Association between triglyceride-glucose index and acute kidney injury in patients with acute myocardial infarction based on medical information mart for intensive care database: A cross-sectional study.

Background: The relationship between triglyceride glucose (TyG) index and the incidence of acute kidney injury (AKI) in patients with acute myocardial infarction (AMI) is unclear. This study aims to explore the relationship between the two. Methods: Participants were enrolled from Medical Information Mart for Intensive Care IV (MIMICIV) and grouping of subjects based on the quartile interval of the TyG index. With the presence of AKI as the main outcome, a logistic regression model was constructed. The correlation of the TyG index with the results obtained was examined by using a restricted cubic spline (RCS) model.

Prospects of molecular hydrogen in cancer prevention and treatment.

Gas signaling molecules, including carbon monoxide (CO), nitric oxide (NO), and hydrogen sulfide (H2S), have been shown to have cancer therapeutic potential, pointing to a new direction for cancer treatment. In recent years, a series of studies have confirmed that hydrogen (H2), a weakly reductive gas, also has therapeutic effects on various cancers and can mitigate oxidative stress caused by radiation and chemotherapy, reducing tissue damage and immunosuppression to improve prognosis. Meanwhile, H2 also has immunomodulatory effects, inhibiting T cell exhaustion and enhancing T cell anti-tumor function. It is worth noting that human intestinal flora can produce large amounts of H2 daily, which becomes a natural barrier to maintaining the body's resistance to diseases such as tumors. Although the potential anti-tumor mechanisms of H2 are still to be investigated, previous studies have shown that H2 can selectively scavenge highly toxic reactive oxygen species (ROS) and inhibit various ROS-dependent signaling pathways in cancer cells, thus inhibiting cancer cell proliferation and metastasis. The ROS scavenging ability of H2 may also be the underlying mechanism of its immunomodulatory function. In this paper, we review the significance of H2 produced by intestinal flora on the immune homeostasis of the body, the role of H2 in cancer therapy and the underlying mechanisms, and the specific application of H2 to provide new ideas for the comprehensive treatment of cancer patients.

Low Pneumoperitoneum Pressure Reduces Gas Embolism During Laparoscopic Liver Resection: A Randomized Controlled Trial.

OBJECTIVE: To compare the effect of low and standard pneumoperitoneal pressure (PP) on the occurrence of gas embolism during laparoscopic liver resection (LLR). BACKGROUND: LLR has an increased risk of gas embolism. Although animal studies have shown that low PP reduces the occurrence of gas embolism, clinical evidence is lacking. METHODS: This parallel, dual-arm, double-blind, randomized controlled trial included 141 patients undergoing elective LLR. Patients were randomized into standard ("S," 15 mm Hg; n = 70) or low ("L," 10 mm Hg; n = 71) PP groups. Severe gas embolism (≥ grade 3, based on the Schmandra microbubble method) was detected using transesophageal echocardiography and recorded as the primary outcome. Intraoperative vital signs and postoperative recovery profiles were also evaluated. RESULTS: Fewer severe gas embolism cases (n = 29, 40.8% vs n = 47, 67.1%, P = 0.003), fewer abrupt decreases in end-tidal carbon dioxide partial pressure, shorter severe gas embolism duration, less peripheral oxygen saturation reduction, and fewer increases in heart rate and lactate during gas embolization episodes was found in group L than in group S. Moreover, a higher arterial partial pressure of oxygen and peripheral oxygen saturation were observed, and fewer fluids and vasoactive drugs were administered in group L than in group S. In both groups, the distensibility index of the inferior vena cava negatively correlated with central venous pressure throughout LLR, and a comparable quality of recovery was observed. CONCLUSIONS: Low PP reduced the incidence and duration of severe gas embolism and achieved steadier hemodynamics and vital signs during LLR. Therefore, a low PP strategy can be considered a valuable choice for the future LLR.

HSK3486 Inhibits Colorectal Cancer Growth by Promoting Oxidative Stress and ATPase Inhibitory Factor 1 Activation.

