Fabrication of bimetallic Ag@ZnO nanocomposite and its anti-cancer activity on cervical cancer via impeding PI3K/AKT/mTOR pathway.

INTRODUCTION: Bimetallic nanoparticles, specifically Zinc oxide (ZnO) and Silver (Ag), continue to much outperform other nanoparticles investigated for a variety of biological uses in the field of cancer therapy. This study introduces biosynthesis of bimetallic silver/zinc oxide nanocomposites (Ag@ZnO NCs) using the Crocus sativus extract and evaluates their anti-cancer properties against cervical cancer. METHODS: The process of generating bimetallic nanoparticles (NPs), namely Ag@ZnO NCs, through the utilization of Crocus sativus extract proved to be uncomplicated and eco-friendly. Various methods, such as UV-vis, DLS, FTIR, EDX, and SEM analyses, were utilized to characterize the generated Ag@ZnO NCs. The MTT assay was employed to assess the cytotoxic properties of biosynthesized bimetallic Ag@ZnO NCs against the HeLa cervical cancer cell line. Moreover, the impact of Ag@ZnO NCs on HeLa cells was assessed by examining cell survival, ROS production, MMP levels, and induced apoptosis. Through western blot analysis, the expression levels of the PI3K, AKT, mTOR, Cyclin D, and CDK proteins seemed to be ascertained. Using flow cytometry, the cancer cells' progression through necrosis and apoptosis, in addition to the cell cycle analysis, were investigated. RESULTS: Bimetallic Ag@ZnO NCs that were biosynthesized showed a high degree of stability, as demonstrated by the physicochemical assessments. The median size of the particles in these NCs was approximately 80-90 nm, and their zeta potential was -14.70 mV. AgNPs and ZnO were found, according to EDX data. Further, Ag@ZnO NCs hold promise as a potential treatment for cervical cancer. After 24 hours of treatment, a dosage of 5 µg/mL or higher resulted in a maximum inhibitory effect of 58 ± 2.9. The concurrent application of Ag/ZnO NPs to HeLa cells resulted in elevated apoptotic signals and a significant generation of reactive oxygen species (ROS). As a result, the bimettalic Ag@ZnO NCs treatment has been recognized as a chemotherapeutic intervention by inhibiting the production of PI3K, AKT, and mTOR-mediated regulation of propagation and cell cycle-regulating proteins. CONCLUSIONS: The research yielded important insights into the cytotoxic etiology of biosynthesized bimetallic Ag@ZnO NCs against HeLa cells. The biosynthesized bimetallic Ag@ZnO NCs have a significant antitumor potential, which appears to be associated with the development of oxidative stress, which inhibits the development of the cell cycle and the proliferation of cells. Therefore, in the future, biosynthesized bimetallic Ag@ZnO NCs may be used as a powerful anticancer drug to treat cervical cancer.

Norfloxacin adsorption by urban green waste biochar: characterization, kinetics, and mechanisms.

Biochar, as a potential adsorbent, has been widely employed to remove pollutants from sewage. In this study, a lignin-based biochar (CB-800) was prepared by a simple high-temperature pyrolysis using urban green waste (Cinnamomum camphora leaves) as a feedstock to remove norfloxacin (NOR) from water. Batch adsorption test results indicated that CB-800 had a strong removal capacity for NOR at a wide range of pH values. The maximum adsorption achieved in the study was 50.90 ± 0.64 mg/g at 298 K. The pseudo-first and second-order kinetic models and the Dubinin-Radushkevich isotherm fitted the experimental data well, indicating that NOR adsorption by CB-800 was a complex process involving both physi-sorption and chemi-sorption. The physical properties of CB-800 were characterized by SEM and BET. The mesoporous structures were formed hierarchically on the surface of CB-800 (with an average pore size of 2.760 nm), and the spatial structure of NOR molecules was more easily adsorbed by mesoporous structures. Combined with Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) analysis, it was showed that the main NOR adsorption mechanisms by CB-800 included ion exchange, π-electron coordination, hydrogen bonding, and electrostatic adsorption. Meanwhile, the reduction of C = O and pyridine nitrogen, and the presence of C-F2, also indicated the occurrence of substitution, addition, and redox. This study not only determined the reaction mechanism between biochar and NOR, but also provides guidance to waste managers for the removal of NOR from water by biochar. It is envisaged that the results will broaden the utilization of urban green waste.

