Cardiolipin oxidized by ROS from complex II acts as a target of gasdermin D to drive mitochondrial pore and heart dysfunction in endotoxemia.

Cardiac dysfunction, an early complication of endotoxemia, is the major cause of death in intensive care units. No specific therapy is available at present for this cardiac dysfunction. Here, we show that the N-terminal gasdermin D (GSDMD-N) initiates mitochondrial apoptotic pore and cardiac dysfunction by directly interacting with cardiolipin oxidized by complex II-generated reactive oxygen species (ROS) during endotoxemia. Caspase-4/11 initiates GSDMD-N pores that are subsequently amplified by the upregulation and activation of NLRP3 inflammation through further generation of ROS. GSDMD-N pores form prior to BAX and VDAC1 apoptotic pores and further incorporate into BAX and VDAC1 oligomers within mitochondria membranes to exacerbate the apoptotic process. Our findings identify oxidized cardiolipin as the definitive target of GSDMD-N in mitochondria of cardiomyocytes during endotoxin-induced myocardial dysfunction (EIMD), and modulation of cardiolipin oxidation could be a therapeutic target early in the disease process to prevent EIMD.

Comparing GDF9 in mature follicles and clinical outcomes across different PCOS phenotype.

Background: Polycystic ovary syndrome (PCOS) is main cause of anovulatory infertility in women with gestational age. There are currently four distinct phenotypes associated with individualized endocrinology and metabolism. Growth differentiation factor 9 (GDF9) is a candidate as potential biomarker for the assessment of oocyte competence. The effect on oocyte capacity has not been evaluated and analyzed in PCOS phenotypes. Objective: We aimed to screen the expression levels of GDF9 in mature follicles of women with controlled ovarian hyperstimulation (COS) with different PCOS phenotypes. To determine the correlation between the expression level of GDF9 and oocyte development ability. Methods: In Part 1, we conducted a retrospective study comparing the clinical outcomes and endocrine characteristics of patients with PCOS according to different subgroups (depending on the presence or absence of the main features of polycystic ovarian morphology (PCOM), hyperandrogenism (HA), and oligo-anovulation (OA)) and non-PCOS control group. We stratified PCOS as phenotype A (n = 29), phenotype B (n = 18) and phenotype D (n = 24). In Part 2, the expression of GDF9 in follicular fluid (FF) and cumulus cells (CCs) were detected by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. Results: In Part 1, the baseline clinical, hormonal, and ultrasonographic characteristics of the study population were matched with the presence or absence of the cardinal features of each PCOS phenotypes showed a clear difference. Phenotypes A and D had statistically significant associations with blastocyst formation and clinical pregnancy compared with phenotypes B (p < 0.001). In Part 2, the levels of GDF9 in FF and CCs for phenotype A and B were significantly were higher than those of phenotype D (P = 0.019, P = 0.0015, respectively). Multivariate logistic regression analysis showed that GDF9 was an important independent predictor of blastocyst formation (P＜0.001). The blastocyst formation rate of phenotype A was higher than that of phenotype B and D (P＜0.001). Combining the results of the two parts, GDF9 appears to play a powerful role in the development of embryos into blastocysts. Conclusions: GDF9 expression varies with different PCOS phenotypes. Phenotype A had higher GDF9 levels and blastocyst formation ability.

Ill-fitting prosthesis is associated with an increased risk of elevated blood pressures.

OBJECTIVE: Previous studies focused on the benefits of adequate prosthodontic treatment, while few studies have investigated the prosthodontic-related risks to health. As a modifiable oral health indicator, the association of ill-fitting prosthesis (IFP) with hypertension has not been fully explored. METHODS: This cross-sectional study involved 158,659 adults in Beijing (2009-2017) receiving intra-oral examinations and blood pressure measurements. Logistic regression models were applied to assess the association of IFP with the prevalence of hypertension, systolic blood pressure (SBP) ≧ 140 mmHg and diastolic blood pressure (DBP) ≧ 90 mmHg, as well as subgroup analyses by different fixed IFP subgroups (according to involved teeth number) and removable IFP subgroup. We further investigated effect modifications among stratified populations. RESULTS: 158,659 individuals were included for analysis, 346 (26.86%) in IFP group and 27,380 (17.40%) in non-IFP group (p < 0.001) were hypertensive. After adjustment of sex, age, obesity, dyslipidaemia, diabetes, hsCRP, family history of CVD, self-reported smoking, self-reported drinking and WC, ORs of hypertension, SBP ≧ 140 mmHg and DBP ≧ 90 mmHg were 1.330 (95% CI: 1.162-1.522), 1.277 (95% CI: 1.098-1.486) and 1.376 (95% CI: 1.186-1.596), respectively (p < 0.05). Furthermore, after full adjustment, the number of involved teeth showed a significant incremental trend with hypertension risk in the population with and without IFP (p for trend <0.001). The IFP-blood pressure associations were more pronounced in females, 18-60 years, non-obese and diabetic participants. CONCLUSION: As a modifiable oral indicator, IFP was significantly associated with a higher risk of hypertension.

Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression.

Nonalcoholic fatty liver (NAFL) remains relatively benign, but high-risk to end-stage liver diseases become highly prevalent when it progresses into nonalcoholic steatohepatitis (NASH). Our current understanding of the development of NAFL to NASH remains insufficient. In this study, we revealed MAP kinase (MAPK) activation as the most notable molecular signature associated with NASH progression across multiple species. Furthermore, we identified suppressor of IKKε (SIKE) as a conserved and potent negative controller of MAPK activation. Hepatocyte-specific overexpression of Sike prevented NASH progression in diet- and toxin-induced mouse NASH models. Mechanistically, SIKE directly interacted with TGF-ß-activated kinase 1 (TAK1) and TAK1-binding protein 2 (TAB2) to interrupt their binding and subsequent TAK1-MAPK signaling activation. We found that indobufen markedly up-regulated SIKE expression and effectively improved NASH features in mice and macaques. These findings identify SIKE as a MAPK suppressor that prevents NASH progression and provide proof-of-concept evidence for targeting the SIKE-TAK1 axis as a potential NASH therapy.

Identification of novel biomarkers and immune infiltration characteristics of ischemic stroke based on comprehensive bioinformatic analysis and machine learning.

Background: Ischemic stroke (IS) is one of most common causes of disability in adults worldwide. However, there is still a lack of effective and reliable diagnostic markers and therapeutic targets in IS. Furthermore, immune cell dysfunction plays an important role in the pathogenesis of IS. Hence, in-depth research on immune-related targets in progressive IS is urgently needed. Methods: Expression profile data from patients with IS were downloaded from the Gene Expression Omnibus (GEO) database. Then, differential expression analysis and weighted gene coexpression network analysis (WGCNA) were performed to identify the significant modules and differentially expressed genes (DEGs). Key genes were obtained and used in functional enrichment analyses by overlapping module genes and DEGs. Next, hub candidate genes were identified by utilizing three machine learning algorithms: least absolute shrinkage and selection operator (LASSO), random forest, and support vector machine-recursive feature elimination (SVM-RFE). Subsequently, a diagnostic model was constructed based on the hub genes, and receiver operating characteristic (ROC) curves were constructed to validate the performances of the predictive models and candidate genes. Finally, the immune cell infiltration landscape of IS was explored with the CIBERSORT deconvolution algorithm. Results: A total of 40 key DEGs were identified based on the intersection of the DEGs and module genes, and we found that these genes were mainly enriched in the regulation of lipolysis in adipocytes, neutrophil extracellular trap formation and complement and coagulation cascades. Based on the results from three advanced machine learning algorithms, we obtained 7 hub candidate genes (ABCA1, ARG1, C5AR1, CKAP4, HMFN0839, SDCBP and TLN1) as diagnostic biomarkers of IS and developed a reliable nomogram with high predictive performance (AUC = 0.987). In addition, immune cell infiltration dysregulation was implicated in IS, and compared with those in the normal group, IS patients had increased fractions of gamma delta T cells, monocytes, M0 macrophages, M2 macrophages and neutrophils and clearly lower percentages of naive B cells, CD8 T cells, CD4+ memory T cells, follicular helper T cells, regulatory T cells (Tregs) and resting dendritic cells. Furthermore, correlation analysis indicated a significant correlation between the hub genes and immune cells in progressive IS. Conclusion: In conclusion, our study identified 7 hub genes as diagnostic biomarkers and established a reliable model to predict the occurrence of IS. Meanwhile, we explored the immune cell infiltration pattern and investigated the relationship between candidate genes and immune cells in the pathogenesis of IS. Hence, our study provides new insights into the diagnosis and treatment of IS.

Long-term PM2.5 exposure and early-onset diabetes: Does BMI link this risk?

