Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APC^min/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

Objective To analyze the role of the key items list in the quality control of running medical records by com-paring the improvements of the quality of medical records,and to explore more effective ways of quality management of medical records.Methods Based on the goal setting theory and influencing factors of goal incentive utility,a list of key items for medi-cal record quality management was formulated,which was implemented in a children's hospital in Tianjin since April 2023.A to-tal of 4 823 operating medical records were collected from June 2022 to September 2023,and the defect rates of quality control items were compared by using statistical methods.Results After the implementation of the key items list,the average score of operating medical records was improved,and the defect rate decreased from 13.63％to 7.94％.Moreover,the defect rates of admission records,first-trip records,senior physician rounds records,consultation records,and surgical records decreased from 4.25％,3.07％,8.26％,and 10.56％to 1.61％,1.56％,4.41％,and 5.06％.Conclusion The implementation of key i-tems list management can effectively improve the quality of running medical records,reduce the defects of medical records,and improve the effects of medical record management.

OBJECTIVE Optimizing the water extraction technology of Xiangqin jiere granules. METHODS The orthogonal test of 3 factors and 3 levels was designed， and comprehensive scoring was conducted for the above indexes by using G1-entropy weight to obtain the optimized water extraction technology of Xiangqin jiere granules with water addition ratio， extraction time and extraction times as factors， using the contents of forsythoside A， baicalin， phillyrin， oroxylin A-7-O-β-D-glycoside， wogonoside， baicalein and wogonin， and extraction rate as evaluation indexes. BP neural network modeling was used to optimize the network model and water extraction process using the results of 9 groups of orthogonal tests as test and training data， the water addition multiple， decocting time and extraction times as input nodes， and the comprehensive score as output nodes. Then the two analysis methods were compared by verification test to find the best water extraction process parameters. RESULTS The water extraction technology optimized by the orthogonal test was 8-fold water， extracting 3 times， extracting for 1 h each time. Comprehensive score was 96.84 （RSD＝0.90%）. The optimal water extraction technology obtained by BP neural network modeling included 12-fold water， extracting 4 times， extracting for 0.5 h each time. The comprehensive score was 92.72 （RSD＝0.77%）， which was slightly lower than that of the orthogonal test. CONCLUSIONS The water extraction technology of Xiangqin jiere granules is optimized successfully in the study， which includes adding 8-fold water， extracting 3 times， and extracting for 1 hour each time.

