Traditional development of small protein scaffolds has relied on display technologies and mutation-based engineering, which limit sequence and functional diversity, thereby constraining their therapeutic and application potential. Protein design tools have significantly advanced the creation of novel protein sequences, structures, and functions. However, further improvements in design strategies are still needed to more efficiently optimize the functional performance of protein-based drugs and enhance their druggability. Here, we extended an evolution-based design protocol to create a novel minibinder, BindHer, against the human epidermal growth factor receptor 2 (HER2). It not only exhibits super stability and binding selectivity but also demonstrates remarkable properties in tissue specificity. Radiolabeling experiments with ^99mTc, ⁶⁸Ga, and ¹⁸F revealed that BindHer efficiently targets tumors in HER2-positive breast cancer mouse models, with minimal nonspecific liver absorption, outperforming scaffolds designed through traditional engineering. These findings highlight a new rational approach to automated protein design, offering significant potential for large-scale applications in therapeutic mini-protein development.

Objective:To analyze the effect of birth parity on life expectancy (LE) and healthy life expectancy (HLE) among rural women.Method:A total of 15 304 women aged 40 to 79 years who participated in baseline and follow-up surveys were selected from a rural cohort in Henan province. The LE and HLE of women with different birth parity were calculated by using multi-state life table.Results:There were 1 195 (7.8%), 7 782 (50.8%), 3 867 (25.3%) and 2 460 (16.1%) women with 1, 2, 3 and 4 birth parities, respectively, and the M ( Q1 and Q3) of age were 50.3 (47.3, 53.4) and 53.3 (48.8, 60.7), 62.6 (55.4, 66.9) and 69.5 (64.7, 73.4) years old, respectively. LE at 40 years old was 44.5, 44.8, 45.1 and 45.4 years old, and HLE was 17.7, 18.3, 18.8 and 19.3 years old, respectively. LE at age 40 increased by 0.3, 0.6, and 0.9 years in women with 2, 3, and 4 birth parities or more and HLE increased by 0.5, 1.1, and 1.6 years, respectively, compared with women with 1 birth parity. For women with higher and lower socioeconomic status who had 4 birth parities or more, the LE at age 40 was 47.1 and 43.9 years, respectively, an increase of 0.2 and 0.1 years over women with 1 birth parity, respectively; and the HLE was 20.4 and 18.7 years, respectively, an increase of 1.4 and 1.3 years over women with 1 birth parity, respectively. Conclusion:LE and HLE show an upward trend with the increase of birth parity among rural women.

Objective:To analyze the effect of birth parity on life expectancy (LE) and healthy life expectancy (HLE) among rural women.Method:A total of 15 304 women aged 40 to 79 years who participated in baseline and follow-up surveys were selected from a rural cohort in Henan province. The LE and HLE of women with different birth parity were calculated by using multi-state life table.Results:There were 1 195 (7.8%), 7 782 (50.8%), 3 867 (25.3%) and 2 460 (16.1%) women with 1, 2, 3 and 4 birth parities, respectively, and the M ( Q1 and Q3) of age were 50.3 (47.3, 53.4) and 53.3 (48.8, 60.7), 62.6 (55.4, 66.9) and 69.5 (64.7, 73.4) years old, respectively. LE at 40 years old was 44.5, 44.8, 45.1 and 45.4 years old, and HLE was 17.7, 18.3, 18.8 and 19.3 years old, respectively. LE at age 40 increased by 0.3, 0.6, and 0.9 years in women with 2, 3, and 4 birth parities or more and HLE increased by 0.5, 1.1, and 1.6 years, respectively, compared with women with 1 birth parity. For women with higher and lower socioeconomic status who had 4 birth parities or more, the LE at age 40 was 47.1 and 43.9 years, respectively, an increase of 0.2 and 0.1 years over women with 1 birth parity, respectively; and the HLE was 20.4 and 18.7 years, respectively, an increase of 1.4 and 1.3 years over women with 1 birth parity, respectively. Conclusion:LE and HLE show an upward trend with the increase of birth parity among rural women.

