Objective: To explore the potential application of PAK4-PROTAC targeted degradation drug (PpD) in renal cancer immunotherapy. Methods: TIMER 2.0 and TISIDB databases were used to analyze the relationship among PAK4 expression, tumor purity and abundance of immune cell infiltration in renal tumor microenvironment (TEM).Renal cancer cell lines OS-RC-2, 786-O and ACHN were treated with 0, 125 and 250 nmol/L PpD, and the effects of Jurkat cell co-culture on the results were investigated.The cell apoptosis was detected with flow cytometry, and the expression of programmed cell death 1 ligand 1 (PD-L1) in renal cancer cells was detected with immunoblotting. Results: The high expression of PAK4 was positively related to immune purity, and inhibited the abundance of immune killer cells in TEM, such as CD8 T cells, CD4 T cells, natural killer cells and dendritic cells.With 250 nmol/L PpD treatment, there were 21.02% apoptotic cells in OS-RC-2, 29.67% apoptotic cells in 786-O, and 15.39% apoptotic cells in ACHN, respectively.However, with the same concentration of 250 nmol/L PpD treatment, cell apoptotic rate was sharply increased to 70.13% in OS-RC-2/Jurkat, 70.68% in 780-O/Jurkat, and 60.27% in ACHN/Jurkat co-culture models, respectively. Conclusion: PpD can promote apoptosis of renal cancer cells by reducing the expression of PAK4 protein, and enhance the killing effects of immune cells on tumor cells.

Abstract Modern western medicine typically focuses on treating specific symptoms or diseases, and traditional Chinese medicine (TCM) emphasizes the interconnections of the body’s various systems under external environment and takes a holistic approach to preventing and treating diseases. Phenomics was initially introduced to the field of TCM in 2008 as a new discipline that studies the laws of integrated and dynamic changes of human clinical phenomes under the scope of the theories and practices of TCM based on phenomics. While TCM Phenomics 1.0 has initially established a clinical phenomic system centered on Zhenghou (a TCM definition of clinical phenome), bottlenecks remain in data standardization, mechanistic interpretation, and precision intervention. Here, we systematically elaborates on the theoretical foundations, technical pathways, and future challenges of integrating digital medicine with TCM phenomics under the framework of “TCM phenomics 2.0”, which is supported by digital medicine technologies such as artificial intelligence, wearable devices, medical digital twins, and multi-omics integration. This framework aims to construct a closed-loop system of “Zhenghou–Phenome–Mechanism–Intervention” and to enable the digitization, standardization, and precision of disease diagnosis and treatment. The integration of digital medicine and TCM phenomics not only promotes the modernization and scientific transformation of TCM theory and practice but also offers new paradigms for precision medicine. In practice, digital tools facilitate multi-source clinical data acquisition and standardization, while AI and big data algorithms help reveal the correlations between clinical Zhenghou phenomes and molecular mechanisms, thereby improving scientific rigor in diagnosis, efficacy evaluation, and personalized intervention. Nevertheless, challenges persist, including data quality and standardization issues, shortage of interdisciplinary talents, and insufficiency of ethical and legal regulations. Future development requires establishing national data-sharing platforms, strengthening international collaboration, fostering interdisciplinary professionals, and improving ethical and legal frameworks. Ultimately, this approach seeks to build a new disease identification and classification system centered on phenomes and to achieve the inheritance, innovation, and modernization of TCM diagnostic and therapeutic patterns.

