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In 2022, new guidelines for the diagnosis and treatment of pulmonary hypertension (PH) revised the hemodynamic definition, reducing the mean pulmonary artery pressure threshold from ≥ 25 to > 20 mmHg. The optimal threshold of transthoracic echocardiography (TTE) parameters and the predictive capability require further validation. This study aims to investigate the diagnostic value of TTE parameters under the new hemodynamic criteria. Retrospective analysis of PH patients who underwent right heart catheterization and TTE examination between 2017 and 2022 in a single center. Logistic regression was employed to ascertain the predictive capacity of parameters across various conditions. Receiver operating characteristic curves were used to determine the optimal cutoff values based on the new criteria. In a cohort of 213 patients, the optimal cutoff values identified were a tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary arterial pressure (sPAP) ratio of < 0.50 mm/mmHg, a right ventricular outflow tract acceleration time (RVOT-AT) of < 93 ms, and a right atrial area (RAA) > of 14.5 cm . Regardless of the inclusion of tricuspid regurgitation velocity (TRV) and related parameters, RVOT-AT < 93 ms manifested as an effective predictive parameter. A combination of RVOT-AT < 93 ms, main pulmonary artery diameter > 25 mm and RAA > 14.5 cm exhibited better specificity. The threshold values for TAPSE/sPAP, RVOT-AT, and RAA should be adjusted to improve the predictive capacity of PH based on revised criteria in this single-center dataset. RVOT-AT was a promising indirect parameter, and the utilization of combined indirect indicators may enhance diagnostic accuracy, particularly in instances where satisfactory TRV measurements are unavailable.

Impedance cardiography (ICG) offers a potential alternative for hemodynamic assessment in pulmonary arterial hypertension (PAH) as a non-invasive technique. A total of 132 patients who underwent right heart catheterization (RHC) were included. Cardiac output (CO) and stroke volume (SV) measured by thermodilution during RHC (COTD) and ICG (COICG) were compared. The capacity of ICG in PAH risk stratification and clinical deterioration prediction was also analyzed. Ninety-three pre-capillary pulmonary hypertension patients were enrolled, 54 (58.06%) patients belong to Group 1 PAH, and 39 (41.94%) patients were diagnosed with chronic thromboembolic pulmonary hypertension. The mean COTD was 4.93 ± 1.06 L/min, while the COICG was 4.41 ± 1.23 L/min, showing a moderate correlation (r = 0.49, P < .001). In Group 1 PAH patients, the COTD was 5.13 ± 1.10 L/min, and COICG was 4.57 ± 1.22 L/min (r = 0.52, P < .001). Bland-Altman analysis indicated a mean difference of 0.52 L/min and limits of agreement from -1.76 to 2.80 L/min. The mean SVTD was 64.63 ± 17.10 mL, and the SVICG was 60.94 ± 18.03 mL (r = 0.53, P < .001) with a mean difference of 3.69 mL. After a 1-year follow-up, the CIICG and SVIICG showed potential power in predicting clinical deterioration in PAH patients, with area under the curves of 0.76 and 0.81, respectively. Impedance cardiography measured CO and SV presented an acceptable correlation with RHC in PAH patients. Stroke volume index and cardiac index measured by ICG is potent to identify the low-risk status and predict clinical deterioration in PAH patients.

Background Efferocytosis is a biological process in which phagocytes remove apoptotic cells and vesicles from tissues. This process is initiated by the release of inflammatory mediators from apoptotic cells and plays a crucial role in resolving inflammation. The signals associated with efferocytosis have been found to regulate the inflammatory response and the tumor microenvironment (TME), which promotes the immune escape of tumor cells. However, the role of efferocytosis in glioblastoma multiforme (GBM) is not well understood and requires further investigation. Methods In this study, we conducted a comprehensive analysis of 22 efferocytosis-related genes (ERGs) by searching for studies related to efferocytosis. Using bulk RNA-Seq and single-cell sequencing data, we analyzed the expression and mutational characteristics of these ERGs. By using an unsupervised clustering algorithm, we obtained ERG clusters from 549 GBM patients and evaluated the immune infiltration characteristics of each cluster. We then identified differential genes (DEGs) in the two ERG clusters and classified GBM patients into different gene clusters using univariate cox analysis and unsupervised clustering algorithms. Finally, we utilized the Boruta algorithm to screen for prognostic genes and reduce dimensionality, and the PCA algorithm was applied to create a novel efferocytosis-related scoring system. Results Differential expression of ERGs in glioma cell lines and normal cells was analyzed by rt-PCR. Cell function experiments, on the other hand, validated TIMD4 as a tumor risk factor in GBM. We found that different ERG clusters and gene clusters have distinct prognostic and immune infiltration profiles. The ERG signature we developed provides insight into the tumor microenvironment of GBM. Patients with lower ERG scores have a better survival rate and a higher likelihood of benefiting from immunotherapy. Conclusions Our novel efferocytosis-related signature has the potential to be used in clinical practice for risk stratification of GBM patients and for selecting individuals who are likely to respond to immunotherapy. This can help clinicians design appropriate targeted therapies before initiating clinical treatment.

