Deactivation of the mitochondrial pyruvate dehydrogenase complex (PDC) is important for the metabolic switching of cancer cell from oxidative phosphorylation to aerobic glycolysis. Studies examining PDC activity regulation have mainly focused on the phosphorylation of pyruvate dehydrogenase (E1), leaving other post-translational modifications largely unexplored. Here, we demonstrate that the acetylation of Lys 488 of pyruvate dehydrogenase complex component X (PDHX) commonly occurs in hepatocellular carcinoma, disrupting PDC assembly and contributing to lactate-driven epigenetic control of gene expression. PDHX, an E3-binding protein in the PDC, is acetylated by the p300 at Lys 488, impeding the interaction between PDHX and dihydrolipoyl transacetylase (E2), thereby disrupting PDC assembly to inhibit its activation. PDC disruption results in the conversion of most glucose to lactate, contributing to the aerobic glycolysis and H3K56 lactylation-mediated gene expression, facilitating tumor progression. These findings highlight a previously unrecognized role of PDHX acetylation in regulating PDC assembly and activity, linking PDHX Lys 488 acetylation and histone lactylation during hepatocellular carcinoma progression and providing a potential biomarker and therapeutic target for further development.
Humans ; Acetylation ; Carcinoma, Hepatocellular/genetics* ; Liver Neoplasms/genetics* ; Pyruvate Dehydrogenase Complex/genetics* ; Gene Expression Regulation, Neoplastic ; Animals ; Mice ; Cell Line, Tumor ; Protein Processing, Post-Translational ; Histones/metabolism* ; Disease Progression

Lactic acid (LA) accumulation in tumor microenvironments (TME) has been implicated in immune suppression and tumor progress. Diverse roles of LA have been elucidated, including microenvironmental pH regulation, signal transduction, post-translational modification, and metabolic remodeling. This review summarizes LA functions within TME, focusing on the effects on tumor cells, immune cells, and stromal cells. Reducing LA levels is a potential strategy to attack cancer, which inevitably affects the physiological functions of normal tissues. Alternatively, transporting LA into the mitochondria as an energy source for immune cells is intriguing. We underscore the significance of LA in both tumor biology and immunology, proposing the burning of LA as a potential therapeutic approach to enhance antitumor immune responses.
Humans ; Tumor Microenvironment/immunology* ; Neoplasms/therapy* ; Lactic Acid/immunology* ; Mitochondria/metabolism* ; Animals ; Signal Transduction

Objective:To understand the epidemiological characteristics of injury deaths in local residents in Nanjing from 2009 to 2023, and provide evidence for the development of injury prevention and control strategies.Methods:The injury mortality data in Nanjing from 2009 to 2023 were analyzed based on the death cause surveillance system. In the recorded 33 542 injury death cases, 19 906 (59.35%) were men, and 13 636 (40.65%) were women. The crude mortality rate, age-standardized mortality rate, age-specific mortality rate, cause-eliminated life expectancy (CELE), potential gains in life expectancy (PGLEs) and life loss rate, were calculated. Joinpoint 5.0 software was used to estimate the average annual percentage change (AAPC) and its 95% CI to assess temporal trends of injury deaths. Results:In Nanjing, the crude injury mortality rate showed an upward trend (AAPC=2.11%), while the age-standardized mortality rate exhibited a downward trend (AAPC=-1.27%) from 2009 to 2023. The ranking of injury deaths in all causes of death declined from the 4 th in 2009 to the 6 th in 2023. The crude and age-standardized injury mortality rates in men were consistently higher than those in women. The primary cause of injury deaths was fall (31.42%). Drowning was the primary cause of injury deaths in age group 0-14 years (35.94%), while traffic accident was the primary cause in age group 15-64 years. For residents aged ≥65 years, fall was the primary cause of injury deaths. From 2009 to 2023, the CELE (AAPC=0.61%, 95% CI: 0.34%-0.89%, P<0.05) and the PGLEs (AAPC=1.73%, 95% CI: 0.21%-3.29%, P<0.05) showed increasing trends. The PGLEs and life loss rate due to injury were consistently higher in men than in women, but the AAPC of PGLEs and life loss rate was higher in women. Conclusions:From 2009 to 2023, the age-standardized injury mortality rate decreased, but the life loss due to injury deaths showed an upward trend in Nanjing, indicating that injury still has non-negligible negative impact on life expectancy.