BACKGROUND: HSK3486 (ciprofol), a new candidate drug similar to propofol, exerts sedative and hypnotic effects through gamma-aminobutyric acid type A receptors; however, its potential role in colorectal cancer is currently unknown. AIMS: This study aimed to evaluate the effects of HSK3486 on colorectal cancer cell proliferation. METHODS: Imaging was performed to detect reactive oxygen species and mitochondrial membrane potential. Western blotting was used to determine the expression of target signals. The HSK3486 molecular mechanism was investigated through ATPase inhibitory factor 1 knockdown and xenograft model experiments to assess mitochondrial function in colorectal cancer cells. RESULTS: Cell Counting Kit-8 and Annexin V/propidium iodide double staining assays showed that HSK3486 inhibited colorectal cancer cell proliferation in a concentration-dependent manner. In addition, HSK3486 treatment increased the expression of B-cell lymphoma-2-associated X, cleaved caspase 3, and cleaved poly (ADP-ribose) polymerase, whereas myeloid cell leukemia-1 and B-cell lymphoma 2 expression decreased. HSK3486 promoted mitochondrial dysfunction by inducing ATPase inhibitor factor 1 expression. Furthermore, HSK3486 promoted oxidative stress, as shown by the increase in reactive oxygen species and lactate dehydrogenase levels, along with a decrease in mitochondrial membrane potential and ATP levels. ATPase inhibitor factor 1 small interfering RNA pretreatment dramatically increased the mitochondrial membrane potential and tumor size in a xenograft model following exposure to HSK3486. CONCLUSION: Collectively, our findings revealed that HSK3486 induces oxidative stress, resulting in colorectal cancer cell apoptosis, making it a potential candidate therapeutic strategy for colorectal cancer.

The Causality between Gut Microbiota and Hypertension and Hypertension-related Complications: A Bidirectional Two-Sample Mendelian Randomization Analysis.

BACKGROUND: Recent studies have highlighted a connection between gut microbiota and hypertension, yet the precise nature of this relationship remains unclear. OBJECTIVE: This research aims to analyze the causal link between gut microbiota and hypertension, along with associated complications, utilizing two-sample bidirectional Mendelian randomization (MR). MATERIALS AND METHODS: Summary data from genome-wide association studies (GWAS) meta-analyses, including gut microbiota GWAS data from 24 cohorts, and the latest GWAS data for hypertension-related conditions were acquired. Employing various MR methods, including Inverse-variance weighted (IVW), MR-Egger, Weighted Median, Simple Mode, and Weighted Mode, we investigated the association between gut microbiota and hypertension-related conditions. Sensitivity analyses were conducted for result stability, and reverse MR analysis assessed the potential for reverse causality. RESULTS: The Mendelian randomization analysis involving 199 microbial taxa and four phenotypes identified 46 microbial taxa with potential causal links to hypertension and its complications. Following Bonferroni correction, genus.Victivallis showed a robust causal relationship with hypertension (OR = 1.08, 95% CI = 1.04-1.12, P = 9.82e-5). This suggests an 8% increased risk of hypertension with each unit rise in genus.Victivallis abundance. CONCLUSION: In conclusion, this study establishes a causal connection between gut microbiota and hypertension, along with common associated complications. The findings unveil potential targets and evidence for future hypertension and complication treatment through gut microbiota interventions, offering a novel avenue for therapeutic exploration.

Ferritin-mediated neutrophil extracellular traps formation and cytokine storm via macrophage scavenger receptor in sepsis-associated lung injury.

BACKGROUND: Sepsis is a severe systemic inflammatory disorder manifested by a dysregulated immune response to infection and multi-organ failure. Numerous studies have shown that elevated ferritin levels exist as an essential feature during sepsis and are able to suggest patients' prognoses. At the same time, the specific mechanism of ferritin-induced inflammatory injury remains unclear. METHODS: Hyper-ferritin state during inflammation was performed by injecting ferritin into a mouse model and demonstrated that injection of ferritin could induce a systemic inflammatory response and increase neutrophil extracellular trap (NET) formation.Padi4-/-, Elane-/- and Cybb-/- mice were used for the NETs formation experiment. Western blot, immunofluorescence, ELISA, and flow cytometry examined the changes in NETs, inflammation, and related signaling pathways. RESULTS: Ferritin induces NET formation in a peptidylarginine deiminase 4 (PAD4), neutrophil elastase (NE), and reactive oxygen species (ROS)-dependent manner, thereby exacerbating the inflammatory response. Mechanistically, ferritin induces the expression of neutrophil macrophage scavenger receptor (MSR), which promotes the formation of NETs. Clinically, high levels of ferritin in patients with severe sepsis correlate with NETs-mediated cytokines storm and are proportional to the severity of sepsis-induced lung injury. CONCLUSIONS: In conclusion, we demonstrated that hyper-ferritin can induce systemic inflammation and increase NET formation in an MSR-dependent manner. This process relies on PAD4, NE, and ROS, further aggravating acute lung injury. In the clinic, high serum ferritin levels are associated with elevated NETs and worse lung injury, which suggests a poor prognosis for patients with sepsis. Our study indicated that targeting NETs or MSR could be a potential treatment to alleviate lung damage and systemic inflammation during sepsis. Video Abstract.

