Development of a staging system for hepatoid adenocarcinoma of the stomach based on multicenter data: A retrospective cohort study: A Staging System for Hepatoid Adenocarcinoma of the Stomach.

BACKGROUND: Hepatoid adenocarcinoma of the stomach (HAS) is a rare subtype of gastric cancer (GC) with a poor prognosis. Furthermore, the current pathological staging system for HAS does not distinguish it from that for common gastric cancer (CGC). METHODS: The clinicopathological data of 251 patients with primary HAS who underwent radical surgery at 14 centers in China from April 2004 to December 2019 and 5082 patients with primary CGC who underwent radical surgery at 2 centers during the same period were retrospectively analyzed. A modified staging system was established based on the differences in survival. RESULTS: After 1:4 propensity score matching (PSM), 228 patients with HAS and 828 patients with CGC were analyzed. Kaplan-Meier (K-M) analysis showed patients with HAS had a poorer prognosis compared with CGC. Multivariate analysis identified pN stage, CEA level, and perineural invasion (PNI) as independent prognostic factors in patients with HAS. A modified pT (mpT) staging was derived using recursive partitioning analysis (RPA) incorporating PNI and pT staging. The modified pathological staging system (mpTNM) integrated the mpT and the 8th American Joint Committee on Cancer (AJCC) pN definitions. Multivariate analysis showed that mpTNM stage outperformed other pathological variables as independent predictors of OS and RFS in patients with HAS. The mpTNM staging system exhibited significantly higher predictive accuracy for 3-year OS in patients with HAS (0.707, 95% CI: 0.650-0.763) compared to that of the 8th AJCC staging system (0.667, 95% CI: 0.610-0.723, P<0.05). Analysis using the Akaike information criterion favored the mpTNM staging system over the 8th AJCC staging system (824.69 vs. 835.94) regarding the goodness of fit. The mpTNM stages showed improved homogeneity in survival prediction (likelihood ratio: 41.51 vs. 27.10). Comparatively the mpTNM staging system outperformed the 8th AJCC staging system in survival prediction, supported by improvements in the net reclassification index (NRI: 47.7%) and integrated discrimination improvement (IDI: 0.083, P<0.05). Time-dependent ROC curve showed that the mpTNM staging system consistently outperformed the 8th AJCC staging system with increasing observation time. CONCLUSION: The mpTNM staging system exhibited superior postoperative prognostic accuracy for patients with HAS compared to the 8th AJCC staging system.

Utilization of Water-Insoluble Carbon Nitride-Phosphotungstic Acid Hybrids in Composite Proton Exchange Membranes.

Phosphotungstic acid (HPW) can retain water in proton exchange membranes to increase proton conductivity; however, its water-soluble nature limits further application. In this work, we combined HPW and graphitic carbon nitride (g-C3N4) via sintering to prepare water-insoluble hybrids (HWN), where HPW was chemically linked to g-C3N4 to fix HPW. Then, HWN fillers were added to a sulfonated polyether ether ketone (SPEEK) matrix to prepare composite membranes. The conductivity of the composite membrane with 10 wt% HWN is up to 0.066 S cm-1 at room temperature, which is 53% higher than that of the SPEEK control membrane (0.043 S cm-1). The composite membrane also showed stable proton conductivity after being immersed in water for 2000 h. Therefore, our study demonstrates that preparing water-insoluble nanofillers containing HPW components through sintering is a promising approach.

The application of ERAS in the perioperative period management of patients for lung transplantation.