Objective:To analyze the external quality control assessment results of fluoride testing laboratories in endemic disease prevention and control institutions nationwide from 2006 to 2023, investigate the quality control capabilities of these laboratories in various provinces, prefectures, cities, and counties nationwide, and ensure the accuracy and reliability of surveillance data on endemic fluorosis nationwide.Methods:Using retrospective analysis, the external quality control assessment results of all participating fluoride testing laboratories of national endemic disease prevention and control institutions from 2006 to 2023 were summarized and analyzed. The assessment results from 2006 to 2008 were tested for outliers using Grubbs method, homogeneity of variance using Cochran method, excluding the assessment data of unqualified laboratories, calculating the total mean and total standard deviation, Z-score method was used to test the assessment of laboratories, and statistical analysis and judgment were done when the result of │Z│ < 3. The assessment results from 2009 - 2023 were obtained from all laboratories. In 2010, two tests were conducted in the first and second half of the year, and the Z-ratio scores of each laboratory were calculated using robust statistics. When │Z│≤2, the assessment was qualified; when 2 < │Z│ < 3, the assessment was basically qualified; when│Z│≥3, the assessment was unqualified, and the consensus value came from all participating laboratories in the assessment.Results:From the beginning of quality control operation in 2006 to 2023, the number of laboratories participated in external quality control assessments had significantly increased. The number of laboratories participated in water fluoride assessment increased from 30 in 2006 to 1 277 in 2023, and the number of laboratories participated in urine fluoride assessment increased from 29 to 497. The number of laboratories participated in the brick tea fluorine assessment had increased from 43 in 2014 to 193 in 2023. The assessment results showed that when │Z│ < 3, the total qualified rate of fluoride external quality control in fluoride testing laboratories of national endemic disease control institutions was 95.2%, with the lowest being 87.1% (27/31) in 2008 and the highest being 100.0% (394/394) in 2014. When │Z│≤2, the total feedback pass rate was 88.4%, with the lowest being 79.3% (288/363) in the first half of 2010 and the highest being 99.5% (392/394) in 2014. The assessment results showed that when │Z│ < 3, the total pass rate of urine fluoride external quality control in fluoride testing laboratories of national endemic disease control institutions was 98.0%, with the lowest being 86.2% (25/29) in 2006 and 2007, respectively, and the highest being 100.0% (68/68) in 2014. When │Z│≤2, the total qualification rate was 93.7%, with the lowest being 86.5% (64/74) in the second half of 2010 and the highest being 100.0% (68/68) in 2014. The assessment results showed that when│Z│ < 3, the total pass rate of extra-fluoride quality control of brick tea in fluoride testing laboratories of national endemic disease control institutions was 95.4%, with the lowest being 85.0% (164/193) in 2023, and the highest being 100.0% (43/43, 51/51, 79/79) in 2014, 2015 and 2016, respectively. When │Z│≤2, the total pass rate was 89.2%, with the lowest being 72.7% (32/44) in 2017 and the highest being 100.0% (43/43) in 2014. From 2009 to 2023, there were a total of 21 provincial-level laboratories that passed the water fluoride detection assessment, including 3 provinces where all prefecture level and county-level laboratories were qualified. The assessment results of urinary fluorine showed that there were 11 qualified provincial-level laboratories and 1 prefecture-level laboratory. From 2014 to 2023, the assessment results of brick-tea fluorine showed that there were 5 provincial-level laboratories that passed the tea fluorine testing assessment and no prefecture-level laboratory.Conclusions:Conclusion: From 2006 to 2023, the number of fluoride testing laboratories participating in external quality control assessment has increased year by year, and most provincial, municipal and county-level laboratories have good fluoride testing capabilities, which can meet the testing needs of endemic disease prevention and monitoring. For some laboratories with problems, targeted rectification should be carried out to improve the quality of detection, in order to provide better technical support for the monitoring of endemic fluorosis areas.

Background Chronic intermittent hypobaric hypoxia (CIHH) can effectively alleviate type 2 diabetes mellitus (T2DM). In this process, the underlying mechanism in its association with the epigenetic regulation of DNA methylation in the promoter regions of glucose metabolism key enzyme genes remains unclear yet. Objective To investigate the effects of CIHH on expression and promoter region methylation of key enzyme genes related to glucose metabolism in diabetes mice, and to explore the underlying mechanism by which CIHH regulates glucose metabolism. Methods Forty C57BL/6J male mice were divided randomly into a normobaric normoxic control (NN/CON) group, a chronic intermittent hypobaric hypoxia intervention control (CIHH/CON) group, a normobaric normoxic diabetic model (NN/DM) group, and a chronic intermittent hypobaric hypoxia intervention diabetic model (CIHH/DM) group. The mice in the NN/DM and the CIHH/DM groups were fed for 7 weeks with high-fat and high-sugar diet. Subsequently, these mice were intraperitoneally injected consecutively with 50 mmol·L⁻¹ streptozotocin (STZ) for 5 d at a dose of 40 mg·kg⁻¹ (body weight) per day to create T2DM model mice. The mice in the CIHH/DM and the CIHH/CON groups were intervened by simulating hypobaric hypoxia at 5000 m altitude for 6 h per day, while the mice in the NN/DM and the NN/CON groups were always placed in a normobaric normoxic environment. All mice were continuously treated for 4 weeks, and blood glucose were monitored during this period. After the CIHH intervention experiment, the glucose tolerance and insulin sensitivity of mice were evaluated. A set of indicators involved in key glycolytic enzymes glucokinase (GK) and pyruvate kinase (PK), as well as key gluconeogenic enzymes phosphoenolpyruvate carboxyl kinase (PEPCK) and glucose-6-phosphatase (G6P) were measured in the liver of mice, including enzyme activity, relative mRNA expression level, and DNA methylation level in the gene promoter regions. Results Compared with the mice in the NN/DM group, the blood glucose levels of the mice in the CIHH/DM group decreased after the 25^th day of the CIHH intervention (P<0.05). Regarding the diabetic glucose tolerance curves, the area under the curve (AUC) of the mice in the CIHH/DM group was lower than that of the NN/DM group (P<0.05). Compared with the mice in the NN/DM group, the mice in the CIHH/DM group showed that the serum insulin content and HOMA of insulin resistance index (HOMA-IRI) decreased (P<0.05), the enzyme activities of GK and PK increased and the relative mRNA expression levels of their genes were up-regulated (P<0.05), while the enzyme activities of PEPCK and G6P decreased and the relative mRNA expression levels of their genes were down-regulated (P<0.05) in liver. The average DNA methylation levels in the promoter regions of GK, PK, PEPCK, and G6P genes in liver of mice in each group were not significantly different (P>0.05), and their correlations with mRNA expression levels were also not statistically significant (P>0.05). Conclusion CIHH intervention may reduce blood glucose level, improve glucose tolerance, alleviate insulin resistance, and regulate the key enzyme activities of glucose metabolism and the relative mRNA expression of their corresponding genes in T2DM mice, but the above phenomena are not related to the DNA methylation levels in the promoter regions of these key enzymes.

