Good Prognostic Value Research Articles

Predictive value and regulatory mechanism of serum miR-499a-5p on myocardial dysfunction in sepsis

BackgroundThis study sought to investigate the predictive value and regulatory mechanism of serum miR-499a-5p in sepsis-induced myocardial dysfunction (SIMD).MethodsA total of 60 patients with sepsis and 60 healthy volunteers were enrolled in this study. The serum levels of miRNAs (miR-451, miR-378 and miR-499a-5p) were detected. Receiver operating characteristic curve and logistic regression analysis were used to evaluate the diagnostic and prognostic value of miR-499a-5p in SIMD patients. AC16 cells were used to establish SIMD model in vitro using lipopolysaccharide (LPS). An analysis was conducted for miR-499a-5p expression, cell viability, and the concentration of creatine kinase-MB isoform (CK-MB), brain natriuretic peptide (BNP), superoxide dismutase (SOD) and cytochrome C oxidase IV (COX IV). The downstream target of miR-499a-5p was verified.ResultsOur results revealed a poor expression of miR-499a-5p in the serum of SIMD patients, while no significant difference was evident for miR-451 and miR-378. The level of miR-499a-5p in the survival group was higher than the non-survival group. miR-499a-5p elicited good diagnostic and prognostic value for SIMD. Our findings revealed that miR-499a-5p was decreased significantly in LPS-treated cardiomyocytes. After overexpression of miR-499a-5p, the cell viability increased, and the concentrations of CK-MB and BNP were decreased, while the concentrations of SOD and COX IV were increased. EIF4E was validated as the target of miR-499a-5p. After overexpression of EIF4E, the cell viability was decreased and the concentrations of CK-MB and BNP were increased while the concentrations of SOD and COX IV were decreased.ConclusionThe level of miR-499a-5p is weak in SIMD patients. miR-499a-5p has a good diagnostic and prognostic value for SIMD by inhibiting EIF4E transcription.

Exploration of a Novel Prognostic Risk Signature and Its Effect on the Immune Response in Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic carcinoma with different molecular characteristics and clinical outcomes. In this work, we aimed to establish a novel gene signature that could predict the prognosis of NPC patients. A total of 13 significant genes between the recurrence/metastasis (RM) group and the no recurrence/metastasis (no-RM) group were identified by machine learning from RNA-Seq data including 60 NPC tumor biopsies. Based on these genes, a 4-mRNA signature (considering U2AF1L5, TMEM265, GLB1L and MLF1) was identified. Receiver operating characteristic (ROC) and Kaplan-Meier (K-M) analyses indicated that this signature had good prognostic value for NPC. The overall survival (OS) and progression-free survival (PFS) of the patients in the high-risk group were significantly shorter than those of the patients in the low-risk group (p = 0.00126 and p = 0.000059, respectively). The area under the ROC curve (AUC) values of the 4-mRNA signature were higher than those of T stage and N stage for OS (0.893 vs 0.619 and 0.582, respectively) and PFS (0.86 vs 0.538 and 0.622, respectively). Furthermore, the 4-mRNA signature was closely associated with cell proliferation and the immune response. The expression of GLB1L and TMEM265 was associated with the level of tumor-infiltrating immune cells (r > 0.4, p < 0.05). We have validated the model through measuring the expression levels of the 4-mRNA signature by qRT-PCR, in an independent cohort of NPC patients. Here, we report a novel gene signature that can serve as a new tool for predicting the prognosis of NPC patients.

Integrative Analysis of Metallothioneins Identifies MT1H as Candidate Prognostic Biomarker in Hepatocellular Carcinoma.

Background: Metallothioneins (MTs) play crucial roles in the modulation of zinc/copper homeostasis, regulation of neoplastic growth and proliferation, and protection against apoptosis. The present study attempted to visualize the prognostic landscape of MT functional isoforms and identify potential prognostic biomarkers in hepatocellular carcinoma (HCC). Methods: The transcriptional expression, comprehensive prognostic performances, and gene–gene interaction network of MT isoforms in HCC were evaluated via Oncomine, GEPIA, Kaplan–Meier plotter, and GeneMANIA databases. Characterized by good prognostic value in three external cohorts, MT1H was specifically selected as a potential prognostic biomarker in HCC with various clinicopathological features. Functional and pathway enrichment analyses of MT1H status were performed using cBioPortal, the Database for Annotation, Visualization, and Integrated Discovery (DAVID), and ssGSVA method. Results: MT1E/1F/1G/1H/1M/1X/2A was greatly downregulated in HCC. Prognostic analyses elucidated the essential correlations between MT1A/1B/1H/1X/2A/4 attenuation and poor overall survival, between MT1B/1H/4 downregulation and worse relapse-free survival, and between MT1A/1B/1E/1H/1M/2A/4 downregulation and diminished progression-free survival in HCC. Taken together, these results indicated the powerful prognostic value of MT1H among MTs in HCC. In-depth analyses suggested that MT1H may be more applicable to alcohol-derived HCC and involved in the downregulation of the inflammatory pathway, Jak–STAT pathway, TNF pathway, and Wnt signaling pathway. Conclusion: MT-specific isoforms displayed aberrant expression and varying prognostic value in HCC. MT1H repression in HCC was multi-dimensionally detrimental to patient outcomes. Therefore, MT1H was possibly associated with carcinogenesis and exploited as a novel prognostic biomarker and candidate therapeutic target for HCC.