Objective: To explore the application of enhanced recovery after surgery (ERAS) in the perioperative period of lung transplantation. Methods: We retrospectively collected the clinical data of 27 lung transplant patients who underwent ERAS during the perioperative period, while 12 lung transplant patients receiving routine treatment served as controls. General information was collected, including the specific implementation plan of ERAS, the incidence of complications and survival rate during the perioperative period (<30 d), postoperative hospitalization indicators, the postoperative length of stay, and numerical rating scale (NRS) scores. Results: Comparison of postoperative hospitalization indicators, the ERAS group compared with the control group, there were significant differences in postoperative ICU stay time (2.0(2.0,4.0) vs 4.5(3.0,6.0), p = 0.005), postoperative hospital stay time (18(15,26) vs 24(19.5,32.75), p = 0.016), duration of nasogastric tube (3(2,3) vs 4(2.25,4.75), p = 0.023), and first ambulation time (4(3,5) vs 5.8(4.5,7.5), p = 0.004). There was no significant difference in postoperative invasive mechanical ventilation time, time to eat after surgery, duration of urinary catheter and duration of chest tube between the ERAS group and the control group (p>0.05). The perioperative survival of the ERAS group was 81.5%, which was higher than the control group (66.7%), but there is no statistically significant difference. Comparison of post-extubation NRS scores, the ERAS group had lower NRS scores at 12 h (5.30 ± 0.14 vs 6.25 ± 0.75), 24 h (3.44 ± 0.64 vs 5.58 ± 0.9), 48 h (2.74 ± 0.66 vs 4.08 ± 0.79) and 72 h (1.11 ± 0.80 vs 2.33 ± 0.49) than the control group, the difference was statistically significant (p<0.01). Intra-group comparison, post-extubation 12 h comparison post-extubation 24 h, 48 h, 72 h, the NRS scores showed a gradual downward trend, the difference was statistically significant (p<0.01). In the comparison of perioperative complications, the ERAS group had a lower postoperative infection incidence than the control group, the difference was statistically significant (44.4% vs 83.3%, p = 0.037). The ERAS group had lower postoperative delirium incidence than the control group, the difference was statistically significant (11.1% vs 50%, p = 0.014). There was no significant difference in the incidence of acute rejection, primary graft loss (PGD), gastrointestinal (GI) complications and airway complications between two groups (p>0.05). Conclusion: The ERAS can be applied to lung transplant patients to relieve postoperative pain, shorten postoperative tube time, and shorten postoperative stay. Perioperative pulmonary rehabilitation exercises are beneficial to reducing the occurrence of postoperative pulmonary complications.

Elucidating the role of 4-hydroxy-2(3H)-benzoxazolone in chronic alcoholic liver disease via transcriptomics and metabolomics.

Background: Chronic alcoholic liver disease (CALD) is a global health problem which includes multiple pathological processes such as immune inflammation and oxidative stress. 4-hydroxy-2(3H)-benzoxazolone (HBOA), an alkaloid isolated from Acanthus ilicifolius L, has been shown to exert hepatoprotective and immunomodulatory effects. However, its effects on CALD remain unclear. This study aimed to investigate the effects and underlying mechanisms of HBOA on CALD. Methods: Rats were administered alcohol by gavage continuously for 12 weeks to establish the CALD model, and then treated with HBOA by gavage for 4 weeks. Transcriptomics and metabolomics were used to predict the potential mechanisms of the effects of HBOA on CALD. Liver histology and function, oxidative stress, inflammatory cytokines, and the TLR4/NF-κB pathway components were evaluated. Results: HBOA significantly improved alcohol-induced liver injury and steatosis. It decreased the expression levels of pro-inflammatory cytokines (tumour necrosis factor-α [TNF-α], interleukin (IL)-1ß, and IL-6), and increased the activities of antioxidant enzymes (superoxide dismutase [SOD], glutathione [GSH], and glutathione peroxidase [GSH-Px]). Western blotting confirmed that HBOA treatment largely diminished NF-κBp65 nuclear translocation. Comprehensive transcriptomics and metabolomics analyses indicated that HBOA regulated the glycerophospholipid metabolism pathway to achieve therapeutic effects in rats with CALD. Conclusion: HBOA has a therapeutic effect on rats with CALD. Its mechanism of action mainly affects the glycerophospholipid metabolic pathway to promote lipid metabolism homeostasis by regulating the expression of Etnppl, Gpcpd1, and Pla2g4c. In addition, it may also inhibit the TLR4/NF-κB signaling pathway, thereby reducing the immune-inflammatory response.

Facile Synthesis of Fe-Based Metal-Quinone Networks for Mutually Enhanced Mild Photothermal Therapy and Ferroptosis.

Mild photothermal therapy (MPTT) has emerged as a promising therapeutic modality for attenuating thermal damage to the normal tissues surrounding tumors, while the heat-induced upregulation of heat shock proteins (HSPs) greatly compromises the curative efficacy of MPTT by increasing cellular thermo-tolerance. Ferroptosis has been identified to suppress the overexpression of HSPs by the accumulation of lipid peroxides and reactive oxygen species (ROS), but is greatly restricted by overexpressed glutathione (GSH) in tumor microenvironment and undesirable ROS generation efficiency. Herein, a synergistic strategy based on the mutual enhancement of MPTT and ferroptosis is proposed for cleaving HSPs to recover tumor cell sensitivity. A facile method for fabricating a series of Fe-based metal-quinone networks (MQNs) by coordinated assembly is proposed and the representative FTP MQNs possess high photothermal conversion efficiency (69.3%). Upon 808 nm laser irradiation, FTP MQNs not only trigger effective MPTT to induce apoptosis but more significantly, potentiate Fenton reaction and marked GSH consumption to boost ferroptosis, and the reinforced ferroptosis effect in turn can alleviate the thermal resistance by declining the HSP70 defense and reducing ATP levels. This study provides a valuable rationale for constructing a large library of MQNs for achieving mutual enhancement of MPTT and ferroptosis.

