Development of a Mitochondrial Membrane Permeability Transition Prognosis System in Colon Adenocarcinoma: Risk Stratification and Therapeutic Target Identification.

AIMS: Explore the role of mitochondrial membrane permeability transition (MPT) in colon adenocarcinoma (COAD). BACKGROUND: Further exploration of risk stratification for COAD prognostic assessment has important clinical value. MPT-related pathways play a key role in the pathogenesis of many human diseases, including tumorigenesis. Its impact on COAD is still unknown. OBJECTIVE: Bioinformatics analysis was conducted by analyzing the GEO database and TCGA database, and the bioinformatics results were verified by in vitro experiments. METHOD: Through the analysis of the transcriptome data of 1008 COAD samples in the GEO database and TCGA database, the differential expressions of MPT-related genes in COAD were explored, followed by molecular subtype analysis based on MPT characteristics by univariate Cox algorithm analysis and the consensus clustering algorithm. The gene signature associated with MPT molecular subtypes was further identified and the MPT scoring system was established by the LASSO-univariate Cox analysis algorithm. After evaluating the prognostic value of the MPT scoring system in COAD patients via nomogram establishment, the clinical value of the MPT scoring system was comprehensively analyzed through somatic mutation characteristics analysis, immunotherapy response analysis, immunoinfiltration analysis, and drug sensitivity analysis. CCK-8, WB, PCR, colony formation method, and Transwell method were used to verify the effect of the screened target on the proliferation and invasion of COAD cells. RESULT: We successfully established a scoring system related to MPT and validated the prognostic value of COAD patients. The potential clinical value of the MPT scoring system was also analyzed. VSIG4 was selected for further in vitro experiments to verify the effect of the screened targets on the proliferation and invasion ability of COAD cells. CONCLUSIONS: We established an MPT scoring system for effective risk stratification of COAD patients, demonstrating the impact of MPT on the development of COAD and its potential value as an intervention factor.

Nebulized inhalation of plasma-activated water in the treatment of progressive moderate COVID-19 patients with antiviral treatment failure: a randomized controlled pilot trial.

BACKGROUND: Antiviral drugs show significant efficacy in non-severe COVID-19 cases, yet there remains a subset of moderate COVID-19 patients whose pneumonia continues to progress post a complete course of treatment. Plasma-activated water (PAW) possesses anti-SARS-CoV-2 properties. To explore the potential of PAW in improving pneumonia in COVID-19 patients following antiviral treatment failure, we conducted this study. METHODS: This was a randomized, controlled trial. Moderate COVID-19 patients with antiviral treatment failure were randomly assigned to the experimental group or the control group. They inhaled nebulized PAW or saline respectively. This was done twice daily for four consecutive days. We assessed improvement in chest CT on day 5, the rate of symptom resolution within 10 days, and safety. RESULTS: A total of 23 participants were included, with 11 receiving PAW and 12 receiving saline. The baseline characteristics of both groups were comparable. The experimental group showed a higher improvement rate in chest CT on day 5 (81.8% vs. 33.3%, p = 0.036). The cumulative disappearance rate of cough within 10 days was higher in the experimental group. Within 28 days, 4 patients in each group progressed to severe illness, and no patients died. No adverse reactions were reported from inhaling nebulized PAW. CONCLUSION: This pilot trial preliminarily confirmed that nebulized inhalation of PAW can alleviate pneumonia in moderate COVID-19 patients with antiviral treatment failure, with no adverse reactions observed. This still needs to be verified by large-scale studies. TRIAL REGISTRATION: Chinese Clinical Trial Registry; No.: ChiCTR2300078706 (retrospectively registered, 12/15/2023); URL: www.chictr.org.cn .

The short-term efficacy of neoadjuvant SOX versus SOX plus immune checkpoint inhibitor following laparoscopic gastrectomy for locally advanced gastric cancer: a multicenter retrospective cohort study in China.

