The Predictive Value of the MELD Scores for In-Hospital Adverse Events in Normotensive Patients with Acute Pulmonary Embolism.

The model for end-stage liver disease (MELD) and the model for end-stage liver disease excluding international normalized ratio (INR) (MELD-XI) scores, which reflect dysfunction of liver and kidneys, have been reported to be related to the prognosis of patients with right-sided "backward" failure. However, the relationship between the MELD/MELD-XI score and the in-hospital adverse events in pulmonary embolism (PE) patients was unknown. Normotensive PE patients were retrospectively enrolled at China-Japan friendship hospital from January 2017 to February 2020. The primary outcome was defined as death and clinical deterioration during hospitalization. Multivariate logistic analysis was used to explore the association between the MELD and MELD-XI scores for in-hospital adverse events. We also compared the accuracy of the MELD, MELD-XI, and the pulmonary embolism severity index (PESI) score using the time-dependent receiver operating characteristic curve and corresponding areas under the curve (AUC). A total of 222 PE patients were analyzed. Logistic regression analysis showed that the MELD score was independently associated with in-hospital adverse events (odds ratio = 1.115, 95% confidential interval = 1.022-1.217, P = .014). The MELD score has an AUC of 0.731 and was better than PESI (AUC of 0.629) in predicting in-hospital adverse events. Among PE patients with normal blood pressure on admission, the MELD score was associated with increased in-hospital adverse events.

Clinical and electrocardiographic characteristics of immune checkpoint inhibitor-related myocarditis.

BACKGROUND: Immune checkpoint inhibitor (ICI) has become a major breakthrough in the field of tumor therapy, leading to improved survival. This study evaluated the clinical and electrocardiographic characteristics of patients with ICI-related myocarditis. METHODS: Patients with ICI-related myocarditis were enrolled from 4 centers in China until September 2023. Demographic data (age, sex, comorbidity), types of ICI, clinical manifestations, electrocardiogram (ECG) and treatment were analyzed retrospectively. Arrhythmia and characteristics of ECG were compared according to prognosis and grading. RESULTS: A total of 29 participants (13 females with a median age of 63.25 years) with ICI-related myocarditis were enrolled. Lung cancer was the most, with a proportion of 31.03 % (9/29). The median time from the first administration of ICI to the diagnosis of myocarditis was 50 days. Camrelizumab was the main type of ICI (9/29). Most patients had non-specific symptoms, dyspnea (n = 16) and palpitation (n = 9) were common. The overall mortality rate was 37.93 % (11/29) with a median follow-up of 9(4,11) days. Compared with the survivors, P-wave abnormality was more common in participants who were dead (24.14 %vs6.90 %, p = 0.010). A total of 19 patients with severe ICI-related myocarditis were included in this study. The proportions of sinus tachycardia (34.48 %vs0.00 %, p = 0.005), premature ventricular complex (27.59 %vs0.00 %, p = 0.027) and atrioventricular block (34.48 %vs3.45 %, p = 0.044) were higher in severe ICI-related myocarditis. CONCLUSIONS: Clinical manifestations of ICI-related myocarditis usually lacked specificity. ECGs can be manifested as new-onset arrhythmias, ST-T segment changes, fragmented QRS complex, abnormal P wave, prolonged QTc interval and multi­lead low voltage.

Development and validation of an individualized nomogram for gastric cancer patients treated with perioperative chemotherapy followed by radical surgery.