The green financial policy is one of the important policy tools for China to achieve the national carbon peak goal and carbon neutrality through financial means. How financial development affects the growth of international trade has been an important research topic. This paper uses the Pilot Zones for Green Finance Reform and Innovations (PZGFRI) implemented in 2017 as a natural experiment drawing on the relevant data of Chinese provinces’ panel data from 2010 to 2019. It adopts a difference in difference (DID) model to assess the impact of green finance on export green-sophistication (EGS). The results report that the PZGFRI significantly improves EGS, and the result remains robust after robustness checks such as parallel trend and placebo. The PZGFRI improves EGS by boosting total factor productivity, industrial structure upgrading, and green technology innovation. Moreover, the role of PZGFRI in promoting EGS is significantly reflected in the central and western regions and the regions with low-marketization levels. This study confirms that green finance is an important factor influencing the quality improvement of China’s exports, which provides effective evidence from the reality level for China to vigorously promote the construction of a green financial system in recent years.

The gastrointestinal tract is a key source of superoxide so as to be one of the most vulnerable to oxidative stress damage. Ellagic acid (EA), a polyphenol displays widely biological activities owing to its strong antioxidant properties. Here, we investigated the protective benefits of EA on oxidative stress and intestinal barrier injury in paraquet (PQ)-challenged piglets. A total of 40 weaned piglets were randomly divided into five groups: Control, PQ, 0.005% EA-PQ, 0.01% EA-PQ, and 0.02% EA-PQ. Piglets were intraperitoneally injected with 4 mg/kg (BW) PQ or saline on d-18, and sacrificed on d-21 of experiment. EA treatments eliminated growth-check induced by PQ and increased serum superoxide dismutase (SOD) activity but decreased serum malondialdehyde (MDA) level as compared to PQ group. EA supplementation promoted Nrf2 nuclear translocation and enhanced heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (NQO1) protein abundances of small intestinal mucosa. Additionally, EA improved PQ-induced crypt deepening, goblet cells loss, and villi morphological damage. Consistently, EA increased tight junction protein expression as was evident from the decreased serum diamine oxidase (DAO) levels. EA could ameliorate the PQ-induced oxidative stress and intestinal damage through mediating Nrf2 signaling pathway. Intake of EA-rich food might prevent oxidative stress-mediated gut diseases.

Pediatric low-grade gliomas (pLGGs) exhibit heterogeneous prognoses and variable responses to treatment, leading to tumor progression and adverse outcomes in cases where complete resection is unachievable. Early prediction of treatment responsiveness and suitability for immunotherapy has the potential to improve clinical management and outcomes. Here, we present a radiogenomic analysis of pLGGs, integrating MRI and RNA sequencing data. We identify three immunologically distinct clusters, with one group characterized by increased immune activity and poorer prognosis, indicating potential benefit from immunotherapies. We develop a radiomic signature that predicts these immune profiles with over 80% accuracy. Furthermore, our clinicoradiomic model predicts progression-free survival and correlates with treatment response. We also identify genetic variants and transcriptomic pathways associated with progression risk, highlighting links to tumor growth and immune response. This radiogenomic study in pLGGs provides a framework for the identification of high-risk patients who may benefit from targeted therapies. Understanding the molecular and pathological features of paediatric low-grade glioma (pLGG) is crucial to develop targeted therapies. Here, the authors perform a radiogenomic analysis of pLGGs combining treatment-naïve multiparametric MRI and RNA sequencing, enabling prognostication based on immune profiles as well as prediction of treatment response.