Assessment of Clinicopathological Characteristics and Development of an Individualized Prognostic Model for Patients With Hepatoid Adenocarcinoma of the Stomach

Few studies have examined the clinicopathological characteristics and prognoses of patients with hepatoid adenocarcinoma of the stomach (HAS). To explore the clinicopathological characteristics and prognoses of patients with HAS and develop a nomogram to predict overall survival (OS). This prognostic study involved a retrospective analysis of data from 315 patients who received a diagnosis of primary HAS between April 1, 2004, and December 31, 2019, at 14 centers in China. OS and prognostic factors. Patients were randomly assigned to a derivation cohort (n = 220) and a validation cohort (n = 95). A nomogram was developed based on independent prognostic factors identified through a multivariable Cox mixed-effects model. Among 315 patients with HAS (mean [SD] age, 61.9 [10.2] years; 240 men [76.2%]), 137 patients had simple HAS (defined as the presence of histologically contained hepatoid differentiation areas only), and 178 patients had mixed HAS (defined as the presence of hepatoid differentiation areas plus common adenocarcinoma areas). Patients with simple HAS had a higher median preoperative α-fetoprotein level than those with mixed HAS (195.9 ng/mL vs 48.9 ng/mL, respectively; P < .001) and a higher rate of preoperative liver metastasis (23 of 137 patients [16.8%] vs 11 of 178 patients [6.2%]; P = .003). The 3-year OS rates of patients with simple vs mixed HAS were comparable (56.0% vs 60.0%; log-rank P = .98). A multivariable Cox analysis of the derivation cohort found that the presence of perineural invasion (hazard ratio [HR], 2.13; 95% CI, 1.27-3.55; P = .009), preoperative carcinoembryonic antigen levels of 5 ng/mL or greater (HR, 1.72; 95% CI, 1.08-2.74; P = .03), and pathological node category 3b (HR, 3.72; 95% CI, 1.34-10.32; P = .01) were independent risk factors for worse OS. Based on these factors, a nomogram to predict postoperative OS was developed. The concordance indices of the nomogram (derivation cohort: 0.72 [95% CI, 0.66-0.78]; validation cohort: 0.72 [95% CI, 0.63-0.81]; whole cohort: 0.71 [95% CI, 0.66-0.76]) were higher than those derived using the American Joint Committee on Cancer's AJCC Cancer Staging Manual (8th edition) pathological tumor-node-metastasis (pTNM) staging system (derivation cohort: 0.63 [95% CI, 0.57-0.69]; validation cohort: 0.65 [95% CI, 0.56-0.75]; whole cohort: 0.64 [95% CI, 0.59-0.69]) and those derived using a clinical model that included pTNM stage and receipt of adjuvant chemotherapy (derivation cohort: 0.64 [95% CI, 0.58-0.69]; validation cohort: 0.65 [95% CI, 0.56-0.75]; whole cohort: 0.64 [95% CI, 0.59-0.69]). Based on the nomogram cutoff of 10 points, the whole cohort was divided into high-risk and low-risk groups. The 3-year OS rate of patients in the high-risk group was significantly lower than that of patients in the low-risk group (29.7% vs 75.9%, respectively; log-rank P < .001), and the 3-year prognosis of high-risk and low-risk groups could be further distinguished into pTNM stage I to II (33.3% vs 80.2%; exact log-rank P = .15), stage III (34.3% vs 71.3%; log-rank P < .001), and stage IV (15.5% vs 70.3%; log-rank P = .009). This study found that perineural invasion, preoperative carcinoembryonic antigen levels of 5 ng/mL or greater, and pathological node category 3b were independent risk factors associated with worse OS. An individualized nomogram was developed to predict OS among patients with HAS. This nomogram had good prognostic value and may be useful as a supplement to the current American Joint Committee on Cancer TNM staging system.

Applying immune-related lncRNA pairs to construct a prognostic signature and predict the immune landscape of stomach adenocarcinoma

ABSTRACT Background: Long noncoding RNAs (lncRNAs) are associated with the survival of cancer patients. We constructed an immune-related lncRNA (irlncRNA) pair signature for stomach adenocarcinoma (STAD). Research design and methods: irlncRNAs were identified via coexpression analysis with immune-related genes. Differentially expressed irlncRNAs (DEirlncRNAs) were paired. Least absolute shrinkage and selection operator (LASSO) and multivariate Cox proportional hazards regression methods were used to construct the signature. We calculated the area under the receiver operating characteristic (ROC) curve and determined the best cutoff value according to the Akaike information criterion (AIC). Patients were divided into high – and low-risk groups, and differences in immune cell infiltration, tumor mutation burden (TMB) and drug treatment effects between the groups were explored according to the risk score. Results: An 8-irlncRNA-pair signature was constructed and proven to be a strong prognosis predictor in STAD patients through external verification. Moreover, the risk score was identified as an independent prognostic factor. There were significant differences in immune cell infiltration and the response to several drug treatments between patients with high and low risk scores, and the risk score was negatively correlated with TMB. Conclusions: The signature consisting of 8 irlncRNA pairs showed good prognostic predictive value.

