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Research (Washington, D.C.) 2024Hepatocellular carcinoma (HCC) was characterized as being hypervascular. In the present study, we generated a single-cell spatial transcriptomic landscape of the...
Hepatocellular carcinoma (HCC) was characterized as being hypervascular. In the present study, we generated a single-cell spatial transcriptomic landscape of the vasculogenic etiology of HCC and illustrated overexpressed Golgi phosphoprotein 73 (GP73) HCC cells exerting cellular communication with vascular endothelial cells with high pro-angiogenesis potential via multiple receptor-ligand interactions in the process of tumor vascular development. Specifically, we uncovered an interactive GP73-mediated regulatory network coordinated with c-Myc, lactate, Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway, and endoplasmic reticulum stress (ERS) signals in HCC cells and elucidated its pro-angiogenic roles in vitro and in vivo. Mechanistically, we found that GP73, the pivotal hub gene, was activated by histone lactylation and c-Myc, which stimulated the phosphorylation of downstream STAT3 by directly binding STAT3 and simultaneously enhancing glucose-regulated protein 78 (GRP78)-induced ERS. STAT3 potentiates GP73-mediated pro-angiogenic functions. Clinically, serum GP73 levels were positively correlated with HCC response to anti-angiogenic regimens and were essential for a prognostic nomogram showing good predictive performance for determining 6-month and 1-year survival in patients with HCC treated with anti-angiogenic therapy. Taken together, the aforementioned data characterized the pro-angiogenic roles and mechanisms of a GP73-mediated network and proved that GP73 is a crucial tumor angiogenesis niche gene with favorable anti-angiogenic potential in the treatment of HCC.
PubMed: 38939041
DOI: 10.34133/research.0387 -
JACC. Advances Jul 2023Transcatheter aortic valve implantation (TAVI) rates are lower among Black compared with White individuals. However, it is unclear whether racial residential...
BACKGROUND
Transcatheter aortic valve implantation (TAVI) rates are lower among Black compared with White individuals. However, it is unclear whether racial residential segregation, which remains common in the United States, contributes to observed disparities in TAVI rates.
OBJECTIVES
The purpose of this study was to evaluate the association between county-level racial segregation, and aortic stenosis (AS) diagnosis, management, and outcomes.
METHODS
We identified Black and White Medicare fee-for-service beneficiaries age ≥65 years living in metropolitan areas of the United States (2016-2019). Using the American Community Survey's Black-White residential segregation index, a measure of geographic racial distribution, we determined segregation in each beneficiary's county of residence. Using hierarchical modeling, we determined the association between racial segregation and rates of AS diagnosis, TAVI receipt, and 30-day clinical outcomes (mortality, readmission, stroke).
RESULTS
There were 29,264,075 beneficiaries, of whom 22% lived in a high-segregation county. Among Black beneficiaries, high-segregation county residence was associated with decreased rates of AS diagnosis (OR: 0.97; 95% CI: 0.96-0.98) and TAVI (OR: 0.89; 95% CI: 0.86-0.93) compared with low-segregation county residence. In contrast, among White beneficiaries, high-segregation county residence was associated with higher rates of AS diagnosis (OR: 1.02; 95% CI: 1.02-1.03) and no differences in TAVI (OR: 1.00; 95% CI: 0.99-1.00). Segregation and race were not independently associated with 30-day mortality.
CONCLUSIONS
Among Black Medicare fee-for-service beneficiaries, living in a high-segregation county was independently associated with decreased rates of AS diagnosis and TAVI, an association not seen among White beneficiaries. Residential racial segregation may contribute to racial disparities seen in AS care.
PubMed: 38939010
DOI: 10.1016/j.jacadv.2023.100415 -
JACC. Advances Mar 2024Clinical trials suggest that therapeutic-dose heparin may prevent critical illness and vascular complications due to COVID-19, but knowledge gaps exist regarding the...
BACKGROUND
Clinical trials suggest that therapeutic-dose heparin may prevent critical illness and vascular complications due to COVID-19, but knowledge gaps exist regarding the efficacy of therapeutic heparin including its comparative effect relative to intermediate-dose anticoagulation.