Background Anoikis is a specialized form of programmed cell death induced by the loss of cell adhesion to the extracellular matrix (ECM). Acquisition of anoikis resistance is a significant marker for cancer cell invasion, metastasis, therapy resistance, and recurrence. Although current research has identified multiple factors that regulate anoikis resistance, the pathological mechanisms of anoikis-mediated tumor microenvironment (TME) in glioblastoma (GBM) remain largely unexplored. Methods Utilizing single-cell RNA sequencing (scRNA-seq) data and employing non-negative matrix factorization (NMF), we identified and characterized TME cell clusters with distinct anoikis-associated gene signatures. Prognostic and therapeutic response analyses were conducted using TCGA and CGGA datasets to assess the clinical significance of different TME cell clusters. The spatial relationship between BRMS1 + microglia and tumor cells was inferred from spatial transcriptome RNA sequencing (stRNA-seq) data. To simulate the tumor immune microenvironment, co-culture experiments were performed with microglia (HMC3) and GBM cells (U118/U251), and microglia were transfected with a BRMS1 overexpression lentivirus. Western blot or ELISA were used to detect BRMS1, M2 macrophage-specific markers, PI3K/AKT signaling proteins, and apoptosis-related proteins. The proliferation and apoptosis capabilities of tumor cells were evaluated using CCK-8, colony formation, and apoptosis assays, while the invasive and migratory abilities of tumor cells were assessed using Transwell assays. Results NMF-based analysis successfully identified CD8 + T cell and microglia cell clusters with distinct gene signature characteristics. Trajectory analysis, cell communication, and gene regulatory network analyses collectively indicated that anoikis-mediated TME cell clusters can influence tumor cell development through various mechanisms. Notably, BRMS1 + AP-Mic exhibited an M2 macrophage phenotype and had significant cell communication with malignant cells. Moreover, high expression of BRMS1 + AP-Mic in TCGA and CGGA datasets was associated with poorer survival outcomes, indicating its detrimental impact on immunotherapy. Upregulation of BRMS1 in microglia may lead to M2 macrophage polarization, activate the PI3K/AKT signaling pathway through SPP1/CD44-mediated cell interactions, inhibit tumor cell apoptosis, and promote tumor proliferation and invasion. Conclusion This pioneering study used NMF-based analysis to reveal the important predictive value of anoikis-regulated TME in GBM for prognosis and immunotherapeutic response. BRMS1 + microglial cells provide a new perspective for a deeper understanding of the immunosuppressive microenvironment of GBM and could serve as a potential therapeutic target in the future.

Background The role of post-translational modifications(PTMs) in PD-L1-mediated immune resistance and melanoma progression remains poorly understood. Methods We conducted multi-omics analyses and constructed a prognostic model based on PTM-related genes using machine learning to identify key regulators in melanoma. In vitro and in vivo experiments, including cell culture, flow cytometry, and subcutaneous allografts models, were used to investigate USP5’s function. Protein-protein interactions were validated using Western blotting and co-immunoprecipitation, while PD-L1 stability and ubiquitination were assessed using cycloheximide (CHX) chase and ubiquitination assays. Results USP5 was identified as a key DUB that specifically deubiquitinates K48-linked polyubiquitin chains on PD-L1, stabilizing its protein levels. USP5 knockdown reduced PD-L1 expression, enhanced CD8 + T-cell infiltration and activation, and suppressed melanoma progression in both in vitro and in vivo models. Furthermore, combining USP5 knockdown with anti-PD-1 therapy significantly improved therapeutic efficacy by reducing tumor burden and promoting T-cell activation. Conclusion USP5 promotes immune escape in melanoma by stabilizing PD-L1 through deubiquitination, representing a novel mechanism hindering the efficacy of ICIs. Targeting USP5 could enhance anti-PD-1 therapy and improve patient outcomes. These findings underscore the therapeutic potential of USP5 inhibition as a strategy to overcome immune resistance in melanoma. Significance • What is already known on this topic. Immune checkpoint inhibitors (ICIs), such as anti-PD-1 therapies, have revolutionized melanoma treatment, but response rates remain limited due to immune resistance and an immunosuppressive tumor microenvironment (TME). PD-L1, a key immune checkpoint molecule, plays a central role in immune escape by inhibiting T-cell activation. Ubiquitination and its reversal by deubiquitinating enzymes (DUBs) are critical in regulating protein stability and function, including PD-L1. However, the specific DUBs that control PD-L1 stability in melanoma and their impact on immune escape and therapy resistance are poorly understood. • What this study ADDS. This study identifies USP5 as a key regulator of PD-L1 stability through deubiquitination of K48-linked polyubiquitin chains, promoting immune evasion in melanoma. Knockdown of USP5 reduces PD-L1 expression, enhances CD8 + T-cell infiltration and activation, and suppresses tumor growth in both in vitro and in vivo models. Furthermore, the combination of USP5 knockdown with anti-PD-1 therapy demonstrates superior efficacy, significantly reducing tumor burden and enhancing T-cell-mediated immune responses. These findings uncover a novel mechanism of immune escape, highlighting USP5 as a promising therapeutic target to improve the efficacy of ICIs. • How this study might affect research, practice or policy. This study provides a mechanistic foundation for targeting USP5 in combination with ICIs to overcome immune resistance in melanoma. In research, it opens new avenues to explore DUBs as regulators of immune checkpoints across various cancers. Clinically, USP5 inhibitors could be developed as an adjunct to existing immunotherapies to enhance patient response rates. In policy, this work underscores the importance of funding studies on PTM regulators and their roles in cancer immunity, potentially driving the integration of personalized DUB-targeting strategies into future immunotherapy protocols.

