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 prognostic value of baseline 18F-FDG PET/CT metabolic parameters in locally advanced cervical cancer (LACC) after concurrent chemoradiotherapy (CCRT). Methods:From September 2015 to October 2021, the clinical data of 180 LACC patients (age: 22-76 years) who underwent 18F-FDG PET/CT before CCRT at Affiliated Cancer Hospital of Shandong First Medical University were analyzed retrospectively. The metabolic tumor volume (MTV), total lesion glycolysis (TLG), SUV max, and SUV mean were computed by using the margin threshold of 42%SUV max. The optimal threshold for predicting progression-free survival (PFS) was obtained by ROC curve analysis. The Kaplan-Meier method was applied for survival analysis, and the log-rank test was applied to compare the survival rate between groups. Multivariate Cox proportional hazard regression was used to analyze progression for PFS. Results:The median follow-up was 19.1 months, and 54 patients (30.0%, 54/180) suffered from disease progression. ROC curve analysis showed that the optimal cut-off value of MTV was 31.145 ml, with the AUC of 0.641. Para-aortic lymph node (PALN) metastasis had the highest AUC value (0.589) among the clinical factors, followed by International Federation of Gynecology and Obstetrics (FIGO) stage (0.581). The 1-year PFS rates of patients with MTV<31.145 ml ( n=88) and MTV≥31.145 ml ( n=92) were 80.68% and 59.78%, respectively ( χ2=13.72, P<0.001). Multivariate Cox analysis demonstrated that pathological type (hazard ratio ( HR)=3.075, 95% CI: 1.370-6.901, P=0.006), FIGO stage ( HR=1.955, 95% CI: 1.031-3.707, P=0.040), PALN metastasis ( HR=2.136, 95% CI: 1.202-3.796, P=0.010) and MTV ( HR=2.449, 95% CI: 1.341-4.471, P=0.004) were the significant predictors for PFS. Conclusions:Pathological type, FIGO stage, PALN metastasis and MTV are independent prognostic risk factors for PFS. MTV as the baseline 18F-FDG PET/CT metabolic parameter, can realize prognostic stratification analysis.

The incidence and mortality of lung cancer rank first among malignant tumors in the world worldwide. Non-small cell lung cancer (NSCLC) is the main pathological type, with a significant proportion being driver gene-negative NSCLC. When accompanied by brain metastasis, radiotherapy is the optimal local therapy, apart from surgery, and which is widely used applied in clinical practice. With the continuous development of technology and drugs, the survival of patients with brain metastases has been generally improvedprolonged. In the era of precision medicine, the concept and technology of radiotherapy are evolving towards precision and diversification. In this article, the evolution of radiotherapy techniques and its combined application with other treatment methods were reviewed, aiming to provide references for the selection of radiotherapy protocol for driver gene-negative NSCLC patients with brain metastases in clinical practice.

Objective To build a healthcare data quality testing system to solve the problems due to low-quality data.Methods The system was developed based on 11 evaluation indicators in four categories including completeness,accuracy,data scope and timeliness,which was realized with MySQL 5.7 database,Browser/Server(B/S)architecture,Python,Java,Vue language and vscode neovim development tool.There were four functional modules involved in the system for system setup,data management,quality management and quality analysis.Results The system developed managed data quality testing rules flexibly and normatively,which could be used for periodical analysis of data quality and viewing of data testing results conveniently and enhanced the efficiency for testing data quality and solving data quality problems.Conclusion The system developed enhances data quality and provides data support for hospitals.[Chinese Medical Equipment Journal,2024,45(4):7-12]

Objective To design a post-structured technology-based clinical disease database system to solve the problems of the traditional disease database system in dependence on manual judgment,lack of auxiliary annotation and poor availability of electronic medical record data.Methods An entity recognition model was constructed with I2B2 standard and bi-directional long short-term memory(BiLSTM)model to form a medical record template library,and some relational templates were generated and complex medical entities were extracted to realize post-structuring of electronic medical records.Then a clinical disease database system was established based on the post-structured electronic medical record technology,which was composed of the modules for medical record structuring,structured assessment,data annotation,routine functions and system management.Results The system developed transformed the text of electronic medical records into structured language,contributed to data element extraction and intelligent structured service and enhanced the efficiency of clinical treatment and scientific research.Conclusion The system developed improves the data availability of clinical diseases,reduces the workload of user data processing,ensures the quality of data application and lays a foundation for assisted decision making during clinical treatment and scientific research.[Chinese Medical Equipment Journal,2024,45(4):20-26]