OBJECTIVE: Limited studies investigated the association between high-level fine particulate matter (PM2.5) pollution and early-onset diabetes, leaving the possible metabolic mechanisms unclear. We assessed the association of cumulative PM2.5 exposure with diabetes, including early-onset, in high-pollution areas of China and explored whether metabolic factors mediated this association. METHODS: 124,204 participants (≥18 years) from 121 counties in Hunan province, China, were enrolled between 2005 and 2020, with follow-up until 2021. The ground-level air pollution concentrations at each participant's residence were calculated using a high-quality dataset in China. The independent association of PM2.5 with incident diabetes and early-onset diabetes was assessed by Cox proportional hazards models. Restricted cubic splines were utilized to establish the exposure-response relationships. The role of metabolism-related mediators was estimated by mediation analysis. RESULTS: During a median follow-up of 8.47 (IQR, 6.65-9.82) years, there were 3650 patients with new-onset diabetes. Each 1 µg/m3 increase in the level of cumulative PM2.5 exposure was positively related to an increased incidence of diabetes (HR 1.177, 95 % CI 1.172-1.181) among individuals in the PM2.5 > 50 µg/m3 group after adjusting for multiple variables. The relationship of the PM2.5 dose-response curve for diabetes was non-linear. Significant associations between PM2.5 exposure and early-onset diabetes risk were observed, with this risk showing an increase with the earlier age of early diabetes onset. Males, young individuals (≤45 years), and those with a lower body mass index (BMI <24 kg/m2) appeared to be more susceptible to diabetes. Moreover, change in BMI significantly mediated 31.06 % of the PM2.5-diabetes relationship. CONCLUSIONS: Long-term cumulative PM2.5 exposure increased the risk of early-onset diabetes, which is partially mediated by BMI. Sustained air pollution control measures, priority protection of vulnerable individuals, and effective management of BMI should be taken to reduce the burden of diabetes.

Major lipids and lipoprotein levels and risk of blood pressure elevation: a Mendelian Randomisation study.

BACKGROUND: Quantitative nuclear magnetic resonance (NMR) metabolomics techniques provide detailed measurements of lipoprotein particle concentration. Metabolic dysfunction often represents a cluster of conditions, including dyslipidaemia, hypertension, and diabetes, that increase the risk of cardiovascular diseases (CVDs). However, the causal relationship between lipid profiles and blood pressure (BP) remains unclear. We performed a Mendelian Randomisation (MR) study to disentangle and prioritize the potential causal effects of major lipids, lipoprotein particles, and circulating metabolites on BP and pulse pressure (PP). METHODS: We employed single-nucleotide polymorphisms (SNPs) associated with major lipids, lipoprotein particles, and other metabolites from the UK Biobank as instrumental variables. Summary-level data for BP and PP were obtained from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. Two-sample MR and MR Bayesian model averaging approaches (MR-BMA) were conducted to analyse and rank causal associations. FINDINGS: Genetically predicted TG was the most likely causal exposure among the major lipids to increase systolic blood pressure (SBP) and diastolic blood pressure (DBP), with marginal inclusion probabilities (MIPs) of 0.993 and 0.847, respectively. Among the majority of lipoproteins and their containing lipids, including major lipids, genetically elevated TG in small high-density lipoproteins (S_HDL_TG) had the strongest association with the increase of SBP and DBP, with MIPs of 0.416 and 0.397, respectively. HDL cholesterol (HDL_C) and low-density lipoprotein cholesterol (LDL_C) were potential causal factors for PP elevation among the major lipids (MIP = 0.927 for HDL_C and MIP = 0.718 for LDL_C). Within the sub-lipoproteins, genetically predicted atherogenic lipoprotein particles (i.e., sub-very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and LDL particles) had the most likely causal impact on increasing PP. INTERPRETATION: This study provides genetic evidence for the causality of lipids on BP indicators. However, the effect size on SBP, DBP, and PP varies depending on the lipids' components and sizes. Understanding this potential relationship may inform the potential benefits of comprehensive management of lipid profiles for BP control. FUNDING: Key Research and Development Program of Hubei Province, Science and Technology Innovation Project of Huanggang Central Hospital of Yangtze University, the Hubei Industrial Technology Research Institute of Heart-Brain Diseases, and the Hubei Provincial Engineering Research Centre of Comprehensive Care for Heart-Brain Diseases.

LncRNA DANA1 promotes drought tolerance and histone deacetylation of drought responsive genes in Arabidopsis.