Background Gut health plays a vital role in the overall health and disease control of human and animals. Intestinal oxidative stress is a critical player in the induction and progression of cachexia which is conventionally diagnosed and classified by weight loss. Therefore, reduction of intestinal oxidative injury is a common and highly effective strategy for the maintenance of human and animal health. Here we identify intestinal myeloid differentiation primary response gene 88 (MyD88) as a novel target for intestinal oxidative stress using canonical oxidative stress model induced by paraquat (PQ) in vitro and in vivo. Methods Intestinal oxidative stress was induced by administration of PQ in intestinal epithelial cells (IECs) and mouse model. Cell proliferation, apoptosis, DNA damage, mitochondrial function, oxidative status, and autophagy process were measured in wild‐type and MyD88‐deficient IECs during PQ exposure. Autophagy inhibitor (3‐methyladenine) and activator (rapamycin) were employed to assess the role of autophagy in MyD88‐deficient IECs during PQ exposure. MyD88 specific inhibitor, ST2825, was used to verify function of MyD88 during PQ exposure in mouse model. Results MyD88 protein levels and apoptotic rate of IECs are increased in response to PQ exposure (P < 0.001). Intestinal deletion of MyD88 blocks PQ‐induced apoptosis (~42% reduction) and DNA damage (~86% reduction), and improves mitochondrial fission (~37% reduction) and function including mitochondrial membrane potential (~23% increment) and respiratory metabolism capacity (~26% increment) (P < 0.01). Notably, there is a marked decrease in reactive oxygen species in MyD88‐deficient IECs during PQ exposure (~70% reduction), which are consistent with high activity of antioxidative enzymes (~83% increment) (P < 0.001). Intestinal ablation of MyD88 inhibits mTOR signalling, and further phosphorylates p53 proteins during PQ exposure, which eventually promotes intestinal autophagy (~74% increment) (P < 0.01). Activation of autophagy (rapamycin) promotes IECs growth as compared with 3‐methyladenine‐treatment during PQ exposure (~173% increment), while inhibition of autophagy (3‐methyladenine) exacerbates oxidative stress in MyD88‐deficient IECs (P < 0.001). In mouse model, inhibition of MyD88 using specific inhibitor ST2825 followed by PQ treatment effectively ameliorates weight loss (~4% increment), decreased food intake (~92% increment), gastrocnemius and soleus loss (~24% and ~20% increment, respectively), and intestinal oxidative stress in an autophagy dependent manner (P < 0.01). Conclusions MyD88 modulates intestinal oxidative stress in an autophagy‐dependent mechanism, which suggests that reducing MyD88 level may constitute a putative therapeutic target for intestinal oxidative injury‐induced weight loss.

The foliar application of zinc (Zn) has been regarded as a practical and economical way to reduce grain cadmium (Cd) accumulation and enhance grain quality in crops. Herein, a two-year field experiment was carried out to examine the efficacy of different application rates of the foliar Zn fertilizer in Cd reduction and microelement biofortification in wheat (Triticum aestivum L.) grains. The results show that the T4 and T5 treatments, 500 and 250-fold dilution of the foliar Zn fertilizer, respectively, increased the grain yield to varying degrees in the two years. When compared with controls and based on the average of the two years’ results, spraying with the foliar Zn fertilizer remarkably decreased grain Cd concentrations (44.5%), Cd translocation from stem to grain (TFStem/Grain) (4.92%), the HRI values of Cd (45.5%), PA/Ca (27.8%), PA/Fe (21.4%) and PA/Mn (5.81%) under the T2 treatment (1000-fold dilution). Furthermore, the T2 treatment significantly increased the Zn (37.8%), Ca (48.9%), Fe (37.6%), Mn (14.8%) and total protein (7.92%) contents and the estimated Zn bioavailability (28.9%) in wheat grains after two years. All these findings suggest that the foliar Zn fertilizer holds considerable promise as a safe crop production technique and a means of mitigating “hidden hunger” in developing countries.