ObjectiveTo compare the annual and age trends of the age-standard incidence rate （ASIR） and the age-standard mortality rate （ASMR） of lung cancer in countries with different human development index （HDI） from 1990 to 2019. MethodsThe data were collected from the global burden of disease study and GLOBOCAN 2020. The average annual percentage change （AAPC） and age trends of ASIR and ASMR in lung cancer were analyzed by the Joinpoint regression model， and the comparison between the four groups was analyzed by Kruskale-Wallis analysis. ResultsIn 2020， the incidence and mortality of lung cancer gradually increased with age and HDI grade. From 1990 to 2019， the global ASIR and ASMR of lung cancer decreased， and the ASIR of lung cancer among male decreased， while the ASIR of lung cancer among female increased. The results showed that ASIR of lung cancer in female residents in countries with very high HDI increased significantly from 1996 to 2011， resulting in an overall upward trend in female ASIR， while the other groups showed a downward trend. It was found that ASIR and ASMR of lung cancer in China and India were on the rise， while ASIR and ASMR of lung cancer in Russia and the United States were on the decline. ConclusionAlthough very high/high HDI countries face a higher burden of lung cancer occurrence and death， the accumulation of lung cancer burden is completed in the transitioning period. Therefore， lung cancer prevention measures in countries in transition are critical for global lung cancer control.

Objective:To investigate the correlation between residual cholesterol (RC) and carotid intima-media thickness (cIMT) in non-diabetic population.Methods:Non-diabetes population received health examination in Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School from January 1, 2018 to December 31, 2021 were retrospectively included. According to the carotid ultrasound results, they were divided into cIMT thickening group (≥1 mm) and non-thickening group (<1 mm). The RC level was calculated according to total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Multivariate logistic regression analysis was used to determine the correlation between RC and cIMT. Results:A total of 1 803 non-diabetes subjects, aged 58.3±15.6 years, including 1 100 males (61.0%), were enrolled. There were 916 patients (50.8%) in the cIMT thickening group and 887 (49.2%) in the non-cIMT thickening group. Compared with the non-cIMT thickening group, cIMT thickening group had significantly higher proportion of male, hypertension, hyperlipidemia, atrial fibrillation, past stroke history, smoking and alcohol consumption, as well as significantly higher age, blood glucose, triglyceride, RC, TC and LDL-C, and significantly lower HDL-C (all P<0.01). Multivariate logistic regression analysis showed that RC was independently associated with cIMT thickening ( Ptrend<0.001). Conclusion:RC is associated with cIMT thickening in non-diabetes population.

【Objective】 To explore the perioperative blood management in patients with pancreatic pseudocyst combiend with coagulation factor Ⅴ(FⅤ) deficiency. 【Methods】 Preoperative: In order to determine the effect of cryoprecipitated antihemophilic factor and fresh frozen plasma (FFP) on the elevation level of factor Ⅴ, we alternately infused cryoprecipitate and FFP in the resting state. TEG, coagulation function and coagulation factor activity were monitored before and 1 h, 24 h and 48 h after infusion, and intraoperative and postoperative blood transfusion strategies were formulated. FFP 600 mL and cryoprecipitate 10 U were supplemented preoperatively. Intraoperative: The operation procedure was performed for 7 hours with an infusion of 600 mL FFP without significant bleeding. Postoperative: FFP was infused. 【Results】 Preoperative: The coagulation factor Ⅴ activity on pre-operation was 1.9% and 1.8%. After alternating infusion cryoprecipitate 10 U and FFP 1 200 mL, the FⅤactivity increased to 5.1% and 6.0%, respectively. There was no significant difference in TEG parameters, PT and ATPP results were decreased to varying degrees. Intraoperative: The operation was successful without obvious bleeding. Postoperative: FFP 500 mL was infused 2 h after operation, and FFP 250-500 mL was injected daily from 1 to 7 days after surgery. No significant bleeding was observed in the wound, the results of TEG, PT, APTT and hemoglobin (Hb) did not change significantly compared with those before surgery. The patient was discharged successfully 12 days after surgery. The genetic test results showed that he had inherited coagulation factor Ⅴ deficiency, which was a compound heterozygous variation. 【Conclusion】 Perioperative blood management in patients with FⅤ deficiency combined with surgical disease, requiring pre-transfusion evaluation and post-transfusion evaluation in combination with laboratory investigations and clinical manifestations, cryoprecipitate and fresh frozen plasma can be effective in supplementing coagulation factors. The TEG seems to be better than the Seven items of coagulation function in judging the clotting status of patients with FⅤ deficiency.