NPSR1 promotes chronic colitis through regulating CD4+ T cell effector function in inflammatory bowel disease.

BACKGROUND: Neuropeptide S receptor 1 (NPSR1) has been implicated in the the onset of inflammatory bowel disease (IBD), though its exact mechanism remains unclear. This study investigates the role of NPSR1 in regulating CD4+ T cell effector function in IBD. METHODS: Peripheral blood and colonic mucosal biopsies from IBD patients, as well as dextran sodium sulfate (DSS)-induced mouse colitis models, were analyzed to assess the effects of NPSR1 on colitis and CD4+ T cell-mediated immune responses. NPSR1 knockdown was conducted both in vitro and in vivo to elucidate underlying mechanisms. Expression of NPSR1 and CD4+ T cell-related factors was measured using quantitative real-time PCR, immunoblotting, cytometric bead array, immunofluorescence, and immunohistochemistry. CD4 + T cell effector functions were evaluated through flow cytometry, EdU incorporation assay, Annexin V-FITC/PI staining, and transwell assay. RESULTS: NPSR1 expression was elevated in the intestinal tissues from IBD patients. Its downregulation provided protection in DSS-induced mouse colitis models. NPSR1 correlated positively with CD4 + T cell-mediated inflammation, and its knockdown reduced CD4+ T cell-mediated immune responses and inhibited CD4+ T cell differentiation. Additionally, NPSR1 knockdown decreased CD4+ T cell proliferation, increased apoptosis, and enhanced CCL2-induced migration in vitro, while significantly reducing Th1 cell chemotaxis in vivo. CONCLUSIONS: This study demonstrates that NPSR1 promotes chronic colitis by regulating CD4 + T cell effector functions in IBD, offering potential new therapeutic strategies for IBD treatment.

Radiomics-Based Risk Assessment Correlates With Outcomes in Patients With Acute Type B Aortic Dissection Undergoing Thoracic Endovascular Repair.

OBJECTIVES: Our study aimed to investigate the correlations between radiomics-based assessment and outcomes, including positive aortic remodeling (PAR), reintervention for dissection at 1 year, and overall survival, in patients with Type B aortic dissection (TBAD) who underwent thoracic endovascular aortic repair (TEVAR). METHODS: This was a single-center, retrospective, cohort study. The cohort comprised 104 patients who had undergone TEVAR of TBAD in our institution between January 2010 and October 2022. We segmented preoperative computed tomography (CT) images of the patients' descending aorta regions, then extracted a comprehensive set of radiomic features, including first-order features, shape features (2D and 3D), gray-level co-occurrence matrix (GLCM), gray-level size zone matrix, gray-level run length matrix, gray-level dependence matrix, neighborhood gray-tone difference matrix, from the regions of interest. Next, we selected radiomics features associated with total descending aorta positive aortic remodeling (TDA-PAR) and reintervention by least absolute shrinkage and selection operator (LASSO) regression and features associated with survival by LASSO-Cox regression. This enabled us to calculate radiomics-based risk scores for each patient. We then allocated the patients to high and low radiomics-based risk groups, the cutoff being the median score. We used 3 different models to validate the radiomics-based risk scores. RESULTS: The patients' baseline characteristics did not differ between those who achieved TDA-PAR and those who did not. The radiomics-based risk scores were significantly and independently associated with all 3 outcomes. As to the impact of specific radiomics features, we found that GLSZM_SmallAreaLowGrayLevelEmphasis and shape_Maximum2DDiameterColumn had positive impacts on both reintervention and survival outcomes, whereas GLCM_Idmn positively affected survival but negatively affected reintervention. We found that radiomics-based risk for TDA-PAR correlated most significantly with zone 6 PAR. CONCLUSIONS: Radiomics-based risk scores were significantly associated with the outcomes of TDA-PAR, reintervention, and overall survival. Radiomics has the potential to make significant contributions to prediction of outcomes in patients with TBAD undergoing TEVAR. CLINICAL IMPACT: In this study of 104 patients with Type B aortic dissection, we demonstrated associations between radiomics-based risk and postoperative outcomes, including total descending aorta positive aortic remodeling, reintervention and survival. These findings highlight radiomics' potential as a tool for risk stratification and prognostication in acute Type B aortic dissection management.

