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.

Cardiac fibrosis is characterized by an elevated amount of extracellular matrix (ECM) within the heart. However, the persistence of cardiac fibrosis ultimately diminishes contractility and precipitates cardiac dysfunction. Circular RNAs (circRNAs) are emerging as important regulators of cardiac fibrosis. Here, we elucidate the functional role of a specific circular RNA CELF1 in cardiac fibrosis and delineate a novel feedback loop mechanism. Functionally, circ-CELF1 was involved in enhancing fibrosis-related markers' expression and promoting the proliferation of cardiac fibroblasts (CFs), thereby exacerbating cardiac fibrosis. Mechanistically, circ-CELF1 reduced the ubiquitination-degradation rate of BRPF3, leading to an elevation of BRPF3 protein levels. Additionally, BRPF3 acted as a modular scaffold for the recruitment of histone acetyltransferase KAT7 to facilitate the induction of H3K14 acetylation within the promoters of the Celf1 gene. Thus, the transcription of Celf1 was dramatically activated, thereby inhibiting the subsequent response of their downstream target gene Smad7 expression to promote cardiac fibrosis. Moreover, Celf1 further promoted Celf1 pre-mRNA transcription and back-splicing, thereby establishing a feedback loop for circ-CELF1 production. Consequently, a novel feedback loop involving CELF1/circ-CELF1/BRPF3/KAT7 was established, suggesting that circ-CELF1 may serve as a potential novel therapeutic target for cardiac fibrosis.

Radiochemotherapy-induced oral mucositis (OM) is a common oral complication in patients with tumors following head and neck radiotherapy or chemotherapy. Erosion and ulcers are the main features of OM that seriously affect the quality of life of patients and even the progress of tumor treatment. To date, differences in clinical prevention and treatment plans for OM have been noted among doctors of various specialties, which has increased the uncertainty of treatment effects. On the basis of current research evidence, this expert consensus outlines risk factors, clinical manifestations, clinical grading, ancillary examinations, diagnostic basis, prevention and treatment strategies and efficacy indicators for OM. In addition to strategies such as basic oral care, anti-inflammatory and analgesic agents, anti-infective agents, pro-healing agents, and photobiotherapy recommended in previous guidelines, we also emphasize the role of traditional Chinese medicine in OM prevention and treatment. This expert consensus aims to provide references and guidance for dental physicians and oncologists in formulating strategies for OM prevention, diagnosis, and treatment, standardizing clinical practice, reducing OM occurrence, promoting healing, and improving the quality of life of patients.
Humans ; Chemoradiotherapy/adverse effects* ; Consensus ; Risk Factors ; Stomatitis/etiology*

Objective To investigate the efficacy of varying doses of methylprednisolone(MP)on mice with acute exacerbations of chronic obstructive pulmonary disease(AECOPD)induced with influenza A virus(IAV).Methods Mouse model of COPD was established using LPS combined with smoking for 12 weeks,and then these COPD mice were treated with administration of 40 μL IAV via nasal drip to establish a AECOPD model.A total of 15 AECOPD mice were randomly divided into low-,medium-and high-dose MP groups,oseltamivir group and blank group.The body weight and survival time were monitored within 10 d after IAV infection.On days 1,3,and 5 post-treatment,lung function was assessed using whole-body plethysmography(WBP),inflammatory factors in bronchoalveolar lavage fluid(BALF)were quantified with ELISA,viral titers in BALF were determined using plaque assays,and colony-forming units were evaluated with blood agar plates.Immunofluorescence analysis:① Pulmonary immunofluorescence assay:Mice were randomly categorized into(n=4):LPS 1-day group,LPS 3-day group,and LPS+MP treatment group.All groups received an initial dose of LPS via atomization;subsequently,the LPS+MP treatment group received a single gavage dose of MP.Lung tissues were harvested from the 1-day LPS group on 1 d post-treatment,and from the 3-day LPS and LPS+MP groups on 3 d for immunofluorescence staining.② Cellular immunofluorescence assay:Mouse bone marrow neutrophils were classified into blank control(no intervention),LPS stimulation(LPS group),MP intervention with LPS stimulation(LPS+MP group),and MP intervention alone(MP group).The above cells were collected in 4 h after corresponding interventions for subsequent cellular immunofluorescence analysis.Results ①The medium-dose MP group demonstrated the most significant improvement in survival rate,weight recovery,and lung function when compared to other groups(P＜0.05).② Treatment of medium-dose MP obviously reduced the levels of IL-6 and neutrophil extracellular traps(NETs)(P＜0.05),while,elevated inflammatory factors and NETs were observed in the high-dose MP group on day 5 post-treatment.③ Notable decline in the lung injury score was found in the medium-dose MP group than the other groups(P＜0.05).④The high-dose MP group exhibited substantial bacterial proliferation and delayed viral clearance since day 5 after treatment.Conclusion Medium-dose MP shows best efficacy in treatment of IAV-induced AECOPD,and the dose neither delays viral clearance nor increases the risk of bacterial infection following viral infection.