Background: Prognostic factors are complicated and changeable for locally advanced gastric cancer (GC) patients. This study aimed to perform a novel prognostic model on survival for locally advanced GC patients who have received neoadjuvant chemotherapy and radical surgery. Methods: The locally advanced GC patients with neoadjuvant chemotherapy were included in this study from Zhongshan Hospital, Fudan University. A nomogram was developed based on independent prognostic factors identified through a multivariable Cox regression model. Model performance was evaluated in training and independent external cohorts in terms of calibration, discrimination, and clinical usefulness. Results: A total of 273 patients received radical resections. The median progression-free survival (PFS) and overall survival (OS) for all patients were 43.8 and 61.2 months, respectively. Nomogram showed that Lauren type made the greatest contribution to prognosis, followed by ypN. The prognostic nomogram had excellent discriminative ability, with a C-index of 0.689 [95% confidence interval (CI): 0.661-0.716], and an area under the receiver operating characteristic (ROC) curve (AUC) of 0.778, 0.746, and 0.725 for 3-, 5- and 10-year OS, respectively. Similar results were obtained in the external validation cohort. Based on the nomogram, the whole cohort was divided into high-risk and low-risk groups. And risk group classification was significantly associated with clinical characteristics, and produced an AUC value of 0.781, 0.748, and 0.727 for 3-, 5- and 10-year OS, respectively. Furthermore, compared with the tumor-node-metastasis (TNM) staging system (8th edition), Japanese criteria, and German criteria, the decision curve analysis (DCA) graphically demonstrated that the new model had more optimal net benefits in predicting the 3-, 5-, and 10-year OS for GC patients. Both C-index and time-dependent ROC curve demonstrated that the nomogram had a stronger capability for accurately predicting prognosis compared with the other staging system. Conclusions: The nomogram model is an effective support tool to predict OS in GC patients undergoing perioperative chemotherapy followed by radical surgery.

Assessing and engineering the IscB-ωRNA system for programmed genome editing.

OMEGA RNA (ωRNA)-guided endonuclease IscB, the evolutionary ancestor of Cas9, is an attractive system for in vivo genome editing because of its compact size and mechanistic resemblance to Cas9. However, wild-type IscB-ωRNA systems show limited activity in human cells. Here we report enhanced OgeuIscB, which, with eight amino acid substitutions, displayed a fourfold increase in in vitro DNA-binding affinity and a 30.4-fold improvement in insertion-deletion (indel) formation efficiency in human cells. Paired with structure-guided ωRNA engineering, the enhanced OgeuIscB-ωRNA systems efficiently edited the human genome across 26 target sites, attaining up to 87.3% indel and 62.2% base-editing frequencies. Both wild-type and engineered OgeuIscB-ωRNA showed moderate fidelity in editing the human genome, with off-target profiles revealing key determinants of target selection including an NARR target-adjacent motif (TAM) and the TAM-proximal 14 nucleotides in the R-loop. Collectively, our engineered OgeuIscB-ωRNA systems are programmable, potent and sufficiently specific for human genome editing.

Efficacy and Safety of Ongericimab in Chinese Patients With Primary Hypercholesterolemia and Mixed Dyslipidemia.

BACKGROUND: A phase 3 trial was conducted to evaluate the efficacy and safety of ongericimab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9, as an add-on treatment to optimized lipid-lowering therapy in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia. METHODS AND RESULTS: A total of 806 patients who were receiving stable and optimized lipid-lowering therapy but did not achieve their low-density lipoprotein cholesterol (LDL-C) targets were enrolled and randomly assigned in a 2:1:2:1 ratio to receive either ongericimab 150 mg or matching placebo every 2 weeks, or ongericimab 300 mg or matching placebo every 4 weeks for 52 weeks. Efficacy and safety were evaluated in 802 patients who received at least 1 dose of ongericimab or placebo. The primary end point was the percentage change in LDL-C from baseline to week 24. Our findings demonstrated that the least-squares mean difference of percentage change in LDL-C from baseline to week 24 was -67.7% (95% CI, -72.5% to -63.0%; P<0.0001) in the ongericimab 150 mg every 2 weeks group compared with the placebo every 2 weeks group, and -61.2% (95% CI, -67.1% to -55.2%; P<0.0001) in the ongericimab 300 mg every 4 weeks group compared with the placebo every 4 weeks group. These reductions were sustained up to week 52. Furthermore, treatment with ongericimab favorably altered other lipid parameters. A similar incidence of adverse events was observed in the ongericimab and placebo groups. CONCLUSIONS: Ongericimab, as an add-on treatment to optimized lipid-lowering therapy, significantly reduced LDL-C and was well-tolerated in Chinese patients with primary hyperlipidemia and mixed dyslipidemia who did not achieve their LDL-C targets. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04781114.

Association between lipoprotein(a) and premature atherosclerotic cardiovascular disease: a systematic review and meta-analysis.