OBJECTIVE: To review the research progress on the lower limb biomechanical characteristics of patients with discoid lateral meniscus (DLM) injury after surgery. METHODS: By searching relevant domestic and international research literature on DLM, the postoperative characteristics of knee joint movement biomechanics, tibiofemoral joint stress distribution, lower extremity force line, and patellofemoral joint changes in patients with DLM injury were summarized. RESULTS: Surgical treatment can lead to varying degrees of changes in the lower limb biomechanical characteristics of patients with DLM injury. Specifically, the kinematic biomechanics of the knee joint can significantly improve, but there are still problems such as extension deficits in the affected knee joint. The peak stress of the tibiofemoral joint decreases with the increase of the residual meniscus volume, and the degree of change is closely related to the residual meniscus volume. Preserving a larger volume of the meniscus, especially the anterior horn volume, helps to reduce stress concentration. The lower extremity force line will deviate outward after surgery, and the more meniscus is removed during surgery, the greater the change in the lower extremity force line after surgery. There are conditions such as cartilage degeneration, position and angle changes in the patellofemoral joint after surgery. CONCLUSION The changes in the lower limb biomechanical characteristics after DLM injury are closely related to the choice of surgical methods and rehabilitation programs. However, the mechanisms of biomechanical changes in multiple lower limb joints and individual differences still need to be further studied and clarified.
Humans ; Biomechanical Phenomena ; Tibial Meniscus Injuries/physiopathology* ; Menisci, Tibial/physiopathology* ; Knee Joint/surgery* ; Lower Extremity/physiopathology* ; Patellofemoral Joint/physiopathology* ; Range of Motion, Articular ; Knee Injuries/physiopathology*

OBJECTIVE: To compare the aesthetic effects of anterior maxilla clockwise rotation combined with segmental Le Fort Ⅰ osteotomy and whole maxilla clockwise rotation on improving paranasal concavity in patients with Class Ⅲ maxillofacial deformity. METHODS: A non-randomized controlled trial was designed, and 21 patients diagnosed with skeletal Class Ⅲ maxillofacial deformity were included. In the study, 11 patients in the test group were treated by segmental Le Fort Ⅰ osteotomy combined with anterior maxilla clockwise rotation, and 10 patients in the control group were treated by whole maxilla clockwise rotation. The CBCT and 3D photography of preoperative (T0), 2 weeks postoperative (T1), and 6 months postoperative (T2) were collected respectively, and the three-dimensional cephalometry was carried out. The differences of specific parameters between the two groups were compared by independent sample t-test, including saggital displacement of the cheek mass point (CK) and subalare point (SA), nasolabial angle, occlusal plane angle and labial inclination angle of the upper incisor. RESULTS: There were no significant differences of the parameters on T0 between the two groups. The average sagittal displacement of the upper incisors of the test group was (-0.71±1.67) mm and smaller than that of control group [(2.26±1.68) mm], t=-4.052, P < 0.05. The average angle of the occlusal plane clockwise rotation of the test group was 1.46°±2.38° and smaller than that of the control group (4.31°±1.83°), t=-3.047, P < 0.05. The angle of anterior maxilla clockwise rotation was 11.73°±2.81° during the surgery. The average saggital displacement of the paranasal soft tissue landmarks of the test group from T0 to T2 was larger than that of the control group [CK point, (4.96±1.18) mm vs. (2.01± 1.50) mm, P < 0.05;SA point, (5.19±1.17) mm vs. (2.69±1.45) mm, P < 0.05]. The labial inclination angle of the upper incisor of the test group was 112.15°±5.40° in T2 and significantly smaller than that of the control group (122.38°±8.83°), t=-3.237, P < 0.05. The nasolabial angle of the test group was 106.54°±12.82° in T2 and significantly larger than that of the control group (93.90°±12.46°), t=2.288, P < 0.05. CONCLUSION Compared with whole maxilla clockwise rotation, anterior maxilla clockwise rotation combined with segmental Le Fort Ⅰ osteotomy can increase the saggital displacement of the paranasal soft tissue, correct labial inclination of the upper incisors and the acute naso-labial angle and better improve the paranasal aesthetic defects in patients with Class Ⅲ maxillofacial deformity with less changing on the saggital orientation of the upper incisors and the occlusal plane angle.
Humans ; Maxilla/surgery* ; Female ; Male ; Osteotomy, Le Fort/methods* ; Malocclusion, Angle Class III/surgery* ; Adult ; Cephalometry ; Young Adult ; Rotation ; Adolescent