Association of sodium-glucose cotransporter 2 inhibitors with risk of incident dementia and all-cause mortality in older patients with type 2 diabetes: A retrospective cohort study using the TriNetX US collaborative networks.

BACKGROUND: Limited evidence exists to support any specific medication over others to prevent dementia in older patients with type 2 diabetes (T2D). We investigated whether treatment with sodium-glucose cotransporter 2 (SGLT-2) inhibitors is associated with a lower risk of incident dementia and all-cause mortality, relative to dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RA). METHODS: In this retrospective, active-comparator cohort study, we used data from the TriNetX electronic health records network. Our primary cohort comprised patients with T2D aged ≥50 years, registered between January 2012 and December 2022. Patients with a history of dementia were excluded. We used Kaplan-Meier survival analysis to estimate the incidence of dementia and all-cause mortality in our cohort after they had used glucose-lowering drugs for at least 12 months. Propensity score matching was performed to balance the SGLT-2 inhibitor, DPP-4 inhibitor and GLP-1 RA cohorts. Subgroup analyses for sex and age were also conducted. RESULTS: Our first cohort comprised 193 948 patients treated with metformin and SGLT-2 inhibitors and an equal number of patients treated with metformin and DPP-4 inhibitors. In this cohort, the risk of dementia and all-cause mortality was lower in patients treated with SGLT-2 inhibitors than in those treated with DPP-4 inhibitors (hazard ratio [HR]: 0.62, 95% confidence interval [CI]: 0.59-0.65, for dementia; HR: 0.54, 95% CI: 0.52-0.56, for all-cause mortality). Our second cohort comprised 165 566 patients treated with metformin and SGLT-2 inhibitors and an equal number of patients treated with metformin and GLP-1 RAs. In this cohort, the risk of dementia and all-cause mortality was lower in those treated with SGLT-2 inhibitors than in those treated with GLP-1 RAs (HR: 0.92, 95% CI: 0.87-0.98, for dementia; HR: 0.88, 95% CI: 0.85-0.91, for all-cause mortality). CONCLUSIONS: The use of SGLT-2 inhibitor was associated with a lower risk of incident dementia and all-cause mortality in older adults with T2D compared to DPP-4 inhibitor and GLP-1 RA.

Causal relationship between systemic circulatory inflammatory regulators and intervertebral disc degeneration: A bidirectional 2-sample Mendelian randomization study.

In the context of the development of intervertebral disc degeneration (IDD), inflammatory mediators play a pivotal role. Nevertheless, due to the influence of the inflammatory microenvironment, the causal relationship between specific inflammatory mediators and the development of IDD remains uncertain. The understanding of the causal relationship between inflammatory mediators and IDD is of great importance in preventing and delaying disc degeneration in the future. We utilized genetic data concerning systemic circulating inflammatory regulators obtained from a Genome-Wide Association Study (GWAS) analyzing 41 serum cytokines in a cohort of 8293 individuals from Finland. The genetic data for IDD were derived from the most recent GWAS summary statistics conducted within the FinnGen consortium, encompassing 37,636 IDD cases and 270,964 controls. Our analysis employed bidirectional 2-sample Mendelian randomization (MR) techniques, which included several MR methods such as MR Egger, weighted median, inverse variance weighted, weighted mode, and simple mode. Additionally, the MR-PRESSO method was employed to identify horizontal pleiotropy, heterogeneity was quantified using the Cochran Q statistic, and MR-Egger intercept analysis was performed to assess pleiotropy. We established causal relationships between 3 specific inflammatory factors and IDD. Elevated levels of MIP-1ß (OR = 0.956, 95% CI: -0.08 to -0.006; P = .02) and IFN-G (OR = 0.915, 95% CI: -0.16 to -0.02; P = .01) expression were associated with a reduced risk of IDD. Conversely, genetic susceptibility to IDD was linked to a decrease in IL-13 levels (OR = 0.967, 95% CI: -0.063 to -0.004; P = .03). In this study, we have identified inflammatory factors that exhibit a causal relationship with the onset and progression of IDD, as supported by genetic predictions.

Targeting IL-33 reprograms the tumor microenvironment and potentiates antitumor response to anti-PD-L1 immunotherapy.