Objective:To investigate the diagnostic value of metagenomic next-generation sequencing (mNGS) for pyogenic spinal infections.Methods:A total of 255 patients diagnosed with pyogenic spinal infections were enrolled between September 2022 and September 2024 at Qingdao University Affiliated Hospital, Fuzhou Second General Hospital, First Affiliated Hospital of Nanchang University, Shandong University Affiliated Public Health Clinical Center, and the Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. Among them, 155 were male and 100 were female, with an average age of 62.5±14.2 years (ranging from 13 to 90 years). All patients had samples of infected tissue and/or pus collected for microbial culture and mNGS testing. The number, types, and positive rates of pathogens detected by microbial culture and mNGS were compared. Using culture results as the gold standard, receiver operating characteristic (ROC) curve analysis was performed for mNGS testing and the combined method of mNGS and microbial culture, calculating the area under the curve (AUC) and 95% CI. Results:All 255 cases were clinically diagnosed as pyogenic spinal infections, with 194 cases providing microbiological evidence. The most common Gram-positive bacterium was Staphylococcus aureus, while the most common Gram-negative bacterium was Escherichia coli. A total of 33 pathogenic microorganisms were detected by mNGS, while microbial culture detected 18 pathogenic microorganisms. The positive rate of mNGS was 72.2% (184 out of 255), which was significantly higher than that of 30.2% (77 out of 255) for microbial culture, showing a significant difference (χ 2=90.150, P<0.001); the positive rate of mNGS combined with microbial culture was 76.1% (194 out of 255) with significant difference compared to mNGS alone (χ 2=8.100, P<0.001). Among 178 culture-negative samples, the detection rate of mNGS was 65.7% (117 out of 178); among 77 culture-positive samples, the detection rate of mNGS was 87.0% (67 out of 77), and 97.0% (65 out of 67) of the detected pathogens matched the culture results at the species level. The AUCs of the ROC curves for mNGS testing and the combination of mNGS with microbial culture were 0.606 [95% CI (0.534, 0.678)] and 0.671 [95% CI (0.606, 0.736)], respectively, with significant differences compared to microbial culture ( P=0.007; P=0.007). Conclusions:mNGS demonstrates superior performance over conventional culture in identifying pathogens in pyogenic spinal infections. Moreover, combining mNGS with culture further improves diagnostic yield, supporting its integration into clinical practice.

Stereotactic radiotherapy is widely favored because of its high treatment precision and less fractionations.ZND-A is a new domestic gamma-ray cone-beam focused stereotactic radiotherapy system.Herein the technical characteristics of ZND-A system are described in detail from the aspects of the treatment frame,gamma-ray module,collimator module,six-dimensional treatment couch module and image-guided system module,and the main parameters are compared with the mainstream gamma knife equipments at home and abroad.With reference to Response Evaluation Criteria in Solid Tumors(RECIST 1.1),the initial efficacy of the patients treated by the ZND-A system is analyzed to evaluate the advantages and disadvantages of the ZND-A system for providing a reference for the hospital clinical use of this type of gamma knife.

IL-32 is a multifunctional cytokine with both pro-inflammatory and anti-inflammatory properties.It has been proved that expression of IL-32 increases with progression of gastric mucosal diseases and severity of gastric cancer(GC),thus participating in process of gastric"inflammation-cancer"transformation.However,how IL-32 affects malignant transformation of gastric"inflamma-tion-cancer"and finally leads to adverse outcome of GC invasion and migration is still controversial.In order to better clarify regulatory effect and possible mechanism of abnormal expression of IL-32 on different histopathological stages of gastric"inflammation-cancer"transformation,and to explore new directions and breakthroughs in molecular mechanism of early truncation and treatment of gastric precancerous lesion(GPL),we searched literatures related to IL-32 in six authoritative databases at home and abroad,such as Pubmed,Web of Science and CNKI,in past 30 years.It was found that pathogenicity or protective function of IL-32 in different histo-pathological stages of gastric"inflammation-cancer"transformation depended on its different subtypes,secretory forms,surrounding cytokine environment,disease status and genetic factors.IL-32 may regulate polarization of macrophages through NF-κB,MAPK,COX2,PR3,IDO,NOD,PKCδ,FAK and STAT3,amplify or inhibit chronic inflammatory stimulation of gastric mucosa,and thus participate in process of gastric"inflammation-cancer"transformation.Our new understanding of role of IL-32 in different stages of Cor-rea cascade may contribute to development of cytokine-directed therapy,and therapy aimed at regulating different alternative splicing subtypes of IL-32 and targeting IL-32 signals can be used as a new strategy for medical treatment of GPL and GC in future.

