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 explore the efficacy and safety profile of sofosbuvir/velpatasvir/voxilaprevir ± ribavirin (SOF/VEL/VOX±RBV) for salvage treatment of chronic hepatitis C patients who have failed direct-acting antivirals (DAAs).Methods:Patients with chronic hepatitis C who failed DAAs±RBV treatment and were treated in five hospitals in Chongqing, Guangdong, Guizhou, and Guangxi from January 2022 to December 2023 were included in this retrospective study. One or more courses of DAAs±RBV therapy were evaluated for all patients who had been previously treated. Virological rebound occurrence was observed during the follow-up. SOF/VEL/VOX±RBV was used for one course of salvage treatment. Virological and biochemical indicators were analyzed before salvage therapy, post-treatment, and drug discontinuation at 12 weeks. Adverse drug events were recorded during treatment. Data between groups were compared using t-tests or non-parametric tests.Results:A total of 26 cases of chronic hepatitis C who had failed DAAs±RBV were included in this study, with an age of (52.9±9.6) years. Twenty-one cases (80.8%) were male, sixteen (61.5%) had a history of drug abuse, two (7.7%) had combined human immunodeficiency virus infection, and fourteen (53.8%) had combined cirrhosis. The previous DAA regimen of 21 cases (80.8%) included SOF/VEL. The baseline HCV RNA load of salvage treatment was (5.8±1.6) log 10 IU/ml, and 16 cases (61.5%) were genotype 3. All patients completed the 12-week SOF/VEL/VOX±RBV salvage treatment and achieved sustained virological response (SVR) at the end of treatment. All 22 cases were followed up for 12 weeks following treatment completion and attained SVR12, including patients with genotype 3 and cirrhosis. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) had normalized return rates of 94.1% and 93.8%, respectively, following therapy. ALT, AST, FIB-4 index, APRI, and aPMAP scores were significantly lower than those before treatment ( Z=-3.980, -3.875, -3.461, -3.582, P<0.05). The proportion of patients in the high-risk group of liver cancer dropped (52.6% before treatment and 33.3% after treatment), and more patients were reclassified to medium-and low-risk groups. Two cases (7.7%) experienced nausea and diarrhea, one case (3.8%) had a headache, and one case (3.8%) had fatigue, all of which were well managed during treatment. There were no serious adverse events, deaths, or interruptions of treatment due to adverse reactions. Conclusions:SOF/VEL/VOX is a safe and effective salvage treatment option for chronic hepatitis C patients who have failed DAAs therapy, and may be particularly beneficial to refractory populations infected with genotype 3 and combined with cirrhosis.

Objective:To explore the efficacy and safety profile of sofosbuvir/velpatasvir/voxilaprevir ± ribavirin (SOF/VEL/VOX±RBV) for salvage treatment of chronic hepatitis C patients who have failed direct-acting antivirals (DAAs).Methods:Patients with chronic hepatitis C who failed DAAs±RBV treatment and were treated in five hospitals in Chongqing, Guangdong, Guizhou, and Guangxi from January 2022 to December 2023 were included in this retrospective study. One or more courses of DAAs±RBV therapy were evaluated for all patients who had been previously treated. Virological rebound occurrence was observed during the follow-up. SOF/VEL/VOX±RBV was used for one course of salvage treatment. Virological and biochemical indicators were analyzed before salvage therapy, post-treatment, and drug discontinuation at 12 weeks. Adverse drug events were recorded during treatment. Data between groups were compared using t-tests or non-parametric tests.Results:A total of 26 cases of chronic hepatitis C who had failed DAAs±RBV were included in this study, with an age of (52.9±9.6) years. Twenty-one cases (80.8%) were male, sixteen (61.5%) had a history of drug abuse, two (7.7%) had combined human immunodeficiency virus infection, and fourteen (53.8%) had combined cirrhosis. The previous DAA regimen of 21 cases (80.8%) included SOF/VEL. The baseline HCV RNA load of salvage treatment was (5.8±1.6) log 10 IU/ml, and 16 cases (61.5%) were genotype 3. All patients completed the 12-week SOF/VEL/VOX±RBV salvage treatment and achieved sustained virological response (SVR) at the end of treatment. All 22 cases were followed up for 12 weeks following treatment completion and attained SVR12, including patients with genotype 3 and cirrhosis. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) had normalized return rates of 94.1% and 93.8%, respectively, following therapy. ALT, AST, FIB-4 index, APRI, and aPMAP scores were significantly lower than those before treatment ( Z=-3.980, -3.875, -3.461, -3.582, P<0.05). The proportion of patients in the high-risk group of liver cancer dropped (52.6% before treatment and 33.3% after treatment), and more patients were reclassified to medium-and low-risk groups. Two cases (7.7%) experienced nausea and diarrhea, one case (3.8%) had a headache, and one case (3.8%) had fatigue, all of which were well managed during treatment. There were no serious adverse events, deaths, or interruptions of treatment due to adverse reactions. Conclusions:SOF/VEL/VOX is a safe and effective salvage treatment option for chronic hepatitis C patients who have failed DAAs therapy, and may be particularly beneficial to refractory populations infected with genotype 3 and combined with cirrhosis.