Analysis of Serum Interleukin-37 Level and Prognosis in Patients with ACS.

Objective To explore the level of serum interleukin-37 in patients with acute coronary syndrome (ACS) and its prognostic value. Methods Altogether, 121 continuous ACS cases from September 2017 to June 2020 were selected as the research group (RG), and 107 healthy individuals during the same period were obtained as the control group (CG). ELISA was applied to test IL-37 in the serum of the CG and the RG. Chemiluminescence immunoassay was applied to test NT-pro BNP and hs-cTnI in each group and immune scattering turbidimetry to test hs-CRP. The correlation of IL-37 with serum NT-pro BNP, hs-cTnI, and CRP was analyzed, and the value of IL-37 in diagnosis and prognosis prediction of patients with ACS was tested. Logistic regression was applied to test the independent risk factors affecting poor prognosis of patients with ACS. Results IL-37 was poorly expressed in patients with ACS, which had a high diagnostic value for ACS (sensitivity: 94.39%, specificity: 74.38%, and area under curve: 0.945). There was a negative correlation of IL-37 with serum NT-pro BNP, hs-cTnI, and CRP. IL-37 in patients with poor prognosis was markedly declined compared with that of patients with good prognosis, and the predicted AUC was 0.965. Logistic regression revealed that low IL-37, diabetes, high CRP, NT-pro BNP, and hs-cTnI in the blood were independent risk factors for poor prognosis in patients with ACS. Conclusion IL-37 is low expressed in patients with ACS, which has a good diagnostic and prognostic value for ACS, and may be applied as an important marker for the prediction of patients with ACS.

Thyroid Hormone Levels During Hospital Admission Inform Disease Severity and Mortality in COVID-19 Patients

Background: Illness severity in patients infected with COVID-19 is variable. Methods: Here, we conducted an observational, longitudinal, and prospective cohort study to investigate serum thyroid hormone (TH) levels in adult COVID-19 patients, admitted between June and August 2020, and to determine whether they reflect the severity or mortality associated with the disease. Results: Two hundred forty-five patients [median age: 62 (49-75) years] were stratified into non-critical (181) and critically ill (64) groups. Fifty-eight patients (23.6%) were admitted to the intensive care unit, and 41 (16.7%) died. Sixteen (6.5%) exhibited isolated low levels of free triiodothyronine (fT3). fT3 levels were lower in critically ill compared with non-critical patients [fT3: 2.82 (2.46-3.29) pg/mL vs. 3.09 (2.67-3.63) pg/mL, p = 0.007]. Serum reverse triiodothyronine (rT3) was mostly elevated but less so in critically ill compared with non-critical patients [rT3: 0.36 (0.28-0.56) ng/mL vs. 0.51 (0.31-0.67) ng/mL, p = 0.001]. The univariate logistic regression revealed correlation between in-hospital mortality and serum fT3 levels (odds ratio [OR]: 0.47; 95% confidence interval [CI 0.29-0.74]; p = 0.0019), rT3 levels (OR: 0.09; [CI 0.01-0.49]; p = 0.006) and the product fT3 × rT3 (OR: 0.47; [CI 0.28-0.74]; p = 0.0026). Serum thyrotropin, free thyroxine, and fT3/rT3 values were not significantly associated with mortality and severity of the disease. A serum cutoff level of fT3 (≤2.6 pg/mL) and rT3 (≤0.38 ng/mL) was associated with 3.46 and 5.94 OR of mortality, respectively. We found three COVID-19 mortality predictors using the area under the receiver operating characteristic (ROC) curve (AUC score): serum fT3 (AUC = 0.66), rT3 (AUC = 0.64), and the product of serum fT3 × rT3 (AUC = 0.70). Non-thyroidal illness syndrome (fT3 < 2.0 pg/mL) was associated with a 7.05 OR of mortality ([CI 1.78-28.3], p = 0.005) and the product rT3 × fT3 ≤ 1.29 with an 8.08 OR of mortality ([CI 3.14-24.2], p < 0.0001). Conclusions: This prospective study reports data on the largest number of hospitalized moderate-to-severe COVID-19 patients and correlates serum TH levels with illness severity, mortality, and other biomarkers to critical illness. The data revealed the importance of early assessment of thyroid function in hospitalized patients with COVID-19, given the good prognostic value of serum fT3, rT3, and fT3 × rT3 product. Further studies are necessary to confirm these observations.