OBJECTIVES
The authors performed 2 complementary secondary analyses of a completed randomized clinical trial: 1) a prespecified per-protocol analysis; and 2) an exploratory dose-based analysis to compare the effect of therapeutic-dose heparin with low- and intermediate-dose heparin.
METHODS
Patients who received initial anticoagulation dosed consistently with randomization were included. The primary outcome was organ support-free days (OSFDs), a combination of in-hospital death and days free of organ support through day 21.
RESULTS
Among 2,860 participants, 1,761 (92.8%) noncritically ill and 857 (89.1%) critically ill patients were treated per-protocol. Among noncritically ill per-protocol patients, the posterior probability that therapeutic-dose heparin improved OSFDs as compared with usual care was 99.3% (median adjusted OR: 1.36; 95% credible interval [CrI]: 1.07-1.74). Therapeutic heparin had a high posterior probability of efficacy relative to both low- (94.6%; adjusted OR: 1.26; 95% CrI: 0.95-1.64) and intermediate- (99.8%; adjusted OR: 1.80; 95% CrI: 1.22-2.62) dose thromboprophylaxis. Among critically ill per-protocol patients, the posterior probability that therapeutic heparin improved outcomes was low.
CONCLUSIONS
Among noncritically ill patients hospitalized for COVID-19 who were randomized to and initially received therapeutic-dose anticoagulation, heparin, compared with usual care, was associated with improved OSFDs, a combination of in-hospital death and days free of organ support. Therapeutic heparin appeared superior to both low- and intermediate-dose thromboprophylaxis.
PubMed: 38938844
DOI: 10.1016/j.jacadv.2023.100780 -
JACC. Advances Mar 2024Left ventricular noncompaction (LVNC) is characterized by excessive trabeculations of the left ventricular (LV) wall.
BACKGROUND
Left ventricular noncompaction (LVNC) is characterized by excessive trabeculations of the left ventricular (LV) wall.
OBJECTIVES
The authors aimed to examine changes in LV function and morphology in 2 to 4-year-old children with and without LVNC at birth and to describe the prevalence of LVNC in first-degree relatives.
METHODS
Echocardiograms in children with and without LVNC (matched 1:4) were performed at 2 to 4 years and in first-degree relatives. LVNC was blindly assessed and defined as a ratio of non-compact to compact myocardium of ≥2 in ≥1 LV segment. Trabeculations were expressed as a percentage of the number of segments with LVNC out of the total number of segments.
RESULTS
In total, 14 (median age 3 years, 71% male) of 16 children with LVNC at birth and 56 children without (median age 4 years, 71% male), 37 first-degree relatives of children with LVNC (median age 31 years, 46% male) and 146 first-degree relatives of children without (median age 33 years, 50% male) were included. In children with LVNC, trabeculation (8% vs 13%, = 0.81) and LV ejection fraction (50% vs 49%, = 0.91) were unchanged from birth to follow-up but LV ejection fraction was lower compared to children without LVNC (49% vs 60%, < 0.001). In relatives of children with LVNC, 11 of 37 (30%) fulfilled LVNC criteria compared to no relatives to children without LVNC ( < 0.001).
CONCLUSIONS
At 2 to 4 years, children with LVNC diagnosed at birth had reduced systolic function compared to children without but did not have progression of LV dysfunction or extent of trabeculations. In first-degree relatives to children with LVNC, 30% fulfilled criteria.
PubMed: 38938835
DOI: 10.1016/j.jacadv.2024.100829 -
JACC. Advances Mar 2024Patients with likely pathogenic/pathogenic desmoplakin () variants are poorly characterized. Some of them meet diagnostic criteria for arrhythmogenic right ventricular...
BACKGROUND
Patients with likely pathogenic/pathogenic desmoplakin () variants are poorly characterized. Some of them meet diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC), but it is unclear how risk stratification strategies for ARVC perform in this setting.