Aims: High lipoprotein(a) [Lp(a)] level has been demonstrated as an important risk factor for atherosclerotic cardiovascular diseases (ASCVD) amongst the older populations, whereas its effects in the younger population remain unclear. This study evaluated the associations between Lp(a) and the risk of premature ASCVD. Method and results: PubMed and Embase were searched for related studies until 12 November 2023. Fifty-one studies including 100 540 participants were included. Mean age of patients ranged from 35.3 to 62.3 years. The proportion of male participants ranged from 0% to 100%. The mean follow-up was provided in five studies ranging from 1 year to 40 years. The definition of elevated Lp(a) varied among studies, such as >30 mg/dL, >50 mg/dL, the top tertiles, the top quartiles, the top quintiles, and so on. Higher Lp(a) was significantly associated with the composite ASCVD [odds ratio (OR): 2.15, 95% confidence interval (95% CI): 1.53-3.02, P < 0.001], especially for coronary artery disease (OR: 2.44, 95% CI: 2.06-2.90, P < 0.001) and peripheral arterial disease (OR: 2.56, 95% CI: 1.56-4.21, P < 0.001). This association remained significant in familial hypercholesterolaemia (FH) (OR: 3.11, 95% CI: 1.63-5.96, P < 0.001) and type 2 diabetes mellitus (T2DM) patients (OR: 2.23; 95% CI: 1.54-3.23, P < 0.001).Significant results were observed in South Asians (OR: 3.71, 95% CI: 2.31-5.96, P < 0.001), Caucasians (OR: 3.17, 95% CI: 2.22-4.52, P < 0.001), and patients with baseline low-density lipoprotein cholesterol (LDL-c) level ≥ 2.6 mmol/L. Conclusion: Elevated Lp(a) predicts the risk of the composite or individual ASCVD in young, regardless of study design, gender, population characteristics (community or hospitalized), different premature definitions, and various Lp(a) measurement approaches. This association was important in South Asians, Caucasians, FH patients, T2DM patients, and patients with baseline LDL-c level ≥ 2.6 mmol/L.

Cardiovascular adverse events associated with immune checkpoint inhibitors: A retrospective multicenter cohort study.

BACKGROUND: Over the past decade, immune checkpoint inhibitors (ICIs) have significantly transformed cancer treatment. However, ICIs inevitably may cause a spectrum of immune-related adverse events, among which cardiovascular toxicity, particularly myocarditis, while infrequent, has garnered increasing attention due to its high fatality rate. METHODS: We conducted a multicenter retrospective study to characterize ICI-associated cardiovascular adverse events. Logistic regression was performed to explore the risk factors for the development of myocarditis and severe myocarditis. Receiver operating characteristic curves were conducted to assess the diagnostic abilities of cardiac biomarkers to distinguish different cardiovascular toxicities, and the performance and calibration were evaluated using Hosmer-Lemeshow test. RESULTS: Forty-four patients were identified, including thirty-five myocarditis, five heart failure, three arrhythmias, and one myocardial infarction. Compared with other patients, myocarditis patients had higher cardiac troponin-I (cTnI) levels (p < 0.001), higher creatine kinase levels (p = 0.003), higher creatine kinase isoenzyme-MB (CK-MB) levels (p = 0.013), and shorter time to the incidence of adverse cardiovascular events (p = 0.022) after ICI treatment. Twenty-one patients (60%) were classified as severe myocarditis, and they presented higher cardiac troponin I (cTnI) levels (p = 0.013), higher N-terminal pro-B-type natriuretic peptide levels (p = 0.031), higher creatine kinase levels (p = 0.018), higher CK-MB levels (p = 0.026), and higher neutrophil to lymphocyte ratio (NLR) levels (p = 0.016) compared to non-severe myocarditis patients after ICI treatment. Multivariate logistic regression showed that CK-MB (adjusted odds ratio [OR]: 1.775, 95% confidence interval [CI]: 1.055-2.984, p = 0.031) was the independent risk factor of the development of ICI-associated myocarditis, and cTnI (adjusted OR: 1.021, 95% CI: 1.002-1.039, p = 0.03) and NLR (adjusted OR: 1.890, 95% CI: 1.026-3.483, p = 0.041) were the independent risk factors of ICI-associated severe myocarditis. The receiver operating characteristic curve showed an area under curve of 0.785 (95% CI: 0.642 to 0.928, p = 0.013) for CK-MB, 0.765 (95% CI: 0.601 to 0.929, p = 0.013) for cTnI, and 0.773 for NLR (95% CI: 0.597 to 0.948, p = 0.016). CONCLUSIONS: Elevated CK-MB after ICI treatment is the independent risk factor for the incidence of ICI-associated myocarditis, and elevated cTnI and NLR after ICI treatment are the independent risk factors for the development of ICI-associated severe myocarditis. CK-MB, cTnI, and NLR demonstrated a promising predictive utility for the identification of ICI-associated myocarditis and severe myocarditis.