BACKGROUND: The main challenge against patients with cancer to derive benefits from immune checkpoint inhibitors targeting PD-1/PD-L1 appears to be the immunosuppressive tumor microenvironment (TME), in which IL-33/ST2 signal fulfills critical functions. However, whether IL-33 limits the therapeutic efficacy of anti-PD-L1 remains uncertain. METHODS: Molecular mechanisms of IL-33/ST2 signal on anti-PD-L1 treatment lewis lung carcinoma tumor model were assessed by RNA-seq, ELISA, WB and immunofluorescence (IF). A sST2-Fc fusion protein was constructed for targeting IL-33 and combined with anti-PD-L1 antibody for immunotherapy in colon and lung tumor models. On this basis, bifunctional fusion proteins were generated for PD-L1-targeted blocking of IL-33 in tumors. The underlying mechanisms of dual targeting of IL-33 and PD-L1 revealed by RNA-seq, scRNA-seq, FACS, IF and WB. RESULTS: After anti-PD-L1 administration, tumor-infiltrating ST2+ regulatory T cells (Tregs) were elevated. Blocking IL-33/ST2 signal with sST2-Fc fusion protein potentiated antitumor efficacy of PD-L1 antibody by enhancing T cell responses in tumor models. Bifunctional fusion protein anti-PD-L1-sST2 exhibited enhanced antitumor efficacy compared with combination therapy, not only inhibited tumor progression and extended the survival, but also provided long-term protective antitumor immunity. Mechanistically, the superior antitumor activity of targeting IL-33 and PD-L1 originated from reducing immunosuppressive factors, such as Tregs and exhausted CD8+ T cells while increasing tumor-infiltrating cytotoxic T lymphocyte cells. CONCLUSIONS: In this study, we demonstrated that IL-33/ST2 was involved in the immunosuppression mechanism of PD-L1 antibody therapy, and blockade by sST2-Fc or anti-PD-L1-sST2 could remodel the inflammatory TME and induce potent antitumor effect, highlighting the potential therapeutic strategies for the tumor treatment by simultaneously targeting IL-33 and PD-L1.

Analysis of risk factors for PCI no-reflow in coronary heart disease and construction of related prediction models.

OBJECTIVE: To analyze the risk factors of percutaneous coronary intervention (PCI) no-reflow in patients with coronary heart disease (CHD) and construct a predictive nomogram model. METHODS: This retrospective study included 260 patients with CHD who underwent PCI in the Third Affiliated Hospital of Chongqing Medical University from January 2022 to December 2023. The subjects were divided into a PCI no-reflow group (n = 86) and normal reflow group (n = 174) based on thrombolysis in myocardial infarction (TIMI) blood flow grading. General data, PCI related data and laboratory indexes of patients were collected. Logistic regression was used to analyze the risk factors of no-reflow after PCI in CHD patients. Based on the significant variables from regression analysis, a nomogram prediction model was constructed by using R language. The accuracy of the model was evaluated by receiver operating characteristic (ROC) curve and calibration curve, and the decision curve was drawn to clarify the clinical utility of the model. Model performance metrics included area under the curve (AUC), accuracy, sensitivity and specificity. RESULTS: Multivariate logistic regression analysis showed that hypertension, cystatin C (Cys-C), hypersensitive c-reactive protein (hs-CRP) and platelet-to-lymphocyte ratio (PLR) were risk factors for no-reflow after PCI in CHD patients (OR > 1, P < 0.001), while ADAM metallopeptidase with thrombospondin type 1 motif 13 (ADAMTS-13) and lymphocyte (LYM) were protective factors (OR < 1, P < 0.001). The nomogram prediction model based on the above risk factors showed good predictive value. The AUC of the nomogram prediction model in the training set was 0.967 (95% CI: 0.946-0.989), with a specificity of 0.923 and a sensitivity of 0.908. In the validation set, the AUC was 0.894 (95% CI: 0.817-0.971), with a specificity of 0.807 and a sensitivity of 0.857. The calibration curve indicated good agreement between the predicted and actual probabilities, and the decision curve showed clinical benefit across a range of threshold probabilities in both the training and validation sets (0.0-0.99). CONCLUSION: The risk factors affecting the occurrence of no-reflow after PCI in patients with CHD include hypertension, serum Cys-C, hs-CRP, PLR, ADAMTS-13 and LYM levels. The nomogram risk prediction model based on the above factors is valuable for identifying patients with high risk of no-reflow after PCI.

Chronic polystyrene microplastics exposure-induced changes in thick-shell mussel (Mytilus coruscus) metaorganism: A holistic perspective.

