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 explore the expression and clinical significance of programmed death receptor 1 (PD-1), Th1, Th2, and Th17 cytokines in multiple myeloma (MM). METHODS: A total of 76 MM patients treated in the Tengzhou Central People's Hospital from May 2021 to May 2023 were collected as MM group, and 48 healthy individuals who underwent physical examination during the same period were included as control group. The expression of PD-1 on the surface of CD4⁺ and CD8⁺ T cells and the levels of serum Th1 cytokines ［interleukin (IL) -2, interferon γ (IFN-γ), tumor necrosis factor α (TNF-α)］, Th2 cytokines (IL-4, IL-6, IL-10) and Th17 cytokines (IL-17) were detected in the two groups. Spearman correlation was used to examine the relationship between PD-1, Th1, Th2 and Th17 cytokines and clinical stage and immune typing of MM patients. Multivariate logistic regression analysis was used to analyze the related factors affecting the efficacy of chemotherapy in MM patients, and the factors were tested for multicollinearity. Receiver operating characteristic (ROC) curve was drawn to analyze the predictive value of PD-1, Th1, Th2 and Th17 cytokines in chemotherapy efficacy of MM patients. RESULTS: The levels of CD4⁺T PD-1, CD8⁺T PD-1, IL-4, IL-6, IL-10, and IL-17 in the MM group were higher than those in the control group, while the levels of IL-2, IFN-γ, and TNF-α were lower (all P <0.001). The levels of CD4⁺T PD-1, CD8⁺T PD-1, IL-4, IL-6, IL-10, and IL-17 in R-ISS stage III patients were higher than those in stage II and I patients, and the levels in stage II patients were higher than those in stage I patients (all P <0.05). The IL-2 level in R-ISS stage III patients was lower than that in stage II and I patients, and IL-2 level in R-ISS stage II patients was lower than that in stage I patients (all P <0.05). The levels of CD4⁺T PD-1, CD8⁺T PD-1, IL-4, IL-6, IL-10, and IL-17 in IgG patients were higher than those in IgA, light chain, and non secretory patients, while the level of IL-2 was lower (all P <0.05). Correlation analysis showed that CD4⁺T PD-1, CD8⁺T PD-1, IL-4, IL-6, IL-10, and IL-17 were positively correlated with R-ISS staging in MM patients (r =0.623, 0.635, 0.728, 0.330, 0.742, 0.412), and negatively correlated with immune classification (r =-0.664, -0.756, -0.642, -0.479, -0.613, -0.323). IL-2 was negatively correlated with R-ISS staging in MM patients (r =-0.280), and positively correlated with immune classification (r =0.483). The levels of CD4⁺T PD-1, CD8⁺T PD-1, IL-4, IL-6, IL-10, and IL-17 in the non-remission group were higher than those in the remission group, while the level of IL-2 was lower (all P <0.001). Multivariate logistic regression analysis showed that the increased CD4⁺T PD-1, CD8⁺T PD-1, IL-4, IL-6, IL-10 and IL-17 were risk factors for the efficacy of chemotherapy in MM patients (OR >1, P <0.05), while the increased IL-2 was a protective factor (OR < 1, P <0.05). The results of multicollinearity test showed that the tolerance of the seven factors included was between 0.714-0.885, and the variance inflation factor was between 1.130-1.400. There was no multicollinearity. The ROC curve analysis results showed that the area under the curve for the combined prediction of chemotherapy efficacy in MM patients by the above 7 factors was 0.942, with specificity of 0.741 and sensitivity of 0.909. CONCLUSION The expression levels of PD-1 on the surface of CD4⁺ and CD8⁺ T cells and serum Th2 and Th17 cytokines in MM patients are high, while Th1 cytokines are low. PD-1, Th1, Th2, and Th17 cytokines are related to clinical stage and immune classification of MM patients. The combined detection of these indicators can help predict the chemotherapy efficacy of MM patients.
Humans ; Programmed Cell Death 1 Receptor/metabolism* ; Multiple Myeloma/blood* ; Cytokines/metabolism* ; Th17 Cells/metabolism* ; Th1 Cells/metabolism* ; Th2 Cells/metabolism* ; Female ; Male ; Interleukin-10 ; Interferon-gamma ; Middle Aged ; Interleukin-17 ; Interleukin-2 ; Interleukin-4 ; Tumor Necrosis Factor-alpha ; Interleukin-6 ; Aged

