CuO (111) Microcrystalline Evoked Indium-Organic Framework for Efficient Electroreduction of CO2 to Formate.

Electrochemical reduction of carbon dioxide (CO2RR) to formate is economically beneficial but suffers from poor selectivity and high overpotential. Herein, enriched microcrystalline copper oxide is introduced on the surface of indium-based metal-organic frameworks. Benefiting from the CuO (111) microcrystalline shell and formed catalytic active In-Cu interfaces, the obtained MIL-68(In)/CuO heterostructure display excellent CO2RR to formate with a Faradaic efficiency (FE) as high as 89.7% at low potential of only -0.7 V vs. RHE in a flow cell. Significantly, the membrane electrode assembly (MEA) cell based on MIL-68(In)/CuO exhibit a remarkable current density of 640.3 mA cm-2 at 3.1 V and can be stably operated for 180 h at 2.7 V with a current density of 200 mA cm-2. The ex/in situ electrochemical investigations reveal that the introduction of CuO increases the formation rate of the carbon dioxide reduction intermediate *HCOO- and inhibits the competitive hydrogen evolution reaction. This work not only provides an in-depth study of the mechanism of the CO2RR pathways on In/Cu composite catalyst but also offers an effective strategy for the interface design of electrocatalytic carbon dioxide reduction reaction.

Lipid metabolic reprogramming mediated by circulating Nrg4 alleviates metabolic dysfunction-associated steatotic liver disease during the early recovery phase after sleeve gastrectomy.

BACKGROUND: The metabolic benefits of bariatric surgery that contribute to the alleviation of metabolic dysfunction-associated steatotic liver disease (MASLD) have been reported. However, the processes and mechanisms underlying the contribution of lipid metabolic reprogramming after bariatric surgery to attenuating MASLD remain elusive. METHODS: A case-control study was designed to evaluate the impact of three of the most common adipokines (Nrg4, leptin, and adiponectin) on hepatic steatosis in the early recovery phase following sleeve gastrectomy (SG). A series of rodent and cell line experiments were subsequently used to determine the role and mechanism of secreted adipokines following SG in the alleviation of MASLD. RESULTS: In morbidly obese patients, an increase in circulating Nrg4 levels is associated with the alleviation of hepatic steatosis in the early recovery phase following SG before remarkable weight loss. The temporal parameters of the mice confirmed that an increase in circulating Nrg4 levels was initially stimulated by SG and contributed to the beneficial effect of SG on hepatic lipid deposition. Moreover, this occurred early following bariatric surgery. Mechanistically, gain- and loss-of-function studies in mice or cell lines revealed that circulating Nrg4 activates ErbB4, which could positively regulate fatty acid oxidation in hepatocytes to reduce intracellular lipid deposition. CONCLUSIONS: This study demonstrated that the rapid effect of SG on hepatic lipid metabolic reprogramming mediated by circulating Nrg4 alleviates MASLD.