Spatial transcriptomics and single-nucleus RNA sequencing reveal a transcriptomic atlas of adult human spinal cord.

Despite the recognized importance of the spinal cord in sensory processing, motor behaviors, and neural diseases, the underlying organization of neuronal clusters and their spatial location remain elusive. Recently, several studies have attempted to define the neuronal types and functional heterogeneity in the spinal cord using single-cell or single-nucleus RNA sequencing in animal models or developing humans. However, molecular evidence of cellular heterogeneity in the adult human spinal cord is limited. Here, we classified spinal cord neurons into 21 subclusters and determined their distribution from nine human donors using single-nucleus RNA sequencing and spatial transcriptomics. Moreover, we compared the human findings with previously published single-nucleus data of the adult mouse spinal cord, which revealed an overall similarity in the neuronal composition of the spinal cord between the two species while simultaneously highlighting some degree of heterogeneity. Additionally, we examined the sex differences in the spinal neuronal subclusters. Several genes, such as SCN10A and HCN1, showed sex differences in motor neurons. Finally, we classified human dorsal root ganglia (DRG) neurons using spatial transcriptomics and explored the putative interactions between DRG and spinal cord neuronal subclusters. In summary, these results illustrate the complexity and diversity of spinal neurons in humans and provide an important resource for future research to explore the molecular mechanisms underlying spinal cord physiology and diseases.

Efficacy and safety of patient-controlled epidural analgesia versus patient-controlled intravenous analgesia following open hepatectomy: A single-center retrospective study.

Background: Postoperative analgesia is an essential component of enhanced recovery after surgery following abdominal surgery. Studies comparing the effectiveness of epidural analgesia with that of other analgesic modalities after liver surgery have reported inconsistent results. Consequently, the use of epidural analgesia for open hepatectomy is controversial. Objective: The present single-center retrospective study aimed to compare the efficacy and safety of patient-controlled epidural analgesia (PCEA) and patient-controlled intravenous analgesia (PCIA) in adults undergoing open hepatectomy. Methods: Patients who underwent open hepatectomy between January 2018 to December 2019 at Zhongshan Hospital, Fudan University were retrospectively analyzed. Propensity score matching was used to adjust baseline information between the PCEA and PCIA groups. The primary outcome measure was scores of the numeric rating scales (NRSs) for resting, exercise, and nocturnal pain at postoperative 24 h (postoperative day 1 [POD1]) and 48 h (POD2). The secondary outcome indicators included postoperative nausea and vomiting (PONV), hypotension, pruritus, respiratory depression, functional activity score (FAS), effective analgesic pump compression ratio, analgesic relief rate, discontinuation of the analgesic pump, reasons for discontinuation of the analgesic pump, and patient satisfaction with postoperative analgesia. Results: The NRS scores of the PCEA group on POD1 were significantly lower than those of the PCIA group (P < 0.05). On POD2, the difference between the two groups was significant only for motion NRS scores (P < 0.05). The PCIA group had significantly more patients with lower FAS functional class than the PCEA group (P < 0.001). The effective analgesic pump compression ratio and the analgesic relief rate at 2 days after the surgery were lower in the PCEA group than in the PCIA group (P < 0.001). The incidence of pump discontinuation was higher in the PCEA group than in the PCIA group on POD2 (P = 0.044). Moreover, on POD1 and POD2, the PCEA group showed a higher incidence of pruritus and hypotension than the PCIA group (P < 0.001). Both groups showed no significant difference in PONV incidence. Conclusion: In patients undergoing open hepatectomy, PCEA was more effective than PCIA in relieving moderate to severe pain on POD1. However, improving the safety and effectiveness of PCEA remains a challenge.

Targeting NEDD8 suppresses surgical stress-facilitated metastasis of colon cancer via restraining regulatory T cells.

