BACKGROUND: The primary limitation to kidney transplantation is organ shortage. Recent progress in gene editing and immunosuppressive regimens has made xenotransplantation with porcine organs a possibility. However, evidence in pig-to-human xenotransplantation remains scarce, and antibody-mediated rejection (AMR) is a major obstacle to clinical applications of xenotransplantation. METHODS: We conducted a kidney xenotransplantation in a brain-dead human recipient using a porcine kidney with five gene edits (5GE) on March 25, 2024 at Xijing Hospital, China. Clinical-grade immunosuppressive regimens were employed, and the observation period lasted 22 days. We collected and analyzed the xenograft function, ultrasound findings, sequential protocol biopsies, and immune surveillance of the recipient during the observation. RESULTS: The combination of 5GE in the porcine kidney and clinical-grade immunosuppressive regimens prevented hyperacute rejection. The xenograft kidney underwent delayed graft function in the first week, but urine output increased later and the single xenograft kidney maintained electrolyte and pH homeostasis from postoperative day (POD) 12 to 19. We observed AMR at 24 h post-transplantation, due to the presence of pre-existing anti-porcine antibodies and cytotoxicity before transplantation; this AMR persisted throughout the observation period. Plasma exchange and intravenous immunoglobulin treatment mitigated the AMR. We observed activation of latent porcine cytomegalovirus toward the end of the study, which might have contributed to coagulation disorder in the recipient. CONCLUSIONS 5GE and clinical-grade immunosuppressive regimens were sufficient to prevent hyperacute rejection during pig-to-human kidney xenotransplantation. Pre-existing anti-porcine antibodies predisposed the xenograft to AMR. Plasma exchange and intravenous immunoglobulin were safe and effective in the treatment of AMR after kidney xenotransplantation.
Transplantation, Heterologous/methods* ; Kidney Transplantation/methods* ; Heterografts/pathology* ; Immunoglobulins, Intravenous/administration & dosage* ; Graft Survival/immunology* ; Humans ; Animals ; Sus scrofa ; Graft Rejection/prevention & control* ; Kidney/pathology* ; Gene Editing ; Species Specificity ; Immunosuppression Therapy/methods* ; Plasma Exchange ; Brain Death ; Biopsy ; Male ; Aged

BACKGROUND: This study aimed to investigate programmed death-ligand 1 tumor proportion score in predicting the safety and efficacy of PD-1/PD-L1 antibody-based therapy in treating patients with advanced non-small cell lung cancer (NSCLC) in a real-world setting. METHODS: This retrospective, multicenter, observational study enrolled adult patients who received PD-1/PD-L1 antibody-based therapy in China and met the following criteria: (1) had pathologically confirmed, unresectable stage III-IV NSCLC; (2) had a baseline PD-L1 tumor proportion score (TPS); and (3) had confirmed efficacy evaluation results after PD-1/PD-L1 treatment. Logistic regression, Kaplan-Meier analysis, and Cox regression were used to assess the progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) as appropriate. RESULTS: A total of 409 patients, 65.0% ( n = 266) with a positive PD-L1 TPS (≥1%) and 32.8% ( n = 134) with PD-L1 TPS ≥50%, were included in this study. Cox regression confirmed that patients with a PD-L1 TPS ≥1% had significantly improved PFS (hazard ratio [HR] 0.747, 95% confidence interval [CI] 0.573-0.975, P = 0.032). A total of 160 (39.1%) patients experienced 206 irAEs, and 27 (6.6%) patients experienced 31 grade 3-5 irAEs. The organs most frequently associated with irAEs were the skin (52/409, 12.7%), thyroid (40/409, 9.8%), and lung (34/409, 8.3%). Multivariate logistic regression revealed that a PD-L1 TPS ≥1% (odds ratio [OR] 1.713, 95% CI 1.054-2.784, P = 0.030) was an independent risk factor for irAEs. Other risk factors for irAEs included pretreatment absolute lymphocyte count >2.5 × 10 9 /L (OR 3.772, 95% CI 1.377-10.329, P = 0.010) and pretreatment absolute eosinophil count >0.2 × 10 9 /L (OR 2.006, 95% CI 1.219-3.302, P = 0.006). Moreover, patients who developed irAEs demonstrated improved PFS (13.7 months vs. 8.4 months, P <0.001) and OS (28.0 months vs. 18.0 months, P = 0.007) compared with patients without irAEs. CONCLUSIONS A positive PD-L1 TPS (≥1%) was associated with improved PFS and an increased risk of irAEs in a real-world setting. The onset of irAEs was associated with improved PFS and OS in patients with advanced NSCLC receiving PD-1/PD-L1-based therapy.
Humans ; Carcinoma, Non-Small-Cell Lung/metabolism* ; Male ; Female ; Retrospective Studies ; Middle Aged ; Lung Neoplasms/metabolism* ; Aged ; B7-H1 Antigen/metabolism* ; Programmed Cell Death 1 Receptor/metabolism* ; Adult ; Aged, 80 and over ; Immune Checkpoint Inhibitors/therapeutic use*