Development and validation of a machine learning-based predictive model for assessing the 90-day prognostic outcome of patients with spontaneous intracerebral hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage (sICH) is associated with significant mortality and morbidity. Predicting the prognosis of patients with sICH remains an important issue, which significantly affects treatment decisions. Utilizing readily available clinical parameters to anticipate the unfavorable prognosis of sICH patients holds notable clinical significance. This study employs five machine learning algorithms to establish a practical platform for the prediction of short-term prognostic outcomes in individuals afflicted with sICH. METHODS: Within the framework of this retrospective analysis, the model underwent training utilizing data gleaned from 413 cases from the training center, with subsequent validation employing data from external validation center. Comprehensive clinical information, laboratory analysis results, and imaging features pertaining to sICH patients were harnessed as training features for machine learning. We developed and validated the model efficacy using all the selected features of the patients using five models: Support Vector Machine (SVM), Logistic Regression (LR), Random Forest (RF), XGboost and LightGBM, respectively. The process of Recursive Feature Elimination (RFE) was executed for optimal feature screening. An internal five-fold cross-validation was employed to pinpoint the most suitable hyperparameters for the model, while an external five-fold cross-validation was implemented to discern the machine learning model demonstrating the superior average performance. Finally, the machine learning model with the best average performance is selected as our final model while using it for external validation. Evaluation of the machine learning model's performance was comprehensively conducted through the utilization of the ROC curve, accuracy, and other relevant indicators. The SHAP diagram was utilized to elucidate the variable importance within the model, culminating in the amalgamation of the above metrics to discern the most succinct features and establish a practical prognostic prediction platform. RESULTS: A total of 413 patients with sICH patients were collected in the training center, of which 180 were patients with poor prognosis. A total of 74 patients with sICH were collected in the external validation center, of which 26 were patients with poor prognosis. Within the training set, the test set AUC values for SVM, LR, RF, XGBoost, and LightGBM models were recorded as 0.87, 0.896, 0.916, 0.885, and 0.912, respectively. The best average performance of the machine learning models in the training set was the RF model (average AUC: 0.906 ± 0.029, P < 0.01). The model still maintains a good performance in the external validation center, with an AUC of 0.817 (95% CI 0.705-0.928). Pertaining to feature importance for short-term prognostic attributes of sICH patients, the NIHSS score reigned supreme, succeeded by AST, Age, white blood cell, and hematoma volume, among others. In culmination, guided by the RF model's variable importance weight and the model's ROC curve insights, the NIHSS score, AST, Age, white blood cell, and hematoma volume were integrated to forge a short-term prognostic prediction platform tailored for sICH patients. CONCLUSION: We constructed a prediction model based on the results of the RF model incorporating five clinically accessible predictors with reliable predictive efficacy for the short-term prognosis of sICH patients. Meanwhile, the performance of the external validation set was also more stable, which can be used for accurate prediction of short-term prognosis of sICH patients.

FeCoNi molybdenum-based oxides for efficient electrocatalytic oxygen evolution reaction.

The search for highly efficient and inexpensive electrocatalysts is crucial to the advancement of environmentally friendly and sustainable energy sources. Here, adopting a one-step hydrothermal method, we have effectively fabricated a self-supported multi-metal molybdenum-based oxide (FeCoNi-MoO4) on nickel foam (NF). In addition to changing the catalyst's microstructure, the introducing of Fe and Co, enhanced its active center count, improved its electronic structure, and in turn reduced the difficulty for high-valence Ni and Fe species to form, which accelerates the oxygen evolution reaction (OER) kinetics by promoting the development of the actual active materials, NiOOH and FeOOH. FeCoNi-MoO4 has outstanding OER performance, requiring just 204 mV overpotentials at 10 mA cm-2 and 271 mV at 100 mA cm-2. Its exceptional OER kinetics at both low and high currents are indicated by a Tafel slope of 50.6 mV dec-1, which is attributed to the combined effect of its multi-metal composition and a higher number of active sites. Moreover, the FeCoNi-MoO4 electrode was operated continuously for over 48 h. Furthermore, the density functional theory (DFT) results demonstrated that the introducing of Fe and Co, which quickens the rate of electron transfer during the electrocatalytic process, improves the ability of oxygen intermediate species to adsorb, and ultimately lowers the overpotential, is responsible for the increased electrocatalytic activity of FeCoNi-MoO4. This work offers hope for further developments in the sector by proposing an efficient approach for creating multi-active electrocatalysts that are stable, economical, and efficient.

STX4 as a potential biomarker for predicting prognosis and guiding clinical treatment decisions in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) represents a frequent subtype of kidney cancer, with the prognosis remaining poor for individuals with metastatic disease. Given its resistance to both radiation and chemotherapy, targeted therapies and immunotherapies have emerged as critical for effective ccRCC treatment. Within this context, the SNARE protein STX4, which is associated with malignant cancer cell migration, provides a promising focus. The underlying mechanism, however, requires further illumination. Furthermore, the influence of STX4 on the ccRCC tumor microenvironment remains to be determined. In our research, we utilized multiple databases and immunohistochemical staining to confirm differential STX4 expression and its prognostic implications. We evaluated the potential tumor-promoting function of STX4 in ccRCC cell lines through molecular studies. Additionally, we conducted functional enrichment analysis to delve deeper into the underlying mechanisms and performed immune infiltration and drug sensitivity analyses to assess the potential of STX4 as a prognostic biomarker and therapeutic target. Our study reveals that STX4 contributes to cancer progression by enhancing AKT expression and stimulating the activation of VEGF signaling pathways. Additionally, STX4 further fosters CD8+ T-cell infiltration and diminishes the percentage of CAFs and M2-TAMs. Our findings suggest that patients presenting higher STX4 levels may exhibit enhanced responsiveness to immunotherapy and higher sensitivity to the medications axitinib and everolimus. Finally, we propose STX4 expression assessment as a novel approach to predict patient response to respective immunotherapies and targeted treatments, hence potentially improving patient outcomes.