Bioinspired Mechanically Robust and Recyclable Hydrogel Microfibers Based on Hydrogen-Bond Nanoclusters.

Mechanically robust hydrogel fibers have demonstrated great potential in energy dissipation and shock-absorbing applications. However, developing such materials that are recyclable, energy-efficient, and environmentally friendly remains an enormous challenge. Herein, inspired by spider silk, a continuous and scalable method is introduced for spinning a polyacrylamide hydrogel microfiber with a hierarchical sheath-core structure under ambient conditions. Applying pre-stretch and twist in the as-spun hydrogel microfibers results in a tensile strength of 525 MPa, a toughness of 385 MJ m-3, and a damping capacity of 99%, which is attributed to the reinforcement of hydrogen-bond nanoclusters within the microfiber matrix. Moreover, it maintains both structural and mechanical stability for several days, and can be directly dissolved in water, providing a sustainable spinning dope for re-spinning into new microfibers. This work provides a new strategy for the spinning of robust and recyclable hydrogel-based fibrous materials.

Effects of anti-osteoporosis treatment in elderly patients with osteoporosis and lumbar discectomy and fusion.

BACKGROUND: The effect of anti-osteoporosis treatment in elderly patients with osteoporosis and lumbar discectomy and fusion (LIF) for lumbar degenerative diseases is not well known. OBJECTIVE: This study aimed to evaluate the effect of perioperative anti-osteoporosis treatment in the patients with osteoporosis and LIF. METHODS: From January to December 2022, patients were divided into three groups according to the inclusive criteria: the normal group (Group A), the osteopenia group (Group B) and the osteoporosis group (Group C). Quantitative computed tomography (QCT), height of the intervertebral space (HIS), segmental sagittal angle (SSA), visual analogue scale (VAS) score and Oswestry Disability Index (ODI) were compared between the groups at the follow-up time. The serum Ca2 + , osteocalcin (OC), propeptide of type I procollagen (PINP) C-terminal cross-linking telopeptide of type I collagen (ß-CTX) and 25-OH vitamin D (25-OH VD) levels were compared between the groups at the time of follow-up. Interbody fusion was graded on the X-ray and CT images at the follow-up time. RESULTS: There were 165 patients in this study. There were significant differences in the mean age, mean score, HIS and SSA between the groups at the different follow-up times. There were significant differences in the concentrations of serum Ca2 + , OC, ß-CTX, 25-OH VD and PINP at the sixth month after surgery between the groups. There were significant differences in the concentrations of serum Ca2 + , ß-CTX and 25-OH VD between the pre-surgery and at six months after surgery in Group B and ß-CTX and 25-OH VD in Group C. There was a significant difference in the degree of fusion between Group B and C (χ2= 5.6243, P< 0.05). CONCLUSION: In elderly patients with LIF and osteoporosis, anti-osteoporosis therapy could reduce bone resorption and thus facilitate fusion. Anti-osteoporosis medication tends to enhance radiological, functional, and fusion short-term outcomes.

Quantum Light Generation Based on GaN Microring toward Fully On-Chip Source.

An integrated quantum light source is increasingly desirable in large-scale quantum information processing. Despite recent remarkable advances, a new material platform is constantly being explored for the fully on-chip integration of quantum light generation, active and passive manipulation, and detection. Here, for the first time, we demonstrate a gallium nitride (GaN) microring based quantum light generation in the telecom C-band, which has potential toward the monolithic integration of quantum light source. In our demonstration, the GaN microring has a free spectral range of 330 GHz and a near-zero anomalous dispersion region of over 100 nm. The generation of energy-time entangled photon pair is demonstrated with a typical raw two-photon interference visibility of 95.5±6.5%, which is further configured to generate a heralded single photon with a typical heralded second-order autocorrelation g_{H}^{(2)}(0) of 0.045±0.001. Our results pave the way for developing a chip-scale quantum photonic circuit.