AIM: To evaluate the performance of three distinct large language models(LLM), including GPT-3.5, GPT-4, and PaLM2, in responding to queries within the field of ophthalmology, and to compare their performance with three different levels of medical professionals: medical undergraduates, master of medicine, and attending physicians.METHODS: A total of 100 ophthalmic multiple-choice tests, which covered ophthalmic basic knowledge, clinical knowledge, ophthalmic examination and diagnostic methods, and treatment for ocular disease, were conducted on three different kinds of LLM and three different levels of medical professionals(9 undergraduates, 6 postgraduates and 3 attending physicians), respectively. The performance of LLM was comprehensively evaluated from the aspects of mean scores, consistency and confidence of response, and it was compared with human.RESULTS: Notably, each LLM surpassed the average performance of undergraduate medical students(GPT-4:56, GPT-3.5:42, PaLM2:47, undergraduate students:40). Specifically, performance of GPT-3.5 and PaLM2 was slightly lower than those of master's students(51), while GPT-4 exhibited a performance comparable to attending physicians(62). Furthermore, GPT-4 showed significantly higher response consistency and self-confidence compared with GPT-3.5 and PaLM2.CONCLUSION: LLM represented by GPT-4 performs well in the field of ophthalmology, and the LLM model can provide clinical decision-making and teaching aids for clinicians and medical education.

Objective To analyze and summarize the epidemiological characteristics of gastric Helicobacter pylori in pa-tients experiencing gastric discomfort in Yuexiu Dongshan Community,Guangzhou.Methods A total of 312 patients who visited Yuexiu District Dongshan Community Health Service Center for stomach upset testing between April 2023 and July 2023 were en-rolled in the study.The distribution characteristics of positive Helicobacter pylori were analyzed among the patients of different age and gender.Results Out of the 312 cases in the population,93 cases tested positive and 219 tested negative,with a positive de-tection rate of 29.81%.Specifically,28 cases tested positive,and 74 cases tested negative in the male population,with a positive detection rate of 27.45%.In the female population,65 cases tested positive,and 145 cases tested negative,with a positive detec-tion rate of 30.95%.The difference in positive rates by gender was not statistically significant(X2 =0.402,P=0.526).Among the male patients infected with Helicobacter,the mean value of delta over baseline of the C13 urea breath test(DOB)was(17.31±11.84).The DOB value was insignificantly higher in the males than in the females(t =1.430,P=0.156).There was no signifi-cant increasing or decreasing trend in the distribution of positive rates by age.The composition ratio of positive patients was predom-inant in the group aged 40 and above,accounting for 79.57%of the total number of positive cases.Among the individuals aged less than 60 infected with Helicobacter pylori,the mean duration of the breath test was(14.95±11.87),while among those aged over 61,the mean duration of the breath test was(24.66±22.71).The disparity between the two groups was statistically significant(t =2.643,P=0.009 7).Conclusion Gastric Helicobacter pylori can be detected in individuals of all genders and ages,and it is a primary cause of gastric discomfort.Community-based C13 breath tests can detect the presence of infections of helicobacter py-lori at an early stage.Antibiotics can be administered to treat the infections,thereby reducing the incidence of gastric tumors.