Microplastics have emerged as a significant global concern, particularly in marine ecosystems. While extensive research has focused on the toxicological effects of microplastics on marine animals and/or their associated microorganisms as two separate entities, the holistic perspective of the adaptability and fitness of a marine animal metaorganism-comprising the animal host and its microbiome-remains largely unexplored. In this study, mussel metaorganisms subjected chronic PS-MPs exposure experienced acute mortality but rapidly adapted. We investigated the response of innate immunity, digestive enzymes and their associated microbiomes to chronic PS-MPs exposure. We found that PS-MPs directly and indirectly interacted with the host and microbe within the exposure system. The adaptation was a joint effort between the physiological adjustments of mussel host and genetic adaptation of its microbiome. The mussel hosts exhibited increased antioxidant activity, denser gill filaments and increased immune cells, enhancing their innate immunity. Concurrently, the gill microbiome and the digestive gland microbiome respective selectively enriched for plastic-degrading bacteria and particulate organic matter-utilizing bacteria, facilitating the microbiome's adaptation. The microbial adaptation to chronic PS-MPs exposure altered the ecological roles of mussel microbiome, as evidenced by alterations in microbial interactions and nutrient cycling functions. These findings provided new insights into the ecotoxicological impact of microplastics on marine organisms from a metaorganism perspective.

Disrupting YAP1-mediated glutamine metabolism induces synthetic lethality alongside ODC1 inhibition in osteosarcoma.

PURPOSE: Osteosarcoma, a highly malignant primary bone tumor primarily affecting adolescents, frequently develops resistance to initial chemotherapy, leading to metastasis and limited treatment options. Our study aims to uncover novel therapeutic targets for metastatic and recurrent osteosarcoma. METHODS: In this study, we proved the potential of modulating the YAP1-regulated glutamine metabolic pathway to augment the response of OS to DFMO. We initially employed single-cell transcriptomic data to gauge the activation level of polyamine metabolism in MTAP-deleted OS patients. This was further substantiated by transcriptome sequencing data from recurrent and non-recurrent patient tissues, confirming the activation of polyamine metabolism in progressive OS. Through high-throughput drug screening, we pinpointed CIL56, a YAP1 inhibitor, as a promising candidate for a combined therapeutic strategy with DFMO. In vivo, we utilized PDX and CDX models to validate the therapeutic efficacy of this drug combination. In vitro, we conducted western blot analysis, qPCR analysis, immunofluorescence staining, and PuMA experiments to monitor alterations in molecular expression, distribution, and tumor metastasis capability. We employed CCK-8 and colony formation assays to assess the proliferative capacity of cells in the experimental group. We used flow cytometry and reactive oxygen probes to observe changes in ROS and glutamine metabolism within the cells. Finally, we applied RNA-seq in tandem with metabolomics to identify metabolic alterations in OS cells treated with a DFMO and CIL56 combination. This enabled us to intervene and validate the role of the YAP1-mediated glutamine metabolic pathway in DFMO resistance. RESULTS: Through single-cell RNA-seq data analysis, we pinpointed a subset of late-stage OS cells with significantly upregulated polyamine metabolism. This upregulation was further substantiated by transcriptomic profiling of recurrent and non-recurrent OS tissues. High-throughput drug screening revealed a promising combination strategy involving DFMO and CIL56. DFMO treatment curbs the phosphorylation of YAP1 protein in OS cells, promoting nuclear entry and initiating the YAP1-mediated glutamine metabolic pathway. This reduces intracellular ROS levels, countering DFMO's anticancer effect. The therapeutic efficacy of DFMO can be amplified both in vivo and in vitro by combining it with the YAP1 inhibitor CIL56 or the glutaminase inhibitor CB-839. This underscores the significant potential of targeting the YAP1-mediated glutamine metabolic pathway to enhance efficacy of DFMO. CONCLUSION: Our findings elucidate YAP1-mediated glutamine metabolism as a crucial bypass mechanism against DFMO, following the inhibition of polyamine metabolism. Our study provides valuable insights into the potential role of DFMO in an "One-two Punch" therapy of metastatic and recurrent osteosarcoma.

Current perspectives on mesenchymal stem cells as a potential therapeutic strategy for non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) has emerged as a significant health challenge, characterized by its widespread prevalence, intricate natural progression and multifaceted pathogenesis. Although NAFLD initially presents as benign fat accumulation, it may progress to steatosis, non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. Mesenchymal stem cells (MSCs) are recognized for their intrinsic self-renewal, superior biocompatibility, and minimal immunogenicity, positioning them as a therapeutic innovation for liver diseases. Therefore, this review aims to elucidate the potential roles of MSCs in alleviating the progression of NAFLD by alteration of underlying molecular pathways, including glycolipid metabolism, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. The insights are expected to provide further understanding of the potential of MSCs in NAFLD therapeutics, and support the development of MSC-based therapy in the treatment of NAFLD.