Structures of human γδ T cell receptor-CD3 complex.

Gamma delta (γδ) T cells, a unique T cell subgroup, are crucial in various immune responses and immunopathology1-3. The γδ T cell receptor (TCR), generated by γδ T cells, recognizes a diverse range of antigens independently of the major histocompatibility complex2. The γδ TCR associates with CD3 subunits, initiating T cell activation and holding great potential in immunotherapy4. Here, we report the structures of two prototypical human Vγ9Vδ2 and Vγ5Vδ1 TCR-CD3 complexes5,6, unveiling two distinct assembly mechanisms that depend on Vγ usage. The Vγ9Vδ2 TCR-CD3 complex is monomeric, with considerable conformational flexibility in the TCRγ/TCRδ extracellular domain (ECD) and connecting peptides (CPs). The length of CPs regulates the ligand association and T cell activation. Additionally, a cholesterol-like molecule wedges into the transmembrane region, exerting an inhibitory role in TCR signaling. The Vγ5Vδ1 TCR-CD3 complex displays a dimeric architecture, where two protomers nestle back-to-back via their Vγ5 domains of TCR ECDs. Our biochemical and biophysical assays further corroborate the dimeric structure. Importantly, the dimeric form of the Vγ5Vδ1 TCR is essential for T cell activation. These findings reveal organizing principles of the γδ TCR-CD3 complex, providing insights into the γδ TCR unique properties and facilitating immunotherapeutic interventions.

Self-controlled in silico gene knockdown strategies to enhance the sustainable production of heterologous terpenoid by Saccharomyces cerevisiae.

Microbial bioengineering is a growing field for producing plant natural products (PNPs) in recent decades, using heterologous metabolic pathways in host cells. Once heterologous metabolic pathways have been introduced into host cells, traditional metabolic engineering techniques are employed to enhance the productivity and yield of PNP biosynthetic routes, as well as to manage competing pathways. The advent of computational biology has marked the beginning of a novel epoch in strain design through in silico methods. These methods utilize genome-scale metabolic models (GEMs) and flux optimization algorithms to facilitate rational design across the entire cellular metabolic network. However, the implementation of in silico strategies can often result in an uneven distribution of metabolic fluxes due to the rigid knocking out of endogenous genes, which can impede cell growth and ultimately impact the accumulation of target products. In this study, we creatively utilized synthetic biology to refine in silico strain design for efficient PNPs production. OptKnock simulation was performed on the GEM of Saccharomyces cerevisiae OA07, an engineered strain for oleanolic acid (OA) bioproduction that has been reported previously. The simulation predicted that the single deletion of fol1, fol2, fol3, abz1, and abz2, or a combined knockout of hfd1, ald2 and ald3 could improve its OA production. Consequently, strains EK1∼EK7 were constructed and cultivated. EK3 (OA07△fol3), EK5 (OA07△abz1), and EK6 (OA07△abz2) had significantly higher OA titers in a batch cultivation compared to the original strain OA07. However, these increases were less pronounced in the fed-batch mode, indicating that gene deletion did not support sustainable OA production. To address this, we designed a negative feedback circuit regulated by malonyl-CoA, a growth-associated intermediate whose synthesis served as a bypass to OA synthesis, at fol3, abz1, abz2, and at acetyl-CoA carboxylase-encoding gene acc1, to dynamically and autonomously regulate the expression of these genes in OA07. The constructed strains R_3A, R_5A and R_6A had significantly higher OA titers than the initial strain and the responding gene-knockout mutants in either batch or fed-batch culture modes. Among them, strain R_3A stand out with the highest OA titer reported to date. Its OA titer doubled that of the initial strain in the flask-level fed-batch cultivation, and achieved at 1.23 ± 0.04 g L-1 in 96 h in the fermenter-level fed-batch mode. This indicated that the integration of optimization algorithm and synthetic biology approaches was efficiently rational for PNP-producing strain design.