OBJECTIVES: To evaluate the protective effect of Schistosoma japonicum cystatin (rSj-Cystatin) in a mouse mode of "two-hit" sepsis. METHODS: Sixty male C57BL/6 mice randomized equally into sham-operated group, protein group, "two-hit" modeling group, and protein intervention group. In the former two groups, the mice received an intraperitoneal injection of 100 μL PBS followed by exposure of the cecum and then by intraperitoneal injection of 100 μL PBS or 25 μg rSj-Cystatin 30 min later; In the latter two groups, 100 μL PBS containing LPS (5 mg/kg) was injected intraperitoneally 24 h before cecal ligation and puncture (CLP), and 100 μL PBS or 25 μg rSj-Cystatin were injected 30 min after CLP. At 12 h after rSj-Cystatin treatment, 6 mice from each group were sacrificed for detection of TNF-α, IL-6, IL-10, TGF-β, iNOS and Arg-1 in the serum, spleen, liver, lung and kidney tissues using ELISA, for examinations of liver, lung and kidney pathologies with HE staining, and for analysis of CD3⁺CD4⁺CD25⁺Foxp3⁺ T cell percentage in the spleen using flow cytometry. The remaining mice were observed for general condition and 72-h survival. RESULTS: The 72-h survival rates in the 4 groups were 100%, 100%, 0% and 20%, respectively, showing significant differences between the latter two groups. The mouse models of "two-hit" sepsis exhibited obvious tissue pathologies and significant elevations of TNF-α and IL-6 in both the serum and tissue homogenate, which were significantly ameliorated by rSj-Cystatin treatment. Treatment with rSj-Cystatin also increased IL-10 and TGF-β levels and spleen CD3⁺CD4⁺CD25⁺Foxp3⁺ T cell percentage. The septic mouse models also showed increased iNOS levels in all the detected tissues and a decreased Arg-1 level in the kidney, and these changes were obviously improved by rSj-Cystatin treatment. CONCLUSIONS rSj-Cystatin has a protective effect against "two-hit" sepsis in mice by regulating the inflammatory microenvironment.
Animals ; Mice ; Sepsis/drug therapy* ; Male ; Schistosoma japonicum/chemistry* ; Mice, Inbred C57BL ; Cystatins/therapeutic use* ; Interleukin-10/metabolism* ; Interleukin-6/blood* ; Tumor Necrosis Factor-alpha/blood* ; Disease Models, Animal ; Transforming Growth Factor beta/metabolism*

Instrument separation is a critical complication during root canal therapy, impacting treatment success and long-term tooth preservation. The etiology of instrument separation is multifactorial, involving the intricate anatomy of the root canal system, instrument-related factors, and instrumentation techniques. Instrument separation can hinder thorough cleaning, shaping, and obturation of the root canal, posing challenges to successful treatment outcomes. Although retrieval of separated instrument is often feasible, it carries risks including perforation, excessive removal of tooth structure and root fractures. Effective management of separated instruments requires a comprehensive understanding of the contributing factors, meticulous preoperative assessment, and precise evaluation of the retrieval difficulty. The application of appropriate retrieval techniques is essential to minimize complications and optimize clinical outcomes. The current manuscript provides a framework for understanding the causes, risk factors, and clinical management principles of instrument separation. By integrating effective strategies, endodontists can enhance decision-making, improve endodontic treatment success and ensure the preservation of natural dentition.
Humans ; Root Canal Therapy/adverse effects* ; Consensus ; Root Canal Preparation/adverse effects*

