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

This study employed ultrahigh-performance liquid chromatograph-hybrid quadrupole orbitrap high resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS) to detect the chemical constituents of traditional Chinese medicine in Sizi Dingchuan granules. Network pharmacology and molecular docking techniques were then utilized to predict the effects of Sizi Dingchuan granules on bronchial asthma, along with its target molecules and signaling pathways. UHPLC analysis identified 172 compounds, including 84 flavonoids, 38 organic acids and their derivatives, 22 phenylpropanoids, 16 organic oxygen compounds, 3 phenolic compounds, 2 terpenoids, 2 sugars and glycosides, and 5 other compounds. Typical compound fragmentation patterns were documented. Using network pharmacology methods, 117 compounds were ultimately selected for target prediction, establishing a “drug-component-target-disease” network, which revealed that quercetin, schisandrin A, baicalin, gomisin H, and baicalin exhibit multiple targets related to bronchial asthma, suggesting that they may be the active components responsible for the compound’s efficacy in treating this condition. Protein-protein interaction analysis identified core targets including TNF, IL-6, JAK2, STAT3, BCL2, CASP3, and EGFR, primarily clustered within the JAK-STAT signaling pathway. This suggests that the main components of Sizi Dingchuan granules may regulate the balance between Th17 and Treg cells, as well as Th1 and Th2 cell differentiation, by modulating the JAK-STAT signaling pathway, thereby exerting a positive therapeutic effect on bronchial asthma.

ObjectiveTo investigate the characteristics of serum perfluoroalkyl substances （PFASs） exposure and potential influencing factors among community residents in Songjiang District， Shanghai. MethodsIn August 2021， residents who underwent routine health checkups in a community in Songjiang District， Shanghai were recruited as study subjects. The inclusion criteria were adult residents who had lived in the area for more than 3 years， had no occupational exposure history， no underlying diseases， were not pregnant， and were able to complete the questionnaire independently and sign the informed consent form. A questionnaire survey was conducted and venous blood samples were collected. The concentrations of 15 PFASs in serum were determined using ultra-high performance liquid chromatography-tandem quadrupole mass spectrometry （UPLC-MS/MS）. Ordered multi-class logistic regression， interquartile range （IQR）， and odds ratio （OR） were used to explore the influencing factors and risk magnitude of serum PFASs concentrations. ResultsOf the 15 PFASs， 14 were detected， and the detection rates of 7 PFASs were higher than 50%. The highest detected concentrations among the PFASs were PFOS （perfluorooctane sulfonate）， PFOA （perfluorooctanoic acid）， and PFHxS （perfluorohexane sulfonate）， with median concentrations of 48.61 μg∙L^-1， 37.29 μg∙L^-1， and 36.51 μg∙L^-1， respectively. The strongest correlation was between PFDA and PFUnDA （r=0.93， P<0.05）， followed by PFOS and PFDA （r=0.86， P<0.05）. Age， frequency of plastic product use， time spent indoors per day， personal annual income， tea consumption， and daily water intake were potential factors for exposure to PFASs. Among them， age was positively correlated with PFASs； tea consumption was positively correlated with PFNA and PFOA； PFHpA was negatively correlated with the frequency of plastic product use and personal annual income； and PFOS was negatively correlated with the time spent indoors per day. ConclusionThe exposure to serum PFASs among community residents in Songjiang District was relatively serious， and the main components were traditional PFOA， PFOS， and PFHx. Different sociodemographic characteristics had varying degrees of influence on the concentrations of PFASs in serum. The impact of PFASs exposure on the health of community residents deserves further investigation.

Objective:To investigate the diagnostic accuracy of serological indicators and evaluate the diagnostic value of a new established combined serological model on identifying the minimal hepatic encephalopathy (MHE) in patients with compensated cirrhosis.Methods:This prospective multicenter study enrolled 263 compensated cirrhotic patients from 23 hospitals in 15 provinces, autonomous regions and municipalities of China between October 2021 and August 2022. Clinical data and laboratory test results were collected, and the model for end-stage liver disease (MELD) score was calculated. Ammonia level was corrected to the upper limit of normal (AMM-ULN) by the baseline blood ammonia measurements/upper limit of the normal reference value. MHE was diagnosed by combined abnormal number connection test-A and abnormal digit symbol test as suggested by Guidelines on the management of hepatic encephalopathy in cirrhosis. The patients were randomly divided (7∶3) into training set ( n=185) and validation set ( n=78) based on caret package of R language. Logistic regression was used to establish a combined model of MHE diagnosis. The diagnostic performance was evaluated by the area under the curve (AUC) of receiver operating characteristic curve, Hosmer-Lemeshow test and calibration curve. The internal verification was carried out by the Bootstrap method ( n=200). AUC comparisons were achieved using the Delong test. Results:In the training set, prevalence of MHE was 37.8% (70/185). There were statistically significant differences in AMM-ULN, albumin, platelet, alkaline phosphatase, international normalized ratio, MELD score and education between non-MHE group and MHE group (all P<0.05). Multivariate Logistic regression analysis showed that AMM-ULN [odds ratio ( OR)=1.78, 95% confidence interval ( CI) 1.05-3.14, P=0.038] and MELD score ( OR=1.11, 95% CI 1.04-1.20, P=0.002) were independent risk factors for MHE, and the AUC for predicting MHE were 0.663, 0.625, respectively. Compared with the use of blood AMM-ULN and MELD score alone, the AUC of the combined model of AMM-ULN, MELD score and education exhibited better predictive performance in determining the presence of MHE was 0.755, the specificity and sensitivity was 85.2% and 55.7%, respectively. Hosmer-Lemeshow test and calibration curve showed that the model had good calibration ( P=0.733). The AUC for internal validation of the combined model for diagnosing MHE was 0.752. In the validation set, the AUC of the combined model for diagnosing MHE was 0.794, and Hosmer-Lemeshow test showed good calibration ( P=0.841). Conclusion:Use of the combined model including AMM-ULN, MELD score and education could improve the predictive efficiency of MHE among patients with compensated cirrhosis.