Factors Influencing Breast Cancer Awareness in Rural Southwest China: A Cross-Sectional Study.

Background: This study aimed to explore the current knowledge level of breast cancer among rural women in Southwest China and analyze the influencing factors of breast cancer cognition. Methods: From May to November 2022, 1468 rural women were invited to participate in this study. Demographic information and the Chinese version of the Breast Cancer Awareness Measure (C-BCAM) were collected through one-on-one investigations. The data were analyzed using descriptive statistics, chi-square tests, and multiple regression analysis in SPSS 26.0. Results: The study included a total of 1468 rural women with a median age of 54.0 (IQR, 47.0, 60.0).The average score of breast cancer in the study population was 73.0 (IQR, 66.0, 82.0). Among women in Southwest China, the awareness rates of knowledge on breast cancer symptoms, barriers to seeking medical help, and risk factors were 68.8%, 98.4%, and 62.1%, respectively. The awareness rate was found to increase with higher education levels (P<0.001) and decrease with increasing age (P<0.001). Multivariate logistic regression analysis identified three variables that might influence breast cancer awareness: education level, contraceptive measures, and history of breast disease (all P<0.05). Specifically, history of breast disease (Odds ratio (OR) = 1.907, 95% CI = 1.128 ~ 3.223), middle school education (OR = 2.155, 95% CI = 1.585 ~ 2.928), and junior college education and above (OR = 5.536, 95% CI = 1.898 ~ 16.148) were positive factors for women's breast cancer awareness. Conversely, the use of intrauterine devices (OR = 0.523, 95% CI = 0.384 ~ 0.712) was found to be a negative factor for women's breast cancer awareness. Conclusion: This study highlights the insufficient awareness of breast cancer among women in rural area of Southwest China. It emphasizes the necessity of health education to improve female breast cancer awareness.

Expert consensus on Prospective Precision Diagnosis and Treatment Strategies for Osteoporotic Fractures.

Osteoporotic fractures are the most severe complications of osteoporosis, characterized by poor bone quality, difficult realignment and fixation, slow fracture healing, and a high risk of recurrence. Clinically managing these fractures is relatively challenging, and in the context of rapid aging, they pose significant social hazards. The rapid advancement of disciplines such as biophysics and biochemistry brings new opportunities for future medical diagnosis and treatment. However, there has been limited attention to precision diagnosis and treatment strategies for osteoporotic fractures both domestically and internationally. In response to this, the Chinese Medical Association Orthopaedic Branch Youth Osteoporosis Group, Chinese Geriatrics Society Geriatric Orthopaedics Committee, Chinese Medical Doctor Association Orthopaedic Physicians Branch Youth Committee Osteoporosis Group, and Shanghai Association of Integrated Traditional Chinese and Western Medicine Osteoporosis Professional Committee have collaborated to develop this consensus. It aims to elucidate emerging technologies that may play a pivotal role in both diagnosis and treatment, advocating for clinicians to embrace interdisciplinary approaches and incorporate these new technologies into their practice. Ultimately, the goal is to improve the prognosis and quality of life for elderly patients with osteoporotic fractures.

Multigene and Improved Anti-Collision RRT* Algorithms for Unmanned Aerial Vehicle Task Allocation and Route Planning in an Urban Air Mobility Scenario.