OBJECTIVES
The purpose of this study was to characterize arrhythmic outcomes and to test the performance of the recently validated ARVC risk calculator in patients with likely pathogenic/pathogenic variants fulfilling definite 2010 ARVC Task Force Criteria (-TFC+).
METHODS
-TFC+ patients were enrolled from 20 institutions across 3 continents. Ventricular arrhythmias (VA), defined as a composite of sustained ventricular tachycardia (VT), appropriate implantable cardioverter defibrillator therapies, and ventricular fibrillation/sudden cardiac death events in follow-up, were reported as the primary outcome. We tested the performance of the ARVC risk calculator for VA prediction, reporting c-statistics.
RESULTS
Among 252 -TFC+ patients (age 39.6 ± 16.9 years, 35.3% male), 94 (37.3%) experienced VA over 44.5 [IQR: 19.6-78.3] months. Patients with left ventricle involvement (n = 194) were at higher VA risk (log-rank = 0.0239). History of nonsustained VT (aHR 2.097; = 0.004) showed the strongest association with VA occurrence during the first 5-year follow-up. Neither age ( = 0.723) nor male sex ( = 0.200) was associated with VAs at follow-up. In 204 patients without VA at diagnosis, incident VA rate was high (32.8%; 7.37%/y). The ARVC risk calculator performed poorly overall (c-statistic 0.604 [0.594-0.614]) and very poorly in patients with left ventricular disease (c-statistic 0.558 [0.556-0.560]).
CONCLUSIONS
-TFC+ patients are at substantial risk for VAs. The ARVC risk calculator performs poorly in -TFC+ patients suggesting need for a gene-specific risk algorithm. Meanwhile, -TFC+ patients with nonsustained VT should be considered as high-risk.
PubMed: 38938828
DOI: 10.1016/j.jacadv.2024.100832 -
TH Open : Companion Journal To... Apr 2024Recombinant von Willebrand factor (rVWF, vonicog alfa, Takeda Pharmaceuticals USA) is indicated in adults diagnosed with von Willebrand disease (VWD). In this study,...
Recombinant von Willebrand factor (rVWF, vonicog alfa, Takeda Pharmaceuticals USA) is indicated in adults diagnosed with von Willebrand disease (VWD). In this study, the exposure-response (ER) relationship between VWF activity (VWF:RCo) or factor VIII activity (FVIII:C) and spontaneous bleeding events (BEs) was evaluated in adults with severe VWD receiving rVWF prophylaxis for up to 1 year. This secondary analysis included 23 patients receiving rVWF prophylaxis in the open-label, phase 3 prophylaxis trial (NCT02973087). Population pharmacokinetic (PK) and PK/pharmacodynamic (PD) models were used to characterize VWF activity and endogenous FVIII:C, and PK/PD simulations were linked to spontaneous BEs to develop an ER model. None of the five patients with VWD types 1 or 2A/B experienced spontaneous BEs. Five of 18 patients with VWD type 3 experienced ≥1 spontaneous BEs. An ER relationship was observed whereby higher VWF:RCo levels were associated with a numerically lower spontaneous BE risk ( < 0.10). This relationship was independent of patients' pretrial VWF treatment. A statistically significant ER relationship was observed after accounting for relevant data (average ± standard error exposure estimate for VWF:RCo over 24 hours prior to the spontaneous BE: -0.043 ± 0.021, = 0.041). The model-generated hazard ratio for a 10 IU/dL increment in the average exposure of VWF:RCo 24 hours before a spontaneous BE was 0.651 (95% confidence interval: 0.431-0.982). This ER analysis suggests a causal association between VWF:RCo and spontaneous BEs, with an increase of VWF:RCo exposure leading to a decrease in spontaneous BE risk.
PubMed: 38938750
DOI: 10.1055/s-0044-1787815 -
JACC. Advances Nov 2023The Quality Enhancement Research Initiative (QuERI) in adults with congenital heart disease (ACHD) was developed to improve detection of pulmonary arterial hypertension...