Although many long noncoding RNAs have been discovered in plants, little is known about their biological function and mode of action. Here we show that the drought-induced long intergenic noncoding RNA DANA1 interacts with the L1p/L10e family member protein DANA1-INTERACTING PROTEIN 1 (DIP1) in the cell nucleus of Arabidopsis, and both DANA1 and DIP1 promote plant drought resistance. DANA1 and DIP1 increase histone deacetylase HDA9 binding to the CYP707A1 and CYP707A2 loci. DIP1 further interacts with PWWP3, a member of the PEAT complex that associates with HDA9 and has histone deacetylase activity. Mutation of DANA1 enhances CYP707A1 and CYP707A2 acetylation and expression resulting in impaired drought tolerance, in agreement with dip1 and pwwp3 mutant phenotypes. Our results demonstrate that DANA1 is a positive regulator of drought response and that DANA1 works jointly with the novel chromatin-related factor DIP1 on epigenetic reprogramming of the plant transcriptome during the response to drought.

Protocol for detecting lncRNA-protein interaction in vivo using the yeast three-hybrid assay.

Analyses of long non-coding RNA (lncRNA)-protein interactions provide key clues for understanding the molecular basis of lncRNA-modulated biological processes. Here, we detail a yeast three-hybrid assay to identify the lncRNA-interacting protein. We describe steps for lncRNA bait preparation, screening an RNA-binding proteins (RBPs) cDNA library, and validation of the lncRNA-RBP interaction. The assay can also be further applied to delineate the region of RBP that mediates the RNA-protein interaction. For complete details on the use and execution of this protocol, please refer to Zhang et al.1.

Atlas of Cell Repertoire Within Neointimal Lesions Is Metabolically Altered in Hypertensive Rats.

BACKGROUND: High blood pressure has been suggested to accelerate vascular injury-induced neointimal formation and progression. However, little is known about the intricate relationships between vascular injury and hypertension in the context of arterial remodeling. METHODS: Single-cell RNA-sequencing analysis was used to depict the cell atlas of carotid arteries of Wistar Kyoto rats and spontaneously hypertensive rats with or without balloon injury. RESULTS: We found that hypertension significantly aggravated balloon injury-induced arterial stenosis. A total of 36 202 cells from carotid arteries with or without balloon injury were included in single-cell RNA-sequencing analysis. Cell composition analysis showed that vascular injury and hypertension independently induced distinct aortic cell phenotypic alterations including immune cells, endothelial cells (ECs), and smooth muscle cells. Specifically, our data showed that injury and hypertension-induced specific EC phenotypic alterations, and revealed a transition from functional ECs to hypermetabolic, and eventually dysfunctional ECs in hypertensive rats upon balloon injury. Importantly, our data also showed that vascular injury and hypertension-induced different smooth muscle cell phenotypic alterations, characterized by deferential expression of synthetic signatures. Interestingly, pathway analysis showed that dysregulated metabolic pathways were a common feature in monocytes/macrophages, ECs, and smooth muscle cells in response to injury and hypertension. Functionally, we demonstrate that inhibition of mitochondrial respiration significantly ameliorated injury-induced neointimal formation in spontaneously hypertensive rats. CONCLUSIONS: This study provides the cell landscape changes of the main aortic cell phenotypic alterations in response to injury and hypertension. Our findings suggest that targeting cellular mitochondrial respiration could be a novel therapeutic for patients with hypertension undergoing vascular angioplasty.

The connection between the antibiotic resistome and nitrogen-cycling microorganisms in paddy soil is enhanced by application of chemical and plant-derived organic fertilizers.

Antibiotic resistant genes (ARGs) present significant risks to environments and public health. In particular, there is increasing awareness of the role of soil nitrogen in ARG dissemination. Here, we investigated the connections between antibiotic resistome and nitrogen-cycling microbes in paddy soil by performing five-year field experiments with the treatments of no nitrogen fertilization (CK), reduced chemical nitrogen fertilization (LN), conventional chemical nitrogen fertilization (CN) and plant-derived organic nitrogen fertilization (ON). Compared with CK treatment, CN and ON treatments significantly increased soil NH4+ and TN concentrations by 25.4%-56.5% and 10.4%-20.1%, respectively. Redundancy analysis revealed significantly positive correlation of NH4+ with most ARGs, including tetA, macB and barA. Correspondingly, CN and ON treatments enhanced ARG abundances by 21.9%-23.2%. Moreover, CN and ON treatments promoted nitrate/nitrite-reducing bacteria and linked the corresponding N-cycling functional genes (narG, narH, nirK and nrfA) with most ARGs. Metagenomic binning was performed and identified Gemmatimonadaceae, Caulobacteraceae, Ilumatobacteraceae and Anaerolineaceae as hosts for both ARGs and nitrate/nitrite reduction genes that were enriched by CN and ON treatments. Soil resistome risk score analysis indicated that, although there was increased relation of ARG to nitrogen-cycling microorganisms with nitrogen fertilizer application, the environmental risk of ARGs was not increased due to the lower distribution of ARGs in pathogens. This study contributed to a deeper understanding of the role of soil nitrogen in shaping ARG profiles and controlling soil resistome risk.