Compared to terrestrial transportation systems, the expansion of urban traffic into airspace can not only mitigate traffic congestion, but also foster establish eco-friendly transportation networks. Additionally, unmanned aerial vehicle (UAV) task allocation and trajectory planning are essential research topics for an Urban Air Mobility (UAM) scenario. However, heterogeneous tasks, temporary flight restriction zones, physical buildings, and environment prerequisites put forward challenges for the research. In this paper, multigene and improved anti-collision RRT* (IAC-RRT*) algorithms are proposed to address the challenge of task allocation and path planning problems in UAM scenarios by tailoring the chance of crossover and mutation. It is proved that multigene and IAC-RRT* algorithms can effectively minimize energy consumption and tasks' completion duration of UAVs. Simulation results demonstrate that the strategy of this work surpasses traditional optimization algorithms, i.e., RRT algorithm and gene algorithm, in terms of numerical stability and convergence speed.

The relationship between self-consciousness and depression in college students: the chain mediating effect of meaning life and self-efficacy, with the moderating effect of social support.

BACKGROUND: This study aimed to investigate the impact of self-consciousness on depression of college students, and mainly focus on confirming the mediator role of life meaningful and self-efficacy, as well as the moderator role of social support. METHODS: In the present study, convenient sampling method was adopted, 583 college students were recruited from Harbin city and Wenzhou city in China. All students were assessed using self-assessment scales, including self-consciousness scale, life meaningful scale, self-efficacy scale, social support scale, and self-rating depression scale. Descriptive statistical analysis and correlation analysis, structural equation model analysis were conducted by SPSS 25.0 and M-plus. RESULTS: Results showed that self-consciousness was negatively related to depression, life meaningful and self-efficacy partially mediated the relation between self-consciousness and depression. Moderated mediation analysis further indicated that the relation between self-efficacy and depression were moderated bu social support. Compare with college students who had high social support, depression in those with low social support was more susceptible to the effect of self-efficacy. CONCLUSION: These findings imply that college students with low levels of self-consciousness are more easy to be depressive, enhancing their sense of life meaning and self-efficacy can effectively alleviate depression, and college student with high social support can benefit more from self-efficacy. Therefore we should pay more attention to the mental health problems of low levels self-consciousness college students in university.

Peripheral T cell lymphoma initially presenting in lung biopsies: A diagnostic challenge.

BACKGROUND: Primary or secondary pulmonary involvement by peripheral T cell lymphoma (PTCL) is rare and difficult to diagnose particularly via lung biopsies. METHODS: 22 cases of PTCL diagnosed initially in lung biopsies between January 2006 and November 2020 were retrospectively reviewed followed at Nanjing Drum Tower Hospital and the First Affiliated Hospital of Zhengzhou University, respectively, including clinical manifestations, baseline biochemical indexes, images, histological findings and other available ancillary studies such as immunostaining, Epstein-Barr virus encoded RNA (EBER) in situ hybridization and T-cell receptor rearrangement analysis upon diagnosis. RESULTS: The median age of these patients was 59 years old (range: 29-82 years) at diagnosis. The majority of them complained of fever, cough and fatigue. Computed tomography scans mainly revealed multiple ill-defined nodules/masses of various sizes and densities with or without air bronchogram. Microscopically, most lesions showed lymphoid cells with clear cytoplasm and irregular nuclear contours diffusely infiltrating alveolar septa or alveolar spaces in an inflammatory background. Several cases had a predominance of small neoplastic cells (n = 4) with atypical, irregular nuclei. One case showed a diffuse monotonous pattern of growth. Angioinvasion and necrosis were not uncommon findings. The neoplastic cells in all cases were positive for one or more T-cell markers, and negative for B-cell-lineage antigens and EBER. 19 out of 22 patients had complete follow-up information, and 17 patients were dead at the last follow-up. CONCLUSIONS: Pulmonary involvement by PTCL is rare with dismal outcome. Aggressive clinical course and several clinicopathologic clues, albeit unspecific, may alert the pathologists of the possibilities of pulmonary PTCLs.

The inhibition of MARCO by PolyG alleviates pulmonary fibrosis via regulating mitochondrial function in a silicotic rat model.