Objective:To investigate the association between cytokines and ocular chronic graft-versus-host disease (cGVHD) and identify specific biomarkers for ocular cGVHD to enhance clinical diagnosis, treatment, and evaluation.Methods:A mouse model of cGVHD was established to explore the correlation between cGVHD and serum cytokines. Based on the findings from the animal experiments and literature review, a panel of 16 cytokine combinations was identified. Enzyme-linked immunosorbent assay (ELISA) was used to compare the cytokine concentrations in the serum and tear samples from patients who underwent allogeneic hematopoietic stem cell transplantation from June 2017 to March 2022 at the Medical Center of Hematology, Xinqiao Hospital, Army Medical University.Results:① Compared with the control group, mice with cGVHD exhibited elevated serum IL-1β, IL-6, IL-8, IL-17, IFN-γ, CX3CL1, CXCL11, CXCL13, CCL11, and CCL19 concentrations (all P<0.05). ② Analysis of the cytokine profiles of the serum and tear samples revealed that compared with patients without ocular cGVHD, those with ocular cGVHD exhibited increased serum IL-8 [ P=0.032, area under the curve (AUC) =0.678]; decreased serum IL-10 ( P=0.030, AUC=0.701) ; elevated IL-8, IFN-γ, CXCL9, and CCL17 in tear samples; and lower IL-10 and CCL19 in tear samples (all P<0.05, all AUC>0.7). Moreover, cytokines in tear samples showed correlations with ocular surface parameters related to ocular cGVHD. Conclusions:Tear fluid demonstrates greater specificity and sensitivity as a biomarker for diagnosing ocular cGVHD than serum biomarkers. Among the identified cytokines in tear samples, IL-8, IL-10, IFN-γ, CXCL9, CCL17, and CCL19 serve as diagnostic biomarkers for ocular cGVHD post-transplantation, offering practical reference value for diagnosis.