Objective To evaluate the relationship between systemic inflammation makers and bone mineral density(BMD)in male patients with type 2 diabetes(T2DM).Methods A total of 261 male patients with T2DM were selected and divided into three groups based on diagnostic criteria:the normal bone mass group(96 cases),the reduced bone mass group(111 cases)and the osteoporosis group(54 cases).Differences in systemic inflammation markers and bone metabolic markers were compared between the three groups.Multivariate ordered Logistic regression analysis was used to investigate factors influencing the progression from normal bone mass to osteoporosis in male patients with T2DM.Receiver operating characteristic(ROC)curves were used to evaluate the predictive value of inflammatory markers for osteoporosis in male patients with T2DM.Correlation analysis was conducted to investigate the correlation between inflammatory markers and BMD and bone turnover markers(BTM)in male patients with T2DM.Results Platelet count(PLT),platelet-to-lymphocyte ratio(PLR),systemic inflammatory index(SII)and neutrophil-to-lymphocyte ratio(NLR)were significantly higher in the osteoporosis group than those in the normal bone mass group(P＜0.05).Multivariate ordered Logistic regression analysis showed that PLR and SII were risk factors for the progression from normal bone mass to osteoporosis in male patients with T2DM(P＜0.05).The area under the ROC curve of PLR was 0.590,and the cut-off value was 96.67.The area under the curve of SII was 0.613,with a cut-off value of 307.9,and the area under the combined curve of the above two indicators was 0.612.In patients with osteoporosis and osteopenia,SII,PLR and PLT were negatively correlated with L1-4 BMD and left hip BMD(P＜0.05).SII was also negatively correlated with left femoral neck BMD(P＜0.05).Conclusion Inflammatory markers PLR and SII have predictive values for the progression from normal bone mass to bone loss and osteoporosis in male patients with T2DM.

OBJECTIVE: To investigate the genetic etiology of six adult patients with Dilated cardiomyopathy (DCM), and analyze the structure of the identified variants, for providing reference for the diagnosis of DCM. METHODS: Six adult patients with DCM (patients 1-6) admitted to the Department of Cardiology of Zhumadian Central Hospital from January 2023 to December 2023 were recruited. Clinical data of the patients were retrospectively collected. And 5 mL of peripheral blood was collected from each patient. Pathogenic variants of the patients were detected by whole exome sequencing (WES), and candidate variants were verified by Sanger sequencing. The possible functional significance of the identified missense variants was evaluated using software including SIFT, PolyPhen-2 and Mutation Taster. Specific regions of the MYBPC protein encoded by the MYBPC3 gene from different species were aligned using Mutation Taster. The wild-type and mutant MYBPC proteins were constructed using homologous modeling software MODELLER v10.4 and three-dimensional structures were visualized using PyMOL software. The molecular interaction between MYBPC-C5 domain and myosin with or without the mutation was further analyzed using ZDOCK module in Discovery Studio 2019 software. Pathogenicity ratings for the detected variant sites were performed in accordance with the Standards and Guidelines for the Interpretation of Sequence variants by the American College of Medical Genetics and Genomics (ACMG) (hereafter referred to as the ACMG Guidelines). This study was reviewed and approved by the Ethics Committee of Zhumadian Central Hospital (Approval No. 2022092007). RESULTS: The six DCM patients had typical symptoms of heart failure, and echocardiography showed whole-heart dilation and decreased ventricular wall motion, left ventricular end-diastolic dimension (LVEDD) was 59-74 mm, left ventricular ejection fraction (LVEF) was 35%-43%, and left ventricular fractional shortening (LVFS) was 17%-28%. Variations of the DCM related genes, including a c.98473A>T (p.Lys32825*) variation of the TTN gene and a c.1976T>C (p.Ile659Thr) variation of the MYBPC3 gene, were identified in two patients. Multiple software predicted that both mutations were deleterious. MYBPC3-Ile659Thr mutation affected the highly conserved residue within the C5 domain of MYBPC. Three-dimensional structural analysis of homologous modeling revealed the alterations in amino acid properties and interactions with surrounding amino acids caused by the MYBPC3-Ile659Thr mutation. Further molecular docking analysis showed that the Ile659Thr mutation altered both the hydrogen bond and salt-bridge interactions between the MYBPC-C5 domain and the ligand myosin. CONCLUSION Two mutations associated with DCM were identified in this study. The abnormal conformation of the mutant protein further affected its interaction with the ligand myosin, resulting in the phenotype of DCM.
Humans ; Cardiomyopathy, Dilated/genetics* ; Male ; Adult ; Female ; Carrier Proteins/chemistry* ; Middle Aged ; Mutation ; Exome Sequencing ; Mutation, Missense ; Retrospective Studies ; Myosin Binding Protein C