The Coefficient of Variation of Red Blood Cell Distribution Width Combined with Cancer Antigen 125 Predicts Postoperative Overall Survival in Endometrial Cancer.

PurposeThis study assessed the prognostic value of red blood cell distribution width (RDW) and cancer antigen 125 (CA125) in predicting the prognosis of endometrial cancer (EC) patients.Patients and MethodsIn this study, we included 525 patients with EC between January 2013 and January 2019. Demographic and clinical indicators were collected, and the receiver operating characteristics curve (ROC) and cutoff values were calculated between the early and advanced stages of EC. Independent risk factors associated with EC prognosis were assessed using Cox regression analyses and the Kaplan–Meier method.ResultsCompared to women in the early stage of EC, women with advanced stage had significantly elevated RDW coefficient of variation (RDW-CV) and CA125 levels and lower mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) (both P < 0.05). Consequently, RDW-CV and CA125 were found to be independent risk factors for EC by using ROC curve and multivariate logistic regression analysis. The survival analysis curve was used to assess the diagnostic value of RDW-CV, CA125, and their combination in the prognosis of EC. The results showed that patients with high expression of RDW-CV and CA125 had worse overall survival than those with low expression. Moreover, multivariate Cox regression analysis indicated that RDW-CV+CA125=2 was an independent prognostic factor.ConclusionThese findings suggest that CA125 combined with RDW-CV has a good prognostic value for EC. Thus, the RDW-CV+CA125 score is a promising prognostic marker for the clinical decision-making process regarding EC outcomes.

Novel immune-related signature for risk stratification and prognosis in prostatic adenocarcinoma.

A substantial proportion of prostatic adenocarcinoma (PRAD) patients experience biochemical failure (BCF) after radical prostatectomy (RP). The immune microenvironment plays a vital role in carcinogenesis and the development of PRAD. This study aimed to identify a novel immune‐related gene (IRG)‐based signature for risk stratification and prognosis of BCF in PRAD. Weighted gene coexpression network analysis was carried out to identify a BCF‐related module in a discovery cohort of patients who underwent RP at the Massachusetts General Hospital. The median follow‐up time was 70.32 months. Random forest and multivariate stepwise Cox regression analyses were used to identify an IRG‐based signature from the specific module. Risk plot analyses, Kaplan‐Meier curves, receiver operating characteristic curves, univariate and multivariate Cox regression analyses, stratified analysis, and Harrell’s concordance index were used to assess the prognostic value and predictive accuracy of the IRG‐based signature in the internal discovery cohort; The Cancer Genome Atlas database was used as a validation cohort. Tumor immune estimation resource database analysis and CIBERSORT algorithm were used to assess the immunophenotype of PRAD. A novel IRG‐based signature was identified from the specific module. Five IRGs (BUB1B, NDN, NID1, COL4A6, and FLRT2) were verified as components of the risk signature. The IRG‐based signature showed good prognostic value and predictive accuracy in both the discovery and validation cohorts. Infiltrations of various immune cells were significantly different between low‐risk and high‐risk groups in PRAD. We identified a novel IRG‐based signature that could function as an index for assessing tumor immune status and risk stratification in PRAD.

Association Between Serum Human Epididymis Protein 4 Levels and Cardiovascular Events in Obese Patients with Breast Cancer.

BackgroundPatients with cancer have a higher incidence of cardiovascular diseases (CVDs). We aimed to evaluate the relationship between serum human epididymal protein 4 (HE4) levels and cardiovascular events in obese patients with breast cancer.MethodsSerum HE4 levels in 316 obese patients with breast cancer were measured at baseline and then prospectively followed up for approximately 36 months. The prognostic value of serum HE4 for predicting cardiovascular events was analyzed by the Cox proportional hazard model.ResultsSerum HE4 was significantly associated with CVD history after adjustment for confounding factors (OR= 1.50; 95% CI 1.23–3.43; P=0.038) using multivariable logistic regression analysis. The multivariable Cox proportional hazard analysis suggested that serum HE4 had an independent prognostic value for predicting cardiovascular events in patients with breast cancer (HR=2.21, 95% CI 1.60–5.13, P<0.001). Additionally, sensitivity analysis showed that the independent association still existed. Stratified analysis showed that this relationship was not affected by chemoradiotherapy.ConclusionSerum HE4 is significantly related to cardiovascular events and poses good prognostic value for predicting cardiovascular events in obese patients with breast cancer. Serum HE4 may be a valuable indicator for the early detection of cardiovascular complications in obese patients with breast cancer.

A Novel Ferroptosis-Related Pathway for Regulating Immune Checkpoints in Clear Cell Renal Cell Carcinoma.