BACKGROUND: This study aims to evaluate the short-term efficacy for locally advanced gastric cancer (LAGC) who accepted laparoscopic gastrectomy (LG) after neoadjuvant SOX versus SOX plus immune checkpoint inhibitors (ICIs). METHODS: LAGC patients who accepted LG after neoadjuvant SOX (SOX-LG, n = 169) and SOX plus ICIs (SOX + ICIs-LG, n = 140) in three medical centers between Jan 2020 and Mar 2024 were analyzed. We compared the tumor regression, treatment-related adverse events (TRAEs), perioperative safety between two groups, and explored the risk factors of postoperative complications (POCs) for LG after neoadjuvant therapy. RESULTS: The baseline characteristics were comparable between two groups (P > 0.05). SOX + ICIs-LG group acquired a higher proportion of objective response (63.6% vs. 46.7%, P = 0.003), major pathological response (43.6% vs. 31.4%, P = 0.001), and pathological complete response (17.9% vs. 9.5%, P = 0.030). There were no significant differences in the TRAEs rates, operation time, R0 resection, retrieved lymph nodes, postoperative first flatus, and hospitalized days, overall and severe POCs between two groups (P > 0.05). Patients in the SOX-ICIs-LG group had lower estimated blood loss (EBL) compared with SOX-LG (P = 0.001). Multivariate analysis showed that more EBL (P = 0.003) and prognostic nutritional index (PNI) < 40 (P = 0.005) were independent risk factors of POCs for LG after neoadjuvant therapy. CONCLUSION: Neoadjuvant SOX plus ICIs brings better tumor regression and similar TRAEs compared with SOX alone for LAGC. SOX + ICIs-LG is safe and feasible to conduct with less EBL. Surgeons should focus on the perioperative management to control POCs for patients with PNI < 40 and more EBL.

Patient self-inflicted lung injury associated pneumothorax/pneumomediastinum is a risk factor for worse outcomes of severe COVID-19: a case-control study.

We aimed to determine the clinical characteristics of patient self-inflicted lung injury (P-SILI)-associated pneumothorax/pneumomediastinum, to reveal its risk factors, and to assess its impact on severe COVID-19 cases. In total, 229 patients were included in this case-control study. They were randomly divided into either the case group or the control group as per the inclusion and exclusion criteria. The two groups were further analyzed to reveal the risk factors of spontaneous pneumothorax/pneumomediastinum (SP/P). Finally, risk factors for death were analyzed in the case group and the relationship between death and SP/P was also analyzed among all patients. The mean age of patients was 59.69 ± 17.01 years, most of them were male (74.2%), and 62.0% of them had comorbidities upon admission. A respiratory rate higher than 30 BPM was a risk factor for SP/P (OR 7.186, 95% CI 2.414-21.391, P < 0.001). Patients with delayed intubation due to early application of HFNC or NIV had a higher mortality rate when they developed SP/P (P < 0.05). Additionally, advanced age increased the risk of death (P < 0.05). Finally, SP/P may be a risk factor for death among patients with severe COVID-19 (OR 2.047). P-SILI occurs in severe COVID-19 with acute respiratory failure. It is necessary to identify the risk factors of P-SILI, the indicators of severe P-SILI, and the preventive measures.

Resistive spontaneous breathing exacerbated lipopolysaccharide-induced lung injury in mice.

Background: Spontaneous respiratory mechanical force interacted with the primary lung injury and aggravated the progression of ARDS clinically. But the exact role and involved mechanism of it in the pathogenesis of ARDS animal model remained obscure. Aim: This study was to investigate the effect of spontaneous respiratory mechanical force on lung injury of ARDS in mice. Methods: Female C57BL/6 mice were subjected to resistive spontaneous breathing (RSB) by tracheal banding after 4-6 h of intranasal inhalation of LPS. Pulmonary function was examined by Buxco system, partial pressures of oxygen and carbon dioxide (PO2 and PCO2) were measured by a blood gas analyzer, and lung pathological changes were analyzed with hematoxylin and eosin staining. The levels of inflammatory markers were quantified by ELISA, total protein assay, and FACS analysis. The expression levels of mechanosensitive ion channels were detected by qRT-PCR and immunohistochemistry. Results: The airway resistance (Raw) was increased and the tidal volume (TV) was decreased remarkedly in RSB group. RSB treatment did not affect PO2, PCO2, pathology and inflammation levels of lung in mice. The Raw increased and ventilatory indicators decreased in RSB + ARDS compared to ARDS significantly. Besides, RSB treatment deteriorated the changes of PO2, PCO2 and level of lactic acid induced by LPS. Meanwhile, RSB significantly promoted LPS-induced pulmonary histopathological injury, and elevated the levels of IL-1ß, IL-6, TNF-α and total proteins, increased neutrophils infiltration. The expression level of Piezo1 in RSB + ARDS group was remarkably reduced compared to ARDS group and consistent with the severity of pulmonary damage. Conclusion: RSB exacerbated LPS-induced ARDS hypoxemia and hypercapnia, inflammation and damage. The mechanosensitive protein Piezo1 expression decreased and may play an important role in the process.