The Level of Expectations Regarding Aging Among Older Adults: A Systematic Review and Meta-analysis.

OBJECTIVE: To systematically review the level of expectations regarding aging (ERA) among older adults. DESIGN: Systematic review and meta-analysis. SETTING AND PARTICIPANTS: Adults aged 60 years and older in any setting. METHODS: We searched 11 databases for cross-sectional studies that reported ERA scores among older adults using the ERA survey from inception to May 1, 2022, without language restrictions. Two researchers independently selected studies, extracted data, and assessed quality. The mean scores and standard deviations of the ERA survey and its subscales were pooled using the Stata software (version 17.0). RESULTS: Twelve studies with 3664 participants were included in this study. The pooled mean scores of overall ERA were 37.85 (95% CI, 33.54-42.16). Specifically, the pooled scores for expectations regarding physical health, mental health, and cognitive function were 31.67 (95% CI, 27.42-35.92), 43.69 (95% CI, 38.99-48.39), and 33.28 (95% CI, 29.56-37.00), respectively. No statistically significant differences between groups were observed in any subgroup analysis. CONCLUSIONS AND IMPLICATIONS: The level of ERA among older adults is relatively low, particularly concerning cognitive function and physical health dimensions. These findings may provide a valuable reference for public health professionals and policymakers to intervene and manage the health problems of older adults.

Efficacy and safety of patients with chronic kidney disease undergoing left atrial appendage closure for atrial fibrillation.

BACKGROUND: The relative safety and efficacy of left atrial appendage closure (LAAC) for atrial fibrillation (AF) in patients with chronic kidney disease (CKD) have not been well defined. To evaluate the results in this cohort, we conducted a systematic review and meta-analysis of observational studies. METHODS: We searched the PubMed, EMBASE, Web of Science, and Cochrane Library databases from inception to January 2023 for all relevant studies. Our inclusion criteria were met by twelve observational studies that included 61324 patients altogether. RESULTS: Compared with no CKD group, in-hospital mortality (OR: 2.84, 95% CI: 2.12-3.81, p<0.01, I2 = 0%), acute kidney injury (AKI) (OR: 4.39,95% CI:4.00-4.83, P<0.01, I2 = 3%), major bleeding events (OR: 1.44, 95% CI: 1.29-1.60, p<0.01 I2 = 0%), and pericardial effusion/tamponade (OR 1.30; 95% CI 1.13-1.51, p < 0.01; I2 = 0%) were more common in the CKD group, especially in patients with end-stage renal disease (ESRD). No significant difference was observed in the occurrence of stroke (OR: 1.24, 95% CI: 0.86-1.78, P = 0.25, I2 = 0%), LAAC success rates (OR: 1.02, 95% CI: 0.33-3.16, p = 0.97, I2 = 58%) and vascular access complications (OR: 1.13, 95% CI: 0.91-1.39, p = 0.28, I2 = 0%) between the two groups. During the follow-up, there was no difference in the risk of stroke between the two groups. CONCLUSIONS: CKD patients who receive LAAC have a greater risk of in-hospital mortality, AKI, pericardial effusion/tamponade, and major bleeding events than those without CKD, especially in patients with ESRD. No significant difference in the risk of stroke was found in the long-term follow-up after LAAC between the two groups, demonstrating a similar efficacy of LAAC to prevent stroke in CKD patients.

Effects of a mindfulness-based interventions on stress, burnout in nurses: a systematic review and meta-analysis.