Non-high-density lipoprotein cholesterol levels as a risk factor for short-term mortality in elderly Chinese: a large-scale, population-based cohort study.

OBJECTIVES: To explore the association between non-high-density lipoprotein (non-HDL) and mortality risk, both short-term and long-term, in Chinese people. DESIGN: A prospective cohort study. SETTING: The National Basic Public Health Service (BPHS) in China. PARTICIPANTS: Including 621 164 elderly individuals around Hunan Province who underwent healthcare management receiving check-ups in China BPHS from 2010 to 2020. EXCLUSION CRITERIA: (1) missing information on gender; (2) missing records of lipid screening; (3) missing information on key covariates; and (4) missing records of comorbidities (cardiovascular disease, hypertension, diabetes, cancer.) PRIMARY AND SECONDARY OUTCOME MEASURES: The study's primary endpoint was all-cause and cause-specific mortality, sourced from Hunan's CDC(Center for Disease Control and Prevention)-operated National Mortality Surveillance System, tracking participants until 24 February 2021. RESULTS: 26 758 (4.3%) deaths were recorded, with a median follow-up of 0.83 years. Association between non-HDL and mortality was non-linear after multivariable adjustment, with the optimum concentration (OC) being 3.29 and 4.85 mmol/L. Compared with OC, the risk increased by 1.12-fold for non-HDL <3.29 mmol/L (HR: 1.12 (1.09 to 1.15)) and 1.08-fold for non-HDL ≥4.85 mmol/L (HR: 1.08 (1.02 to 1.13)) for all-cause mortality. Furthermore, there is also an increased risk of cardiovascular mortality (HR for non-HDL <3.29: 1.10 (1.06 to 1.32) and HR for non-HDL ≥4.85: 1.07 (1.01 to 1.14)). However, cancer mortality risk was significantly increased only for non-HDL <3.29 mmol/L (HR: 1.11 (1.04 to 1.18)). Non-optimum concentration of non-HDL had significant effects on both the long-term and the short-term risk of mortality, especially for risks of mortality for all-cause (log HR:0 .086 (0.038 to 0.134)), cardiovascular (log HR:0 .082 (0.021 to 0.144)), and cancer (log HR:0 .187 (0.058 to 0.315)) within 3 months. A two-sided value of p <0.05 was considered to be statistically significant. CONCLUSIONS: Non-HDL was non-linearly associated with the risk of mortality, and non-optimal concentrations of non-HDL significantly increased short-term mortality in elderly Chinese, which needs more attention for cardiovascular disease prevention.

Association between questionnaire-based and accelerometer-based physical activity and the incidence of chronic kidney disease using data from UK Biobank: a prospective cohort study.

Background: Prior studies on the relationship between chronic kidney disease (CKD) and physical activity (PA) mainly relied on subjective PA data and rarely considered the genetic risk. This study aims to thoroughly investigate this relationship by utilizing both accelerometer-measured and questionnaire-measured PA data. Methods: This prospective cohort study encompasses two cohorts from the UK Biobank. The questionnaire-based cohort involves 448,444 CKD-free participants who completed an International Physical Activity Questionnaire between 2006 and 2010 and had genetic data. PA was categorized into distinct activities: leisure, housework, job-related, and transportation. The accelerometer-based cohort involves 89,296 CKD-free participants who provided a full week of accelerometer-based physical activity data between 2013 and 2015 and had genetic data. PA was classified as light-intensity, moderate-intensity, vigorous-intensity, moderate to vigorous-intensity PA (LPA, MPA, VPA, MVPA), and total PA. Incident CKD was ascertained from linked hospital inpatient and death records. Genetic risk was assessed using polygenic risk scores. Cox proportional hazard models with restricted cubic splines were used for the analysis. Findings: In the questionnaire-based cohort, 18,184 (4.05%) participants developed CKD during 13.6 years of follow-up. Engaging in strenuous sports, other exercises, walking for pleasure, stair climbing, and heavy DIY were associated with a reduced risk of CKD. In the accelerometer-based cohort, 2297 (2.57%) participants developed CKD during 7.9 years of follow-up. Higher levels [highest quartile vs lowest quartile] of MPA (HR 0.639, 95% CI 0.554-0.737), VPA (HR 0.639, 95% CI 0.549-0.745), MVPA (HR 0.630, 95% CI 0.545-0.729), and total PA (HR 0.649, 95% CI 0.563-0.750) were associated with a lower CKD risk. There were significant interactions between MPA and genetic risk on the risk of CKD incidence (P for interaction = 0.025). A linear dose-response relationship was observed between MPA, total PA, and the risk of CKD incidence with no minimal or maximal threshold. These associations are robust in different subgroups and a series of sensitivity analyses. Interpretation: Engaging in multiple types of PA and higher levels of total PA, MPA, VPA, and MVPA may be associated with a lower risk of developing CKD, regardless of genetic risk. This finding holds substantial implications for clinical approaches to CKD prevention and provides evidence to inform future PA guideline development. Funding: Medical Science Advancement Program of Wuhan University, and the National Science Foundation of China.