Objective To observe the value of 18F-FDG PET/CT combined with tumor markers for diagnosis of non stageⅠ A limited-stage small cell lung cancer(LS-SCLC).Methods Totally 87 cases of non stage Ⅰ A LS-SCLC(LS-SCLC group),137 of non stage Ⅰ A non-small cell lung cancer(NSCLC,NSCLC group)and 48 cases of pulmonary inflammatory lesions(inflammatory group)were enrolled.Patients'general data,tumor marker levels and PET/CT findings were comparatively analyzed.Logistic regression analysis was performed to evaluate the efficacy of parameters for diagnosing non stage Ⅰ A LS-SCLC.Results There were significant differences of patients'age,neuron-specific enolase(NSE),pro-gastrin-releasing peptide(ProGRP),carcinoembryonic antigen(CEA),squamous cell carcinoma antigen(SCCA)and cytokeratin-19-fragment(CYFRA21-1),as well as of the maximum lesion diameter,maximum standard uptake value(SUVmax),morphology,spiculation sign,relationship between long axis and bronchus,lymph node fusion and proportion of lymph node with higher SUVmax than primary lesion among 3 groups(all P＜0.05).The area under the curve(AUC)of the combination of spiculation sign,NSE＞23.5 μg/L,ProGRP＞111.8 ng/L,SCCA≤2.5 μg/L and CYFRA21-1≤7.4 μg/L for differentiating LS-SCLC and NSCLC was 0.91,higher than that of each single parameter(all P＜0.05).AUC of the combination of SUVmax＞8.1,NSE＞19.4 μg/L,ProGRP＞72.5 ng/L and lymph node fusion for differentiating LS-SCLC and pulmonary inflammatory lesions was 0.99,higher than each single parameter(all P＜0.05).Conclusion 18F-FDG PET/CT combined with tumor markers ProGRP and NSE was helpful for diagnosing non stage ⅠA LS-SCLC.

Objective:To compare the differences in the prevalence of mild micro-hepatic encephalopathy (MHE) among patients with cirrhosis by using the psychometric hepatic encephalopathy score (PHES) and the Stroop smartphone application (Encephal App) test.Methods:This prospective, multi-center, real-world study was initiated by the National Clinical Medical Research Center for Infectious Diseases and the Portal Hypertension Alliance and registered with International ClinicalTrials.gov (NCT05140837). 354 cases of cirrhosis were enrolled in 19 hospitals across the country. PHES (including digital connection tests A and B, digital symbol tests, trajectory drawing tests, and serial management tests) and the Stroop test were conducted in all of them. PHES was differentiated using standard diagnostic criteria established by the two studies in China and South Korea. The Stroop test was evaluated based on the criteria of the research and development team. The impact of different diagnostic standards or methods on the incidence of MHE in patients with cirrhosis was analyzed. Data between groups were differentiated using the t-test, Mann-Whitney U test, and χ2 test. A kappa test was used to compare the consistency between groups. Results:After PHES, the prevalence of MHE among 354 cases of cirrhosis was 78.53% and 15.25%, respectively, based on Chinese research standards and Korean research normal value standards. However, the prevalence of MHE was 56.78% based on the Stroop test, and the differences in pairwise comparisons among the three groups were statistically significant (kappa = -0.064, P < 0.001). Stratified analysis revealed that the MHE prevalence in three groups of patients with Child-Pugh classes A, B, and C was 74.14%, 83.33%, and 88.24%, respectively, according to the normal value standards of Chinese researchers, while the MHE prevalence rates in three groups of patients with Child-Pugh classes A, B, and C were 8.29%, 23.53%, and 38.24%, respectively, according to the normal value standards of Korean researchers. Furthermore, the prevalence rates of MHE in the three groups of patients with Child-Pugh grades A, B, and C were 52.68%, 58.82%, and 73.53%, respectively, according to the Stroop test standard. However, among the results of each diagnostic standard, the prevalence of MHE showed an increasing trend with an increasing Child-Pugh grade. Further comparison demonstrated that the scores obtained by the number connection test A and the number symbol test were consistent according to the normal value standards of the two studies in China and South Korea ( Z = -0.982, -1.702; P = 0.326, 0.089), while the other three sub-tests had significant differences ( P < 0.001). Conclusion:The prevalence rate of MHE in the cirrhotic population is high, but the prevalence of MHE obtained by using different diagnostic criteria or methods varies greatly. Therefore, in line with the current changes in demographics and disease spectrum, it is necessary to enroll a larger sample size of a healthy population as a control. Moreover, the establishment of more reliable diagnostic scoring criteria will serve as a basis for obtaining accurate MHE incidence and formulating diagnosis and treatment strategies in cirrhotic populations.