Ferroptosis is a novel form of cell death and plays a role in various diseases, especially tumors. It has been reported that ferroptosis is involved in the growth and progression of clear cell renal cell carcinoma (ccRCC); however, the specific molecular mechanisms are still unclear. In this study, we constructed a four-gene signature (FeSig) of ferroptosis-related genes via Cox regression analysis. ROC and survival analyses indicated that FeSig had good diagnostic and prognostic value. Further analysis revealed that ferroptosis was associated with tumor immunity in ccRCC. Next, weighted gene co-expression network analysis was performed to identify the potential regulatory mechanisms. Combined with correlation and survival analyses, the TAZ/WNT10B axis was identified as a tumor immune-related regulatory pathway. In conclusion, these findings suggest that ferroptosis is correlated with tumor immunity. The TAZ/WNT10B axis may be a novel biomarker and therapeutic target for immunotherapy in ccRCC.

Development and Validation of a Nomogram and a Comprehensive Prognostic Analysis of an LncRNA-Associated Competitive Endogenous RNA Network Based on Immune-Related Genes for Locally Advanced Rectal Cancer With Neoadjuvant Therapy.

Colorectal cancer (CRC) is a common digestive tract tumor worldwide. In recent years, neoadjuvant chemoradiotherapy (CRT) has been the most comprehensive treatment for locally advanced rectal cancer (LARC). In this study, we explored immune infiltration in rectal cancer (RC) and identified immune-related differentially expressed genes (IRDEGs). Then, we identified response markers in datasets in GEO databases by principal component analysis (PCA). We also utilized three GEO datasets to identify the up- and downregulated response-related genes simultaneously and then identified genes shared between the PCA markers and three GEO datasets. Based on the hub IRDEGs, we identified target mRNAs and constructed a ceRNA network. Based on the ceRNA network, we explored prognostic biomarkers to develop a prognostic model for RC through Cox regression. We utilized the specimen to validate the expression of the two biomarkers. We also utilized LASSO regression to screen hub IRDEGs and built a nomogram to predict the response of LARC patients to CRT. All of the results show that the nomogram and prognostic model offer good prognostic value and that the ceRNA network can effectively highlight the regulatory relationship. hsa-mir-107 and WDFY3-AS2 may be prognostic biomarkers for RC.

Safety, feasibility and prognostic value of stress perfusion CMR in patients with pacemaker

Abstract Funding Acknowledgements Type of funding sources: None. BACKGROUND Several studies have shown the excellent prognostic value of stress cardiovascular magnetic resonance (CMR). However, its prognostic value in patients with pacemaker (PM) remains unknown because most studies excluded PM patients. PURPOSE This study aimed to assess the prognostic value of vasodilator stress perfusion CMR in patients with PM. METHODS Consecutive patients with MR-conditional pacemakers referred for stress perfusion CMR at 1.5 T were followed for the occurrence of major adverse cardiovascular events (MACE), defined by cardiovascular death or nonfatal myocardial infarction. Cox regressions analyses were performed to determine the prognostic value of CMR-parameters. The quality of CMR was rated by two observers blinded to clinical details. Data on pacemaker and leads were collected pre- and post-CMR. RESULTS Of 224 patients who completed the stress CMR protocol, 2 patients had inconclusive stress CMR due to artefact and 203 patients (72.9% male, mean age 71.4 ± 8.7 years) completed the follow-up (median [interquartile range], 7.0 [5.2-7.3] years). Among those, 23 experienced a MACE (11.3%). Stress CMR was well tolerated with no major adverse events. All scans were completed successfully with no significant change in lead thresholds or pacing parameters. Overall, the image quality was rated good or excellent in 84.1% of segments. Using Kaplan-Meier analysis, inducible ischemia and late gadolinium enhancement (LGE) were significantly associated with the occurrence of MACE (hazard ratio, HR: 11.80 [95% CI, 4.63-30.30]; and HR: 6.74 [95% CI, 2.47-18.40], both p &amp;lt; 0.001; respectively). In multivariable Cox regression, inducible ischemia and LGE were independent predictors of a higher incidence of MACE (HR: 5.24 [95% CI, 2.61-14.40]; and HR: 2.98 [95% CI, 2.25-4.02]; both p &amp;lt; 0.001; respectively). In patients with ischemia, CMR-related coronary revascularization showed no benefit in reducing MACE (p = 0.25). CONCLUSION Stress CMR is safe, feasible and has a good discriminative prognostic value in consecutive patients with PM.