PBK correlates with prognosis, immune escape and drug response in LUAD.

PBK (PDZ-binding kinase) is a protein-coding gene that encodes a serine/threonine protein kinase associated with the dual-specific mitogen-activated protein kinase (MAPKK) family. Overexpression of this gene is closely linked to tumor development. In this study, we aimed to investigate the role of PBK in lung adenocarcinoma (LUAD) progression, prognosis, and immune evasion. We conducted a pan-cancer analysis of PBK to examine its expression and prognostic value. In the LUAD cohort, we analyzed PBK expression, prognosis, mutational features, and immune infiltration in groups with different PBK expression levels. We constructed a PBK-associated genomic model, integrated it into a nomogram, and compared high and low-risk subgroups. In our pan-cancer analysis, PBK was significantly upregulated, particularly in LUAD patients, and displayed poor prognosis. The high PBK expression group had many deletion mutations but still showed gene upregulation. Immune infiltration analysis indicated that PBK-triggered immune escape in the high expression group might relate to antigen presentation, dendritic cell, and CD8+ T cell infiltration. We constructed a 5-gene prognostic model and a nomogram to quantify individual survival probabilities. The PBK-associated gene prognostic model reliably predicted patient prognosis and drug response. Our findings offer new insights into PBK-induced immune escape and targeted therapy during LUAD development, providing valuable suggestions for clinical treatment approaches.

[Immune Thrombocytopenia Induced by Sintilimab in Lung Cancer: 
A Case Report and Literature Review].

Immune checkpoint inhibitors (ICIs) show unique advantages in the treatment of lung cancer, making the treatment of lung cancer enter the era of immunotherapy, but ICIs will also have adverse reactions, and the incidence of immune-induced hematological toxicity is not very high. Immunotherapy-induced thrombocytopenia is a rare adverse event.We report one case of thrombocytopenia induced by ICIs and review the literature on thrombocytopenia associated with ICIs and discuss the clinical features, possible mechanisms, and optimal treatment. 
.

Attenuated Salmonella carrying siRNA-CD24 improved the effect of oxaliplatin on HCC.

Oxaliplatin is a chemotherapy drug currently utilized in the treatment of advanced cancer patients. However, its tolerability poses a limitation to its clinical application. Studies have demonstrated that the presence of tumor-associated macrophages is positively correlated with poor prognosis in various solid tumors, including hepatocellular carcinoma (HCC), and is a significant factor contributing to oxaliplatin resistance. Therefore, targeting tumor-associated macrophages may be an effective strategy to improve the efficacy of oxaliplatin in the treatment of HCC patients. CD24 is a novel target for tumor therapy that can interact with the inhibitory receptor Siglec-10 on tumor-associated macrophages, transmitting immune inhibitory signals and inhibiting macrophage phagocytosis function. In this study, we utilized RNAi technology to inhibit the expression of CD24 in tumor cells and combined it with oxaliplatin, resulting in reduced tumor invasion, migration, and proliferation, as well as increased cell apoptosis. Furthermore, immunofluorescence and flow cytometry results indicated that both the single treatment group and combination treatment group enhanced the infiltration of immune cells. This study presents a novel approach to identifying combination therapy and targets for the clinical treatment of HCC with oxaliplatin.

The noncanonical inflammasome-induced pyroptosis and septic shock.