Regulatory T cells (Tregs) are a key determinant for the immunosuppressive and premetastatic niche for cancer progression after surgery resection. However, the precise mechanisms regulating Tregs function during surgical stress-facilitated cancer metastasis remain unknown. This study aims to unravel the mechanisms and explore potential strategies for preventing surgical stress-induced metastasis by targeting NEDD8. Using a surgical stress mouse model, we found that surgical stress results in the increased expression of NEDD8 in Tregs. NEDD8 depletion abrogates postoperative lung metastasis of colon cancer cells by inhibiting Treg immunosuppression and thereby partially recovering CD8+T cell and NK cell-mediated anti-tumor immunity. Furthermore, Treg mitophagy and mitochondrial respiration exacerbated in surgically stressed mice were attenuated by NEDD8 depletion. Our observations suggest that cancer progression may result from surgery-induced enhancement of NEDD8 expression and the subsequent immunosuppressive function of Tregs. More importantly, depleting or inhibiting NEDD8 can be an efficient strategy to reduce cancer metastasis after surgery resection by regulating the function of Tregs.

Association of clonal haematopoiesis with severe postoperative complications in patients undergoing radical oesophagectomy.

BACKGROUND: Clonal haematopoiesis (CH) is an age-associated clonal expansion of blood cells driven by leukaemia-associated somatic mutations. Although CH has been reported to be a risk factor for leukaemia and a number of non-haematopoietic diseases, its role in perioperative medicine remains unexplored. METHODS: This was a single-centre, prospective, observational study. Patients undergoing radical oesophagectomy were enrolled, and peripheral blood samples were collected for DNA sequencing. Patients with haematopoietic somatic mutations (variant allele frequencies ≥1%) in the DNMT3A gene, TET2 gene, or both were defined as CH carriers. The primary outcome was the incidence of severe postoperative complications (Clavien-Dindo classification ≥3). The secondary outcomes included the major types of postoperative complications, mortality, and other common perioperative variables. RESULTS: Clonal haematopoiesis was found in 21.2% (33/156) of the patients (mean age: 66 yr [range: 26-79 yr]; 83% males). Some 14/33 (42.4%) patients with CH had severe postoperative complications, compared with patients without CH carriers (28/123 [22.8%]; P=0.024). Multivariable logistic regression analysis showed that CH was associated with an increased risk of developing severe postoperative complications (odds ratio, 3.63; 95% confidence interval, 1.37-9.66; P=0.010). Among the major postoperative complications, the incidence of pulmonary complications was significantly higher in the patients with CH than in those without CH (15 in 33 [45.5%] vs 30 in 123 [24.4%], P=0.018). CONCLUSIONS: Clonal haematopoiesis was associated with a higher incidence of severe postoperative complications in patients undergoing radical oesophagectomy, suggesting that clonal haematopoiesis can play an important role in perioperative medicine. CLINICAL TRIAL REGISTRATION: ChiCTR2100044175 (Chinese Clinical Trial Registry, http://www.chictr.org.cn/showproj.aspx?proj=123193).

Opioid-free anesthesia reduces the severity of acute postoperative motion-induced pain and patient-controlled epidural analgesia-related adverse events in lung surgery: randomized clinical trial.

Background: Opioids have been used as pain relievers for thousands of years. However, they may also cause undesirable side effects. We therefore performed this study to compare the effect of opioid-free anesthesia (OFA) versus opioid-sparing anesthesia (OSA) on postoperative pain and patient-controlled epidural analgesia (PCEA)-related events. Methods: This is a single center randomized clinical trial that was recruited patients aged from 18 to 70 years who received video-assisted lung surgery between October 2021 and February 2022. Participants were 1:1 randomly assigned to OFA or OSA. Patients in the OFA group received propofol, rocuronium, esmolol, lidocaine, and magnesium sulfate intravenously with epidural ropivacaine. Patients in the OSA group received propofol, rocuronium, remifentanil, and sufentanil intravenously with epidural hydromorphone and ropivacaine. Results: A total number of 124 patients were randomly allocated to the OFA or OSA group. In the OFA group, the severity of pain during coughs on the first postoperative days (PODs; VAS score 1.88 ± 0.88 vs. 2.16 ± 1.1, p = 0.044) was significantly lower than that in the OSA group. The total ratio of PCEA-related adverse events in the OFA group [11 (19.6%) vs. 26 (47.3%), p = 0.003] was significantly lower than in the OSA group. Conclusion: OFA in patients who received video-assisted lung surgery led to lower severity of acute postoperative motion-induced pain and fewer PCEA-related adverse events on the first POD than in the patients in the OSA group. Clinical trial registration: clinicaltrials.gov, identifier (NCT05063396).