Prognostic interest of vasodilator stress perfusion cardiovascular magnetic resonance after a first inconclusive stress testing

Abstract Funding Acknowledgements Type of funding sources: None. BACKGROUND While current guidelines recommend to perform a noninvasive test to detect coronary artery disease, stress tests are deemed inconclusive in almost a third of cases. The strategy for risk stratification after inconclusive stress testing is not well standardized. PURPOSE To assess the prognostic value of stress cardiovascular magnetic resonance (CMR) parameters and CMR-based coronary revascularization in patients after inconclusive stress testing. METHODS Between 2008 and 2020, consecutive patients with a first inconclusive stress test referred for vasodilator stress perfusion CMR were followed for the occurrence of major adverse cardiovascular events (MACE), defined by cardiovascular death or nonfatal myocardial infarction. CMR-related coronary revascularization was defined as any revascularisation occurring within 90 days after CMR. Univariable and multivariable Cox regressions were performed to determine the prognostic value of each parameter. RESULTS Of 1,563 patients who completed the CMR protocol, 1,402 patients (66.7% male, mean age 69.5 ± 11.0 years) completed the follow-up (median[interquartile range], 6.5 [5.6-7.5] years); 197 experienced a MACE (14.1%). Stress CMR was well tolerated without severe adverse events. Using Kaplan-Meier analysis, inducible ischemia and late gadolinium enhancement (LGE) were significantly associated with the occurrence of MACE (hazard ratio, HR: 2.88 [95%CI, 2.18-3.81]; and HR: 1.46 [95%CI, 1.16-1.89], both p &amp;lt; 0.001; respectively). In multivariable Cox regression, the presence and extent of inducible ischemia were independent predictors of a higher incidence of MACE (HR: 2.53 [95%CI, 1.89-3.40]; and HR: 1.58 [95%CI, 1.47-1.71]; both p &amp;lt; 0.001; respectively). After adjustment, the extent of inducible ischemia showed the best improvement in model discrimination above traditional risk factors (C-statistic 0.75 [95%CI: 0.69-0.81] with C-statistic improvement: 0.12). The study showed no benefit of CMR-related coronary revascularization in reducing MACE. CONCLUSION In patients with a first inconclusive stress test, stress CMR has good prognostic value to predict MACE offering an incremental prognostic value over traditional risk factors.

Abstract 2802: Rare earth albumin nanoparticles engineered to target cytotoxic T cells to evaluate response to immunotherapy

Abstract Checkpoint immunotherapy, through the reversal of tumor-mediated inactivation of the immune system, has shown promise in the treatment of several types of cancer. This has culminated in the approval of seven immune checkpoint inhibitors (ICIs). However, only a small population of patients respond to these drugs. Because of the physical and economic burden of ICIs on the patient, there is a critical need to identify biomarkers that can inform on the potential response to ICIs. The presence of tumor infiltrating lymphocytes (TILs) has demonstrated good prognostic value in determining if a patient should receive ICIs. Current clinical methods to assess TILs involve invasive biopsies and immunohistochemistry, which suffer from intratumoral heterogeneity, observer variability, and a lack of real-time feedback. Here, we report on near infrared light excitable rare earth metal-based nanoparticles, termed rare earth albumin nanocomposites (ReANCs), that emit shortwave infrared (SWIR) light, allowing for deep tissue imaging and high signal-to-noise ratios compared to visible or near infrared fluorescence probes. Tumor-targeted ReANCs have been previously employed to monitor tumor progression and response to chemotherapy in mouse models of breast cancer metastasis. In this study, to target CD3+ T cells, ReANCs were conjugated using the zero-length cross-linker 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) to a peptide derived from the sequence of the CD3-ϵ receptor sub-unit. Target specific binding was validated by flow cytometry as a measure of increased uptake of peptide-conjugated ReANCs by Jurkat cells. To specifically target cytotoxic T lymphocytes, we employed the fragment antigen binding (Fab) derived from enzymatic digestion of a CD8 antibody (clone 53-6.7) with papain. The Fab fragments were conjugated to ReANCs with sulfo-succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (sulfo-SMCC). Conjugation was confirmed by non-reducing gel electrophoresis and high performance liquid chromatography (HPLC). A loading efficiency of approximately 60% was achieved. Target specific binding was validated by flow cytometry as a measure of increased uptake of Fab-conjugated ReANCs by T cells isolated from splenocytes. We generated a metric for measuring immune burden around tumor spheroids by pre-labeling T cells with ReANCs and co-culturing them with tumor cell spheroids in vitro. Imaging of T cells with CD3 and CD8-targeted ReANCs provides a basis for future in vivo small animal imaging studies where we will investigate the potential of this technology to track immune cells in relation to a tumor in real time. Metrics of immune cell imaging will then inform on the potential of immunotherapy and monitor response to treatment in a longitudinal study. Citation Format: Jay V. Shah, Jake N. Siebert, Amber Gonda, Rahul Pemmaraju, Shashank Kosuri, Carolina Bobadilla Mendez, Xinyu Zhao, Shuqing He, Richard E. Riman, Mei Chee Tan, Mark C. Pierce, Edmund C. Lattime, Prabhas V. Moghe, Vidya Ganapathy. Rare earth albumin nanoparticles engineered to target cytotoxic T cells to evaluate response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2802.