Sepsis remains one of the most common and lethal conditions globally. Currently, no proposed target specific to sepsis improves survival in clinical trials. Thus, an in-depth understanding of the pathogenesis of sepsis is needed to propel the discovery of effective treatment. Recently attention to sepsis has intensified because of a growing recognition of a non-canonical inflammasome-triggered lytic mode of cell death termed pyroptosis upon sensing cytosolic lipopolysaccharide (LPS). Although the consequences of activation of the canonical and non-canonical inflammasome are similar, the non-canonical inflammasome formation requires caspase-4/5/11, which enzymatically cleave the pore-forming protein gasdermin D (GSDMD) and thereby cause pyroptosis. The non-canonical inflammasome assembly triggers such inflammatory cell death by itself; or leverages a secondary activation of the canonical NLRP3 inflammasome pathway. Excessive cell death induced by oligomerization of GSDMD and NINJ1 leads to cytokine release and massive tissue damage, facilitating devastating consequences and death. This review summarized the updated mechanisms that initiate and regulate non-canonical inflammasome activation and pyroptosis and highlighted various endogenous or synthetic molecules as potential therapeutic targets for treating sepsis.

Survival analysis of patients with advanced non-small cell lung cancer receiving EGFR-TKI treatment of Yunnan in southwestern China: a real-world study.

Importance: Patients with EGFR mutations who have advanced-stage non-small cell lung cancer (NSCLC) already receive tyrosine kinase inhibitors (TKIs) as the standard first-line therapy. Notably, Yunnan is a regional high incidence area of lung cancer in the highlands with a high rate of rare EGFR mutations. Overall, lung cancer patients in Xuanwei may present a distinct subgroup globally. Recent studies suggested that the NSCLC cohort in Xuanwei harbored a significantly higher uncommon mutation rate. However, little was known about the clinicopathological features and treatment efficacy of EGFR-TKI in Yunnan NSCLC patients. Objective: This study aimed to investigate the clinical impact of histologic type on the survival outcomes of patients with stage IIIB and IV NSCLC receiving EGFR-TKI treatment of Yunnan in southwestern China. Methods: In this retrospective study, we enrolled advanced NSCLC patients (IIIB-IV) with EGFR mutations who were first diagnosed and treated at Yunnan Cancer hospital from January 2016 to December 2019. Sociodemographics, lifestyle, survival, and clinicopathological characteristics of the patients were collected. The Kaplan-Meier method was used to assess the OS and PFS of patients. An analysis of prognostic factors was conducted using Cox regression. Results: A total of 468 eligible patients were included. The median progression-free survival (PFS) and overall survival(OS) were 11.30(95% CI, 10.12-12.48) months and 30.30(95% CI, 26.24-34.36) months. Based on survival analysis among all the patients,females(HR=0.815;95% CI:0.671-0.989; P=0.017), Xuanwei origin (HR=0.776; 95% CI: 0.609-0.989; P=0.040), sample types(HR=0.780; 95% CI: 0.642-0.947; P=0.012) had a longer PFS. Multivariable analysis showed that only the sample type was an independent factor on median PFS with EGFR-TKI therapy. Patients less than 60 years old (HR=1.433; 95% CI:1.134-1.812, P=0.003)had better OS, but objectives with BMI≥24kg/m2(HR=0.653; 95% CI: 0.500-0.864; P=0.002), females(HR=0.776; 95% CI:0.613-0.982; P=0.035)and patients with tissue sample type (HR=0.760; 95% CI:0.600-.0961; P=0.022) had better OS. Notably, subgroup analysis of our study also found that PFS was significantly better in patients with G719X, L861Q, S768I, G719X+L861Q, and G719X+S768I in Xuanwei than classical mutation ones, including 19-Del and L858R (median 22.7 vs. 12.0 months, HR=0.523, P=0.010), while PFS was inferior in patients with rare mutations of EGFR in non-Xuanwei than the classical mutation ones (median 5.10 vs. 11.10 months, HR=1.760, P=0.015). Conclusion: NSCLC patients in Yunnan displayed a unique EGFR mutation profile, especially a higher prevalence of EGFR uncommon and compound mutations subtype. This study indicates prognostic factors of NSCLC treated with EGFR-TKI in Yunan and Xuanwei. This study will provide new clinical evidence for EGFR-TKI-targeted therapy in patients with rare EGFR mutations in China and worldwide. More researchs were needed for NSCLC EGFR-TKI therapy and medical insurance policy-making in Yunnan, Xuanwei area and uncommon especially.