CLCA1 exacerbates lung inflammation via p38 MAPK pathway in acute respiratory distress syndrome.

Recent research has revealed that airway epithelial calcium-activated chloride channel-1 (CLCA1) is implicated in the inflammation of multiple human respiratory diseases, but the specific role in acute respiratory distress syndrome (ARDS) remains unknown. To investigate the role of CLCA1 in ARDS, 80 participants, including 26 ARDS patients, 26 patients with community-acquired pneumonia (CAP) and 28 control subjects, were enrolled in this study. As the result shows, the level of CLCA1 was significantly increased in ARDS patients and positively correlated with neutrophil infiltration and the poor prognosis of ARDS. Then, the level of CLCA1 also elevated in the LPS-induced ARDS mouse model, and the administration of CLCA1 significantly regulated the phenotypes of ARDS in mice, such as lung injury score, BALF protein concentration, neutrophils infiltration and the secretions of inflammatory factors. Furthermore, administration of CLCA1 substantially altered the phosphorylation of p38 in the ARDS mouse model, whereas repressing the expression of CLCA1 or inhibiting the activation of p38 both alleviated the inflammatory response of ARDS. In summary, CLCA1 was notably correlated with ARDS and exacerbated the ARDS phenotypes through the p38 MAPK pathway.

Safety and feasibility of minimally invasive gastrectomy after neoadjuvant immunotherapy for locally advanced gastric cancer: a propensity score-matched analysis in China.

Background: The effect of neoadjuvant immunotherapy on minimally invasive gastrectomy (MIG) for locally advanced gastric cancer (LAGC) remains controversial. This study aimed to compare short-term outcomes between MIG after neoadjuvant chemo-immunotherapy (NICT-MIG) and MIG after neoadjuvant chemotherapy alone (NCT-MIG), and determine risk factors for post-operative complications (POCs). Methods: This retrospective study included clinicopathologic data from 193 patients who underwent NCT-MIG or NICT-MIG between January 2020 and February 2023 in the Department of General Surgery, Chinese People's Liberation Army General Hospital First Medical Center (Beijing, China). Propensity score-matched analysis at a ratio of 1:2 was performed to reduce bias from confounding patient-related variables and short-term outcomes were compared between the two groups. Results: The baseline characteristics were comparable between 49 patients in the NICT-MIG group and 86 patients in the NCT-MIG group after propensity score matching. Objective and pathologic complete response rates were significantly higher in the NICT-MIG group than in the NCT-MIG group (P < 0.05). The overall incidence of treat-related adverse events, intraoperative bleeding, operation time, number of retrieved lymph nodes, time to the first flatus, post-operative duration of hospitalization, overall morbidity, and severe morbidity were comparable between the NCT-MIG and NICT-MIG groups (P > 0.05). By multivariate logistic analysis, estimated blood loss of >200 mL (P = 0.010) and prognostic nutritional index (PNI) score of <45 (P = 0.003) were independent risk factors for POCs after MIG following neoadjuvant therapy. Conclusions: Safety and feasibility of NICT were comparable to those of NCT in patients undergoing MIG for LAGC. Patients with an estimated blood loss of >200 mL or a PNI score of <45 should be carefully evaluated for increased POCs risk.

Mfn2/Hsc70 Complex Mediates the Formation of Mitochondria-Lipid Droplets Membrane Contact and Regulates Myocardial Lipid Metabolism.

The heart primarily derives its energy through lipid oxidation. In cardiomyocytes, lipids are stored in lipid droplets (LDs) and are utilized in mitochondria, although the structural and functional connections between these two organelles remain largely unknown. In this study, visible evidence have presented indicating that a complex is formed at the mitochondria-LD membrane contact (MLC) site, involving mitochondrion-localized Mfn2 and LD-localized Hsc70. This complex serves to tether mitochondria to LDs, facilitating the transfer of fatty acids (FAs) from LDs to mitochondria for ß-oxidation. Reduction of Mfn2 induced by lipid overload inhibits MLC, hinders FA transfer, and results in lipid accumulation. Restoring Mfn2 reinstates MLC, alleviating myocardial lipotoxicity under lipid overload conditions both in-vivo and in-vitro. Additionally, prolonged lipid overload induces Mfn2 degradation through the ubiquitin-proteasome pathway, following Mfn2 acetylation at the K243 site. This leads to the transition from adaptive lipid utilization to maladaptive lipotoxicity. The experimental findings are supported by clinical data from patients with obesity and age-matched non-obese individuals. These translational results make a significant contribution to the molecular understanding of MLC in the heart, and offer new insights into its role in myocardial lipotoxicity.