BACKGROUND
The Quality Enhancement Research Initiative (QuERI) in adults with congenital heart disease (ACHD) was developed to improve detection of pulmonary arterial hypertension (PAH) after repair of systemic-to-pulmonary arterial shunt lesions.
OBJECTIVES
This study sought to standardize use of accepted criteria for PAH diagnosis and evaluate utility in at-risk patients with ACHD.
METHODS
Patients ≥18 years of age with ACHD repaired ≥1 year before enrollment and with additional risk factors for developing PAH were eligible. History, physical examination, electrocardiogram, transthoracic echocardiogram, World Health Organization functional class, and 6-minute walk distance were evaluated at baseline and yearly for 3 years. Pop-up reminders of patient-specific evidence-based recommendations for PAH detection appeared during data entry.
RESULTS
Among 217 eligible patients, mean age (enrollment) was 44.0 ± 15.9 years, 72.3% were women, and 82.0% were World Health Organization functional class I. Electrocardiogram was performed in >80% and TTE in >70% of patients annually; capture of required transthoracic echocardiography (TTE) measures and alignment between study- and core-center interpretation improved over time, with more frequent assessment of pulmonary arterial flow acceleration time and documentation of right ventricular outflow tract Doppler notching. Approximately 40% of patients had ≥2 high-risk features for PAH on TTE, but only 7% (6/82) underwent right heart catheterization (RHC). Using current definitions, 2 patients were confirmed by RHC to have a diagnosis of PAH (maximum follow-up 3 years).
CONCLUSIONS
A structured protocol may improve screening for patients with repaired ACHD at risk of developing PAH. RHC may be underutilized in patients with ACHD with TTE findings suggestive of PAH. (Adult Congenital Heart Disease Registry [QuERI]; NCT01659411).
PubMed: 38938704
DOI: 10.1016/j.jacadv.2023.100649 -
Frontiers in Cardiovascular Medicine 2024The relationship between the blood urea nitrogen to creatinine ratio (BCR) and the risk of in-hospital mortality among intensive care unit (ICU) patients diagnosed with...
BACKGROUND
The relationship between the blood urea nitrogen to creatinine ratio (BCR) and the risk of in-hospital mortality among intensive care unit (ICU) patients diagnosed with venous thromboembolism (VTE) remains unclear. This study aimed to assess the relationship between BCR upon admission to the ICU and in-hospital mortality in critically ill patients with VTE.
METHODS
This retrospective cohort study included patients diagnosed with VTE from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. The primary endpoint was in-hospital mortality. Univariate and multivariate logistic regression analyses were conducted to evaluate the prognostic significance of the BCR. Receiver operating characteristic (ROC) curve analysis was utilized to determine the optimal cut-off value of BCR. Additionally, survival analysis using a Kaplan-Meier curve was performed.
RESULTS
A total of 2,560 patients were included, with a median age of 64.5 years, and 55.5% were male. Overall, the in-hospital mortality rate was 14.6%. The optimal cut-off value of the BCR for predicting in-hospital mortality in critically ill VTE patients was 26.84. The rate of in-hospital mortality among patients categorized in the high BCR group was significantly higher compared to those in the low BCR group (22.6% vs. 12.2%, < 0.001). The multivariable logistic regression analysis results indicated that, even after accounting for potential confounding factors, patients with elevated BCR demonstrated a notably increased in-hospital mortality rate compared to those with lower BCR levels (all < 0.05), regardless of the model used. Patients in the high BCR group exhibited a 77.77% higher risk of in-hospital mortality than those in the low BCR group [hazard ratio (HR): 1.7777; 95% CI: 1.4016-2.2547].
CONCLUSION
An elevated BCR level was independently linked with an increased risk of in-hospital mortality among critically ill patients diagnosed with VTE. Given its widespread availability and ease of measurement, BCR could be a valuable tool for risk stratification and prognostic prediction in VTE patients.
PubMed: 38938654
DOI: 10.3389/fcvm.2024.1400915 -
Frontiers in Cardiovascular Medicine 2024Malignant mesothelioma (MM) is a rare and aggressive tumor that is found in the pleura and peritoneum. A few cases of MM in the pericardium and tunica vaginalis testis...