OBJECTIVE: To explore the advantages and effectiveness of the independently developed intelligent orthopedic robot-assisted distal locking of femoral intramedullary nails. METHODS: Thirty-two adult cadaveric femur specimens were randomly divided into two groups, with 16 specimens in each group. The experimental group used the intelligent orthopedic robot to assist in the distal locking of femoral intramedullary nail holes, while the control group used the traditional method of manual locking under X-ray fluoroscopy. The locking time, fluoroscopy times, and the success rate of first locking were recorded and compared between the two groups. RESULTS: The locking time of the experimental group was (273.94±38.67) seconds, which was shorter than that of the control group [(378.38±152.72) seconds], and number of fluoroscopies was (4.56±0.81) times, which was less than that of the control group [(8.00±3.98) times]. The differences were significant [ MD=73.054 (-37.187, 85.813), P=0.049; MD=1.969 (-1.437, 2.563), P=0.002]. The first locking success rate of the experimental group was 100% (16/16), which was significantly higher than that of the control group (68.75%, 11/16) ( P=0.043). CONCLUSION The efficiency of distal locking of femoral intramedullary nails assisted by the intelligent orthopedic robot is significantly higher than that of the traditional manual locking method under fluoroscopy, as it can markedly reduce the time required for distal locking of femoral intramedullary nails, decrease intraoperative radiation exposure, and increase the success rate of locking.
Humans ; Fracture Fixation, Intramedullary/instrumentation* ; Bone Nails ; Fluoroscopy ; Femur/diagnostic imaging* ; Femoral Fractures/surgery* ; Robotic Surgical Procedures/instrumentation* ; Cadaver ; Adult ; Robotics ; Male

Programmed death 1 (PD-1) and its ligand (PD-L1) serve as crucial targets in cancer immunotherapy, and their inhibitors have significantly improved the prognosis of many patients with malignant tumors. However, the issues of drug resistance and limited overall response rate associated with monotherapy remain prevalent. As a new generation of immune checkpoints, lymphocyte activation gene 3 (LAG-3) synergistically enhances the suppression of T cells alongside PD-1 in various cancers. Combining the blockade of both PD-1 and LAG-3 yields stronger anti-tumor immune effects compared to blocking either target alone, thereby reversing the immunosuppressive state of the tumor microenvironment and reducing the occurrence of resistance. This review covers the structural characteristics of LAG-3 and unveils its specific interactions with PD-1 across multiple cancers, providing a novel reference for overcoming the limitations of single-agent therapy.
Humans ; Neoplasms/immunology* ; Immunotherapy/methods* ; Programmed Cell Death 1 Receptor/metabolism* ; Lymphocyte Activation Gene 3 Protein ; Antigens, CD/metabolism* ; Animals ; Tumor Microenvironment/immunology* ; Immune Checkpoint Inhibitors/therapeutic use*