Objective:To investigate the evaluation efficacy and predictive prognostic value of alpha-fetoprotein (AFP) response in tyrosine kinase inhibitors (TKIs) in combination with PD-1 inhibitors (α-PD-1) for intermediate-to-advanced hepatocellular carcinoma (HCC).Methods:The retrospective cohort study was conducted. The clinicopathological data of 205 patients with intermediate-to-advanced HCC who were admitted to 9 medical centers, including Mengchao Hepatobiliary Hospital of Fujian Medical University et al, from March 2020 to July 2022 were collected. There were 178 males and 27 females, aged (52±12)years. Based on AFP response at 6-8 weeks after treatment, patients were divided into the AFP response group (AFP level decreased by ≥50% compared to baseline) and the AFP no response group (AFP level decreased by <50% compared to baseline). Observation indicators: (1) AFP response evaluation of anti-tumor efficacy; (2) comparison of patient prognosis; (3) analysis of factors affecting patient prognosis. Measurement data with normal distrubution were represented as Mean± SD, and measurement data with skewed distribution were represented as M(range) and M( Q1, Q3). Count data were described as absolute numbers, and comparison between groups was conducted using the chi-square test. The Kaplan-Meier method was used to draw survival curve and calculate survival rate, and the Log-Rank test was used for survival analysis. The COX proportional risk model was used for univariate analysis and the COX stepwise regression model was used for multivariate analysis. Results:(1) AFP response evaluation of anti-tumor efficacy. Before treatment, all 205 patients were positive of AFP, with a baseline AFP level of 1 560(219,3 400)μg/L. All 205 patients were treated with TKIs in combination with α-PD-1, and the AFP level was 776(66,2 000)μg/L after 6 to 8 weeks of treatment. Of the 205 patients, 88 cases were classified as AFP response and 117 cases were classified as AFP no response. According to the response evaluation criteria in solid tumors version 1.1, the objective response rate (ORR) and disease control rate (DCR) were 42.05%(37/88) and 94.32%(83/88) in patients of the AFP response group and 16.24% (19/117) and 64.10% (75/117) in patients of the AFP no response group, showing significant differences between them ( χ2=16.846, 25.950, P<0.05). According to the modified response evaluation criteria in solid tumors, the ORR and DCR were 69.32% (61/88) and 94.32% (83/88) in patients of the AFP response group and 33.33% (39/117) and 64.10% (75/117) in patients of the AFP no response group, showing significant differences between them ( χ2=26.030, 25.950, P<0.05). (2) Comparison of patient prognosis. All 205 patients were followed up for 12.4(range, 2.4-34.0)months after treatment. The median progression free survival time and total survival time were 5.5 months and 17.8 months, respectively. The 1-year, 2-year progression free survival rates were 20.8% and 7.2%, and the 1-year, 2-year overall survival rates were 68.7% and 31.5%, respectively. The median progression free survival time, 1-year and 2-year progression free survival rates were 9.7 months, 39.6% and 14.2% in patients of the AFP response group and 3.7 months, 7.8% and 2.0% in patients of the AFP no response group, showing a significant difference in progression free survival between them ( χ2=43.154, P<0.05). The median overall survival time, 1-year and 2-year overall survival rates were not reached, 85.2% and 56.3% in patients of the AFP response group and 14.6 months, 56.3% and 14.5% in patients of the AFP no response group, showing a significant difference in overall survival between them ( χ2=33.899, P<0.05). (3) Analysis of factors affecting patient prognosis. Results of multivariate analysis showed that invasion of large blood vessels, extrahepatic metastasis, combined hepatic artery intervention therapy, and AFP response were independent factors influencing progression free survival in patients with intermediate-to-advanced HCC who were treated with TKIs in combination with α-PD-1 ( hazard ratio=1.474, 1.584, 0.631, 0.367, 95% confidence interval as 1.069-2.033, 1.159-2.167, 0.446-0.893, 0.261-0.516, P<0.05), and Eastern Cooperative Oncology Group score, invasion of large blood vessels, extrahepatic metastasis, and AFP response were independent factors influencing overall survival in patients with intermediate-to-advanced HCC who were treated with TKIs in combination with α-PD-1 ( hazard ratio= 1.347, 1.914, 1.673, 0.312, 95% confidence interval as 1.041-1.742, 1.293-2.833, 1.141-2.454, 0.197-0.492, P<0.05). Conclusions:AFP response at 6-8 weeks after treatment can effectively evaluate anti-tumor efficacy of TKIs in combination with α-PD-1 for intermediate-to-advanced HCC. AFP response is the independent factor influencing progression free survival and overall survival in patients with intermediate-to-advanced HCC who were treated with TKIs in combination with α-PD-1.