As a representative chemotherapeutic drug, docetaxel (DTX) has been used for breast cancer treatment for decades. However, the poor solubility of DTX limits its efficacy, and the DTX based therapy increases the metastasis risk due to the upregulation of C-X-C chemokine receptor type 4 (CXCR4) expression during the treatment. Herein, we conjugated CXCR4 antagonist peptide (CTCE) with DTX (termed CTCE-DTX) as an anti-metastasis agent to treat breast cancer. CTCE-DTX could self-assemble to nanoparticles, targeting CXCR4-upregulated metastatic tumor cells and enhancing the DTX efficacy. Thus, the CTCE-DTX NPs achieved promising efficacy on inhibiting both bone-specific metastasis and lung metastasis of triple-negative breast cancer. Our work provided a rational strategy on designing peptide-drug conjugates with synergistic anti-tumor efficacy.

Objective:To investigate the CT features of lung injury induced by paraquat poisoning and its relationship with prognosis, and to provide reference for the judgment of the condition and prognosis of paraquat poisoning.Methods:146 cases of paraquat poisoning patients were treated in the Third People's Hospital of Xuzhou City from January 2013 to April 2016. The cases were divided into mild group, moderate-severe group and fulminant group according to the concentration of paraquat in urine. The clinical data and CT imaging findings were analyzed and reconstructed in three-dimensional reconstruction. The extent of the lesion was observed and the relationship between CT and prognosis was explored.Results:Paraquat lung injury has many manifestations on CT images, and it's performance can be intersecting at the same time. Early lesions lighter cases, late CT imaging lesions can be completely absorbed or residual fibrosis, the prognosis was good; the early lesion was pulmonary consolidation, pleural effusion cases, the late CT image was usually pleural thickening and bronchiectasis, the prognosis was relatively good; early lesions were large patches of ground glass opacity cases, finally, pulmonary fibrosis was common, the mortality rate of 56.57%. There were significant differences in the extent of lung injury between different groups ( P<0.001) , and the difference in mortality was statistically significant when the lung injury was different ( P<0.001) . Multivariate stepwise Logistic regression analysis showed that ground-glass opacity ( OR value=2.013) , interstitial lung fibrosis ( OR=3.779) and mediastinal emphysema ( OR=33.118) were risk factors for death of lung injury caused by paraquat poisoning ( P<0.05) . Conclusion:There were many manifestations on CT images of paraquat lung injury, and the manifestations of paraquat lung injury can be intersecting at the same time. The pulmonary manifestations and outcomes of different paraquat types were different. The CT manifestations of lung injury in paraquat poisoning were mainly exudative changes at early stage, and can be gradually absorbed or evolved into interstitial changes at later stage. The cumulative damage range can be used as a reference for evaluating the prognosis. Ground-glass opacity, interstitial pulmonary fibrosis and mediastinal emphysema are the risk factors for death of lung injury caused by paraquat poisoning.