Epilepsy and long-term risk of arrhythmias.

BACKGROUND AND AIMS: Previous evidence has mainly supported transient changes in cardiac function during interictal or peri-ictal phases in people with epilepsy, but the long-term risk of cardiac arrhythmias is poorly described. This study aimed to assess the long-term association of epilepsy with cardiac arrhythmias, considering the potential role of genetic predisposition and antiseizure medications (ASMs) in any associations observed. METHODS: This population-based study evaluated UK Biobank data for individuals recruited between 2006 and 2010. Cox proportional hazards models and competing risk models were used to examine the association of epilepsy history with the long-term incidence risk of cardiac arrhythmias and arrhythmias subtypes. Polygenic risk scores (PRS) were calculated to investigate the effect of genetic susceptibility. The role of ASMs was also evaluated by integrating observational and drug target Mendelian randomization (MR) evidence. RESULTS: The study included 329 432 individuals, including 2699 people with epilepsy. Compared with those without epilepsy, people with epilepsy experienced an increased risk of all cardiac arrhythmias [hazard ratio (HR) 1.36, 95% confidence interval (CI) 1.21-1.53], atrial fibrillation (HR 1.26, 95% CI 1.08-1.46), and other cardiac arrhythmias (HR 1.56, 95% CI 1.34-1.81). The associations were not modified by genetic predisposition as indicated by PRS. Competing and sensitivity analyses corroborated these results. Individuals with epilepsy using ASMs, especially carbamazepine and valproic acid, were at a higher risk for cardiac arrhythmias. This observation was further supported by drug target MR results (PSMR < .05 and PHEIDI > .05). CONCLUSION: This study revealed the higher risk of cardiac arrhythmias persists long term in people with epilepsy, especially among those using carbamazepine and valproic acid. These findings highlight the need for regular heart rhythm monitoring and management in people with epilepsy in order to reduce the risk of further cardiovascular complications.

Meta-Analysis of Single-Cell RNA-Seq Data Reveals the Mechanism of Formation and Heterogeneity of Tertiary Lymphoid Organ in Vascular Disease.

BACKGROUND: Tertiary lymphoid organs (TLOs) are ectopic lymphoid organs developed in nonlymphoid tissues with chronic inflammation, but little is known about their existence in different types of vascular diseases and the mechanism that mediated their development. METHODS: To take advantage of single-cell RNA sequencing techniques, we integrated 28 single-cell RNA sequencing data sets containing 5 vascular disease models (atherosclerosis, abdominal aortic aneurysm, intimal hyperplasia, isograft, and allograft) to explore TLOs existence and environment supporting its growth systematically. We also searched Medline, Embase, PubMed, and Web of Science from inception to January 2022 for published histological images of vascular remodeling for histological evidence to support TLO genesis. RESULTS: Accumulation and infiltration of innate and adaptive immune cells have been observed in various remodeling vessels. Interestingly, the proportion of such immune cells incrementally increases from atherosclerosis to intimal hyperplasia, abdominal aortic aneurysm, isograft, and allograft. Importantly, we uncovered that TLO structure cells, such as follicular helper T cells and germinal center B cells, present in all remodeled vessels. Among myeloid cells and lymphocytes, inflammatory macrophages, and T helper 17 cells are the major lymphoid tissue inducer cells which were found to be positively associated with the numbers of TLO structural cells in remodeled vessels. Vascular stromal cells also actively participate in vascular TLO genesis by communicating with myeloid cells and lymphocytes via CCLs (C-C motif chemokine ligands), CXCL (C-X-C motif ligand), lymphotoxin, BMP (bone morphogenetic protein) chemotactic, FGF-2 (fibroblast growth factor-2), and IGF (insulin growth factor) proliferation mechanisms, particularly for lymphoid tissue inducer cell aggregation. Additionally, the interaction between stromal cells and immune cells modulates extracellular matrix remodeling. Among TLO structure cells, follicular helper T, and germinal center B cells have strong interactions via TCR (T-cell receptor), CD40 (cluster of differentiation 40), and CXCL signaling, to promote the development and maturation of the germinal center in TLO. Consistently, by reviewing the histological images from the literature, TLO genesis was found in those vascular remodeling models. CONCLUSIONS: Our analysis showed the existence of TLOs across 5 models of vascular diseases. The mechanisms that support TLOs formation in different models are heterogeneous. This study could be a valuable resource for understanding and discovering new therapeutic targets for various forms of vascular disease.