Targeting autophagy in diabetic cardiomyopathy: From molecular mechanisms to pharmacotherapy.

Diabetic cardiomyopathy (DCM) is a cardiac microvascular complication caused by metabolic disorders. It is characterized by myocardial remodeling and dysfunction. The pathogenesis of DCM is associated with abnormal cellular metabolism and organelle accumulation. Autophagy is thought to play a key role in the diabetic heart, and a growing body of research suggests that modulating autophagy may be a potential therapeutic strategy for DCM. Here, we have summarized the major signaling pathways involved in the regulation of autophagy in DCM, including Adenosine 5'-monophosphate-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), Forkhead box subfamily O proteins (FOXOs), Sirtuins (SIRTs), and PTEN-inducible kinase 1 (PINK1)/Parkin. Given the significant role of autophagy in DCM, we further identified natural products and chemical drugs as regulators of autophagy in the treatment of DCM. This review may help to better understand the autophagy mechanism of drugs for DCM and promote their clinical application.

Perioperative versus adjuvant S-1 plus oxaliplatin chemotherapy for stage II/III resectable gastric cancer (RESONANCE): a randomized, open-label, phase 3 trial.

Evidence from Europe shows that perioperative chemotherapy may be beneficial for the treatment of locally advanced gastric cancer, but reliable and robust data is lacking. To rectify this, the phase 3 RESONANCE trial investigated the efficacy and safety of S-1 plus oxaliplatin (SOX) as a perioperative chemotherapy regimen for gastric cancer. This randomized, open-label trial enrolled patients from 19 medical centers with stage II/III resectable gastric cancer who were centrally randomly assigned to either perioperative chemotherapy (PC) arm or adjuvant chemotherapy (AC) arm. Patients in the PC arm received two to four cycles of SOX followed by surgery and four to six cycles of SOX. Patients in the AC arm received upfront surgery and eight cycles of SOX. 386 patients in each group were enrolled and 756 (382 in PC and 374 in AC) were included in the mITT population. The three-year DFS rate was 61.7% in the PC arm and 53.8% in the AC arm (log-rank p = 0.019). The R0 resection rate in the PC arm was significantly higher than that in the AC arm (94.9% vs. 83.7%, p < 0.0001). There was no difference between two arms in surgical outcomes or postoperative complications. Safety-related data were like the known safety profile. In conclusion, from a clinical perspective, this trial indicated a trend towards higher three-year disease-free survival rate with perioperative SOX in stage II/III resectable gastric cancer with well-tolerated toxicity compared to adjuvant SOX, which might provide a theoretical basis for applying perioperative SOX in advanced gastric cancer patients. (ClinicalTrials.gov NCT01583361).

Associations of variability in blood glucose and systolic blood pressure with mortality in patients with coronary artery disease: A retrospective cohort study from the MIMIC-IV database.

AIMS: Variability of metabolic parameters, such as glycemic variability (GV) and systolic blood pressure variability (SBPV), are associated with adverse cardiovascular outcomes. However, whether these parameters have additive effects on mortality in patients with coronary artery disease (CAD) hospitalized in the intensive care unit (ICU) remains unclear. METHODS: We retrospectively enrolled patients with CAD from the Medical Information Mart for Intensive Care-IV database. The highest tertile of variability was defined as high variability. A variability scoring system was established, which assigned 0 points to tertile 1, 1 point to tertile 2, and 2 points to tertile 3 for GV and SBPV. RESULTS: Among 4237 patients with CAD, 400 patients died in hospital, and 967 patients died during 1-year follow-up. High GV and high SBPV were associated with an increased risk of mortality. The effects of GV and SBPV on in-hospital mortality were partially mediated by ventricular arrhythmias (18.0 % and 6.6 %, respectively). The risk of mortality gradually increased with the number of high-variability parameters and increasing variability scores. CONCLUSIONS: GV and SBPV have additive effects on the risk of mortality in patients with CAD hospitalized in the ICU. Ventricular arrhythmias partially mediate the effects of GV and SBPV on in-hospital mortality.