Objective To observe the clinical efficacy of Shuangye San(the prescription mainly composed of Mori Folium and Nelumbinis Folium)in the treatment of type 2 diabetes mellitus(T2DM)complicated with non-alcoholic fatty liver disease(NAFLD)of spleen deficiency and phlegm stasis type.Methods A total of 80 patients with T2DM complicated with NAFLD of spleen deficiency and phlegm stasis type were randomly divided into a treatment group and a control group,with 40 cases in each group.The control group was treated with conventional western medicine for lowering blood glucose and lipid,protecting liver and lowering enzymes.The treatment group was treated with the granules of Shuangye San orally on the basis of treatment for the control group.The course of treatment lasted for three months.The changes of traditional Chinese medicine(TCM)syndrome scores,homeostasis model assessment of insulin resistance(HOMA-IR),fasting insulin(FINS),fasting blood glucose(FBG),2-hour postprandial blood glucose(2hPG),glycosylated hemoglobin(HbA1C),total cholesterol(TC),triglyceride(TG),low-density lipoprotein cholesterol(LDL-C),high-density lipoprotein cholesterol(HDL-C),liver function indicators and B-ultrasound grading of fatty liver in the two groups were observed before and after treatment.After treatment,the clinical efficacy and safety of the two groups were evaluated.Results(1)After three months of treatment,the total effective rate of the treatment group was 85.00％(34/40),and that of the control group was 70.00％(28/40).The intergroup comparison(tested by chi-square test)showed that the efficacy of the treatment group was significantly superior to that of the control group(P＜0.01).(2)After treatment,the scores of TCM symptoms of obese physique,heaviness and weakness in the limbs,shortness of breath and unwilling to talk,tightness and stabbing pain in the chest,abdominal distension and poor appetite in the two groups were decreased compared with those before treatment(P＜0.05),and the decrease of TCM syndrome scores in the treatment group was significantly superior to that in the control group(P＜0.05).(3)After treatment,the levels of glucose and lipid metabolism indicators of FINS,HOMA-IR,FBG,2hPG,HbA1C,TC,TG and LDL-C in the two groups were significantly decreased compared with those before treatment(P＜0.05),and the level of HDL-C was significantly increased compared with that before treatment(P＜0.05).The decrease of FINS,HOMA-IR,FBG,2hPG,HbA1C,TC,TG and LDL-C levels and the increase of HDL-C levels in the treatment group were significantly superior to those in the control group(P＜0.05).(4)After treatment,the levels of liver function indicators of alanine aminotransferase(ALT),aspartate aminotransferase(AST)and gamma-glutamyl transpeptidase(GGT)in the two groups were significantly decreased compared with those before treatment(P＜0.05),and the decrease of liver function indicators in the treatment group was significantly superior to that in the control group(P＜0.05).(5)After treatment,the B-ultrasound grading of fatty liver of the two groups was significantly improved compared with that before treatment(P＜0.05),and the improvement of fatty liver B-ultrasound grading in the treatment group was significantly superior to that in the control group,and the difference was statistically significant(P＜0.05).(6)During the treatment,there were no adverse reactions such as impairment of liver and kidney function and abnormalities in routine blood,urine and stool test in the two groups.Conclusion Shuangye San exerts certain effect in the treatment of T2DM complicated with NAFLD of spleen deficiency and phlegm stasis type.It can alleviate the clinical symptoms of patients,correct the disorder of glucose and lipid metabolism,and improve liver function and fatty liver B-ultrasound grading.

Objective To investigate the clinical application value of MRI Radiomics score(Radscore)combined with clinicopatho-logical features in predicting postoperative progression-free survival(PFS)of patients with endometrial cancer(EC).Methods A total of 127 patients with EC were selected.The radiomic features of the lesions were extracted from T2 WI,diffusion weighted imaging(DWI)and apparent diffusion coefficient(ADC)images.The features were screened by random forest model and Radscore was calcu-lated.Simultaneously,clinical and pathological characteristics of patients were collected and incorporated,and multivariate Cox regression analysis was used to screen the risk factors related to PFS.The MRI Radscore and clinicopathological features were mapped to the nomogram,and the performance of nomogram was evaluated by receiver operating characteristic(ROC)curve and calibration curve.Results Multivariate Cox regression analysis showed that progesterone receptor(PR),human epididymis protein 4(HE4)and MRI Radscore were independent risk factors for predicting PFS in patients with EC(P＜0.05).The area under the curve(AUC)of the predicted PFS at 1,3 and 5 years after surgery were 0.91,0.804 and 0.776,respectively.Calibration curves showed that nomogram had a good fit in predicting PFS in patients with EC 1,3 and 5 years after surgery.Conclusion The nomogram con-structed based on multi-sequence MRI Radscore and clinicopathological features has favorable accuracy and stability in predicting postoperative PFS in individuals diagnosed with EC.