Background: Stress in the healthcare environment causes negative effects in nurses such as burnout, anxiety, and depression. The COVID-19 pandemic has resulted in increased pressure on medical staff globally, highlighting the potential benefits of mindfulness-based interventions in reducing nurses' stress levels. Despite numerous studies exploring the effect of mindfulness-based training on nurses, the results remain inconclusive. Objective: To systematically evaluate the impact of mindfulness training on nurse's performance and increase the certainty of existing evidence. Methods: This study searched various databases, including EBSCO, Embase, Web of Science, PubMed, ProQuest, Scopus, Cochrane Online Library, Wanfang, SinoMed, CNKI, and VIP, for randomized controlled trials on the impact of mindfulness-based interventions for nurses up until 02 December 2022. Two investigators independently screened and extracted data from the articles, while also assessing the risk of bias. The data was analyzed using RevMan 5.4 software. Results: This review identified 15 studies out of the 2,171 records retrieved, consisting of a total of 1,165 participants who were randomized. Post-intervention analysis provided very-low certainty evidence of moderate effectiveness of mindfulness-based training in reducing stress [standardized mean difference (SMD) = -0.81; 95% confidence interval (CI) = -1.11 to -0.52], with no significant effect on anxiety (SMD = -0.30; 95% CI = -0.72 to 0.13) or depression (SMD = -0.24; 95% CI = -0.55 to 0.07). However, the training was effective in reducing burnout, as demonstrated by the lower scores for emotional exhaustion (SMD = -4.27; 95% CI = -5.94 to -2.59) and depersonalization (SMD = -2.89; 95% CI = -4.24 to -1.54) and higher scores for personal accomplishment (SMD = 2.81; 95% CI = 0.12 to 5.50). There was a sustained improvement in stress levels in the short-term (≤3 months), with delayed benefits for burnout. However, only two studies were available for later follow-ups, and there was no significant evidence of long-term effects. Conclusion: Mindfulness-based training may be a viable intervention for improving the psychological wellbeing of nurses, including reducing stress, burnout. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023387081.

Combining radiation and the ATR inhibitor berzosertib activates STING signaling and enhances immunotherapy via inhibiting SHP1 function in colorectal cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have shown a moderate response in colorectal cancer (CRC) with deficient mismatch repair (dMMR) functions and poor response in patients with proficient MMR (pMMR). pMMR tumors are generally immunogenically "cold", emphasizing combination strategies to turn the "cold" tumor "hot" to enhance the efficacy of ICIs. ATR inhibitors (ATRi) have been proven to cooperate with radiation to promote antitumor immunity, but it is unclear whether ATRi could facilitate the efficacy of IR and ICI combinations in CRCs. This study aimed to investigate the efficacy of combining ATRi, irradiation (IR), and anti-PD-L1 antibodies in CRC mouse models with different microsatellite statuses. METHODS: The efficacy of combining ATRi, IR, and anti-PD-L1 antibodies was evaluated in CRC tumors. The tumor microenvironment and transcriptome signatures were investigated under different treatment regimens. The mechanisms were explored via cell viability assay, flow cytometry, immunofluorescence, immunoblotting, co-immunoprecipitation, and real-time quantitative PCR in multiple murine and human CRC cell lines. RESULTS: Combining ATRi berzosertib and IR enhanced CD8+ T cell infiltration and enhanced the efficacy of anti-PD-L1 therapy in mouse CRC models with different microsatellite statuses. The mechanistic study demonstrated that IR + ATRi could activate both the canonical cGAS-STING-pTBK1/pIRF3 axis by increasing cytosolic double-stranded DNA levels and the non-canonical STING signaling by attenuating SHP1-mediated inhibition of the TRAF6-STING-p65 axis, via promoting SUMOylation of SHP1 at lysine 127. By boosting the STING signaling, IR + ATRi induced type I interferon-related gene expression and strong innate immune activation and reinvigorated the cold tumor microenvironment, thus facilitating immunotherapy. CONCLUSIONS: The combination of ATRi and IR could facilitate anti-PD-L1 therapy by promoting STING signaling in CRC models with different microsatellite statuses. The new combination strategy raised by our study is worth investigating in the management of CRC.

A Quick Simulation Method for Aero-Optical Effects Based on a Density Proxy Model.