Objective:To investigate the clinical characteristics, muscle pathological features and treatment in patients with Juvenile idiopathic inflammatory myopathy (JIIM) with positive anti-nuclear matrix protein 2 (NXP2) antibody.Methods:The clinical data of 8 IMM patients with positive anti-NXP2 antibody were collected and the clinical manifestations, auxiliary examinations, muscle pathological changes and therapeutic effects were retrospectively analyzed.Results:The ratio of male to female was 1:3. The median age of disease onset was (6.1±3.8) years. Eight cases had proximal muscle weakness, 7 had dermatomyositis-like rash, 5 had myalgia,4 had calcinosis,3 had skin ulcer, 2 had edema and 1 had abdominal pain. Five cases had elevated serum creatine kinase. Eight cases with lower limb muscle MRI showed abnormal signals in muscle, space between muscles and fat tissue, 3 cases with chest high-resolution CT (HRCT) showed interstitial lung disease. Abdominal CT of 1 case showed irregular thickening, edema and peripheral inflammatory exudation in ascending colon and proximal transverse colon. Pathological biopsy of skeletal muscle showed perifascicular atrophy, inflammatory cell infiltration in fascicular membrane and around small vessels and muscle fiber space. Edema, hyperplasia could be seen in interstitium; but dissolved necrosis, and regenerated muscle fibers were rarely seen. Treatments included glucocorticoids, immunosuppressive agents and biological agents (1 case). After 6 months of follow-up, 5 cases had good outcomes and 3 cases had poor outcomes.Conclusion:Dermatomyositis is the major clinical manifestation of idiopathic inflammatory myopathy with positive anti-NXP2 antibody.It is associated with myasthenia, calcinosis, skin ulcers and intestinal vasculitis. The pathological changes in skeletal muscle are relatively slightmild. Glucocorticoids combined with immunosuppressive agents are effective in most cases.

Objective:To analyze the clinical characteristics and influencing factors of vascular involvement in Beh?et′s Disease (BD) to improve and provideunderstanding of insights for clinicians to better understand this condition.Methods:Clinical data from 220 BD patients admitted to the First Affiliated Hospital of Guangxi Medical University from January 2012 to May 2022 were collected. Clinical manifestations and laboratory findings were compared between BD patients with and without vascular involvement, as well as between those with improved conditions and those with progressive conditions. Binary logistic regression was used to analyze the influencing factors.Results:①The average age of the 220 BD patients was 36.5±15.3 years. Among them, 23 patients (10.5%) had vascular involvement, including 20 males (87.0%).②Compared to BD patients without vascular involvement, those with vascular involvement had significantly higher rates of smoking [6.1%(12/197) vs.34.8%(8/23), χ2=17.19, P<0.001], cardiac involvement [1.5%(3/197) vs. 13.0%(9/23), χ2=6.42, P=0.011], and elevated C-reactive protein(CRP) levels (78.3% vs. 56.3%, χ2=4.08, P=0.043).③ Among BD patients with vascular involvement, 11 cases (47.8%) had venous lesions, and 20 cases (87.0%) had arterial lesions, with 8 cases (34.8%) having both venous and arterial involvement. The most common type of vascular involvement was arterial dilatation (11 cases), mainly aneurysms (10 cases), and deep venous thrombosis of the lower extremities (7 cases).④The 23 BD patients with vascular involvement were followed up for an average of 18.3 months. Among them, 16 patients (69.6%) showed stable improvement, while 7 patients (30.4%) experienced disease progression, including 4 deaths (1 male and 3 females). A total of 91.3% (21/23) of the patients received glucocorticoid therapy. Immunosuppressive therapy was administered to 82.6% (19/23) of the patients, with 65.2% (10/23) receiving with cyclophosphamide and 43.5% receiving with thalidomide. Additionally, 13% (3/23) of the patients were treated with cyclosporine and methotrexate, respectively, and 8.7% (2/23) were treated with received mycophenolate mofetil. Anticoagulant therapy was given to 21.7% (5/23) of the patients, using either warfarin or low molecular weight heparin. Biologic therapy was administered to 17.4% (4/23) of the patients, and surgical intervention was performed in 43.5% (10/23) of the patients. ⑤Binary logistic regression analysis identified male gender [ OR(95% CI)=5.70(1.60, 20.90), P=0.009] as an indepe-ndent risk factor for vascular involvement in BD. Conclusion:The incidence of vascular involvement in BD is 10.5%, with a higher prevalence in males. Arterial involvement is more common than venous involvement, with arterial aneurysms being the most common manifestation. Clinicians should pay attention to CRP and total cholesterol levels in BD patients.