Stereotactic radiotherapy is widely favored because of its high treatment precision and less fractionations.ZND-A is a new domestic gamma-ray cone-beam focused stereotactic radiotherapy system.Herein the technical characteristics of ZND-A system are described in detail from the aspects of the treatment frame,gamma-ray module,collimator module,six-dimensional treatment couch module and image-guided system module,and the main parameters are compared with the mainstream gamma knife equipments at home and abroad.With reference to Response Evaluation Criteria in Solid Tumors(RECIST 1.1),the initial efficacy of the patients treated by the ZND-A system is analyzed to evaluate the advantages and disadvantages of the ZND-A system for providing a reference for the hospital clinical use of this type of gamma knife.

Objectives:To investigate the genetic etiology of six adult patients with Dilated cardiomyopathy (DCM), and analyze the structure of the identified variants, for providing reference for the diagnosis of DCM.Methods:Six adult patients with DCM (patients 1-6) admitted to the Department of Cardiology of Zhumadian Central Hospital from January 2023 to December 2023 were recruited. Clinical data of the patients were retrospectively collected. And 3 mL of peripheral blood was collected from each patients. Pathogenic variants patients were detected by whole exome sequencing (WES), and candidate variants were verified by Sanger sequencing. The possible functional significance of the identified missense variants was evaluated using software including SIFT, PolyPhen-2 and Mutation Taster. Specific regions of the MYBPC protein encoded by the MYBPC3 gene from different species were aligned using Mutation Taster. The wild-type and mutant MYBPC proteins were constructed using homologous modeling software MODELLER v10.4 and three-dimensional structures were visualized using PyMOL software. The molecular interaction between MYBPC-C5 domain and myosin with or without the mutation was further analyzed using ZDOCK module in Discovery Studio 2019 software. Pathogenicity ratings for the detected variant sites were performed in accordance with the Standards and Guidelines for the Interpretation of Sequence variants by the American College of Medical Genetics and Genomics (ACMG) (hereafter referred to as the ACMG Guidelines). This study was reviewed and approved by the Ethics Committee of Zhumadian Central Hospital (Approval No. 2022092007). Results:The six DCM patients had typical symptoms of heart failure, and echocardiography showed whole-heart dilation and decreased ventricular wall motion. Left ventricular end-diastolic dimension (LVEDD) was 57-74 mm, left ventricular ejection fraction (LVEF) was 35%-43%, and left ventricular fractional shortening (LVFS) was 17%-28%. Variation in DCM related genes, the c. 98473A>T(p.Lys32825*) variation of the TTN gene and the c.1976T>C(p.Ile659Thr) variation of the MYBPC3 gene, were identified in two patients with DCM. Multiple software predicted that both mutations were deleterious. MYBPC3-Ile659Thr mutation affected the highly conserved residue within the C5 domain of MYBPC. Three-dimensional structural analysis of homologous modeling revealed the alterations in amino acid properties and interactions with surrounding amino acids caused by the MYBPC3-Ile659Thr mutation. Further molecular docking analysis showed that the Ile659Thr mutation altered both the hydrogen bond and salt-bridge interactions between the MYBPC-C5 domain and the ligand myosin. Conclusions:Two mutations associated with DCM were identified in this study. The abnormal conformation of the mutant protein further affected its interaction with the ligand myosin, resulting in the phenotype of DCM.