Silicon dioxide (SiO2)-induced pulmonary fibrosis is potentially associated with the impairment of mitochondrial function. Previous research found that inhibition of macrophage receptor with collagenous structure (MARCO) could alleviate particle-induced lung injury by regulating phagocytosis and mitigating mitochondrial damage. The present study aims to explore the underlying anti-fibrosis mechanism of polyguanylic acid (PolyG, MARCO inhibitor) in a silicotic rat model. Hematoxylin and eosin and Masson staining were performed to visualize lung tissue pathological changes. Confocal microscopy, transmission electron microscope, western blot analysis, quantitative real-time PCR (qPCR), and adenosine triphosphate (ATP) content assay were performed to evaluate collagen content, mitochondrial function, and morphology changes in SiO2-induced rat pulmonary fibrosis. The results suggested that SiO2 exposure contributed to reactive oxygen species aggregation and the reduction of respiratory complexes and ATP synthesis. PolyG treatment could effectively reduce MARCO expression and ameliorate lung injury and fibrosis by rectifying the imbalance of mitochondrial respiration and energy synthesis. Furthermore, PolyG could maintain mitochondrial homeostasis by promoting peroxisome proliferator-activated receptor-coactivator 1 α (PGC1α)-mediated mitochondrial biogenesis and regulating fusion and fission. Together, PolyG could ameliorate SiO2-induced pulmonary fibrosis via inhibiting MARCO to protect mitochondrial function.

Gram-Scale Synthesis of Black Phosphorus through Shock-Induced Phase Transformation.

This article presents the utilization of a cylindrical double-tube shock loading device in conjunction with amorphous red phosphorus as the precursor to investigate the complete phase transformation of red phosphorus into black phosphorus under the influence of shockwaves. Multiple experiments were conducted by varying the shock pressure and temperature parameters. The characterization of the recovered samples involved analysis of the phase composition and microstructure. The obtained experimental results demonstrate that within the cylindrical double-tube shock loading setup, a pressure of 9 GPa and a temperature of 800 K are optimal for achieving the complete phase transition of amorphous red phosphorus into orthorhombic black phosphorus. By precisely controlling these experimental conditions, a high-quality orthorhombic black phosphorus powder with excellent crystallinity was successfully prepared. This method offers several advantages, including simplicity, cost-effectiveness, and high yield. Consequently, this presents a promising pathway for the industrial-scale production of black phosphorus. The implementation of this approach not only reduces the cost involved in black phosphorus synthesis but also contributes to the broad range of applications for this material.

Percutaneous Curved Vertebroplasty Decrease the Risk of Cemented Vertebra Refracture Compared with Bilateral Percutaneous Kyphoplasty in the Treatment of Osteoporotic Vertebral Compression Fractures.

Purpose: The purpose of this study is to compare the refracture rate of the cemented vertebral body of percutaneous curved vertebroplasty (PCVP) and bilateral percutaneous kyphoplasty (PKP) in the treatment of osteoporotic vertebral compression fractures (OVCF). Methods: Ninety-four patients with single segment thoracolumbar OVCF were randomly divided into two groups (47 patients in each) and underwent PCVP or bilateral PKP surgery, respectively. Refracture of cemented vertebral body, bone cement injection volume and cement pattern, cement leakage rate, total surgical time, intraoperative fluoroscopy time, preoperative and postoperative Cobb angles and anterior vertebral height, Oswestry disability index questionnaire (ODI) and visual analog scales (VAS) were recorded. Results: The PCVP group had significantly lower refracture incidence of the cemented vertebral than the bilateral PKP group (p<0.05). There was a significant postoperative improvement in the VAS score and ODI in both group (p<0.01), and no significant difference was found between two groups. The operation time and intraoperative fluoroscopy times were significantly less in the PCVP group than in the bilateral PKP group (p<0.01). The mean kyphosis angle correction and vertebral height restoration in the PCVP group was significantly less than that in the bilateral PKP group (p<0.01). Conclusion: Both PCVP and PKP were safe and effective treatments for OVCF. The PCVP had lower refracture rate of the cemented vertebral than the bilateral PKP group, and PCVP entailed less exposure to fluoroscopy and shorter operation time than bilateral PKP.