Aero-optical effects caused by high-speed flow fields will interfere with the transmission of starlight, reduce the accuracy of optical sensors, and affect the application of celestial navigation on hypersonic vehicles. At present, the research of aero-optical effects relies heavily on the flow field simulation of computational fluid dynamics (CFD), which requires a great deal of computing resources and time, and cannot satisfy the demand of the rapid analysis of aero-optical effects in the engineering design stage. Therefore, a quick simulation method for aero-optical effects based on a density proxy model (DP-AOQS) is proposed in this paper. A proxy model of the turbulent density field is designed to replace the density field in the CFD simulation, and the proxy model is parametrically calibrated to simulate the optical characteristics of the turbulent boundary layer (TBL) in the external flow field of the optical window. The performance of DP-AOQS in the visible light band is verified from the perspectives of density field distribution, optical path difference (OPD), and fuzzy star map. The simulation results show that the method can quickly provide the distortion results of aero-optical effects in different flight conditions on the premise of ensuring the simulation accuracy. The research in this paper provides a new analytical method for the study of aero-optical effects.

Protective effect of spore oil-functionalized nano-selenium system on cisplatin-induced nephrotoxicity by regulating oxidative stress-mediated pathways and activating immune response.

In clinical practice, cisplatin is the most commonly used chemotherapy drug to treat a range of malignancies. Severe ROS-regulated nephrotoxicity, however, restricts its applicability. Currently, the main mechanisms leading to cisplatin-induced nephrotoxicity in clinical settings involve hydration or diuresis. However, not all patients can be treated with massive hydration or diuretics. Therefore, it is crucial to develop a treatment modality that can effectively reduce nephrotoxicity through a foodborne route. Selenium has been reported to have strong antioxidant as well as anticancer effects when administered as spore oil. Herein, we established cellular and animal models of cisplatin-induced nephrotoxicity and synthesized spore oil-functionalized nano-selenium (GLSO@SeNPs). We found that GLSO@SeNPs inhibit the mitochondrial apoptotic pathway by maintaining oxidative homeostasis and regulating related signaling pathways (the MAPK, caspase, and AKT signaling pathways). In vivo, GLSO@SeNPs could effectively improve cisplatin-induced renal impairment, effectively maintaining oxidative homeostasis in renal tissues and thus inhibiting the process of renal injury. In addition, GLSO@SeNPs were converted into selenocysteine (SeCys2), which may exert protective effects. Furthermore, GLSO@SeNPs could effectively modulate the ratio of immune cells in kidneys and spleen, reducing the proportions of CD3+CD4+ T cells, CD3+CD8+ T cells, and M1 phenotype macrophages and increasing the proportion of anti-inflammatory regulatory T cells. In summary, in this study, we synthesized food-derived spore oil-functionalized nanomaterials, and we explored the mechanisms by which GLSO@SeNPs inhibit cisplatin-induced nephrotoxicity. Our study provides a basis and rationale for the inhibition of cisplatin-induced nephrotoxicity by food-derived nutrients.

S-Species-Evoked High-Valence Ni2+ δ of the Evolved ß-Ni(OH)2 Electrode for Selective Oxidation of 5-Hydroxymethylfurfural.

An efficient NiSx -modified ß-Ni(OH)2 electrode is reported for the selective oxidation reaction of 5-hydroxymethylfurfural (HMFOR) with excellent electrocatalytic 5-hydroxymethylfurfural (HMF) selectivity (99.4%), conversion (97.7%), and Faradaic efficiency (98.3%). The decoration of NiSx will evoke high-valence Ni2+ δ species in the reconstructed ß-Ni(OH)2 electrode, which are the real active species for HMFOR. The generated NiSx /Ni(OH)O modulates the proton-coupled electron-transfer (PCET) process of HMFOR, where the electrocatalytically generated Ni(OH)O can effectively trap the protons from the CHO end in HMF to realize electron transfer. The oxygen evolution reaction (OER) competes with the HMFOR when NiSx /Ni(OH)O continues to accumulate, to generate the NiSx /NiOx (OH)y intermediate. Density functional theory (DFT) calculations and experimental results verify that the adsorption energy of HMF can be optimized through the increased NiSx composition for more efficient capture of protons and electrons in the HMFOR.

DNA from macrophages induces fibrosis and vasculopathy through POLR3A/STING/type I interferon axis in systemic sclerosis.