Antibody-drug conjugates (ADCs) represent a promising class of targeted cancer therapeutics that combine the specificity of monoclonal antibodies with the potency of cytotoxic payloads. Despite their therapeutic potential, the use of ADCs faces significant challenges, including off/on-target toxicity and resistance development. This review examines the current landscape of ADC development, focusing on the critical aspects of target selection and antibody engineering. We discuss strategies to increase ADC efficacy and safety, including multitarget approaches, pH-dependent antibodies, and masked peptide technologies. The importance of comprehensive antigen expression profiling in both tumor and normal tissues is emphasized, highlighting the role of advanced technologies, such as single-cell sequencing and artificial intelligence, in optimizing target selection. Furthermore, we explore combination therapies and innovations in linker‒payload chemistry, which may provide approaches for expanding the therapeutic window of ADCs. These advances pave the way for the development of more precise and effective cancer treatments, potentially extending ADC applications beyond oncology.
Humans ; Immunoconjugates/adverse effects* ; Neoplasms/immunology* ; Animals ; Antibodies, Monoclonal/therapeutic use* ; Antineoplastic Agents/therapeutic use*

Background::There is a need for effective and safe therapies for psoriasis that provide sustained benefits. The aim of this study was to assess the efficacy and safety of tildrakizumab, an anti-interleukin-23p19 monoclonal antibody, for treating moderate-to-severe plaque psoriasis in Chinese patients.Methods::In this multi-center, double-blind, phase III trial, patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned (1:1) to receive subcutaneous tildrakizumab 100 mg or placebo at weeks 0 and 4. Patients initially assigned to placebo were switched to receive tildrakizumab at weeks 12, 16, and every 12 weeks thereafter. Patients in the tildrakizumab group continued with tildrakizumab at week 16, and every 12 weeks until week 52. The primary endpoint was the Psoriasis Area and Severity Index (PASI 75) response rate at week 12.Results::At week 12, tildrakizumab demonstrated significantly higher PASI 75 response rates (66.4% [73/110] vs. 12.7% [14/110]; difference, 51.4% [95% confidence interval (CI), 40.72, 62.13]; P <0.001) and Physician’s Global Assessment (60.9% [67/110] vs. 10.0% [11/110]; difference, 49.1% [95% CI, 38.64, 59.62]; P <0.001) compared to placebo. PASI 75 response continued to improve over time in both tildrakizumab and placebo-switching to tildrakizumab groups, reaching maximal efficacy after 28 weeks (86.8% [92/106] vs. 82.4% [89/108]) and maintained up to 52 weeks (91.3% [95/104] vs. 87.4% [90/103]). Most treatment-emergent adverse events were mild and not related to tildrakizumab. Conclusion::Tildrakizumab demonstrated durable efficacy through week 52 and was well tolerated in Chinese patients with moderate-to-severe plaque psoriasis.Trial registration::ClinicalTrials.gov, NCT05108766.

Background::Limited information exists regarding the impact of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection on psoriasis patients. The objective of this study was to identify clinical factors associated with the prognosis of psoriasis following SARS-CoV-2 infection.Methods::A retrospective, multicenter study was conducted between March and May 2023. Univariable and multivariable logistic regression analyses were employed to identify factors associated with coronavirus disease 2019 (COVID-19)-related psoriasis outcomes. The study included 2371 psoriasis patients from 12 clinical centers, with 2049 of them having been infected with SARS-CoV-2.Results::Among the infected groups, lower exacerbation rates were observed in individuals treated with biologics compared to those receiving traditional systemic or nonsystemic treatments (22.3% [236/1058] vs. 39.8% [92/231] vs. 37.5% [140/373], P <0.001). Psoriasis progression with lesions (adjusted odds ratio [OR] = 8.197, 95% confidence interval [95% CI] = 5.685–11.820, compared to no lesions), hypertension (adjusted OR = 1.582, 95% CI = 1.068–2.343), traditional systemic (adjusted OR = 1.887, 95% CI= 1.263–2.818), and nonsystemic treatment (adjusted OR= 1.602, 95% CI= 1.117–2.297) were found to be associated with exacerbation of psoriasis after SARS-CoV-2 infection, but not biologics (adjusted OR = 0.931, 95% CI = 0.680–1.274, compared to no treatment), according to multivariable logistic regression analysis. Conclusions::A reduced risk of psoriasis exacerbation after SARS-CoV-2 infection was observed with biologics compared to traditional systemic and nonsystemic treatments. Significant risk factors for exacerbation after infection were identified as existing psoriatic lesions and hypertension.