OX40 is a costimulatory receptor that is expressed primarily on activated CD4⁺, CD8⁺, and regulatory T cells. The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion, differentiation, and activation and also promotes dendritic cells to mature to enhance their cytokine production. Therefore, the use of agonistic anti-OX40 antibodies for cancer immunotherapy has gained great interest. However, most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy. Here, we discovered that BGB-A445, a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation, induced optimal T cell activation without impairing dendritic cell function. In addition, BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity. In the MC38 syngeneic model established in humanized OX40 knock-in mice, BGB-A445 demonstrated robust and dose-dependent antitumor efficacy, whereas the ligand-competitive anti-OX40 antibody showed antitumor efficacy characterized by a hook effect. Furthermore, BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody. Taken together, our findings show that BGB-A445, which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies, shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.
Mice ; Animals ; Receptors, Tumor Necrosis Factor/physiology* ; Receptors, OX40 ; Membrane Glycoproteins ; Ligands ; Antibodies, Monoclonal/pharmacology* ; Antineoplastic Agents/pharmacology*

Traumatic cerebrospinal fluid leakage commonly presents in traumatic brain injury patients, and it may lead to complications such as meningitis, ventriculitis, brain abscess, subdural hematoma or tension pneumocephalus. When misdiagnosed or inappropriately treated, traumatic cerebrospinal fluid leakage may result in severe complications and may be life-threatening. Some traumatic cerebrospinal fluid leakage has concealed manifestations and is prone to misdiagnosis. Due to different sites and mechanisms of trauma and degree of cerebrospinal fluid leak, treatments for traumatic cerebrospinal fluid leakage varies greatly. Hence, the Craniocerebral Trauma Professional Group of Neurosurgery Branch of Chinese Medical Association and the Neurological Injury Professional Group of Trauma Branch of Chinese Medical Association organized relevant experts to formulate the " Chinese expert consensus on the diagnosis and treatment of traumatic cerebrospinal fluid leakage in adults ( version 2023)" based on existing clinical evidence and experience. The consensus consisted of 16 recommendations, covering the leakage diagnosis, localization, treatments, and intracranial infection prevention, so as to standardize the diagnosis and treatment of traumatic cerebrospinal fluid leakage and improve the overall prognosis of the patients.

Many efforts have been made to understand excitotoxicity and develop neuroprotectants for the therapy of ischemic stroke. The narrow treatment time window is still to be solved. Given that the ischemic core expanded over days, treatment with an extended time window is anticipated. Bestrophin 1 (BEST1) belongs to a bestrophin family of calcium-activated chloride channels. We revealed an increase in neuronal BEST1 expression and function within the peri-infarct from 8 to 48 h after ischemic stroke in mice. Interfering the protein expression or inhibiting the channel function of BEST1 by genetic manipulation displayed neuroprotective effects and improved motor functional deficits. Using electrophysiological recordings, we demonstrated that extrasynaptic glutamate release through BEST1 channel resulted in delayed excitotoxicity. Finally, we confirmed the therapeutic efficacy of pharmacological inhibition of BEST1 during 6-72 h post-ischemia in rodents. This delayed treatment prevented the expansion of infarct volume and the exacerbation of neurological functions. Our study identifies the glutamate-releasing BEST1 channel as a potential therapeutic target against ischemic stroke with a wide time window.

Objective:To explore the effect of STEM (science, technology, engineering, mathematics) education in the teaching of Comprehensive Nursing Practice course, which is integrated with the concept of social work. Methods:The course of Comprehensive Nursing Practice integrated with the concept of social work was constructed, and two classes of Batch 2019 nursing undergraduates in our university were selected as the research objects, including 46 students in the control group which took traditional teaching, and the other 43 students in the research group which took STEM teaching. Both groups were taught for 2 months (28 class hours). The teaching process, teaching summary and teaching satisfaction of the two groups were evaluated. SPSS 25.0 was used for t-test, Chi-square test and rank-sum test. Results:The scores of STEM literacy, practical ability, inquiry consciousness, learning condition, participation and enthusiasm in the research group were higher than those in the control group ( P < 0.05). After teaching, the scores of problem-solving ability, work display and theoretical knowledge of the research group were higher than those of the control group ( P<0.05). The students in the research group were more satisfied with teaching than those in the control group ( P<0.05). Conclusion:The construction of Comprehensive Nursing Practice course with the concept of social work and the application of STEM education can improve students' learning ability, learning effect and their satisfaction with the course teaching.