Objective:To investigate the genetic risk factors and prognosis of 190 patients with myelodysplastic syndrome(MDS). Methods:The clinical data of 190 patients with MDS admitted to the Department of Hematology,The First Affiliated Hospital of Chongqing Medical University from January 2015 to October 2020 were analyzed retrospectively,and the genetic background and survival curve of the patients were also analyzed. Results:MDS patients with higher risk according to International Prognostic Score System(IPSS)stratification at the time of initial diagnosis had more frequent and complex types of gene mutation and chromosomal abnormalities,indicating poor prognosis.The choice of treatment is associated with the prognosis of MDS patients with intermediate risk(IPSS stratification),and the relative risk of the overall survival rate of patients treated with hypomethylating agents is higher than that of patients on concomitant medication. Conclusion:MDS patients with higher-risk(IPSS stratification)have more complex genetic risk factors and lower survival rate than those with lower-risk(IPSS stratification).MDS patients with multiple genetic risk factors have a poor prognosis,and the type of gene mutation is a predictor of prognosis.

Objective:To investigate the predictors of intracranial hemorrhage in patients with cerebral venous sinus thrombosis (CVST).Methods:Patients with CVST treated in Drum Tower Hospital Affiliated to Medical School of Nanjing University from January 2008 to March 2021 were retrospectively enrolled. The risk factors, clinical manifestations, imaging examination and 90 d follow-up data were collected. The complicated intracranial hemorrhage group and non-intracranial hemorrhage group were compared. Multivariate logistic regression analysis was used to determine the independent predictors of intracranial hemorrhage in patients with CVST. Results:A total of 104 patients with CVST were enrolled, including 42 males and 62 females. Their age was 35.24 ± 10.92 years old (range 22-68 years). Thirty-eight patients (36.84%) were complicated with intracranial hemorrhage, including 34 hemorrhagic cerebral infarction and 4 complicated subarachnoid hemorrhage. Univariate analysis showed that compared with the non-intracerebral hemorrhage group, the intracranial hemorrhage group was more common in puerperal/pregnant patients (60.52% vs. 48.48%; P=0.012), with more acute onset (57.89% vs. 48.48%; P=0.004), focal neurological signs (47.37% vs. 19.70%; P=0.003) and seizure (39.47% vs. 18.18%; P=0.017), and the site of thrombosis was more common in the superior sagittal sinus (57.89% vs. 36.36%; P=0.033). Multivariate logistic regression analysis showed that puerperium/pregnancy (odds ratio 2.857, 95% confidence interval 1.095-7.453; P=0.031) and superior sagittal sinus thrombosis (odds ratio 2.847, 95% confidence interval 1.110-7.302; P=0.027) were the independent predictors of intracranial hemorrhage in patients with CVST. The analysis at 90 d after onset showed that there was no significant difference in the good outcome rate between the intracranial hemorrhage group and the non-intracranial hemorrhage group (86.84% vs. 89.39%; P=0.695). Conclusions:Puerperium/pregnancy and superior sagittalsinus thrombosis are the independent risk factors for intracranial hemorrhage in patients with CVST. However, complicated with intracranial hemorrhage is not associated with 90-day clinical outcomes.