Evaluation the Value of TAT, PIC, tPAIC, TM in Diagnosing Disseminated Intravascular Coagulation in Chinese population: a Multi-Center Prospective Observational Study

Objective: Accurate and early diagnosis are important in the management of disseminated intravascular coagulation (DIC). New specific coagulation markers have always been explored. In this study, we employed new automation technology to detect plasma biomarkers, including Thrombin-Antithrombin Complex (TAT), α2-Plasmininhibitor-Plasmin Complex(PIC), thrombomoduline (TM), tissue plasminogen activator-inhibitor Complex (tPAIC), and evaluated their diagnostic performance for DIC in Chinese population.Method: A prospective observational study was conducted in 9 hospitals located across the entire China. 406 patients suspected DIC and 137 normal people were included. These four molecular markers were measured by qualitative chemiluminescence enzyme immunoassay performed on automated analyzers HISCL. All patients suspected DIC were followed for development of overt-DIC in 7 days, and for mortality in 28 days.Results: The plasm level of TAT, PIC, tPAIC and TM in normal Chinese people were 1.1 (0.7-1.6), 0.44 (0.37-0.56), 7.2(5.1-9.3) and 8.6 (7.3-9.9). According to the ISTH scoring system, 146 patients were diagnosed as overt-DIC, and 37 were diagnosed as pre-DIC. All four biomarkers were significantly higher in DIC group than non-overt DIC group, and tPAIC and TM were significantly higher in pre-DIC group than non-overt DIC group (Table 1). Besides, these molecular markers were different among various underlying diseases(Fig.1). As shown in the ROC assay, the efficiency of TAT, PIC, tPAIC and TM discriminated well between overt- DIC with pre-DIC and non-overt DIC (AUROC, 0.64 (95% CI, 0.58 to 0.69); 0.63 (0.57 to 0.68); 0.63 (0.58 to 0.69);0.73 (0.68 to 0.78), respectively)(Table 2). In the combination assay, the AUROC rose up to 0.955 (0.94 to 0.97) when in addition with global coagulation tests (Fig.2). Moreover, the ISTH DIC scores showed significant correlation with these molecular markers' levels. The mortality of DIC, pre-DIC and non-DIC was 33.56%, 51.35% and 8.97%, respectively. Among the significant diagnostic markers for DIC, TAT, tPAIC and TM were also good predictors of 28-day mortality (AUROC, 0.65, 0,76 and 0.76, respectively), high levels of them were associated with poor outcome(Fig.3).Conclusion: These four biomarkers have good diagnostic performance and prognostic value in DIC patients with different underlying diseases. They can also be applied in classification and stages of DIC. Moreover, combination of four makers demonstrate better behavior than single one. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Safety, feasibility and prognostic value of stress perfusion CMR in patients with pacemaker

Several studies have shown the excellent prognostic value of stress cardiovascular magnetic resonance (CMR). However, its prognostic value in patients with pacemaker (PM) remains unknown because most studies excluded PM patients. This study aimed to assess the prognostic value of vasodilator stress perfusion CMR in patients with PM. Consecutive patients with MR-conditional pacemakers referred for stress perfusion CMR at 1.5 T were followed for the occurrence of major adverse cardiovascular events (MACE), defined by cardiovascular death or nonfatal myocardial infarction. Cox regressions analyses were performed to determine the prognostic value of CMR-parameters. The quality of CMR was rated by two observers blinded to clinical details. Data on pacemaker and leads were collected pre- and post-CMR. Of 224 patients who completed the stress CMR protocol, 2 patients had inconclusive stress CMR due to artefact and 203 patients (72.9% male, mean age 71.4 ± 8.7 years) completed the follow-up [median (interquartile range), 7.0 (5.2–7.3) years]. Among those, 23 experienced a MACE (11.3%). Stress CMR was well tolerated with no major adverse events. Overall, the image quality was rated good or excellent in 84.1% of segments. Using Kaplan–Meier analysis, inducible ischemia and late gadolinium enhancement (LGE) were significantly associated with the occurrence of MACE (HR: 11.80 [95%CI, 4.63–30.30]; and HR: 6.74 [95%CI, 2.47–18.40], both P < 0.001; respectively). In multivariable Cox regression, inducible ischemia and LGE were independent predictors of a higher incidence of MACE [HR: 5.24 (95%CI, 2.61–14.40); and HR: 2.98 (95%CI, 2.25–4.02); both P < 0.001; respectively]. In patients with ischemia, CMR-related coronary revascularization showed no benefit in reducing MACE ( P = 0.25) ( Fig. 1 ). Stress CMR is safe, feasible and has a good discriminative prognostic value in consecutive patients with PM.