Programmed cell death 1 (PD-1) inhibitor therapy for lung adenocarcinoma may induce rare but severe hematologic adverse events, including severe anemia. Although glucocorticoids are recommended for managing immune-related adverse events, therapeutic experience with PD-1 inhibitor-induced severe anemia remains limited, and its efficacy and safety have not been fully validated. This article reports a case of advanced lung adenocarcinoma in which severe anemia developed following combination therapy with chemotherapy and PD-1 inhibitor. After comprehensive evaluation, the patient was diagnosed with anemia of inflammation (AI) and achieved significant hemoglobin recovery following high-dose glucocorticoid treatment. These findings may provide new insights into the recognition and management of this rare hematologic toxicity in clinical practice.
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Humans ; Adenocarcinoma of Lung/drug therapy* ; Programmed Cell Death 1 Receptor/antagonists & inhibitors* ; Anemia/etiology* ; Immunotherapy/adverse effects* ; Lung Neoplasms/immunology* ; Male ; Antibodies, Monoclonal/therapeutic use* ; Middle Aged

BACKGROUND: As research progresses, there is a growing body of evidence indicating that urinary metallothionein (MT) levels may be elevated in individuals exposed to cadmium (Cd). This study aimed to investigate the potential association between urinary MT levels and causes of mortality among residents of the Kakehashi River Basin who have been exposed to Cd. METHOD: The study involved a total of 1,398 men and 1,731 women were conducted between 1981 and 1982, with follow-up until November 2016. The study employed the Cox proportional-hazards model to examine the association between higher urinary MT concentrations and the risk of all-cause or cause-specific mortality within the population. Furthermore, the Fine and Gray competing risks regression model was used to evaluate the links between specific causes of death. RESULTS: The findings revealed that elevated urinary MT concentrations were linked to increased all-cause mortality and higher mortality rates from renal and urinary tract diseases across all participants. Specifically, in men, higher urinary MT levels were associated with elevated all-cause mortality, while in women, increased concentrations were linked to higher mortality from endocrine, nutritional, and metabolic diseases, as well as cardiovascular diseases. Even after adjusting for competing risks, higher urinary MT concentrations were associated with tumor-related mortality in men and continued to be associated with cardiovascular disease mortality in women. CONCLUSIONS In conclusion, the results suggest that women may face a greater risk of adverse health effects due to prolonged exposure to Cd. Urinary MT levels could potentially serve as a biomarker for mortality from these diseases in populations chronically exposed to Cd.
Humans ; Male ; Female ; Cadmium/urine* ; Japan/epidemiology* ; Metallothionein/metabolism* ; Middle Aged ; Cause of Death ; Adult ; Follow-Up Studies ; Aged ; Environmental Exposure/analysis* ; Proportional Hazards Models

BACKGROUND: Older adults in Japan have the highest drowning mortality rate globally due to frequent bathing practices. Low outdoor temperatures have been linked to bath-related deaths; however, previous studies employed limited statistical models and focused on a single prefecture. Given Japan's aging population, preventing bath-related deaths is a public health priority. This study aimed to analyze the association between outdoor temperature and bath-related drowning deaths across Japan from 1995 to 2020 (n = 110,938), examining regional variations and identifying contributing prefectural characteristics. METHODS: Daily counts of bath-related drowning deaths per prefecture were matched with daily mean temperature data from the Japan Meteorological Agency. Prefecture-level demographic and environmental data were obtained from Japan's Official Statistics. We applied a generalized additive mixed model to examine the association between daily mean temperature and bath-related drowning death risk. Meta-regression was used to identify prefecture-level modifiers. RESULTS: Bath-related drowning death risk peaked at a daily mean temperature of 1.8 °C (relative risk [RR] 9.7, 95% confidence interval [CI]: 9.5-9.9), compared with the lowest risk at 30.3 °C. The association was stronger at mid-range temperatures, particularly among males and individuals aged ≥65 years. Among prefectures, Kagoshima-the southernmost prefecture on Japan's main islands-had the highest maximum RR at 19.6 (95% CI: 16.2-23.6), while Hokkaido-the northernmost prefecture-had the lowest at 3.8 (95% CI: 3.4-4.3). Prefecture-level factors that strengthened this relationship included a lower prevalence of double-pane windows as a proxy of housing insulation and higher annual mean temperatures with ratio of RR change per one standard deviation increase of 0.76 (95% CI: 0.69-0.83) and 1.27 (95% CI: 1.18-1.37), respectively. CONCLUSIONS Warmer prefectures in southern regions exhibited greater maximum-to-minimum risk ratios compared to cooler northern prefectures. This paradoxical finding underscores the importance of region-specific interventions to reduce bath-related deaths.
Japan/epidemiology* ; Humans ; Drowning/epidemiology* ; Male ; Aged ; Female ; Baths/statistics & numerical data* ; Middle Aged ; Temperature ; Aged, 80 and over ; Adult ; Young Adult ; Risk Factors ; Adolescent