OBJECTIVE: To clarify the role of RNA polymerase III A (POLR3A)/type I IFN in the pathogenesis of SSc. METHODS: Cytosolic DNA and stimulator of IFN genes (STING) pathway in skin or serum of SSc patients were detected by immunofluorescence, immunohistochemistry and western blotting. DNA from human macrophages was transfected to SSc fibroblasts or human umbilical vein endothelial cells (HUVECs) and then markers of POLR3A/STING pathway were detected by real-time qPCR, western blotting and confocal microscopy. After H151 treatment or knocking down POLR3A/STING, type I IFN response, monocytes adhesion and activation of fibroblasts and HUVECs were evaluated. Regulation of IFN regulatory factor 3 (IRF3) on monocyte chemoattractant protein-1 (MCP-1) was determined by chromatin immunoprecipitation. In bleomycin (BLM)-induced SSc mice, the effect of STING knockout or H151 on vasculopathy and fibrosis was assessed. RESULTS: Cytosolic DNA, colocalization of STING with alpha-smooth muscle actin (α-SMA) or CD31 in the skin, and STING pathway in the serum of SSc patients were increased. Macrophage-derived DNA stimulated the translocation of POLR3A from nucleus to the perinuclear region near STING and activated POLR3A/STING/type I IFN response, monocytes adhesion and MCP-1 expression in fibroblasts/HUVECs and collagen overproduction of fibroblasts. The activated IRF3 bound to the promoter of MCP-1. STING deficiency or H151 administration ameliorated fibrosis and vasculopathy both in vitro and in BLM-induced SSc mice. CONCLUSIONS: SSc presented increased DNA leakage and STING pathway activation. DNA from macrophages induced type I IFN signature of fibroblasts and ECs through POLR3A/STING pathway. Blocking POLR3A/STING axis provides a new therapeutic target for SSc.

Progress and perspectives of platinum nanozyme in cancer therapy.

Malignant tumors, one of the worst-case scenarios within human health problems, are now posing an increasing threat to the well-being of the global population. At present, the treatment of malignant tumors mainly includes surgery, radiotherapy, chemotherapy, immunotherapy, etc. Radiotherapy and chemotherapy are often applied to inoperable tumors, and some other tumors after surgery as important adjuvant therapies. Nonetheless, both radiotherapy and chemotherapy have a series of side effects, such as radiation-induced lung injury, and chemotherapy-induced bone marrow suppression. In addition, the positioning accuracy of radiotherapy and chemotherapy is not assured and satisfactory, and the possibility of tumor cells not being sensitive to radiation and chemotherapy drugs is also problematic. Nanozymes are nanomaterials that display natural enzyme activities, and their applications to tumor therapy have made great progress recently. The most studied one, platinum nanozyme, has been shown to possess a significant correlation with radiotherapy sensitization of tumors as well as photodynamic therapy. However, there are still several issues that limited the usage of platinum-based nanozymes in vivo. In this review, we briefly summarize the representative studies regarding platinum nanozymes, and especially emphasize on the current challenges and the directions of future development for platinum nanozymes therapy.

Cathepsin B/NLRP3/GSDMD axis-mediated macrophage pyroptosis induces inflammation and fibrosis in systemic sclerosis.

BACKGROUND: Pyroptosis is a newly discovered type of programmed cell death associated with inflammatory and fibrotic diseases. Macrophages play an important role in inducing early immune inflammation in systemic sclerosis (SSc). OBJECTIVE: To investigate the effect of macrophages pyroptosis on fibrosis of SSc. METHODS: Pyroptosis/inflammatory markers in serum and skin of SSc patients were detected. Bleomycin (BLM) was subcutaneously injected to establish SSc mouse model. The levels of pyroptosis markers, dermal thickness and collagen deposition in skin were assessed before and after the administration of pyroptosis inhibitors, including MCC950, Disulfiram and necrosulfonamide (NSA). Human-derived monocyte-macrophage cell line (THP-1) or mouse bone marrow-derived macrophages (BMDMs) were primed with lipopolysaccharide (LPS) and stimulated by silicon dioxide (SiO2) to induce cell pyroptosis. Fibroblasts from patients with SSc were co-cultured with pyroptotic THP-1 cells, and the collagen production was assessed. RESULTS: Pyroptotic/inflammatory proteins, including NLRP3, cleaved-Caspase (CASP)1, GSDMD-N terminal and IL-18 were increased in the serum, and ASC aggregation and GSDMD were elevated in macrophages in the skin of SSc patients. SSc mice showed increased pyroptosis markers, dermal thickness and collagen deposition in skins, which were alleviated by MCC950, Disulfiram and NSA. Pyroptosis of THP-1 cells and BMDMs was induced by LPS/SiO2, and it was reduced by the inhibitors of Cathepsin B, NLRP3, CASP1 and GSDMD. Co-culture with pyroptotic THP-1 cells increased the fibrotic proteins in fibroblasts, which were alleviated by pyroptosis inhibitors. CONCLUSIONS: SSc patients and BLM-induced mouse model presented increased pyroptosis. LPS/SiO2-induced macrophage pyroptosis promoted fibrosis of SSc through Cathepsin B/NLRP3/GSDMD pathway.