Aspirin-Mediated Acetylation of SIRT1 Maintains Intestinal Immune Homeostasis.

Aspirin, also named acetylsalicylate, can directly acetylate the side-chain of lysine in protein, which leads to the possibility of unexplained drug effects. Here, the study used isotopic-labeling aspirin-d3 with mass spectrometry analysis to discover that aspirin directly acetylates 10 HDACs proteins, including SIRT1, the most studied NAD+ -dependent deacetylase. SIRT1 is also acetylated by aspirin in vitro. It is also identified that aspirin directly acetylates lysine 408 of SIRT1, which abolishes SIRT1 deacetylation activity by impairing the substrates binding affinity. Interestingly, the lysine 408 of SIRT1 can be acetylated by CBP acetyltransferase in cells without aspirin supplement. Aspirin can inhibit SIRT1 to increase the levels of acetylated p53 and promote p53-dependent apoptosis. Moreover, the knock-in mice of the acetylation-mimic mutant of SIRT1 show the decreased production of pro-inflammatory cytokines and maintain intestinal immune homeostasis. The study indicates the importance of the acetylated internal functional site of SIRT1 in maintaining intestinal immune homeostasis.

Gypenoside induces apoptosis by inhibiting the PI3K/AKT/mTOR pathway and enhances T-cell antitumor immunity by inhibiting PD-L1 in gastric cancer.

Introduction: Gypenoside is a natural extract of Gynostemma pentaphyllum (Thunb.) Makino, a plant in the Cucurbitaceae family. It has been reported to have antitumor effects on the proliferation, migration and apoptosis of various types of cancer cells. However, the use of gypenoside in the treatment of gastric cancer has not been studied. In the present study, we explored the therapeutic effect of gypenoside on gastric cancer and the potential molecular mechanism. Methods and Results: Our results showed that gypenoside induced apoptosis in HGC-27 and SGC-7901 cells in a time-dependent and dose-dependent manner. Network pharmacology analyses predicted that gypenoside exerts its therapeutic effects through the PI3K/AKT/mTOR signaling pathway. Furthermore, molecular docking and western blot experiments confirmed that gypenoside induced the apoptosis of gastric cancer cells through the PI3K/AKT/mTOR signaling pathway. In addition, network pharmacological analysis revealed that the common targets of gypenoside in gastric cancer were enriched in the immune effector process, PD-L1 expression, the PD-1 checkpoint pathway, and the Jak-STAT signaling pathway. Furthermore, molecular docking and western blot assays demonstrated that gypenoside could bind to STAT3 and reduce its phosphorylation. Thus, the transcription of PD-L1 was inhibited in gastric cancer cells. Moreover, coculture experiments of gastric cancer cells with gypenoside and primary mouse CD8+ T cells showed that gastric cancer cells treated with gypenoside could enhance the antitumor ability of T cells. Animal experiments confirmed the antitumor effect of gypenoside, and the expression of PD-L1 was significantly downregulated in the gypenoside-treated group. Conclusion: Gypenoside induced the apoptosis of gastric cancer cells by inhibiting the PI3K/AKT/mTOR pathway and simultaneously inhibited the expression of PD-L1 in gastric cancer cells, thus enhancing the antitumor immunity of T cells. This study provides a theoretical basis for applying gypenoside as a new therapeutic agent to enhance the efficacy of immunotherapy in gastric cancer.

Repolarization of immunosuppressive macrophages by targeting SLAMF7-regulated CCL2 signaling sensitizes hepatocellular carcinoma to immunotherapy.