AIM To study the effects of Liangxue Heying Formula on vascular inflammatory injury in a rat model of thromboangiitis obliterans(TAO).METHODS The rats were randomly divided into the sham operation group,the model group and the low,medium and high dose Liangxue Heying Formula groups(2.25,4.5,9 g/kg).With the rat TAO model successfully established by injection of 0.1 mL sodium laurate(10 mg/mL)into the femoral artery of hind limbs,corresponding doses of drugs by gavage were administered upon the rats.Subsequently,the rats had their morphological changes of the affected limbs observed and assessed;their changes of blood flow in hind limbs scanned by laser Doppler flowmetry;their plasma levels of TNF-α,IL-6,ICAM-1 and VCAM-1 detected by ELISA;their histopathological changes of femoral artery and vein observed by HE staining;and their protein expressions of TNF-α,IL-6,JAK2,p-JAK2,STAT3,p-STAT3,ICAM-1 and VCAM-1 in femoral artery detected by Western blot.RESULTS Compared with the sham operation group,the model group displayed increased morphological score of the affected limb(P＜0.01);decreased blood perfusion ratio of the affected side/healthy side(P＜0.01);increased plasma levels of TNF-α,IL-6,ICAM-1 and VCAM-1(P＜0.01);more existence of thrombotic infiltration containing a larger number of inflammatory cells in femoral artery and femoral vein tissue,and increased protein expressions of TNF-α,IL-6,p-JAK2,p-STAT3,ICAM-1 and VCAM-1 in femoral artery(P＜0.01).Compared with the model group,the medium and high dose Liangxue Heying Formula groups demonstrated decreased morphological score of the affected limb(P＜0.01);increased blood perfusion ratio of the affected side/healthy side(P＜0.01);reduced infiltration of thrombus and inflammatory cells in femoral artery and femoral vein tissue,and decreased protein expressions of IL-6 and p-STAT3 in femoral artery tissue(P＜0.01).All Liangxue Heying Formula groups shared decreased plasma levels of TNF-α,IL-6,ICAM-1 and VCAM-1(P＜0.05,P＜0.01);and reduced protein expressions of TNF-α,ICAM-1,VCAM-1 and p-JAK2 in femoral artery(P＜0.01).CONCLUSION Liangxue Heying Formula can improve the systemic inflammatory state of TAO rats by inhibiting the activation of endothelial cells and reducing vascular inflammatory injury possibly due to the mechanism associated with the regulation of the JAK2/STAT3 signaling pathway.

OBJECTIVE: To explore the expression pattern and clinical significance of Integral membrane protein 2A（ITM2A） in drug resistant patients with chronic myeloid leukemia (CML). METHODS: The expression of ITM2A in CML was evaluated by qRT-PCR, Western blot and immunocytochemistry. In order to understand the possible biological effects of ITM2A, apoptosis, cell cycle and myeloid differentiation antigen expression of CML cells were detected by flow cytometry after over-expression of ITM2A. The nuderlying molecular mechanism of its biological effect was explored. RESULTS: The expression of ITM2A in bone marrow of CML resistant patients was significantly lower than that of sensitive patients and healthy donors（P<0.05）. The CML resistant strain cell K562R was successfully constructed in vitro. The expression of ITM2A in the resistant strain was significantly lower than that in the sensitive strain(P<0.05). Overexpression of ITM2A in K562R cells increased the sensitivity of K562R cells to imatinib and blocked the cell cycle in G₂ phase(P<0.05), but did not affect myeloid differentiation. Mechanistically, up-regulation of ITM2A reduced phosphorylation in ERK signaling (P<0.05). CONCLUSION The expression of ITM2A was low in patients with drug resistance of CML, and the low expression of ITM2A may be the key factor of imatinib resistance in CML.
Humans ; Antineoplastic Agents/pharmacology* ; Apoptosis ; Drug Resistance, Neoplasm ; Imatinib Mesylate/therapeutic use* ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Signal Transduction