Objective To investigate the effects of LBL-007, a novel fully human lymphocyte activation gene 3 (LAG-3) monoclonal antibody, in combination with programmed cell death protein 1 (PD-1) antibody, on the invasion, migration and proliferation of tumor cells, and to elucidate the underlying mechanisms. Methods Human lymphocyte cells Jurkat were co-cultured with A549 and MGC803 tumor cell lines and treated with the isotype control antibody human IgG, LBL-007, anti-PD-1 antibody BE0188, or tumor necrosis factor-alpha (TNF-α, the NF-κB signaling pathway agonist). Tumor cell proliferation was assessed using a colony formation assay; invasion was measured by Transwell^TM assay; migration was evaluated using a wound healing assay. Western blotting was employed to determine the expression levels of NF-κB pathway-related proteins: IκB inhibitor kinase alpha (Ikkα), phosphorylated Ikkα (p-IKKα), NF-κB subunit p65, phosphorylated p65 (p-p65), NF-κB Inhibitor Alpha (IκBα), phosphorylated IκBα (p-IκBα), matrix metalloproteinase 9 (MMP9), and MMP2. Results Compared with the control and IgG isotype groups, LBL-007 and BE0188 significantly reduced tumor cell proliferation, invasion, and migration. They also decreased the phosphorylation of p-IKKα, p-p65 and p-IκBα, and the expression of MMP9 and MMP2 of tumor cells in the co-culture system. The combined treatment of LBL-007 and BE0188 enhanced inhibitory effects. Treatment with the NF-κB signaling pathway agonist TNF-α reversed the suppressive effects of LBL-007 and BE0188 on tumor cell proliferation, invasion, migration, and NF-κB signaling. Conclusion LBL-007 and anti-PD-1 antibody synergistically inhibit the invasion, migration, and proliferation of A549 and MGC803 tumor cells by blocking the NF-κB signaling pathway.
Humans ; Cell Proliferation/drug effects* ; Cell Movement/drug effects* ; Signal Transduction/drug effects* ; NF-kappa B/metabolism* ; Neoplasm Invasiveness ; Antibodies, Monoclonal/pharmacology* ; Programmed Cell Death 1 Receptor/antagonists & inhibitors* ; Cell Line, Tumor ; Antigens, CD/immunology* ; Lymphocyte Activation Gene 3 Protein ; A549 Cells ; I-kappa B Kinase/metabolism* ; Jurkat Cells ; Matrix Metalloproteinase 9/metabolism*

PURPOSE: The purpose of this cadaveric study was to compare the volume and weight of bone graft harvested using the curettage vs. the trephination technique from the anterior iliac crest. METHODS: Embalmed cadavers were studied in this experimental research. The right hemipelvis of each cadaver was used for the trephine bone harvesting technique, whereas the left hemipelvis was used for the conventional curettage technique. The weight and the volume of the harvested bone were measured and statistically compared between the 2 sides. The Wilcoxon Signed-Rank test was employed to compare the graft volume and weight obtained from the right and left sides of the hemipelvis. RESULTS: Ten embalmed adult cadavers were used in this study. All subjects were Caucasian males with a mean age of 59.8 years (range 44 - 73 years) at the time of death. A total of 81 cylindrical bone grafts were harvested from the right iliac crest. In 9 out of 81 (11.1%), the cortex of the ilium was penetrated by the chisel. The mean weight of the bone graft harvested with the trephine technique (26.97 ± 2.32) g was heavier than that harvested with the curettage technique (23.74 ± 2.09) g (p = 0.007). Similarly, the volume of the bone graft was higher in the trephine technique (8.40 ± 0.84) cm³ compared to the curettage technique (6.60 ± 1.26) cm³ (p = 0.011). The trephination technique lasted a mean of (12.76 ± 1.87) min (range 10.30-16.10 min), while the curettage technique lasted a mean of (14.53 ± 0.89) min (range 13.50-16.00 min) (p = 0.028). CONCLUSION: Harvesting anterior iliac crest bone graft with the trephine technique provides a higher bone volume and weight than the conventional curettage technique. The trephine technique might be advocated over the curettage technique, especially when a large amount of autologous bone graft is required. However, a meticulous harvesting technique should be followed to prevent complications. In particular, the three-dimensional anatomy should be kept in mind, and the depth of trephination should be well-controlled. CLINICAL TRIAL REGISTRATION Institutional Review Board registration: 2022/499.
Humans ; Ilium/surgery* ; Male ; Middle Aged ; Aged ; Cadaver ; Curettage/methods* ; Tissue and Organ Harvesting/methods* ; Bone Transplantation/methods* ; Adult ; Trephining/methods*