Comprehensive Pan-Cancer Analyses of Immunogenic Cell Death as a Biomarker in Predicting Prognosis and Therapeutic Response.

Immunogenic cell death (ICD), a form of regulated cell death, is related to anticancer therapy. Due to the absence of widely accepted markers, characterizing ICD-related phenotypes across cancer types remained unexplored. Here, we defined the ICD score to delineate the ICD landscape across 33 cancerous types and 31 normal tissue types based on transcriptomic, proteomic and epigenetics data from multiple databases. We found that ICD score showed cancer type-specific association with genomic and immune features. Importantly, the ICD score had the potential to predict therapy response and patient prognosis in multiple cancer types. We also developed an ICD-related prognostic model by machine learning and cox regression analysis. Single-cell level analysis revealed intra-tumor ICD state heterogeneity and communication between ICD-based clusters of T cells and other immune cells in the tumor microenvironment in colon cancer. For the first time, we identified IGF2BP3 as a potential ICD regulator in colon cancer. In conclusion, our study provides a comprehensive framework for evaluating the relation between ICD and clinical relevance, gaining insights into identification of ICD as a potential cancer-related biomarker and therapeutic target.

A predictive signature based on enhancer RNA associates with immune infiltration and aids treatment decision in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a prevalent urinary malignancy. Despite the recent development of better diagnostic tools and therapy, the five-year survival rate for individuals with advanced and metastatic ccRCC remains dismal. Unfortunately, ccRCC is less susceptible to radiation and chemotherapy. Consequently, targeted therapy and immunotherapy play a crucial role in the treatment of ccRCC. Enhancer RNAs (eRNAs) are noncoding RNAs transcribed by enhancers. Extensive research has shown that eRNAs are implicated in a variety of cancer signaling pathways. However, the biological functions of eRNAs have not been systematically investigated in ccRCC. In this study, we conducted a comprehensive investigation of the role of eRNAs in the onset and management of ccRCC. Patient prognosis-influencing eRNAs and target genes were chosen to construct a predictive signature. On the basis of the median riskscore, ccRCC patients were split into high- and low-risk subgroups. The prediction efficiency was assessed in several cohorts, and multi-omics analysis was carried out to investigate the differences and underlying mechanisms between the high- and low-risk groups. In addition, we investigated its potential to facilitate clinical treatment choices. The riskscore might be used to forecast a patient's response to immunotherapy and targeted therapy, giving a revolutionary method for selecting treatment regimens with pinpoint accuracy.

MicroRNA-621 functions as a metastasis suppressor in colorectal cancer by directly targeting LEF1 and suppressing Wnt/ß-catenin signaling.

AIMS: Colorectal liver metastasis (CRLM) is the leading death-causing among colorectal cancer (CRC) patients. Recently, a novel tumor-related microRNA, miR-621, has been identified as a tumor suppressor in diverse tumor types, but its role in CRLM remains unclear and requires further investigation. MAIN METHODS: To elucidate novel regulators of CRLM progression, we used a well-established CRLM animal model. After serially transplanting human colon carcinoma cell lines Caco-2 into the liver, we obtained liver metastatic variants that exhibited a strong ability for invasion and metastasis. High-throughput sequencing was conducted on these newly established cell lines. After comparison and prediction between the two cell lines: parental Caco-2 (hereafter referred to as F0) and F3, miR-621 was identified as a candidate regulator for lymphoid enhancer-binding factor 1 (LEF1) expression. Further validation was achieved with dual-luciferase reporter assay. KEY FINDINGS: The gain- and loss-of-function validation showed that miR-621 inhibits cell viability, cell cycle progression, colony formation, and proliferation in vitro. Meanwhile, miR-621 could reverse EMT malignant phenotype. LEF1, an important downstream mediator of activated Wnt/ß-catenin signaling pathway, was validated as the direct functional target of miR-621. miR-621 interacts directly with the LEF1 3'-UTR and post-transcriptionally suppresses LEF1 expression. Moreover, LEF1 overexpression reversed the effect of miR-621. LEF1 silencing counteracted miR-621 down-regulation-induced effects. Further in vivo experiments revealed that miR-621 over-expression suppressed CRLM, but LEF1 abrogated the inhibitory effect of miR-621. SIGNIFICANCE: MiR-621 is a vital tumor suppressor in CRC and could be a promising anti-cancer therapeutic target.