Objective: To understand the current status of diagnosis and treatment of chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL) among hematologists, oncologists, and lymphoma physicians from hospitals of different levels in China. Methods: This multicenter questionnaire survey was conducted from March 2021 to July 2021 and included 1,000 eligible physicians. A combination of face-to-face interviews and online questionnaire surveys was used. A standardized questionnaire regarding the composition of patients treated for CLL/SLL, disease diagnosis and prognosis evaluation, concomitant diseases, organ function evaluation, treatment selection, and Bruton tyrosine kinase (BTK) inhibitor was used. Results: ①The interviewed physicians stated that the proportion of male patients treated for CLL/SLL is higher than that of females, and the age is mainly concentrated in 61-70 years old. ②Most of the interviewed physicians conducted tests, such as bone marrow biopsies and immunohistochemistry, for patient diagnosis, in addition to the blood test. ③Only 13.7% of the interviewed physicians fully grasped the initial treatment indications recommended by the existing guidelines. ④In terms of cognition of high-risk prognostic factors, physicians' knowledge of unmutated immunoglobulin heavy-chain variable and 11q- is far inferior to that of TP53 mutation and complex karyotype, which are two high-risk prognostic factors, and only 17.1% of the interviewed physicians fully mastered CLL International Prognostic Index scoring system. ⑤Among the first-line treatment strategy, BTK inhibitors are used for different types of patients, and physicians have formed a certain understanding that BTK inhibitors should be preferentially used in patients with high-risk factors and elderly patients, but the actual use of BTK inhibitors in different types of patients is not high (31.6%-46.0%). ⑥BTK inhibitors at a reduced dose in actual clinical treatment were used by 69.0% of the physicians, and 66.8% of the physicians had interrupted the BTK inhibitor for >12 days in actual clinical treatment. The use of BTK inhibitors is reduced or interrupted mainly because of adverse reactions, such as atrial fibrillation, severe bone marrow suppression, hemorrhage, and pulmonary infection, as well as patients' payment capacity and effective disease progression control. ⑦Some differences were found in the perceptions and behaviors of hematologists and oncologists regarding the prognostic assessment of CLL/SLL, the choice of treatment options, the clinical use of BTK inhibitors, etc. Conclusion: At present, a gap remains between the diagnosis and treatment of CLL/SLL among Chinese physicians compared with the recommendations in the guidelines regarding the diagnostic criteria, treatment indications, prognosis assessment, accompanying disease assessment, treatment strategy selection, and rational BTK inhibitor use, especially the proportion of dose reduction or BTK inhibitor discontinuation due to high adverse events.
Female ; Humans ; Male ; Aged ; Middle Aged ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy* ; Prognosis ; Lymphoma, B-Cell ; Immunohistochemistry ; Immunoglobulin Heavy Chains/therapeutic use*

Chronic refractory wound (CRW) is one of the most challengeable issues in clinic due to complex pathogenesis, long course of disease and poor prognosis. Experts need to conduct systematic summary for the diagnosis and treatment of CRW due to complex pathogenesis and poor prognosis, and standard guidelines for the diagnosis and treatment of CRW should be created. The Guideline forthe diagnosis and treatment of chronic refractory wounds in orthopedic trauma patients ( version 2023) was created by the expert group organized by the Chinese Association of Orthopedic Surgeons, Chinese Orthopedic Association, Chinese Society of Traumatology, and Trauma Orthopedics and Multiple Traumatology Group of Emergency Resuscitation Committee of Chinese Medical Doctor Association after the clinical problems were chosen based on demand-driven principles and principles of evidence-based medicine. The guideline systematically elaborated CRW from aspects of the epidemiology, diagnosis, treatment, postoperative management, complication prevention and comorbidity management, and rehabilitation and health education, and 9 recommendations were finally proposed to provide a reliable clinical reference for the diagnosis and treatment of CRW.

Humans ; Rituximab/therapeutic use* ; Bendamustine Hydrochloride/therapeutic use* ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy* ; Lymphoma, B-Cell ; Protein Kinase Inhibitors/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols ; Treatment Outcome