METTL14 Acts as a Potential Regulator of Tumor Immune and Progression in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is characterized by its insensitivity to chemoradiotherapy and lacks effective diagnostic and prognostic biomarkers. In this study, we focused on the role of m6A RNA methylation regulators for tumor immunity. Based on the expression of 20 m6A regulators, consensus clustering was performed to divide patients into cluster1/cluster2 and showed that there was a survival difference between the two clusters. Through cox regression analysis, five hub m6A regulators were screened to construct a risk model. Further analysis showed that the risk score was an independent prognostic factor. GSEA, GSVA, and KEGG analysis revealed that immune cell pathways played a critical role between the high risk group and low risk group. Combined with CIBERSORT and survival analysis, five hub tumor-infiltrating immune cells (TIICs) were identified for further study. Meanwhile, correlation analysis indicated that IGF2BP2 was positively associated with activated memory CD4 T cell and METTL14 was negatively correlated to the regulatory T cell. Therefore, IGF2BP2 and METTL14 were regarded as key genes. Further study verified that only METTL14 possessed good diagnostic and prognostic value. Then, GSEA exhibited that METTL14 was mainly enriched in chemokine related pathways. We also found that CCL5 was negatively correlated to METTL14 and might serve as a potential target of METTL14. In conclusion, these findings suggest that the METTL14/CCL5/Tregs axis is a potential signaling pathway for regulating tumor immunity, and might become novel therapeutic targets for ccRCC.

RBM8A promotes growth and invasion through the Notch/STAT3 pathway in glioblastoma.

e14038 Background: Glioblastoma (GBM) is a prevalent brain malignance with an extremely poor prognosis, which is attributable to its invasive biological behaviors. The RNA-binding motif protein 8A (RBM8A) has different effects on various human cancers. However, the implication of RBM8A in glioblastoma progression remains unclear. Methods: Glioblastoma (GBM) data set was downloaded from the Cancer Genome Atlas (TCGA). Differential expression analysis was used to screen the differentially expressed genes (DEGs) between GBM and control, RBM8A high and low expression samples, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Gene Genomes (KEGG) analysis were performed on the co-upregulated DEGs. Additionally, We investigated the expression levels of RBM8A in 94 glioblastoma patients and explored the correlation between the RBM8A expressions with prognosis. Using in vitro and in vivo assays, we addressed the functional impacts of RBM8A on and the underlying mechanisms through which RBM8A contribute to glioblastoma progression. In addition, a comprehensive regulatory network of RBM8A regulation was constructed based on STRING database. Molecular docking model was used to predict the possibility of RBM8A binding to target genes. Combined with TCGA and Chinese glioma genome map (CGGA), gene set variance analysis (GSVA) was used to calculate the GSVA scores of the genes involved in the mechanism. Receiver operator characteristic curve (ROC) curve analysis and survival analysis were performed to explore the prognostic and diagnostic ability of GSVA score for GBM. Results: Our results indicate that higher RBM8A expression in glioblastoma tissues was associated with a poor prognosis. In addition, functional enrichment analysis based on genes related to RBM8A expression showed that RBM8A was related to cell cycle and Notch signaling pathway. RBM8A may promote glioblastoma cell proliferation and migration by activating Notch/STAT3 pathway in glioblastoma cells. In vitro and in vivo assays confirmed that knocking down RBM8A inhibited glioblastoma progression and invasion ability. We also observed that the pro-oncogenic effects of RBM8A in glioblastoma tissues were mediated by activation of the Notch/STAT3 pathway. Finally, it was concluded that the GSVA score has good diagnostic and prognostic value for GBM. Conclusions: RBM8A may promote glioblastoma cell proliferation and migration by activating Notch/STAT3 pathway in glioblastoma cells, suggesting that RBM8A may serve as a potential therapeutic target for the treatment of glioblastoma.

Elevated B-type natriuretic peptide (BNP) and soluble thrombomodulin (sTM) indicates severity and poor prognosis of sepsis.

To study the predictive value of B-type natriuretic peptide (BNP) and soluble thrombomodulin (sTM) in the severity stratification and prognosis evaluation of sepsis. The clinical data of 137 sepsis patients diagnosed and treated in Sichuan Provincial People's Hospital from May 2018 to November 2020 were retrospectively analyzed. Meanwhile, 121 healthy individuals were selected as the control group. Patients with sepsis were allocated into the mild group, severe group, and shock group according to the severity. According to the 28-day prognosis, the patients were allocated into the death group and survival group. The plasma BNP and serum sTM levels in different groups were compared, and their prognostic value was evaluated. Patients with sepsis had significantly higher levels of BNP and sTM than the healthy control group (P<0.05). The levels of BNP and sTM in the mild group were significantly lower than those in the severe group and shock group, and both BNP and sTM were positively correlated with Acute Physiology and Chronic Health Status (APACHE) II score (r=0.595, 0.516, P<0.05). The levels of BNP and sTM in the death group were significantly higher than those in the survival group (P<0.05). The area under curve (AUC) of BNP combined with sTM was significantly greater than that of BNP or sTM alone for the prognosis of sepsis (P<0.05). When the cut-off value of BNP was 625.68 pg/mL, the sensitivity and specificity were 77.42% and 89.42%, respectively. When the cut-off value of sTM was 10.53 ng/mL, the sensitivity and specificity were 83.87% and 94.34%, respectively. Patients with sepsis have significantly higher serum BNP and sTM levels which are positively correlated with the severity of the disease. Both of the 2 indexes have good prognostic value, and the predictive value is higher when combined.