Total versus proximal gastrectomy for proximal gastric cancer after neoadjuvant chemotherapy: a multicenter retrospective propensity score-matched cohort study.

BACKGROUND: This study aimed to analyze and compare the short-term and long-term outcomes of proximal gastrectomy (PG) and total gastrectomy (TG) in patients with locally advanced proximal gastric cancer (GC) following neoadjuvant chemotherapy (NACT). METHOD: A multicenter retrospective cohort study and propensity score matching (PSM) were employed. The authors examined 367 patients with proximal GC who received NACT followed by PG ( n =164) or TG ( n =203) at two Chinese medical institutions between December 2009 and December 2022. Clinical and pathological parameters, postoperative complications, and 5-year overall survival (OS) and recurrence-free survival (RFS) were compared between the two groups. The dissection status and metastasis rate of each lymph node station were assessed. RESULTS: After PSM, 80 patients were enrolled in both TG and PG group, and baseline characteristics were comparable between the groups (all P >0.05). The TG group had a higher total number of lymph nodes retrieved ( P <0.001) and longer operative time ( P =0.007) compared to the PG group. The incidence of Clavien-Dindo grade II or higher postoperative complications was similar between the TG group (21.3%, 17/80) and the PG group (17.5%, 14/80) ( P =0.689). The 5-year OS rates were 68.4 for the PG group and 66.0% for the TG group ( P =0.881), while the 5-year RFS rates were 64.8 and 61.9%, respectively ( P =0.571), with no statistically significant differences. Metastasis rates at lymph node stations #4d, #5, #6, and #12a were notably low in the TG group, with values of 2.74, 0.67, 1.33, and 1.74%, respectively. CONCLUSION: For proximal GC patients following NACT, PG maintains comparable curative potential and oncological efficacy to TG, making it a safe option.

Clinical outcomes of KRAS-mutant non-small cell lung cancer under untargeted therapeutic regimes in the real world: a retrospective observational study.

Background: Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation seemingly suffered less effective therapeutic regimens in the absence of widely-accepted targeted drugs compared with other mutation types in non-small cell lung cancer (NSCLC). However, whether these non-selective therapy schedules for KRAS mutation matters is still under debate. Correspondingly, we aimed to compare the long term expectancy of indicated therapeutic regimes and further explore the optimal schemes of KRAS mutated NSCLC in the absence of targeted drugs in this retrospective study cohort. Methods: We conducted a single-center retrospective analysis among 66 patients diagnosed with KRAS-mutant advanced NSCLC from November 2018 to December 2020. These enrolled cases were divided into different subgroups in light of mutant isotypes, pathological characteristics, and therapeutic regimes to uncover indicated long-term survival benefits. Additionally, clinical outcomes of treatment schedules and interventional lines to KRAS-mutant NSCLC were described in detail. Results: This cohort enrolled 8 patients with stage IIIB (12.1%) and 58 patients with stage IV (87.9%) with the median age 62 years, ranging from 32 to 91 years old. Genetically, G12C conducted as the most common KRAS mutation type, accounting for 30.3%. Pemetrexed combined with platinum chemotherapy seemed to be a priority (72.7%), and chemotherapy combined with immunotherapy became an alternative (15.2%) in clinic. Performing further analysis of long-term survival of patients receiving different treatment methods indicated that the median overall survival (mOS) in first-line therapy with antiangiogenesis or untreated was 13 and 12 months, respectively (P=0.79). In the first-line regimen, median survival was 17 months for patients who received combined immune checkpoint inhibitors and 12 months for those who did not (P=0.34). The mOS was 20 months for those who had used immune checkpoint inhibitors and 12 months for those who had not (P=0.11). Survival analysis results of NSCLC patients with different KRAS mutation types showed the median survival time of patients with G12C mutation type and patients without with nonG12C mutation type was 19 and 12 months, respectively (P=0.37). Conclusions: In the absence of KRAS targeted drugs, available treatment plans failed to benefit KRAS mutant sufferers regardless of isotypes, making the KRAS-targeted drugs urgent.

Predictors and outcomes of recurrent retroperitoneal liposarcoma: new insights into its recurrence patterns.