This study aimed to elucidate the effect and underlying mechanism of Bovis Calculus in the treatment of ulcerative colitis(UC) through network pharmacological prediction and animal experimental verification. Databases such as BATMAN-TCM were used to mine the potential targets of Bovis Calculus against UC, and the pathway enrichment analysis was conducted. Seventy healthy C57BL/6J mice were randomly divided into a blank group, a model group, a solvent model(2% polysorbate 80) group, a salazosulfapyridine(SASP, 0.40 g·kg~(-1)) group, and high-, medium-, and low-dose Bovis Calculus Sativus(BCS, 0.20, 0.10, and 0.05 g·kg~(-1)) groups according to the body weight. The UC model was established in mice by drinking 3% dextran sulfate sodium(DSS) solution for 7 days. The mice in the groups with drug intervention received corresponding drugs for 3 days before modeling by gavage, and continued to take drugs for 7 days while modeling(continuous administration for 10 days). During the experiment, the body weight of mice was observed, and the disease activity index(DAI) score was recorded. After 7 days of modeling, the colon length was mea-sured, and the pathological changes in colon tissues were observed by hematoxylin-eosin(HE) staining. The levels of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin-6(IL-6), and interleukin-17(IL-17) in colon tissues of mice were detected by enzyme-linked immunosorbent assay(ELISA). The mRNA expression of IL-17, IL-17RA, Act1, TRAF2, TRAF5, TNF-α, IL-6, IL-1β, CXCL1, CXCL2, and CXCL10 was evaluated by real-time polymerase chain reaction(RT-PCR). The protein expression of IL-17, IL-17RA, Act1, p-p38 MAPK, and p-ERK1/2 was investigated by Western blot. The results of network pharmacological prediction showed that Bovis Calculus might play a therapeutic role through the IL-17 signaling pathway and the TNF signaling pathway. As revealed by the results of animal experiments, on the 10th day of drug administration, compared with the solvent model group, all the BCS groups showed significantly increased body weight, decreased DAI score, increased colon length, improved pathological damage of colon mucosa, and significantly inhibited expression of TNF-α,IL-6,IL-1β, and IL-17 in colon tissues. The high-dose BCS(0.20 g·kg~(-1)) could significantly reduce the mRNA expression levels of IL-17, Act1, TRAF2, TRAF5, TNF-α, IL-6, IL-1β, CXCL1, and CXCL2 in colon tissues of UC model mice, tend to down-regulate mRNA expression levels of IL-17RA and CXCL10, significantly inhibit the protein expression of IL-17RA,Act1,and p-ERK1/2, and tend to decrease the protein expression of IL-17 and p-p38 MAPK. This study, for the first time from the whole-organ-tissue-molecular level, reveals that BCS may reduce the expression of pro-inflammatory cytokines and chemokines by inhibiting the IL-17/IL-17RA/Act1 signaling pathway, thereby improving the inflammatory injury of colon tissues in DSS-induced UC mice and exerting the effect of clearing heat and removing toxins.
Mice ; Animals ; Colitis, Ulcerative/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Interleukin-6/metabolism* ; Interleukin-17/pharmacology* ; TNF Receptor-Associated Factor 2/pharmacology* ; TNF Receptor-Associated Factor 5/metabolism* ; Mice, Inbred C57BL ; Signal Transduction ; Colon ; p38 Mitogen-Activated Protein Kinases/metabolism* ; RNA, Messenger/metabolism* ; Dextran Sulfate/metabolism* ; Disease Models, Animal

Objective To create a recombinant rabies virus overexpressing IL-33 and to clarify the effect of IL-33 overexpression on the phenotypic characteristics of recombinant virus in vitro. Methods The IL-33 gene was obtained and amplified from the brain of a highly virulent strain of rabies infected mouse. It was then inserted between the G and L genes of the parental virus LBNSE genome by reversing genetic manipulation and rescuing a recombinant virus overexpressing IL-33. BSR cells or mouse NA cells were infected with recombinant rabies virus (rLBNSE-IL33) and the parental strain LBNSE. Sequencing and fluorescent antibody virus neutralization assay was employed to detect the stability of recombinant virus at multiplicity of infection=0.01. Viral titres focal forming units (FFU) were detected to plot multi-step growth curves (multiplicity of infection=0.01). Cytotoxicity assay kit was used to detect cellular activity. ELISA was adopted to identify the IL-33 in the supernatant of infected cells of different multiplicity of infection. Results Rescued rLBNSE-IL33 overexpressing IL-33 remained stable for at least 10 consecutive generations and had virus titers of approximately 10⁸ FFU/mL. rLBNSE-IL33 was able to express IL-33 at high levels in a dose-dependent manner, but no high expression of IL-33 was detected in the supernatant of cells infected by LBNSE. Examination of the titers of rLBNSE-IL33 and the parental strain LBNSE in BSR and NA cells over 5 days showed no significant differences and similar kinetic properties in growth. Overexpression of IL-33 had no significant effect on the proliferation and activity of infected cells. Conclusion Overexpression of IL-33 does not significantly affect the phenotypic characteristics of recombinant rabies virus in vitro.
Animals ; Cricetinae ; Mice ; Cell Line ; Interleukin-33/genetics* ; Rabies virus/genetics* ; Phenotype