Circulating vitamin levels mediate the causal relationship between gut microbiota and cholecystitis: a two-step bidirectional Mendelian randomization study.

Background: The relationship between gut microbiota and the occurrence of cholecystitis remains unclear. Existing research lacks a clear understanding of how circulating vitamin levels modulate this relationship. Therefore, our study aims to investigate whether circulating vitamin levels mediate the causal relationship between gut microbiota and cholecystitis using a two-step bidirectional Mendelian randomization approach. Methods: In this study, we initially employed Linkage Disequilibrium Score Regression (LDSC) analysis to assess the genetic correlation of five circulating vitamin level genome-wide association study (GWAS) summary datasets, thereby avoiding potential sample overlap. Subsequently, we conducted a two-step analysis to investigate the causal effects between gut microbiota and cholecystitis. In the second step, we explored the causal relationship between circulating vitamin levels and cholecystitis and identified the mediating role of vitamin D. The primary method used for causal analysis was the inverse variance-weighted approach. We performed additional sensitivity analyses to ensure result robustness, including the cML-MA method and reverse Mendelian randomization (MR) analysis. Results: An increment of one standard deviation in RuminococcaceaeUCG003 was associated with a 25% increased risk of cholecystitis (OR = 1.25, 95%CI = 1.01-1.54, p = 0.04), along with a 3% decrease in 25-hydroxyvitamin D levels (OR = 0.97, 95%CI = 0.944-0.998, p = 0.04). However, following the rigorous Bonferroni correction, every one standard deviation decrease in circulating vitamin D levels was associated with a 33% increased risk of cholecystitis (OR = 0.67, 95%CI = 0.49-0.90, p = 0.008, Padjust = 0.04). Thus, the potential link between gut microbiota and cholecystitis risk might be mediated by circulating vitamin D levels (proportion mediated = 5.5%). Sensitivity analyses provided no evidence of pleiotropy. Conclusion: Our study results suggest that an elevated abundance of specific gut microbiota is associated with an increased susceptibility to cholecystitis, with the causal relationship being mediated by circulating vitamin D levels. Further large-scale randomized controlled trials are necessary to validate the causal effects of gut microbiota on cholecystitis risk. This study provides novel insights into cholecystitis prevention through the regulation of gut microbiota.

METTL3-mediated N6-methyladenosine exacerbates ferroptosis via m6A-IGF2BP2-dependent mitochondrial metabolic reprogramming in sepsis-induced acute lung injury.

Neutrophil extracellular traps (NETs), released by polymorphonuclear neutrophils (PMNs), exert a robust antimicrobial function in infectious diseases such as sepsis. NETs also contribute to the pathogenesis and exacerbation of sepsis. Although the lung is highly vulnerable to infections, few studies have explored the role of NETs in sepsis-induced acute lung injury (SI-ALI). We demonstrate that NETs induce SI-ALI via enhanced ferroptosis in alveolar epithelial cells. Our findings reveal that the excessive release of NETs in patients and mice with SI-ALI is accompanied by upregulation of ferroptosis depending on METTL3-induced m6A modification of hypoxia-inducible factor-1α (HIF-1α) and subsequent mitochondrial metabolic reprogramming. In addition to conducting METTL3 overexpression and knockdown experiments in vitro, we also investigated the impact of ferroptosis on SI-ALI caused by NETs in a caecum ligation and puncture (CLP)-induced SI-ALI model using METTL3 condition knockout (CKO) mice and wild-type mice. Our results indicate the crucial role of NETs in the progression of SI-ALI via NET-activated METTL3 m6A-IGF2BP2-dependent m6A modification of HIF-1α, which further contributes to metabolic reprogramming and ferroptosis in alveolar epithelial cells.

Fasting-mimicking diet alleviates inflammatory pain by inhibiting neutrophil extracellular traps formation and neuroinflammation in the spinal cord.