BACKGROUND: The clinical profiles of recurrent retroperitoneal liposarcoma (RLS) need to be explored. The recurrence patterns of RLS are controversial and ambiguous. METHODS: A total of 138 patients with recurrent RLS were finally recruited in the study. The analysis of overall survival (OS) and recurrence-free survival (RFS) was performed by Kaplan‒Meier analysis. To identify independent prognostic factors, all significant variables on univariate Cox regression analysis (P ≤ 0.05) were subjected to multivariate Cox regression analysis. The corresponding nomogram model was further built to predict the survival status of patients. RESULTS: Among patients, the 1-, 3-, and 5-year OS rates were 70.7%, 35.9% and 30.9%, respectively. The 1-, 3- and 5-year RFS rates of the 55 patients who underwent R0 resection were 76.1%, 50.8% and 34.4%, respectively. The multivariate analysis revealed that resection method, tumor size, status of pathological differentiation, pathological subtypes and recurrence pattern were independent risk factors for OS or RFS. Patients with distant recurrence (DR) pattern usually had multifocal tumors (90.5% vs. 74.7%, P < 0.05); they were prone to experience changes of pathological differentiation (69.9% vs. 33.3%, P < 0.05) and had a better prognosis than those with local recurrence (LR) pattern. R0 resection and combined organ resection favored the survival of patients with DR pattern in some cases. CONCLUSIONS: Patients with DR pattern had better prognosis, and they may benefit more from aggressive combined resection than those with LR pattern. Classifying the recurrence patterns of RLS provides guidance for individualized clinical management of recurrent RLS.

Predictors and outcomes of recurrent retroperitoneal liposarcoma with multiple tumors.

Background: Retroperitoneal liposarcoma (RLS) is a rare but severe disease. Repeated postoperative recurrence with multiple tumors is a therapeutic dilemma. The clinical outcomes and survival predictors of recurrent RLS with multiple tumors remain to be explored. Methods: Patients with recurrent RLS were retrospectively analyzed. Univariate and multivariate analysis was performed to find independent prognostic factors that were correlated with Overall survival (OS) or progression-free survival (PFS). Factors significant in univariate analysis were further included into multivariate Cox proportional hazards regression model. The nomogram model was built to predict the survival status of patients. Variables that were significant in multivariable analysis were added to the internally validated nomogram models. The analysis of OS and PFS was performed by Kaplan-Meier analysis and log-rank test. Results: A total of 113 recurrent RLS patients with multiple tumors were enrolled in the study. The 1-, 3-, and 5-years OS (PFS) rates were 70.7% (76.1%), 35.9% (76.1%), and 30.9% (76.1%), respectively. Univariate and multivariate analyses showed that number of surgeries, resection methods, tumor size, status of pathological differentiation, pathological subtypes, and recurrence patterns were important prognostic factors for OS or PFS (each p < 0.05). Nomogram models were established to efficiently predict the prognostic status of patients. Patients with the local recurrence (LR) pattern had a poor prognosis and would derive no survival benefit from combined organ resection and R0/R1 resection (each p < 0.05). Conclusion: RLS patients recurrence with multiple tumors had a poor prognosis. Those patients should be followed up more frequently after surgery. The strategies of aggressive resection may not improve the survival of patients with LR pattern in the retroperitoneum. Prognostic factors in the efficient nomogram models should be considered in the individualized clinical management of recurrent RLS with multiple tumors.

Five-year long-term comparison of robotic and laparoscopic gastrectomy for gastric cancer: a large single-center cohort study.

BACKGROUND: Robotic gastrectomy (RG) has been reported to be technically feasible and safe for patients with gastric cancer. However, 5-year long-term survival and recurrence outcomes for advanced gastric cancer have rarely been reported. This study aimed to compare the long-term oncologic outcomes between RG and laparoscopic gastrectomy (LG) for gastric cancer. METHODS: The general clinicopathological data of 1905 consecutive patients who underwent RG and LG were retrospectively collected at the Chinese People's Liberation Army General Hospital between November 2011 and October 2017. Propensity score matching (PSM) was used to match groups. The primary endpoints were 5-year disease-free survival (DFS) and overall survival (OS). RESULTS: After PSM, a well-balanced cohort of 283 patients in the RG group and 701 patients in the LG group were included in the analysis. The 5-year cumulative DFS rates were 67.28% in the robotic group and 70.41% in the laparoscopic group. The 5-year OS rate was 69.01% in the robotic group and 69.58% in the laparoscopic group. No significant differences in Kaplan-Meier survival curves for DFS (HR = 1.08, 95% CI 0.83-1.39, Log-rank P = 0.557) and OS (HR = 1.02, 95% CI 0.78-1.34, Log-rank P = 0.850) were observed between the 2 groups. In the subgroup analyses for potential confounding variables, there were no significant differences in 5-year DFS and 5-year OS survival between the 2 groups (P > 0.05), except for patients with pathological stage III and pathological stage N3 (P < 0.05). CONCLUSION: For patients with early gastric cancer, robotic and laparoscopic approaches have similar long-term survival. For patients with advanced gastric cancer, further studies need to be conducted to assess the long-term survival outcomes of RG.