Comprehensive analysis to identify the RP11-478C19.2/ E2F7 axis as a novel biomarker for treatment decisions in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC), accounting for 70-80% of all renal cell carcinomas, is a common malignancy. Survival rates decrease significantly in patients with advanced and metastatic ccRCC. Furthermore, ccRCC is less responsive to radiation and chemotherapy than other cancers. Therefore, targeted therapy and immunotherapy are particularly important for ccRCC management. A growing body of literature recognizes that competitive endogenous RNA (ceRNA) regulatory networks play a crucial role in various cancers. However, the biological functions of the ceRNA network in ccRCC require further investigation. In this study, we built the ceRNA network for ccRCC using the "GDCRNATools" package. After survival analysis, the RP11-478C19.2/hsa-miR-181b-5p, hsa-miR-181a-5p, and hsa-miR-181c-5p/E2F7 axes were obtained for further analysis. Unsupervised clustering was conducted basing on this ceRNA network. The results indicated that the prognosis and immune infiltration levels differed between the two clusters. Furthermore, we conducted correlation analysis, immune infiltration analysis, tumor mutation burden analysis, GSEA analysis, drug sensitivity analysis and pan-cancer analysis of E2F7 to explore its potential role in oncogenesis. Experiments in vitro were performed to confirm the pro-oncogenic impact of E2F7. The results suggest that the RP11-478C19.2/E2F7 axis might be a biomarker for the inclusion of cabozantinib, pazopanib, sunitinib, and immunotherapy in the therapeutic regimen. In summary, we found that the ceRNA-based RP11-478C19.2/E2F7 axis is involved in ccRCC and that it could be a novel biomarker for treatment decisions and a possible therapeutic target to increase the success of targeted therapy and immunotherapy in ccRCC.

Inhibition of JAK1/STAT3 pathway by 2-methoxyestradiol ameliorates psoriatic features in vitro and in an imiquimod-induced psoriasis-like mouse model.

Psoriasis is characterized by hyperproliferative keratinocytes, dilated capillaries and leukocyte infiltration. 2-Methoxyestradiol (2-ME) has shown significant inhibition on proliferation, angiogenesis and inflammation. To evaluate the anti-psoriatic potential of 2-ME, psoriasis-like dermatitis was induced by topical application of imiquimod (IMQ) on the dorsal skin of C57BL/6 mice for seven consecutive days, followed by treatment of vehicle or 2-ME ointment from Day 4 on. The psoriasis area and severity index (PASI) was assessed daily. On Day 8, skin histology and spleen index were assessed. The effects of 2-ME on the proliferation, apoptosis, cell cycle, vascular endothelial growth factor A (VEGFA), and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways of HaCaT cells stimulated by interleukin-17 (IL-17A) were detected, together with its effect on the proliferation, tube formation and VEGF receptor expression of human umbilical vein endothelial cells (HUVECs). We found that topical 2-ME treatment significantly improved IMQ-induced psoriasis-like dermatitis and decreased the PASI scores, the activation of STAT3 in the skin (P < 0.05), and the spleen index in mice (P < 0.01). In vitro, 2-ME inhibited the proliferation of HaCaT cells by inducing apoptosis and G2/M phase arrest (P < 0.01). Moreover, 2-ME suppressed IL-17A-induced VEGFA (2.5 µM: P < 0.05; 5 µM: P < 0.01) and phosphorylation of STAT3 by blocking p-JAK1 in HaCaT cells and prevented tube formation (P < 0.01) and proliferation by targeting VEGF receptors 1 (VEGFR1) and 2 (VEGFR2) in HUVECs. We conclude that 2-ME alleviated psoriasis in vivo and in vitro by inhibiting JAK1/STAT3 pathway and was a promising therapeutic agent for psoriasis.