BACKGROUND: Neutrophil extracellular traps (NETs) promote neuroinflammation and, thus, central nervous system (CNS) disease progression. However, it remains unclear whether CNS-associated NETs affect pain outcomes. A fasting-mimicking diet (FMD) alleviates neurological disorders by attenuating neuroinflammation and promoting nerve regeneration. Hence, in this study, we explore the role of NETs in the CNS during acute pain and investigate the role of FMD in inhibiting NETs and relieving pain. METHODS: The inflammatory pain model was established by injecting complete Freund's adjuvant (CFA) into the hind paw of mice. The FMD diet regimen was performed during the perioperative period. PAD4 siRNA or CI-amidine (PAD4 inhibitor) was used to inhibit the formation of NETs. Monoamine oxidase-B (MAO-B) knockdown occurred by AAV-GFAP-shRNA or AAV-hSyn-shRNA or was inhibited by selegiline (an MAO-B inhibitor). The changes in NETs, neuroinflammation, and related signaling pathways were examined by western blot, immunofluorescence, ELISA, and flow cytometry. RESULTS: In the acute phase of inflammatory pain, NETs accumulate in the spinal cords of mice. This is associated with exacerbated neuroinflammation. Meanwhile, inhibition of NETs formation alleviates allodynia and neuroinflammation in CFA mice. FMD inhibits NETs production and alleviates inflammatory pain, which is enhanced by treatment with the NETs inhibitor CI-amidine, and reversed by treatment with the NETs inducer phorbol 12-myristate 13-acetate (PMA). Mechanistically, the neutrophil-recruiting pathway MAO-B/5-hydroxyindoleacetic acid (5-HIAA) / G-protein-coupled receptor 35 (GPR35) and NETs-inducing pathway MAO-B/ Reactive oxygen species (ROS) are significantly upregulated during the development of inflammatory pain. MAO-B is largely expressed in astrocytes and neurons in the spinal cords of CFA mice. However, knockdown or inhibition of MAO-B effectively attenuates CFA-induced inflammatory pain, NETs formation, and neuroinflammation in the spinal cord. Moreover, within rescue experiments, MAO-B inhibitors synergistically enhance FMD-induced pain relief, NETs inhibition, and neuroinflammation attenuation, whereas supplementation with MAO-B downstream molecules (i.e., 5-HIAA and PMA) abolished this effect. CONCLUSIONS: Neutrophil-released NETs in the spinal cord contribute to pain development. FMD inhibits NETs formation and NETs-induced neuroinflammation by inhibiting the MAO-B/5-HIAA/GPR35 and MAO-B/ROS pathways in astrocytes and neurons, thereby relieving pain progression. Video Abstract.

Fasting-Mimicking Diet Drives Antitumor Immunity against Colorectal Cancer by Reducing IgA-Producing Cells.

As a safe, feasible, and inexpensive dietary intervention, fasting-mimicking diet (FMD) exhibits excellent antitumor efficacy by regulating metabolism and boosting antitumor immunity. A better understanding of the specific mechanisms underlying the immunoregulatory functions of FMD could help improve and expand the clinical application of FMD-mediated immunotherapeutic strategies. In this study, we aimed to elucidate the role of metabolic reprogramming induced by FMD in activation of antitumor immunity against colorectal cancer. Single-cell RNA sequencing analysis of intratumoral immune cells revealed that tumor-infiltrating IgA+ B cells were significantly reduced by FMD treatment, leading to the activation of antitumor immunity and tumor regression in murine colorectal cancer models. Mechanistically, FMD delayed tumor growth by repressing B-cell class switching to IgA. Therefore, FMD-induced reduction of IgA+ B cells overcame the suppression of CD8+ T cells. The immunoregulatory and antitumor effects of FMD intervention were reversed by IgA+ B-cell transfer. Moreover, FMD boosted fatty acid oxidation (FAO) to trigger RUNX3 acetylation, thus inactivating Cα gene transcription and IgA class switching. IgA+ B-cell expansion was also impeded in patients placed on FMD, while B-cell expression of carnitine palmitoyl transferase 1A (CPT1A), the rate-limiting enzyme of FAO, was increased. Furthermore, CPT1A expression was negatively correlated with both IgA+ B cells and IgA secretion within colorectal cancer. Together, these results highlight that FMD holds great promise for treating colorectal cancer. Furthermore, the degree of IgA+ B cell infiltration and FAO-associated metabolic status are potential biomarkers for evaluating FMD efficacy. SIGNIFICANCE: Metabolic reprogramming of B cells induced by fasting-mimicking diet suppresses IgA class switching and production to activate antitumor immunity and inhibit tumor growth. See related commentary by Bush and Perry, p. 3493.