Cuproplasia characterization in colon cancer assists to predict prognosis and immunotherapeutic response.

Introduction: Colon cancer is the 3rd most prevalent cancer worldwide, with more than 900,000 deaths annually. Chemotherapy, targeted treatment, and immunotherapeutic treatment are the three cornerstones of colon cancer treatment; however, the occurrence of immune therapy resistance is the most pressing problem to solve. Copper is a mineral nutrient that is both beneficial and potentially toxic to cells and is increasingly implicated in cell proliferation and death pathways. Cuproplasia is characterized by copper-dependent cell growth and proliferation. This term encompasses both neoplasia and hyperplasia and describes the primary and secondary effects of copper. The connection between copper and cancer has been noted for decades. However, the relationship between cuproplasia and colon cancer prognosis remains unclear. Method: In this study, we applied bioinformatics approaches including WGCNA, GSEA and etc. to delineate cuproplasia characterization of colon cancer, set up a robust Cu_riskScore model based on cuproplasia-relevant genes and found its relevant biological processes use qRT-pCR to validate our results on our cohort. Result: The Cu_riskScore is found to be relevant to Stage and MSI-H subtype, and some biological processes including MYOGENESIS and MYC TARGETS. The Cu_riskScore high and low groups also showed different immune infiltration pattern and genomic traits. Finally, the result of our cohort showed the Cu_riskScore gene RNF113A has a marked effect in predicting immunotherapy response. Discussion: In conclusion, we identified a cuproplasia-related gene expression signature consisting of six genes and studied the landscape of the clinical and biological characterization of this model in Colon Cancer. Furthermore, the Cu_riskScore was demonstrated to be a robust prognostic indicator and predictive factor for the benefits of immunotherapy.

Exosome-Based Mitochondrial Delivery of circRNA mSCAR Alleviates Sepsis by Orchestrating Macrophage Activation.

Sepsis is one of the most common causes of death, which is closely related to the uncontrolled systemic inflammation. Dysregulation of M1 macrophage polarization is the primary contributor to serious inflammation. In this study, it is revealed that the murine homologue of circRNA SCAR (steatohepatitis-associated circRNA ATP5B regulator), denoted as circRNA mSCAR hereafter, decreases in the macrophages of septic mice, which correlates with the excessive M1 polarization. To restore circRNA mSCAR in mitochondria, exosomes encapsulated with circRNA mSCAR are further electroporated with poly-D-lysine-graft-triphenylphosphine (TPP-PDL), and thus TPP-PDL facilitates the bound circRNA delivered into mitochondria when the exosomes engulf by the recipient cells. In in vivo septic mouse model and in vitro cell model, it is shown that the exosome-based mitochondria delivery system delivers circRNA mSCAR into mitochondria preferentially in the macrophages, favoring macrophage polarization toward M2 subtype. Accordingly, the systemic inflammation is attenuated by exosome-based mitochondrial delivery of circRNA mSCAR, together with alleviated mortality. Collectively, the results uncover the critical role of circRNA mSCAR in sepsis, and provide a promising approach to attenuate sepsis via exosome-based mitochondrial delivery of circRNA mSCAR.

Combining neoadjuvant chemotherapy with PD-1/PD-L1 inhibitors for locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma: A systematic review and meta-analysis.