Establishing a Classification System for Predicting Flow-Limiting Dissection After Balloon Angioplasty Using Explainable Machine-Learning Models: A Multicenter Retrospective Cohort Study.

OBJECTIVE: Percutaneous transluminal angioplasty (PTA) is the primary method for treatment in peripheral arterial disease. However, some patients experience flow-limiting dissection (FLD) after PTA. We utilized machine learning and SHapley Additive exPlanations to identify and optimize a classification system to predict FLD after PTA. METHODS: This was a multi-center, retrospective, cohort study. The cohort comprised 407 patients who underwent treatment of the femoropopliteal (FP) arteries in 3 institutions between January 2021 and June 2023. Preoperative computed tomography angiography images were evaluated to identify FP artery grading, chronic total occlusion (CTO), and vessel calcification (peripheral artery calcium scoring system [PACSS]). After PTA, FLD was identified by angiography. We trained and validated 6 machine-learning models to estimate FLD occurrence after PTA, and the best model was selected. Then, the sum of the Shapley values for each of CTO, FP, and PACSS was calculated for each patient to produce the CTO-FP-PACSS value. The CTO-FP-PACSS classification system was used to classify the patients into classes 1 to 4. Univariate and multivariate analyses were performed to validate the effectiveness of the CTO-FP-PACSS classification system for predicting FLD. RESULTS: Overall, 407 patients were analyzed, comprising 189 patients with FLD and 218 patients without FLD. Differences in sex (71% males vs 54% males, p<0.001), CTO (72% vs 43%, p<0.001), FP (3.26±0.94 vs 2.66±1.06, p<0.001), and PACSS (2.39±1.40 vs 1.74±1.35, p<0.001) were observed between patients with and without FLD, respectively. The random forest model demonstrated the best performance (validation set area under the curve: 0.82). SHapley Additive exPlanations revealed CTO, PACSS, and FP as the 3 most influential FLD predictors, and the univariate and multivariate analyses confirmed CTO-FP-PACSS classification as an independent FLD predictor (multivariate hazard ratio 4.13; p<0.001). CONCLUSION: The CTO-FP-PACSS classification system accurately predicted FLD after PTA. This user-friendly system may guide surgical decision-making, helping choose between PTA and additional devices to reduce FLD in FP artery treatment. CLINICAL IMPACT: We utilised machine-learning techniques in conjunction with SHapley Additive exPlanations to develop a clinical classification system that predicts the probability of flow-limiting dissection (FLD) after plain old balloon angioplasty. This classification system categorises lesions into Classes 1-4 based on three factors: chronic total occlusion, femoropopliteal grading, and peripheral artery calcium scoring. Each class demonstrated a different probability of developing FLD. This classification system may be valuable for surgeons in their clinical practice, as well as serving as a source of inspiration for other researchers.

Surface Oxygen Vacancies and Corona Polarization of Bi4Ti3O12 Nanosheets for Synergistically Enhanced Sonopiezoelectric Therapy.

Sonopiezoelectric therapy, an ultrasound-activated piezoelectric nanomaterial for tumor treatment, has emerged as a novel alternative modality. However, the limited piezoelectric catalytic efficiency is a serious bottleneck for its practical application. Excellent piezoelectric catalysts with high piezoelectric coefficients, good deformability, large mechanical impact surface area, and abundant catalytically active sites still need to be developed urgently. In this study, the classical ferroelectric material, bismuth titanate (Bi4Ti3O12, BTO), is selected as a sonopiezoelectric sensitizer for tumor therapy. BTO generates electron-hole pairs under ultrasonic irradiation, which can react with the substrates in a sonocatalytic-driven redox reaction. Aiming to further improve the catalytic activity of BTO, modification of surface oxygen vacancies and treatment of corona polarization are envisioned in this study. Notably, modification of the surface oxygen vacancies reduces its bandgap and inhibits electron-hole recombination. Additionally, the corona polarization treatment immobilized the built-in electric field on BTO, further promoting the separation of electrons and holes. Consequently, these modifications greatly improve the sonocatalytic efficiency for in situ generation of cytotoxic ROS and CO, effectively eradicating the tumor.

The relationship between the collagen score at the anastomotic site of esophageal squamous cell carcinoma and anastomotic leakage.