Simultaneous assessment of stress hyperglycemia ratio and glycemic variability to predict mortality in patients with coronary artery disease: a retrospective cohort study from the MIMIC-IV database.

BACKGROUND: Stress hyperglycemia and glycemic variability (GV) can reflect dramatic increases and acute fluctuations in blood glucose, which are associated with adverse cardiovascular events. This study aimed to explore whether the combined assessment of the stress hyperglycemia ratio (SHR) and GV provides additional information for prognostic prediction in patients with coronary artery disease (CAD) hospitalized in the intensive care unit (ICU). METHODS: Patients diagnosed with CAD from the Medical Information Mart for Intensive Care-IV database (version 2.2) between 2008 and 2019 were retrospectively included in the analysis. The primary endpoint was 1-year mortality, and the secondary endpoint was in-hospital mortality. Levels of SHR and GV were stratified into tertiles, with the highest tertile classified as high and the lower two tertiles classified as low. The associations of SHR, GV, and their combination with mortality were determined by logistic and Cox regression analyses. RESULTS: A total of 2789 patients were included, with a mean age of 69.6 years, and 30.1% were female. Overall, 138 (4.9%) patients died in the hospital, and 404 (14.5%) patients died at 1 year. The combination of SHR and GV was superior to SHR (in-hospital mortality: 0.710 vs. 0.689, p = 0.012; 1-year mortality: 0.644 vs. 0.615, p = 0.007) and GV (in-hospital mortality: 0.710 vs. 0.632, p = 0.004; 1-year mortality: 0.644 vs. 0.603, p < 0.001) alone for predicting mortality in the receiver operating characteristic analysis. In addition, nondiabetic patients with high SHR levels and high GV were associated with the greatest risk of both in-hospital mortality (odds ratio [OR] = 10.831, 95% confidence interval [CI] 4.494-26.105) and 1-year mortality (hazard ratio [HR] = 5.830, 95% CI 3.175-10.702). However, in the diabetic population, the highest risk of in-hospital mortality (OR = 4.221, 95% CI 1.542-11.558) and 1-year mortality (HR = 2.013, 95% CI 1.224-3.311) was observed in patients with high SHR levels but low GV. CONCLUSIONS: The simultaneous evaluation of SHR and GV provides more information for risk stratification and prognostic prediction than SHR and GV alone, contributing to developing individualized strategies for glucose management in patients with CAD admitted to the ICU.

Non-insulin-based insulin resistance indexes in predicting atrial fibrillation recurrence following ablation: a retrospective study.

BACKGROUND: Insulin resistance (IR) is involved in the pathophysiological processes of arrhythmias. Increasing evidence suggests triglyceride and glucose (TyG) index, metabolic score for insulin resistance (METS-IR), triglyceride glucose-body mass index (TyG-BMI), and triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio are simple and reliable surrogates for IR. Although they have been associated with atrial fibrillation (AF), evidence supporting this is limited. Here, this is the first study to investigate the association between TyG-BMI index and AF recurrence following radiofrequency catheter ablation (RFCA). The performance of the four non-insulin-based IR indexes in predicting AF recurrence after ablation was explored. METHODS: A total of 2242 AF patients who underwent a de novo RFCA between June 2018 to January 2022 at two hospitals in China were included in this retrospective study. The predictive values of IR indexes for AF recurrence after ablation were assessed. RESULTS: During 1-year follow-up, 31.7% of patients experienced AF recurrence. The multivariable analysis revealed that TyG index, METS-IR, and TyG-BMI index were independent risk factors for AF recurrence. Restricted cubic spline analysis revealed a connection between METS-IR, TyG-BMI index, and AF recurrence (P < 0.001). Furthermore, incorporating the METS-IR or TyG-BMI index to the basic risk model with fully adjusted factors considerably enhanced the forecast of AF recurrence, as demonstrated by the C-statistic, continuous net reclassification improvement, and integrated discrimination improvement. CONCLUSIONS: TyG index, METS-IR, and TyG-BMI index were independently associated with AF recurrence following ablation. Among the four non-insulin-based IR indexes, TyG-BMI had the highest predictive value, followed by METS-IR.