Objective:To investigate the CT features of lung injury induced by paraquat poisoning and its relationship with prognosis, and to provide reference for the judgment of the condition and prognosis of paraquat poisoning.Methods:146 cases of paraquat poisoning patients were treated in the Third People's Hospital of Xuzhou City from January 2013 to April 2016. The cases were divided into mild group, moderate-severe group and fulminant group according to the concentration of paraquat in urine. The clinical data and CT imaging findings were analyzed and reconstructed in three-dimensional reconstruction. The extent of the lesion was observed and the relationship between CT and prognosis was explored.Results:Paraquat lung injury has many manifestations on CT images, and it's performance can be intersecting at the same time. Early lesions lighter cases, late CT imaging lesions can be completely absorbed or residual fibrosis, the prognosis was good; the early lesion was pulmonary consolidation, pleural effusion cases, the late CT image was usually pleural thickening and bronchiectasis, the prognosis was relatively good; early lesions were large patches of ground glass opacity cases, finally, pulmonary fibrosis was common, the mortality rate of 56.57%. There were significant differences in the extent of lung injury between different groups ( P<0.001) , and the difference in mortality was statistically significant when the lung injury was different ( P<0.001) . Multivariate stepwise Logistic regression analysis showed that ground-glass opacity ( OR value=2.013) , interstitial lung fibrosis ( OR=3.779) and mediastinal emphysema ( OR=33.118) were risk factors for death of lung injury caused by paraquat poisoning ( P<0.05) . Conclusion:There were many manifestations on CT images of paraquat lung injury, and the manifestations of paraquat lung injury can be intersecting at the same time. The pulmonary manifestations and outcomes of different paraquat types were different. The CT manifestations of lung injury in paraquat poisoning were mainly exudative changes at early stage, and can be gradually absorbed or evolved into interstitial changes at later stage. The cumulative damage range can be used as a reference for evaluating the prognosis. Ground-glass opacity, interstitial pulmonary fibrosis and mediastinal emphysema are the risk factors for death of lung injury caused by paraquat poisoning.

Objective: To investigate the expression and distribution of FNDC5/Irisin in pancreatic cancer tissues and adjacent tissues, and to analyze its correlation with clinicopathological features. Methods: Collection of archived wax blocks from 64 patients diagnosed with pancreatic cancer after surgical treatment from January 2015 to December 2018 in the Department of Pathology, Affiliated Qingdao Municipal Hospital of Qingdao University, and 30 tissues collected intraoperatively from January 2016 to December 2018 Samples, all collected samples included tumor tissue and corresponding adjacent tissues (>2 cm from the tumor edge). Real-time quantitative PCR (qRT-PCR) and immunohistochemistry were used to detect the expression of FNDC5/Irisin mRNA and its positivity in pancreatic cancer tissues and adjacent tissues, and to analyze its relationship with clinicopathological features of pancreatic cancer. Results: qRT-PCR showed that the expression of FNDC5/Irisin mRNA in pancreatic cancer tissues was higher than that in the corresponding adjacent pancreatic tissues, the difference was statistically significant (P<0.05). The immunohistochemistry results showed that the positivity of FNDC5/Irisin in pancreatic cancer tissues was 59.4%, and the positivity of FNDC5/Irisin in adjacent tissues was 28.1%, and the positivity of FNDC5/Irisin in cancer tissues and adjacent pancreatic tissues was significantly different (P<0.05); the expression level of FNDC5/Irisin was not related with the gender, age, tumor size, degree of differentiation, and tumor stage.(P>0.05), but FNDC5/Irisin expression was associated with liver and lymph node metastasis (P<0.05). Conclusion The positivity of FNDC5/Irisin in pancreatic cancer tissues is significantly higher than that in adjacent pancreatic tissues, and it is correlated with liver and lymph node metastasis in pancreatic cancer.

OBJECTIVETo observe the impacts of the intervention with electric thermalstone and air suction cup on blood perfusion (BP) at meridian points and explore the approach of accurate measurement and regulation of meridianand blood balance in "precise acupuncture".

METHODSThe laser Doppler line scanner (LDLS) was used to measure BP at bilateraln-primary points at the pericardium meridian, the triple energizer meridian, the gallbladder meridian and the liver meridian (small cycle oftomeridians) at 31 healthy receptors. The bias ratio of blood perfusion (BPBR) deviated to the reference value was calculated. The electric thermalstone and air suction cup were used in the intervention at the-sea points of the affected meridians in which BPBR was relatively higher at the-primary points. The electric thermalstone therapy was used when BPBR was less than -30% and the air suction cupping therapy was used when BPBR was higher than 30%. BP was measured twice before intervention and it was measured separately at the moment after intervention and in 20 min after intervention. The means of BP before and after intervention and the change ratio of blood perfusion (BPCR) before intervention, at the moment after intervention and 20 min after intervention were calculated.