BACKGROUND
Malignant mesothelioma (MM) is a rare and aggressive tumor that is found in the pleura and peritoneum. A few cases of MM in the pericardium and tunica vaginalis testis have been reported. Moreover, primary occurrence in the atrium is extremely rare. The visual appearance of this tumor is similar to that of a common atrial myxoma, which makes it challenging for clinicians and radiologists to diagnose and treat this disease.
CASE DEMONSTRATION
An 18-year-old woman presented with symptoms of chest pain, shortness of breath, cough, and expectoration for 7 days. Echocardiography was performed on the patient, which revealed an atrial mass. Myxoma was one of the differential diagnoses. The tumor was an elliptical mass with tips, and the cut surface was jelly-like, similar to myxoma. After surgery, a pathologic examination of the biopsied tumor confirmed epithelial-type MM. During postoperative follow-up, no recurrence of the tumor was observed.
CONCLUSIONS
MM originating in the atrium is considered to be extremely rare. Consequently, clinicians can easily misdiagnose atrial MM as a myxoma. Moreover, to confirm the diagnosis, histopathologic biopsy, histomorphological characterization, immunohistochemistry, and molecular genetic testing are required. Therefore, clinical diagnosis and treatment of MM are challenging.
PubMed: 38938650
DOI: 10.3389/fcvm.2024.1398311 -
PeerJ 2024Patients with lung adenocarcinoma (LUAD) often develop a poor prognosis. Currently, researches on prognostic and immunotherapeutic capacity of aneuploidy-related genes...
Integrated bulk and single-cell RNA sequencing identifies an aneuploidy-based gene signature to predict sensitivity of lung adenocarcinoma to traditional chemotherapy drugs and patients' prognosis.
BACKGROUND
Patients with lung adenocarcinoma (LUAD) often develop a poor prognosis. Currently, researches on prognostic and immunotherapeutic capacity of aneuploidy-related genes in LUAD are limited.
METHODS
Genes related to aneuploidy were screened based on bulk RNA sequencing data from public databases using Spearman method. Next, univariate Cox and Lasso regression analyses were performed to establish an aneuploidy-related riskscore (ARS) model. Results derived from bioinformatics analysis were further validated using cellular experiments. In addition, typical LUAD cells were identified by subtype clustering, followed by SCENIC and intercellular communication analyses. Finally, ESTIMATE, ssGSEA and CIBERSORT algorithms were employed to analyze the potential relationship between ARS and tumor immune environment.
RESULTS
A five-gene ARS signature was developed. These genes were abnormally high-expressed in LUAD cell lines, and in particular the high expression of CKS1B promoted the proliferative, migratory and invasive phenotypes of LUAD cell lines. Low ARS group had longer overall survival time, higher degrees of inflammatory infiltration, and could benefit more from receiving immunotherapy. Patients in low ASR group responded more actively to traditional chemotherapy drugs (Erlotinib and Roscovitine). The scRNA-seq analysis annotated 17 cell subpopulations into seven cell clusters. Core transcription factors (TFs) such as CREB3L1 and CEBPD were enriched in high ARS cell group, while TFs such as BCLAF1 and UQCRB were enriched in low ARS cell group. CellChat analysis revealed that high ARS cell groups communicated with immune cells SPP1 (ITGA4-ITGB1) and MK (MDK-NCl) signaling pathways.
CONCLUSION
In this research, integrative analysis based on the ARS model provided a potential direction for improving the diagnosis and treatment of LUAD.
Topics: Humans; Adenocarcinoma of Lung; Lung Neoplasms; Aneuploidy; Prognosis; Single-Cell Analysis; CDC2-CDC28 Kinases; Cell Line, Tumor; Sequence Analysis, RNA; Antineoplastic Agents; Gene Expression Regulation, Neoplastic; Computational Biology; Male
PubMed: 38938612
DOI: 10.7717/peerj.17545