Immune checkpoint inhibitors have limited efficacy in hepatocellular carcinoma (HCC). Macrophages are the most abundant immune cells in HCC, suggesting that a better understanding of the intrinsic processes by which tumor cells regulate macrophages could help identify strategies to improve response to immunotherapy. As signaling lymphocytic activation molecule (SLAM) family members regulate various immune functions, we investigated the role of specific SLAM receptors in the immunobiology of HCC. Comparison of the transcriptomic landscapes of immunotherapy-responsive and non-responsive advanced HCC patients identified SLAMF7 upregulation in immunotherapy-responsive HCC, and HCC patients who responded to immunotherapy also displayed higher serum levels of SLAMF7. Loss of Slamf7 in liver-specific knockout mice led to increased hepatocarcinogenesis and metastasis, elevated immunosuppressive macrophage infiltration, and upregulated PD-1 expression in CD8+ T cells. HCC cell-intrinsic SLAMF7 suppressed MAPK/ATF2-mediated CCL2 expression to regulate macrophage migration and polarization in vitro. Mechanistically, SLAMF7 associated with SH2 domain-containing adaptor protein B (SHB) through its cytoplasmic 304 tyrosine site to facilitate the recruitment of SHIP1 to SLAMF7 and inhibit the ubiquitination of TRAF6, thereby attenuating MAPK pathway activation and CCL2 transcription. Pharmacological antagonism of the CCL2/CCR2 axis potentiated the therapeutic effect of anti-PD-1 antibody in orthotopic HCC mouse models with low SLAMF7 expression. In conclusion, this study highlights SLAMF7 as a regulator of macrophage function and a potential predictive biomarker of immunotherapy response in HCC. Strategies targeting CCL2 signaling to induce macrophage repolarization in HCC with low SLAMF7 might enhance the efficacy of immunotherapy.

Improving Clinical Outcomes: Hightibialosteotomy Plate Placement Combined with Arthroscopic Surgery.

Objective: Our study aimed to investigate the clinical efficacy of hightibialosteotomy (HTO) posterior plate placement combined with arthroscopic surgery for degenerative injury of the posterior horn of the medial meniscus with poor force lines in the lower extremity, improve joint function or relieve pain. Methods: The case data of 98 patients with osteoarthritis of the knee admitted to the Department of Orthopedics in our hospital from January 2019 to January 2023 were selected for retrospective analysis. The patients were divided into 54 patients, each in the study group and the comparison group according to the different treatment regimens. The study group received hightibialosteotomy plate placement combined with arthroscopic surgery, while the comparison group underwent hightibialosteotomy plate placement alone. The differences in knee scores, knee Lysholm scores, Lysholm scores, Healthcare Security and Safety (HSS) scores, Tegner scores, Visual Analog Scale (VAS), lower extremity force lines, femorotibial angles, and tibial plateau were counted and compared between the two groups. Results: HSS knee function scores, Lysholm scores, and VAS scores of the study group were statistically significant compared with those of the comparison group at the final follow-up of patients, and the postoperative clinical outcomes improved significantly (P < .05). The differences in Hip-Knee-Ankle(HKA) angle andMedial-Pateral Tibial Angle (MPTA) of patients in the study group were statistically significant compared with the comparison group, and the increase in HKA (12.31±2.13)°, MPTA (11.84±2.32)° and lower limb force line was significantly improved (P < .05). Preoperatively, there was no statistically significant comparison between the visual analog scores of the knee joint in the study group and the comparison group. After surgery, the difference between the two groups was statistically significant (P < .05). The relative position of the mechanical axis of the lower limb through the tibial plateau, the femorotibial angle, and the posterior tibial plateau angle increased in patients after surgery, and the differences were statistically significant when compared with the preoperative period (P < .05). Both the tibial posterior displacement distance and the lateral knee gap opening were reduced compared with the preoperative period, and the differences were statistically significant (P < .05). Conclusion: Hightibialosteotomy after plate placement combined with arthroscopic surgery has better clinical efficacy in the early stage and can effectively treat the degenerative injury of the posterior horn of the medial meniscus with poor force lines in the lower limb, improve the joint function, and relieve the symptoms of patients.