Objective:To evaluate the diagnostic value of relative lesion length in differentiating extrahepatic bile duct infiltrating cholangiocarcinoma with inflammation.Methods:From October 2014 to February 2018, 24 cases of infiltrating extrahepatic cholangiocarcinomas confirmed operatively and pathologically and 23 cases of extrahepatic bile duct inflammation confirmed clinically from the Third People′s Hospital of Datong City were respectively enrolled in this study. Upper abdomen MR and/or CT image data of all patients were respectively reviewed. The extrahepatic duct wall was defined as wall thickening with obvious enhancement. The length of the lesion was measured. L lesion/L duct was referred as the ratio of the lengths of lesion to extrahepatic bile duct (common hepatic duct+common bile duct)was calculated. The difference in the average values of L lesion/L ductbetween the cholangiocarcinomas group and inflammation group was analyzed with t test, and the differential diagnostic efficacy of L lesion/L ductratio was analyzed with receiver operating characteristic curve (ROC) test. Results:Significant difference was found in the length of lesion between the extrahepatic cholangiocarcinoma group [(22.01±1.86) mm] and the cholangitis group [(47.36±2.81) mm] ( P<0.01). The average ratio of L lesion/L ductwere 0.26±0.02 for the cholangiocarcinomas group and 0.54±0.03 for the inflammation group, respectively ( P<0.01). The area under the ROC curve of L lesion/L duct in diagnosis of the infiltrating extrahepatic cholangiocarcinomas was 0.92. With <0.40 as cut-off point, the diagnostic sensitivity and specificity were 87.5% and 82.6%, respectively. Conclusion:The L lesion/L ductmight be taken as an important diagnostic sign in differentiation between infiltrating extrahepatic cholangiocarcinomas and extrahepatic bile duct inflammation.

Objective:To analyze the clinicopathological features in diabetic kidney disease (DKD) and non-diabetic kidney disease (NDKD) patients, and provide reference for patients who will receive renal biopsy with diabetes mellitus complicated with chronic kidney disease.Methods:The patients with type 2 diabetes mellitus complicated with chronic kidney disease who underwent renal biopsy were collected through the database at the Nanfang Hospital of Southern Medical University from February 2002 to June 2018. According to the results of renal biopsy, they were divided into DKD group and NDKD group (including DKD+NDKD). The clinical manifestations and pathological types were compared between the two groups.Results:A total of 507 patients were eventually included in the study. There were 114 cases (22.5%) with DKD and 393 cases (77.5%) with NDKD. Pathologically, the most common pathological types of NDKD were membranous nephropathy (30.0%) and IgA nephropathy (19.1%). Among NDKD patients, 5.6% patients had DKD combing with NDKD. In term of the clinical manifestations, DKD patients had a longer history of diabetes (>1 year, 76.3% vs 36.1%, P<0.001), higher quantity of urinary protein [3.69(1.70, 6.74) g/24 h vs 2.21(0.91, 4.97) g/24 h, P<0.001], higher serum creatinine [117.5(85.8, 194.5) μmol/L vs 89.0(68.0, 143.8) μmol/L, P<0.001] than NDKD patients. But the hemoglobin [(105.07±20.85) g/L vs (124.41±25.02) g/L, P=0.002] and cholesterol [(5.69±1.87) mmol/L vs (6.43±2.75) mmol/L, P=0.001] in DKD patients were lower than those in NDKD patients. Logistic regression analysis showed that diabetes mellitus history ( OR=4.162, 95% CI 1.717-10.098, P=0.002) , higer systolic pressure (every 1 mmHg, OR=1.028, 95% CI 1.011-1.045, P=0.001) , history of antihypertensive medication ( OR=3.141, 95% CI 1.496-6.591, P=0.002), diabetic retinopathy ( OR=5.561, 95% CI 2.361-13.100, P<0.001) and higher glycated hemoglobin level (every 1%, OR=1.680, 95% CI 1.333-2.118, P<0.001) were related factors of DKD, while hematuria ( OR=2.781, 95% CI 1.334-5.798, P=0.006) and higher hemoglobin level (every 1 g/L, OR=1.022, 95% CI 1.008-1.037, P=0.002) were related factors of NDKD. Conclusions:There are differences in clinical manifestations and pathological types between DKD and NDKD. The history of diabetes, antihypertensive medication, fundus examination, higher of proteinuria and glycosylated hemoglobin may predict DKD, while hematuria and higher level of hemoglobin may have certain guiding significance for the diagnosis of NDKD. The indication of renal biopsy in patients with diabetes mellitus complicated with chronic kidney disease should include comprehensive clinical manifestations.