RESULTS1. After the intervention of electric thermalstone, BP mean was increased from (103.51±41.21) PU to (121.97±56.22) PU (<0.05). Before intervention, at the moment after intervention and 20 min after intervention, separately, BRCR were (-0.58±16.18)%, (23.58±48.85) % and (25.62±65.89) %. BPCR at the moment after treatment was increased significantly as compared with that before intervention (<0.01). The difference was not significant in 20 min after intervention and before intervention (>0.05), but the change ratio was highly remained. 2. After intervention with air suction cup, BP mean was reduced from (194.83±81.14) PU to (173.88±88.26) PU. Before intervention, at the moment after intervention and 20 min after intervention, separately, BPCR were (7.62±30.49)%, (-12.12±18.20)% and (-14.35±21.25)%. BPCR at the moment after intervention and in 20 min after intervention were significantly different from that before intervention (both<0.01). .

CONCLUSIONThe electric thermalstone increases the blood flow at the-primary point when acting on the-sea point of the same meridian. The influence of the air suction cup is opposite.

Objective To assess the feasibility of the log file-based three-dimensional independent dose verification system for the quality assurance of clinical radiotherapy.Methods The statistical values of the percentage depth dose,off-axis curves and output factor calculated by the Mobius system were statistically compared with the measured data by three-dimensional water tank.The three-dimensional independent dose verification in clinical radiotherapy plan and the acceleratr log file-based three-dimensional dose verification during the treatment were performed in 17 patients with nasopharyngeal cancer.The accuracy of dose calculation and reconstruction of Mobius system was assessed.A statistical analysis was performed on the intra-fractionalγpass rate (3％/3 mm) for each patient to evaluate the stability of intra-fractional radiotherapy.Results The percentage depth dose,off-axis curve and output factor statistically calculated by the Mobius system matched well with the data measured by three-dimensional water tank.The dose-volume histogram (DVH) parameters between the target area and organ at risk during clinical radiotherapy plan were statistically compared in 17 patients with nasopharyngeal cancer.The maximum deviation was-2.16％ for the three-dimensional independent dose verification in the clinical radiotherapy plan,and 0.18 Gy for the accelerator log file-based three-dimensional dose verification.The averageγpass rate for 17 nasopharyngeal cancer patients was 99.26％,and the maximum deviation of intra-fractional radiotherapy was below 0.5％.Conclusions The function of dose reconstruction and independent calculation of the Mobius system yeilds the same accuracy with the treatment planning system,which can quickly perform three-dimensional independent dose verification in the clinical radiotherapy plan and accelerator log file-based three-dimensional dose verification throughout the treatment,thereby guarantting and providing the safe and reliable technical support for clinical treatment.

Objective To investigate value of peripheral NLR and PLR for the survival of patients with neuroblastoma.Methods The clinical data of 41 neuroblastoma patients were analyzed by the Kaplan-Meier,Log-rank test,and multivariate COX regression.Results NLR,PLR levels of neuroblastoma patients were significantly higher than that in the healthy control group (1.81 ±0.29 vs.1.07 ±0.29,P ＜ 0.01) (169 ± 23 vs.76 ± 3,P ＜ 0.01);The elder the age,the higher the clinical stages,the higher the serum levels of NSE,and urine VMA were,the higher was the NLR (x2 =3.93,6.286,7.676,6.689,all P＜0.05) and PLR (x2 =4.111,5.707,8.019,8.922,all P ＜0.05).The higher the serum level of LDH,the higher was the NLR (x2 =7.769,P =0.02).3-year overall survival in low NLR group was 84％ and that in high NLR group was 73％ (x2 =4.002,P =0.045);3-year progression-free survival in low NLR group was 74％ and that in high NLR group was 50％ (x2 =4.082,P =0.043);3-year progression-free survival of low PLR group was 85％ and high PLR group was 38％ (x2 =9.388,P =0.002).The clinical stages,MYCN genetic expression,NLR levels were independent factors for the overall survial in patients with neuroblastoma (P ＜ 0.05).Conclusion Pretreatment NLR level can effectively predict the prognosis of neuroblastoma.