Background: Immune checkpoint inhibitors (ICIs) have shown promising prospects in locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma (GC/GEJC) immunotherapy, but their efficacy in neoadjuvant settings remains unclear. This study aimed to assess the efficacy and safety of integrating programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors into neoadjuvant chemotherapy (NACT) of GC/GEJC treatment. Methods: PubMed, Cochrane Library, Embase, ClinicalTrials.gov, and main oncology conference databases were systematically searched up to 19 November 2022, and randomized controlled trials (RCTs) and cohort studies that evaluated the efficacy and safety of PD-1/PD-L1 inhibitors plus NACT were included. The main outcomes were pathological complete response (pCR), major pathological response (MPR), R0 resection rate, and treatment-related adverse events (TRAEs). Results: A total of 753 patients from 20 prospective studies were included in this meta-analysis. The pooled pCR and MPR rates from studies reporting were 21.7% [95% confidence interval (CI), 18.1%-25.5%] and 44.0% (95% CI, 34.1%-53.8%), respectively. The pooled incidence rate of total TRAEs was 89.1% (95% CI, 82.7%-94.3%), and the incidence rate of grade 3 to 4 TRAEs was 34.4% (95% CI, 17.8%-66.5%). The pooled R0 resection rate was reported to be 98.9% (95% CI, 97.0%-99.9%). Subgroup analysis has not found significant differences in efficacy and safety among different PD-1/PD-L1 inhibitors. Moreover, the efficacy in patients with positive PD-L1 expression (combined positive score ≥1) was comparable with that in the entire study population [pCR, 22.5% vs. 21.2% (p > 0.05); MPR, 48.6% vs. 43.7% (p > 0.05)]. Conclusion: This systematic review and meta-analysis found that PD-1/PD-L1 inhibitors combined with NACT for locally advanced GC/GEJC were well tolerated and may confer therapeutic advantages. The integration of ICIs into NACT has shown the potential for application in any PD-L1 expression population.

N-glycosylation-mediated CD147 accumulation induces cardiac fibrosis in the diabetic heart through ALK5 activation.

Emerging evidence has implicated the important role of fibrosis in diabetic cardiomyopathy (DCM), while the underlying mechanism remains unclear. Considering the distinct and overlapping roles of Cluster of Differentiation 147 (CD147) in the pathogenesis of fibrotic diseases, we aim to investigate the role of CD147 in the fibrosis of DCM and explore its underlying mechanism. AAV9-mediated cardiac-specific CD147 silencing attenuated cardiac fibrosis and cardiac function in diabetic mice. CD147 knockdown significantly inhibited high glucose (HG)-induced activation of CFs. Mechanistically, CD147 directly bound to type I transcription growth factor ß (TGF-ß) receptor I (ALK5), promoting ALK5 activation and endocytosis to induce SMAD2/3 phosphorylation and nuclear translocation. In addition, HG prevented the ubiquitin-proteasome-dependent degradation of CD147 by promoting GNT-V-mediated N-glycosylation. As a result, cardiac-specific CD147 overexpression in control mice mimicked diabetes-induced cardiac fibrosis, aggravating cardiac function. Importantly, CD147 was also upregulated in serum and myocardial specimens from patients with diabetes compared with non-diabetes, accompanied by echocardiographic indices of cardiac dysfunction and excessive collagen deposition. Our study provides the first evidence that CD147 acts as a pivotal factor to promote diabetic cardiac fibrosis, and may contribute to the development of future CD147-based therapeutic strategies for DCM.

Gut-microbiome-based predictive model for ST-elevation myocardial infarction in young male patients.

Background: ST-segment elevation myocardial infarction (STEMI) in young male patients accounts for a significant proportion of total heart attack events. Therefore, clinical awareness and screening for acute myocardial infarction (AMI) in asymptomatic patients at a young age is required. The gut microbiome is potentially involved in the pathogenesis of STEMI. The aim of the current study is to develop an early risk prediction model based on the gut microbiome and clinical parameters for this population. Methods: A total of 81 young males (age < 44 years) were enrolled in this study. Forty-one young males with STEMI were included in the case group, and the control group included 40 young non-coronary artery disease (CAD) males. To identify the differences in gut microbiome markers between these two groups, 16S rRNA-based gut microbiome sequencing was performed using the Illumina MiSeq platform. Further, a nomogram and corresponding web page were constructed. The diagnostic efficacy and practicability of the model were analyzed using K-fold cross-validation, calibration curves, and decision curve analysis (DCA). Results: Compared to the control group, a significant decrease in tendency regarding α and ß diversity was observed in patients in the case group and identified as a significantly altered gut microbiome represented by Streptococcus and Prevotella. Regarding clinical parameters, compared to the control group, the patients in the case group had a higher body mass index (BMI), systolic blood pressure (SBP), triglyceride (TG), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) and low blood urea nitrogen (BUN). Additionally, BMI and SBP were significantly (p<0.05) positively correlated with Streptococcus and [Ruminococcus]. Further, BMI and SBP were significantly (p<0.05) negatively correlated with Prevotella and Megasphaera. A significant negative correlation was only observed between Prevotella and AST (p < 0.05). Finally, an early predictive nomogram and corresponding web page were constructed based on the gut microbiome and clinical parameters with an area under the receiver-operating characteristic (ROC) curve (AUC) of 0.877 and a C-index of 0.911. For the internal validation, the stratified K-fold cross-validation (K = 3) was as follows: AUC value of 0.934. The calibration curves of the model showed good consistency between the actual and predicted probabilities. The DCA results showed that the model had a high net clinical benefit for use in the clinical setting. Conclusion: In this study, we combined the gut microbiome and common clinical parameters to construct a prediction model. Our analysis shows that the constructed model is a non-invasive tool with potential clinical application in predicting STEMI in the young males.

