To develop a prognostic model for neoadjuvant immunochemotherapy efficacy in esophageal squamous cell carcinoma by analyzing the immune microenvironment.

Objective: The choice of neoadjuvant therapy for esophageal squamous cell carcinoma (ESCC) is controversial. This study aims to provide a basis for clinical treatment selection by establishing a predictive model for the efficacy of neoadjuvant immunochemotherapy (NICT). Methods: A retrospective analysis of 30 patients was conducted, divided into Response and Non-response groups based on whether they achieved major pathological remission (MPR). Differences in genes and immune microenvironment between the two groups were analyzed through next-generation sequencing (NGS) and multiplex immunofluorescence (mIF). Variables most closely related to therapeutic efficacy were selected through LASSO regression and ROC curves to establish a predictive model. An additional 48 patients were prospectively collected as a validation set to verify the model's effectiveness. Results: NGS suggested seven differential genes (ATM, ATR, BIVM-ERCC5, MAP3K1, PRG, RBM10, and TSHR) between the two groups (P < 0.05). mIF indicated significant differences in the quantity and location of CD3+, PD-L1+, CD3+PD-L1+, CD4+PD-1+, CD4+LAG-3+, CD8+LAG-3+, LAG-3+ between the two groups before treatment (P < 0.05). Dynamic mIF analysis also indicated that CD3+, CD8+, and CD20+ all increased after treatment in both groups, with a more significant increase in CD8+ and CD20+ in the Response group (P < 0.05), and a more significant decrease in PD-L1+ (P < 0.05). The three variables most closely related to therapeutic efficacy were selected through LASSO regression and ROC curves: Tumor area PD-L1+ (AUC= 0.881), CD3+PD-L1+ (AUC= 0.833), and CD3+ (AUC= 0.826), and a predictive model was established. The model showed high performance in both the training set (AUC= 0.938) and the validation set (AUC= 0.832). Compared to the traditional CPS scoring criteria, the model showed significant improvements in accuracy (83.3% vs 70.8%), sensitivity (0.625 vs 0.312), and specificity (0.937 vs 0.906). Conclusion: NICT treatment may exert anti-tumor effects by enriching immune cells and activating exhausted T cells. Tumor area CD3+, PD-L1+, and CD3+PD-L1+ are closely related to therapeutic efficacy. The model containing these three variables can accurately predict treatment outcomes, providing a reliable basis for the selection of neoadjuvant treatment plans.

Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling.

Macrophages are phenotypically and functionally diverse in the tumor microenvironment (TME). However, how to remodel macrophages with a protumor phenotype and how to manipulate them for therapeutic purposes remain to be explored. Here, we show that in the TME, RARγ is downregulated in macrophages, and its expression correlates with poor prognosis in patients with colorectal cancer (CRC). In macrophages, RARγ interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), which prevents TRAF6 oligomerization and autoubiquitination, leading to inhibition of nuclear factor κB signaling. However, tumor-derived lactate fuels H3K18 lactylation to prohibit RARγ gene transcription in macrophages, consequently enhancing interleukin-6 (IL-6) levels in the TME and endowing macrophages with tumor-promoting functions via activation of signal transducer and activator of transcription 3 (STAT3) signaling in CRC cells. We identified that nordihydroguaiaretic acid (NDGA) exerts effective antitumor action by directly binding to RARγ to inhibit TRAF6-IL-6-STAT3 signaling. This study unravels lactate-driven macrophage function remodeling by inhibition of RARγ expression and highlights NDGA as a candidate compound for treating CRC.

The Function of Circular RNAs in Myocardial Ischemia-Reperfusion Injury: Underlying Mechanisms and Therapeutic Advancement.

Myocardial ischemia reperfusion injury (MIRI) represents a prevalent and severe cardiovascular condition that arises primarily after myocardial infarction recanalization, cardiopulmonary bypass surgery, and both stable and unstable angina pectoris. MIRI can induce malignant arrhythmias and heart failure, thereby increasing the morbidity and mortality rates associated with cardiovascular diseases. Hence, it is important to assess the potential pathological mechanisms of MIRI and develop effective treatments. The role of circular RNAs (circRNAs) in MIRI has increasingly become a topic of interest in recent years. Moreover, significant evidence suggests that circRNAs play a critical role in MIRI pathogenesis, thereby representing a promising therapeutic target. This review aimed to provide a comprehensive overview of the current understanding of the role of circRNAs in MIRI and discuss the mechanisms through which circRNAs contribute to MIRI development and progression, including their effects on apoptosis, inflammation, oxidative stress, and autophagy. Furthermore, the potential therapeutic applications of circRNAs in MIRI treatment, including the use of circRNA-based therapies and modulation of circRNA expression levels, have been explored. Overall, this paper highlights the importance of circRNAs in MIRI and underscores their potential as novel therapeutic targets.