Maximum stress hyperglycemia ratio within the first 24 h of admission predicts mortality during and after the acute phase of acute coronary syndrome in patients with and without diabetes: A retrospective cohort study from the MIMIC-IV database.

AIMS: The stress hyperglycemia ratio (SHR) is significantly associated with short-term adverse cardiovascular events. However, the association between SHR and mortality after the acute phase of acute coronary syndrome (ACS) remains controversial. METHODS: This study used data from the Medical Information Mart for Intensive Care-IV database. Patients with ACS hospitalized in the intensive care unit (ICU) were retrospectively enrolled. RESULTS: A total of 2668 ACS patients were enrolled. The incidence of in-hospital and 1-year mortality was 4.7 % and 13.2 %, respectively. The maximum SHR had a higher prognostic value for predicting both in-hospital and 1-year mortality than the first SHR. Adding the maximum SHR to the SOFA score could significantly improve the prognostic prediction. In the landmark analysis at 30 days, the maximum SHR was a risk factor for mortality within 30 days regardless of whether patients had diabetes. However, it was no longer associated with mortality after 30 days in patients with diabetes after adjustment (HR = 1.237 per 1-point increment, 95 % CI 0.854-1.790). CONCLUSIONS: The maximum SHR was significantly associated with mortality in patients with ACS hospitalized in the ICU. However, caution is warranted if it is used for predicting mortality after 30 days in patients with diabetes.

DeepRisk network: an AI-based tool for digital pathology signature and treatment responsiveness of gastric cancer using whole-slide images.

BACKGROUND: Digital histopathology provides valuable information for clinical decision-making. We hypothesized that a deep risk network (DeepRisk) based on digital pathology signature (DPS) derived from whole-slide images could improve the prognostic value of the tumor, node, and metastasis (TNM) staging system and offer chemotherapeutic benefits for gastric cancer (GC). METHODS: DeepRisk is a multi-scale, attention-based learning model developed on 1120 GCs in the Zhongshan dataset and validated with two external datasets. Then, we assessed its association with prognosis and treatment response. The multi-omics analysis and multiplex Immunohistochemistry were conducted to evaluate the potential pathogenesis and spatial immune contexture underlying DPS. RESULTS: Multivariate analysis indicated that the DPS was an independent prognosticator with a better C-index (0.84 for overall survival and 0.71 for disease-free survival). Patients with low-DPS after neoadjuvant chemotherapy responded favorably to treatment. Spatial analysis indicated that exhausted immune clusters and increased infiltration of CD11b+CD11c+ immune cells were present at the invasive margin of high-DPS group. Multi-omics data from the Cancer Genome Atlas-Stomach adenocarcinoma (TCGA-STAD) hint at the relevance of DPS to myeloid derived suppressor cells infiltration and immune suppression. CONCLUSION: DeepRisk network is a reliable tool that enhances prognostic value of TNM staging and aid in precise treatment, providing insights into the underlying pathogenic mechanisms.

Ubiquilin-4 induces immune escape in gastric cancer by activating the notch signaling pathway.