PURPOSE: In surgical procedures commonly employed for the management of scaphoid and distal radial fractures, the incision and dissection of the pronator quadratus muscle play a pivotal role. Nevertheless, comprehensive investigations into the anatomical intricacies of the pronator quadratus muscle have been relatively scarce within the clinical community. In light of this, our study endeavors to make a substantive contribution to the medical literature by conducting a meticulous examination of the morphology and morphometry of this muscle. METHODS: This study is a cross-sectional observational study conducted on 22 cadaveric upper extremities (44 sides) preserved between January 2005 and December 2018 at Istanbul University. The study included specimens with intact dissection areas and no prior surgical intervention. Observations focused on the morphometry of the pronator quadratus muscle and related anatomical structures. Statistical analysis was performed using SPSS v23.0, employing Student's t-test and paired t-test, with significance set at p < 0.05. RESULTS: Significant differences were found in the morphometric measurements of the pronator quadratus muscle between the right and left upper extremities, particularly in the vertical distance between the proximal and distal attachment points of the pronator quadratus to the radius (p = 0.008). Additionally, significant differences were observed between male and female samples for radius length (p < 0.001), ulna length (p < 0.001), pronator quadratus width (p < 0.001), and the vertical distance between pronator quadratus attachment points on both the radius (p = 0.001) and ulna (p = 0.001). Furthermore, significant correlations were identified between radius length and parameters such as the vertical distance between pronator quadratus attachment points on both the radius (p = 0.002) and pronator quadratus width (p = 0.030), and between ulna length and parameters including the vertical distances on the radius (p = 0.001) and ulna (p = 0.024). CONCLUSION In light of our comprehensive analysis, which encompasses not only the anatomical features of the pronator quadratus muscle but also its vascular supply and the organization of its neurovascular structures, we posit that our study holds significant implications for the field of orthopedic surgery. We anticipate that this research will furnish valuable insights that can inform and enhance orthopedic procedures.
Humans ; Female ; Male ; Cross-Sectional Studies ; Muscle, Skeletal/anatomy & histology* ; Cadaver ; Aged ; Middle Aged

PURPOSE: Polytrauma is still a challenge for health care organizations. Today, the search for factors to reduce lethality continues. This study aims to describe the causes of death associated with polytrauma in 1 year. METHODS: This retrospective study analyzed autopsy data of trauma deaths in Moscow for the whole of 2017. We identified victims with polytrauma, taking into account the Berlin definition as the main inclusion criteria with penetrating and blunt trauma. Each forensic report had information about the pre-hospital and hospital stages of treatment and autopsy data. The exclusion criteria for this study were: isolated injury, forensic reports not related to the examination of entire corpses, and autopsy studies of children (<18 years old). Statistical analysis was performed according to basic principles, including a comparison of groups using the Chi-squared test with Bonferroni comparison test and Fisher's exact test. The critical level of significance (p value) in testing statistical hypotheses in this study was taken as 0.05. RESULTS: We analyzed 2337 forensic medical examinations of victims who died of trauma in Moscow in 2017, of which 41.5% (n = 969) were polytrauma deaths. Most of the victims (65.4%, n = 634) died on the scene, and only 30.0% were admitted to the hospital. The most frequent cause of death was bleeding (72.0%, n = 698), followed by traumatic brain injury (43.8%, n = 424). They accounted for the first peak (78.4%, p = 0.005) of deaths, occurring in the first hours. Then these causes of death in the first peak go down in a few hours, and the second peak of mortality appears in 3 - 7 days (p = 0.001). CONCLUSIONS This is the largest full-year autopsy study of polytrauma victims. Our data show that the main cause of polytrauma death is massive bleeding, with a lethality peak in the first hours after injury. The time distribution of polytrauma deaths has a bimodal pattern - the second period of polytrauma deaths occurs in 3 - 7 days.
Humans ; Retrospective Studies ; Male ; Female ; Moscow/epidemiology* ; Autopsy ; Multiple Trauma/mortality* ; Adult ; Adolescent ; Middle Aged ; Child ; Child, Preschool ; Cause of Death ; Young Adult ; Infant ; Aged ; Aged, 80 and over