Background: Anastomotic leakage (AL) has always been one of the most serious complications of esophagectomy with gastric conduit reconstruction. There are many strong risk factors for AL in clinical practice. Notably, the tension at the esophagogastric anastomosis and the blood supply to the gastric conduit directly affect the integrity of the anastomosis. However, there has been a lack of quantitative research on the tension and blood supply of the gastric conduit. Changes in extracellular matrix collagen reflect tension and blood supply, which affect the quality of the anastomosis. This study aimed to establish a quantitative collagen score to describe changes in the collagen structure in the extracellular matrix and to identify patients at high risk of postoperative AL. Methods: A retrospective study of 213 patients was conducted. Clinical and pathological data were collected at baseline. Optical imaging of the "donut" specimen at the anastomotic gastric end and collagen feature extraction were performed. Least absolute shrinkage and selection operator (LASSO) regression models were used to select the significant collagen features, compute collagen scores, and validate the predictive efficacy of the collagen scores for ALs. Results: LASSO regression analysis revealed three collagen-related parameters in the gastric donuts: histogram mean, histogram variance, and histogram energy. Based on this analysis, we established a formula to calculate the collagen score. The results of the univariate analysis revealed significant differences in the preoperative low albumin values (P=0.002) and collagen scores between the AL and non-AL groups (P=0.001), while the results of the multivariate analysis revealed significant differences in the collagen scores between the AL and non-AL groups (P=0.002). The areas under the curve (AUCs) of the experimental and validation cohorts were 0.978 [95% confidence interval (CI): 0.931-0.996] and 0.900 (95% CI: 0.824-0.951), respectively. Conclusions: The collagen score established herein was shown to be related to AL and can be used to predict AL in patients who underwent esophagectomy.

Multimode Luminesce Tailoring PMA4Na(In,Sb)Cl8 Organic-inorganic Hybrid Metal Halide via Rigid Benzene Ring Induced Local Lattice Distortion.

Low dimensional organic-inorganic hybrid metal halide materials have attracted extensive attention due to their superior optoelectronic properties. However, low photoluminescence quantum yields (PLQYs) caused by parity-forbidden transition hinder their further application in optoelectronic devices. Herein, a novel yellow-emitting PMA4Na(In,Sb)Cl8 (C7H10N+, PMA+) low-dimensional OIMHs single crystal with a PLQY as high as 88% was successfully designed and synthesized, originating from the fact that the doping of Sb3+ effectively relaxes the parity-forbidden transition by strong spin-orbit (SO) coupling and Jahn-Teller (JT) interaction. The as-prepared crystal shows an efficient dual emission peaking 495 and 560 nm at low temperature, which are ascribed to different levels of 3P1 → 1S0 transitions of Sb3+ in [SbCl6]3- octahedral caused by JT deformation. Moreover, wide-range luminescence tailoring from cyan to orange can be achieved through adjusting excitation energy and temperature because of flexible [SbCl6]3- octahedral in the PNIC lattice. Based on a relative stiff lattice environment, the 560 nm yellow emission under 350 nm light excitation exhibits abnormal anti-thermal quenching from 8 to 400 K owing to the suppression of non-radiative transition. The multimode luminescence regulation enriches PMA4Na(In,Sb)Cl8 great potential in the field of optoelectronics such as temperature sensing,  low temperature anti-counterfeiting and WLED applications.

Multi-Enzyme Mimetic MoCu Dual-Atom Nanozyme Triggering Oxidative Stress Cascade Amplification for High-Efficiency Synergistic Cancer Therapy.

Single-atom nanozymes (SAzymes) with ultrahigh atom utilization efficiency have been extensively applied in reactive oxygen species (ROS)-mediated cancer therapy. However, the high energy barriers of reaction intermediates on single-atom sites and the overexpressed antioxidants in the tumor microenvironment restrict the amplification of tumor oxidative stress, resulting in unsatisfactory therapeutic efficacy. Herein, we report a multi-enzyme mimetic MoCu dual-atom nanozyme (MoCu DAzyme) with various catalytic active sites, which exhibits peroxidase, oxidase, glutathione (GSH) oxidase, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase mimicking activities. Compared with Mo SAzyme, the introduction of Cu atoms, formation of dual-atom sites, and synergetic catalytic effects among various active sites enhance substrate adsorption and reduce the energy barrier, thereby endowing MoCu DAzyme with stronger catalytic activities. Benefiting from the above enzyme-like activities, MoCu DAzyme can not only generate multiple ROS, but also deplete GSH and block its regeneration to trigger the cascade amplification of oxidative stress. Additionally, the strong optical absorption in the near-infrared II bio-window endows MoCu DAzyme with remarkable photothermal conversion performance. Consequently, MoCu DAzyme achieves high-efficiency synergistic cancer treatment incorporating collaborative catalytic therapy and photothermal therapy. This work will advance the therapeutic applications of DAzymes and provide valuable insights for nanocatalytic cancer therapy.