PURPOSE: We aimed to investigate the role of ubiquilin-4 in predicting the immunotherapy response in gastric cancer. METHODS: Retrospective RNA-sequencing and immunohistochemical analysis were performed for patients with gastric cancer who received programmed death-1 blockade therapy after recurrence. Multiplex immunohistochemistry identified immune cell types in gastric cancer tissues. We used immunocompetent 615 mice and immunodeficient nude mice to perform tumorigenic experiments. RESULTS: Ubiquilin-4 expression was significantly higher in responders (p < 0.05, false discovery rate > 2.5) and showed slight superiority over programmed death ligand 1 in predicting programmed death-1 inhibitor therapy response (area under the curve: 87.08 vs. 72.50). Ubiquilin-4-high patients exhibited increased CD4+ and CD8+ T cells, T follicular helper cells, monocytes, and macrophages. Ubiquilin-4-overexpressed mouse forestomach carcinoma cells showed significantly enhanced growth in immunocompetent mice but not in immunodeficient mice. Upregulation or downregulation of ubiquilin-4 synergistically affected programmed death ligand 1 at the protein and messenger RNA levels. Functional enrichment analysis revealed significant enrichment of the Notch, JAK-STAT, and WNT signaling pathways in ubiquilin-4-high gastric cancers. Ubiquilin-4 promoted Numb degaration, activating the Notch signaling pathway and upregulating programmed death ligand 1. CONCLUSIONS: Ubiquilin-4 may contribute to immune escape in gastric cancer by upregulating programmed death ligand 1 expression in tumor cells through Notch signaling activation. Thus, ubiquilin-4 could serve as a predictive marker for programmed death ligand 1 inhibitor therapy response in gastric cancer.

The Prognostic Value of the Age-D-Dimer-Albumin Score in Patients with Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention.

BACKGROUND: The Age-D-dimer-Albumin (ADA), the CREDO-Kyoto, and the PARIS scores have been established to predict thrombotic events. However, the prognostic performance of these scores compared to the GRACE score in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) has not been reported. METHODS: Consecutive AMI patients treated with PCI were retrospectively enrolled at a teaching hospital in China from January 2016 to December 2019. The primary endpoint was all-cause mortality and the secondary endpoint was cardiac death. Harrell's C-index and net reclassification improvement (NRI) were used to compare the prognostic value of these scores with the GRACE score for mortality. RESULTS: Of the 1,578 patients enrolled, the mean age was 62.5 years, and 23.5% were female. During a median follow-up of 3.8 years, 146 all-cause deaths and 80 cardiac deaths occurred. The ADA score showed a better prognostic performance than the GRACE (Harrell's C-index: 0.800 vs. 0.749; p = 0.003), the CREDO-Kyoto (Harrell's C-index: 0.800 vs. 0.765; NRI = 0.348, p < 0.001), and the PARIS scores (Harrell's C-index: 0.800 vs. 0.694; NRI = 0.556, p < 0.001). In the multivariable Cox regression analysis, the ADA score was independently associated with all-cause mortality (hazard ratio [HR] = 1.641 per 10-point increment, 95% confidence interval [CI]: 1.397-1.929) and cardiac death (HR = 1.636 per 10-point increment, 95% CI: 1.325-2.020). The risk of all-cause mortality and cardiac death increased with the rising of the ADA score. CONCLUSION: The ADA score showed a better prognostic performance than the GRACE, the CREDO-Kyoto, and the PARIS scores in patients with AMI undergoing PCI, which was a potential predictive tool for mortality.

A Comparison of the Prognostic Value of Liver Fibrosis Scores in Acute Myocardial Infarction Patients With and Without Type 2 Diabetes.

Liver fibrosis scores have been demonstrated to be associated with poor prognosis after percutaneous coronary intervention (PCI). However, no studies have compared the prognostic value of these scores in acute myocardial infarction (AMI) patients with and without diabetes. We retrospectively enrolled 1576 AMI patients who underwent PCI. There were 177 all-cause deaths and 111 cardiac deaths during follow-up (median 3.8 years). The non-alcoholic fatty liver disease fibrosis score (NFS) showed a better prognostic value than the fibrosis-8 (FIB-8) score (Harrell's C-index: 0.703 vs 0.671, P = .014) and the fibrosis-4 (FIB-4) score (Harrell's C-index: 0.703 vs 0.648, P < .001) in the overall population. In the time-dependent receiver operating characteristic analysis, the NFS also had the highest area under the curve across all time points. Consistent results were observed in diabetic and non-diabetic populations. Adding the NFS to traditional cardiovascular risk factors significantly improved the prediction both for all-cause mortality (Harrell's C-index: 0.806 vs 0.771, P < .001) and cardiac death (Harrell's C-index: 0.800 vs 0.771, P = .014). The NFS showed a better prognostic value than the FIB-8 score and the FIB-4 score in patients with AMI undergoing PCI, which might be preferable for estimating the risk of mortality regardless of the presence or absence of diabetes.