Transcriptomic analysis reveals the contribution of QMrl-7B to wheat root growth and development.

Roots are the major organs for water and nutrient acquisition and substantially affect plant growth, development and reproduction. Improvements to root system architecture are highly important for the increased yield potential of bread wheat. QMrl-7B, a major stable quantitative trait locus (QTL) that controls maximum root length (MRL), essentially contributes to an improved root system in wheat. To further analyze the biological functions of QMrl-7B in root development, two sets of Triticum aestivum near-isogenic lines (NILs), one with superior QMrl-7B alleles from cultivar Kenong 9204 (KN9204) named NILKN9204 and another with inferior QMrl-7B alleles from cultivar Jing 411 (J411) named NILJ411, were subjected to transcriptomic analysis. Among all the mapped genes analyzed, 4871 genes were identified as being differentially expressed between the pairwise NILs under different nitrogen (N) conditions, with 3543 genes expressed under normal-nitrogen (NN) condition and 2689 genes expressed under low-nitrogen (LN) condition. These genes encode proteins that mainly include N O 3 - transporters, phytohormone signaling components and transcription factors (TFs), indicating the presence of a complex regulatory network involved in root determination. In addition, among the 13524 LN-induced differentially expressed genes (DEGs) detected in this study, 4308 and 2463 were specifically expressed in the NILKN9204 and NILJ411, respectively. These DEGs reflect different responses of the two sets of NILs to varying N supplies, which likely involve LN-induced root growth. These results explain the better-developed root system and increased root vitality conferred by the superior alleles of QMrl-7B and provide a deeper understanding of the genetic underpinnings of root traits, pointing to a valuable locus suitable for future breeding efforts for sustainable agriculture.

LncRNA Airn alleviates diabetic cardiac fibrosis by inhibiting activation of cardiac fibroblasts via a m6A-IMP2-p53 axis.

BACKGROUND: Cardiac fibrosis is a leading cause of cardiac dysfunction in patients with diabetes. However, the underlying mechanisms of cardiac fibrosis remain unclear. This study aimed to investigate the role of the long non-coding RNA (LncRNA) Airn in the pathogenesis of cardiac fibrosis in diabetic cardiomyopathy (DCM) and its underlying mechanism. METHODS: Diabetes mellitus (DM) was induced in mice by streptozotocin injection. An intramyocardial adeno-associated virus (AAV) was used to manipulate Airn expression. The functional significance and underlying mechanisms in DCM fibrosis were investigated both in vitro and in vivo. RESULTS: Diabetic hearts showed a significant impairment in cardiac function, accompanied by obviously increased cardiac fibrosis. Interestingly, lncRNA Airn expression was significantly decreased in both diabetic hearts and high glucose (HG)-treated cardiac fibroblasts (CFs). AAV-mediated Airn reconstitution prevented cardiac fibrosis and the development of DCM, while Airn knockdown induced cardiac fibrosis phenotyping DCM. As in vitro, Airn reversed HG-induced fibroblast-myofibroblast transition, aberrant CFs proliferation and section of collagen I. In contrast, Airn knockdown mimicked a HG-induced CFs phenotype. Mechanistically, we identified that Airn exerts anti-fibrotic effects by directly binding to insulin-like growth factor 2 mRNA-binding protein 2 (IMP2) and further prevents its ubiquitination-dependent degradation. Moreover, we revealed that Airn/IMP2 protected p53 mRNA from degradation in m6A manner, leading to CF cell cycle arrest and reduced cardiac fibrosis. As a result, ablation of p53 blunted the inhibitory effects of Airn on fibroblast activation and cardiac fibrosis. CONCLUSIONS: Our study demonstrated for the first time that Airn prevented the development of cardiac fibrosis in diabetic heart via IMP2-p53 axis in an m6A dependent manner. LncRNA Airn could be a promising therapeutic target for cardiac fibrosis in DCM.