Paramyxoviruses are important respiratory pathogens with substantial clinical relevance in pediatric infectious diseases. During infection, multiple forms of programmed cell death (PCD) may be induced, and this plays pivotal roles in viral replication, dissemination, and host immune responses, thereby profoundly influencing the viral life cycle and disease progression. On one hand, PCD facilitates the clearance of infected cells, restricts viral spread, and activates host immune defenses, thereby enhancing antiviral immunity. On the other hand, excessive or dysregulated cell death may lead to tissue damage and immune imbalance, creating a microenvironment conducive to viral replication and exacerbating disease severity. For instance, apoptosis-mediated by both extrinsic and intrinsic pathways-contributes to infection control but may also be hijacked by viruses to promote dissemination. Pyroptosis, driven by inflammasome activation, triggers lytic cell death and the release of pro-inflammatory cytokines. Necroptosis, mediated by the RIPK1-RIPK3-MLKL signaling axis, and pyroptosis both amplify innate immune responses but may concurrently induce inflammatory dysregulation. Immunogenic cell death (ICD), characterized by the release of damage-associated molecular patterns and neoantigens, activates antigen-specific immune responses and holds therapeutic potential for antiviral and antitumor interventions. Emerging evidence suggests that ferroptosis, through the modulation of iron metabolism and associated transporters, may also participate in viral replication and infected cell clearance. This review comprehensively summarizes the roles of apoptosis, pyroptosis, necroptosis, ICD, and ferroptosis in paramyxovirus infection, aiming to deepen the understanding of paramyxovirus pathogenesis and to provide insights for developing novel antiviral strategies.
Humans ; Paramyxoviridae Infections/pathology* ; Pyroptosis ; Apoptosis ; Virus Replication ; Necroptosis ; Inflammasomes ; Immunity, Innate ; Immunogenic Cell Death ; Paramyxoviridae/physiology* ; Signal Transduction

OBJECTIVE: To investigate the expression of co-inhibitory molecules TIGIT/CD155 and PD-1 on CD4⁺T cells and Treg cells in peripheral blood of patients with chronic lymphocytic leukemia (CLL) and analyze their clinical significance. METHODS: The expression of PD-1 and TIGIT on CD4⁺T cells and Treg cells was detected by flow cytometry in 40 CLL patients and 20 healthy controls. Additionally, the expression of CD155 on peripheral blood B cells and DC cells of the enrolled subjects was detected. RESULTS: The proportions of PD-1⁺TIGIT⁺CD4⁺T cells, PD-1⁺TIGIT⁺Treg cells and CD155⁺DC cells in peripheral blood of CLL patients were significantly higher than those of healthy controls ( P < 0.05). The proportions of PD-1⁺TIGIT⁺CD4⁺T cells and PD-1⁺TIGIT⁺Treg cells in CLL patients were significantly higher than those of PD-1⁺TIGIT^-CD4⁺T cells and PD-1⁺TIGIT^-Treg cells, respectively ( P < 0.05). Both PD-1⁺TIGIT⁺CD4⁺T cells and PD-1⁺TIGIT⁺Treg cells were positively correlated with the level of CD155⁺DC cells (r =0.742, r =0.766). With the progression of Binet stage, the proportions of PD-1⁺TIGIT⁺CD4⁺T cells, PD-1⁺TIGIT⁺Treg cells, and CD155⁺DC cells gradually increased ( P < 0.05), and the aforementioned three types cells were all increased in patients with CD38≥30%, IGVH unmutated, or poor prognosis due to chromosomal abnormalities ( P < 0.05). CONCLUSION Co-inhibitory molecules PD-1 and TIGIT may be involved in immunodepletion in patients with advanced CLL, which has clinical prognostic value. Dual inhibitor molecular targeted therapy provides a new direction for the individualized treatment of CLL.
Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/immunology* ; Receptors, Immunologic/metabolism* ; Programmed Cell Death 1 Receptor/metabolism* ; T-Lymphocytes, Regulatory/metabolism* ; Receptors, Virus/metabolism* ; CD4-Positive T-Lymphocytes/metabolism* ; Male ; Female ; Middle Aged ; Flow Cytometry ; Clinical Relevance