PDHA1 Alleviates Myocardial Ischemia-Reperfusion Injury by Improving Myocardial Insulin Resistance During Cardiopulmonary Bypass Surgery in Rats.

OBJECTIVE: Cardiopulmonary bypass (CPB) is a requisite technique for thoracotomy in advanced cardiovascular surgery. However, the consequent myocardial ischemia-reperfusion injury (MIRI) is the primary culprit behind cardiac dysfunction and fatal consequences post-operation. Prior research has posited that myocardial insulin resistance (IR) plays a vital role in exacerbating the progression of MIRI. Nonetheless, the exact mechanisms underlying this phenomenon remain obscure. METHODS: We constructed pyruvate dehydrogenase E1 α subunit (PDHA1) interference and overexpression rats and used ascending aorta occlusion in an in vivo model of CPB-MIRI. We devised an in vivo model of CPB-MIRI by constructing rat models with both pyruvate dehydrogenase E1α subunit (PDHA1) interference and overexpression through ascending aorta occlusion. We analyzed myocardial glucose metabolism and the degree of myocardial injury using functional monitoring, biochemical assays, and histological analysis. RESULTS: We discovered a clear downregulation of glucose transporter 4 (GLUT4) protein content expression in the CPB I/R model. In particular, cardiac-specific PDHA1 interference resulted in exacerbated cardiac dysfunction, significantly increased myocardial infarction area, more pronounced myocardial edema, and markedly increased cardiomyocyte apoptosis. Notably, the opposite effect was observed with PDHA1 overexpression, leading to a mitigated cardiac dysfunction and decreased incidence of myocardial infarction post-global ischemia. Mechanistically, PDHA1 plays a crucial role in regulating the protein content expression of GLUT4 on cardiomyocytes, thereby controlling the uptake and utilization of myocardial glucose, influencing the development of myocardial insulin resistance, and ultimately modulating MIRI. CONCLUSION: Overall, our study sheds new light on the pivotal role of PDHA1 in glucose metabolism and the development of myocardial insulin resistance. Our findings hold promising therapeutic potential for addressing the deleterious effects of MIRI in patients.

Mechanisms of cadmium accumulation (adsorption and absorption) by the freshwater bivalve Corbicula fluminea under hydrodynamic conditions.

Many heavy metals in sediments and water have potential adverse effects on aquatic organisms such as Corbicula fluminea (O.F. Müller, 1774), a bivalve species frequently used as a biomonitor for metal pollution. Studies over the past decades examining the heavy metal uptake by C. fluminea, very few has investigated the effect of hydrodynamic conditions on accumulation of heavy metal by C. fluminea. Therefore, in this study, to investigate the mechanism of intracellular and extracellular accumulation of metal, individuals of C. fluminea were exposed to cadmium (Cd)-treated water under three different hydrodynamic conditions. These included exposures in two set ups: three rates of rotation (500, 350, 200 r/min) in beakers for 10 days, and then exposure to Cd-treated sediment under two naturally turbulent water conditions (14 cm/s and 3.2 cm/s) in experimental flumes for 23 days. Hydrodynamic force increased the burrowing rate but decreased the activity of C. fluminea. After 10 days of exposure, the extracellular concentrations of Cd in the tissues of C. fluminea in the sand group were significantly higher than that in the gravel groups. The intracellular and extracellular concentrations of Cd in the tissues of C. fluminea dramatically increased in the Cd-treated sediment test. Moreover, the concentration of the extracellular Cd adsorbed on the tissues of C. fluminea in the 14 cm/s and 3.2 cm/s groups was significantly higher than that in the control group, whereas the effect of hydrodynamic force on absorption of Cd by C. fluminea was not obvious. These results suggest that hydrodynamic condition plays an important role in extracellular accumulation of Cd by C. fluminea. In future study, when using C. fluminea to assess Cd pollution in aquatic environment, extracellular Cd adsorbed on the tissue should be removed to avoid the influence of hydrodynamics.