Neutrophil extracellular traps contribute to immunothrombosis formation via the STING pathway in sepsis-associated lung injury.

Neutrophil extracellular traps (NETs) are involved in the activation and dysfunction of multiple overlapping and interacting pathways, including the immune response to injury, inflammation, and coagulation, which contribute to the pathogenesis of sepsis-induced acute lung injury (SI-ALI). However, how NETs mediate the relationship between inflammation and coagulation has not been fully clarified. Here, we found that NETs, through stimulator of interferon genes (STING) activation, induced endothelial cell damage with abundant production of tissue factor (TF), which magnified the dysregulation between inflammatory and coagulant responses and resulted in poor prognosis of SI-ALI model mice. Disruption of NETs and inhibition of STING improved the outcomes of septic mice and reduced the inflammatory response and coagulation. Furthermore, Toll-like receptor 2 (TLR2) on the surface of endothelial cells was involved in the interaction between NETs and the STING pathway. Collectively, these findings demonstrate that NETs activate the coagulant cascade in endothelial cells in a STING-dependent manner in the development of SI-ALI.

Ongoing CO2 monitoring verify CO2 emissions and sinks in China during 2018-2021.

Accurate estimating CO2 emissions and sinks is crucial in achieving carbon neutrality in China. However, CO2 emissions from bottom-up inventories are uncertain at regional scales and lack independent verification from atmospheric perspectives. Here we integrated 39 high-precision CO2 stations in China to top-down invert emission-sink variations at 45 km × 45 km and achieved a full range of inventories verification. The results show that China's CO2 emissions are 15% higher than those of five bottom-up inventories, to an annual total of 3.40 Pg C a-1 for 2018-2021. After deducting human and livestock respiration, the annual CO2 emissions were 3.13 Pg C a-1 (11.48 Pg CO2 a-1). The annual increase in emissions slowed from 3.7% in 2019 to 1.1% in 2020 and resumed growth to 4.0% in 2021, consistent with observed CO2 growth rates in China. China's land CO2 sink, deducting farmland sinks and lateral fluxes, was 0.57 Pg C a-1 (2.09 Pg CO2 a-1) for 2018-2021 (higher than most global inverse models), accounting for ∼16.9% of anthropogenic CO2 emissions. The land sink in China decreased by -19.3% in 2019 due to a weak El Niño event and increased by 3.2% in 2020 and 13.7% in 2021. It is worth noting that inverse CO2 emissions and sinks in western China still face large uncertainty due to limited CO2 monitoring. Overall, our top-down estimates demonstrate spatiotemporal variations in CO2 emissions and sinks from atmospheric perspectives and highlight challenges for different provinces in achieving 2060 carbon neutrality with verified estimates.

Effect-site concentrations of remifentanil for smooth emergence from combined epidural-general anesthesia or general anesthesia in patients using video double-lumen tube: A randomized trial.

Objective: The present study aimed to determine the effect-site concentration of remifentanil of 90% (EC90) for smooth emergence in patients with a video DLT (VDLT) under sevoflurane-maintained general anesthesia and to investigate whether the EC90 was affected by epidural anesthesia. Methods: One hundred and twenty patients who underwent video-assisted thoracic surgery (VATS) were enrolled. Patients received either general anesthesia combined with epidural anesthesia (PEA group, n = 60) or general anesthesia (GA group, n = 60). The primary outcome was the EC90 for smooth emergence in both groups. The secondary outcomes were intraoperative emergence, smooth emergence, recovery, and hemodynamic profiles in both groups. Result: The EC90 values for smooth emergence in patients using VDLT were 3.5 ng/ml (95% confidence interval [CI], 3.3-4.4 ng/ml) in the PEA group and 2.7 ng/ml (95% CI, 2.5-3.2 ng/ml) in the GA group. The total amount of remifentanil infusion during emergency was significantly higher in the PEA group (164.6 ± 47.9 µg) than in the GA group (127.1 ± 30.4 µg) (P < 0.001). The number of patients who experienced hypotension during emergency in the PEA group was higher than that in the GA group (46.7% versus 13.3%, P < 0.001). Conclusion: The EC90 of remifentanil for smooth emergence in patients with VDLT under general anesthesia combined with epidural anesthesia (3.5 ng/ml) was higher than that under general anesthesia (2.7 ng/ml). Trial registration: Chinese Clinical Trial Registry, ChiCTR2100054230.