancer tissue was higher than that in adjacent and normal tissues ( χ2=21.976, P<0.001; χ2=22.920, P<0.001). The expression of survivin was correlated with the depth of infiltration ( χ2=20.853, P<0.001). The expression of SIRT6 was correlated with survivin in gastric cancer tissues ( C=0.211, P=0.024). Survival analysis showed that 3-year survival rate was 53.1% in the SIRT6 negative patients, lower than 78.3% in the positive patients, and the difference was statistically significant ( χ2=4.004, P=0.045), while the 3-year survival rates of the survivin positive and negative patients were 53.1% and 78.3%, and the difference was not significant ( χ2=3.717, P=0.054). Cox multivariate regression analysis showed that lymph node metastasis ( RR=6.618, 95% CI: 2.152-20.358, P=0.001) and SIRT6 negative expression ( RR=0.228, 95% CI: 0.081-0.644, P=0.005) were the risk factors for poor prognosis of gastric cancer. Conclusion:SIRT6 is poorly expressed in gastric cancer tissues and is related to the prognosis of gastric cancer, while survivin is highly expressed in gastric cancer tissues. The expression of SIRT6 and survivin is negatively correlated, suggesting that the expression imbalance of SIRT6 and survivin may play an important role in the occurrence and development of gastric cancer.