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Background. Hepatocellular carcinoma (HCC) is a severe global health issue that still lacks of effective treatments. Lenvatinib is a novel tyrosine kinase inhibitor (TKI) that has been approved for the treatment of HCC. However, drug resistance is inevitable and limits the clinical application of lenvatinib. Till now, there is still little knowledge about the mechanisms under the resistance to lenvatinib in HCC. Long noncoding RNA (lncRNA) is a group of noncoding RNAs that play essential roles in various physiological activities including the chemoresistance. In the present study, through RNA sequencing, we discovered that lncRNA XIST was upregulated in HCC cells that was insensitive to lenvatinib. Mechanically, we found that lncXIST promotes lenvatinib resistance via activation of EZH2-NOD2-ERK axis in HCC cells. Our data suggest that targeting lncXIST/EZH2/NOD2/ERK axis might be a promising strategy to enhance the efficacy of lenvatinib against HCC cells.

Tissue sampling of biliary tract carcinomas (BTCs) for molecular characterization is challenging. The aim of this study was to investigate the possibility of identifying individual actionable mutations derived from bile cell-free DNA (cfDNA) using targeted deep sequencing. Ten BTC patients, four with gallbladder carcinomas and six with cholangiocarcinomas, were enrolled in the present study. Using targeted deep sequencing with a panel of 150 tumor-related genes, paired bile cfDNA and tumor DNA were analyzed for mutational variants individually and then compared. The present study, to the best of our knowledge, is the first to reveal that bile cfDNA is predominantly comprised of long DNA fragments, which is not the case for plasma cfDNA. Herein, paired bile cfDNA and tumors from ten BTC patients were examined using targeted deep sequencing. When comparing bile cfDNA and tumor DNA for single nucleotide variation (SNV)/insertion and deletion (Indel), the results using targeted deep sequencing revealed high sensitivity (94.7%) and specificity (99.9%). Additionally, the sensitivity of detecting a copy number variation (CNV) was 75.0%, with a specificity of 98.9%. When comparing two bile extraction methods, including percutaneous transhepatic cholangial drainage and operation, no significant difference in SNV/Indel or CNV detection sensitivity was noted. Moreover, when examining the tumor stage and incidence site, AJCC stage II and the distal bile duct both had significantly decreased CNV detection sensitivities. The present study revealed that targeted deep sequencing can reliably detect mutational variants within bile cfDNA obtained from BTC patients. These preliminary results may shed light on bile cfDNA as a promising liquid biopsy for BTC patients.

Background Malnutrition is common in patients with chronic cardiovascular disease and is associated with significantly higher all-cause mortality. Approximately one-third of patients with heart failure are malnourished. However, the relationship between malnutrition and idiopathic pulmonary arterial hypertension (IPAH) remains unclear. This study aimed to clarify the prognostic value of malnutrition in patients with IPAH. Methods A total of 432 consecutive participants with IPAH were included in this study between March 2013 and August 2021. Three common malnutrition assessment tools, including the geriatric nutritional risk index (GNRI), prognostic nutritional index (PNI), and controlling nutritional status (CONUT) score, were used to evaluate the nutritional status of patients with IPAH. The relationships between the malnutrition tools and long-term adverse outcomes were determined using restricted cubic splines and multivariate Cox regression models. Results During a mean follow-up of 3.1 years, 158 participants experienced clinical worsening or all-cause death. Patients were stratified into the low-, intermediate- and high-risk groups based on the European Society of Cardiology (ESC) risk stratification, and the PNI (55.9 ± 5.7 vs. 54.4 ± 7.2 vs. 51.1 ± 7.1, P = 0.005) and CONUT score (2.1 ± 0.9 vs. 2.5 ± 1.2 vs. 3.3 ± 1.1, P < 0.001) identified these patient groups better than the GNRI. All three malnutrition tools were associated with well-validated variables that reflected IPAH severity, such as the World Health Organization functional class, 6-min walk distance, and N-terminal pro-brain natriuretic peptide level. The CONUT score exhibited better predictive ability than both the GNRI (ΔAUC = 0.059, P < 0.001) and PNI (ΔAUC = 0.095, P < 0.001) for adverse outcomes and significantly improved reclassification and discrimination beyond the ESC risk score. Multivariable Cox regression analysis indicated that only the CONUT score (hazard ratio = 1.363, 95% confidence interval 1.147, 1.619 per 1.0-standard deviation increment, P < 0.001) independently predicted adverse outcomes. Conclusions The malnutrition status was associated with disease severity in patients with IPAH. The CONUT score provided additional information regarding the risk of clinically worsening events, making it a meaningful risk stratification tool for these patients.

Aims: Impairment of right ventricle-to-pulmonary artery coupling (RV-PA coupling) is a major determinant of poor prognosis in patients with pulmonary hypertension. This study sought to evaluate the ability of an echo-derived metric of RV-PA coupling, the ratio between tricuspid annular plane systolic excursion (TAPSE), and pulmonary artery systolic pressure (PASP) and to predict adverse clinical outcomes in chronic thromboembolic pulmonary hypertension (CTEPH). Methods and results: A total of 205 consecutive patients with confirmed CTEPH were retrospectively recruited from Fuwai Hospital between February 2016 and November 2020. Baseline echocardiography, right heart catheterization, and cardiopulmonary exercise testing were analyzed. Patients with lower TAPSE/PASP had a significantly compromised echocardiographic and hemodynamic status and exercise capacity at baseline. The TAPSE/PASP ratio correlated significantly with hemodynamic parameters, including pulmonary vascular resistance (r = −0.48, p < 0.001) and pulmonary arterial compliance (r = 0.45, p < 0.001). During a median period of 1-year follow-up, 63 (30.7%) patients experienced clinical worsening. The relationship between TAPSE/PASP and clinical worsening was assessed using different multivariate Cox regression models. After adjustment for a series of previously screened independent predictors, TAPSE/PASP remained significantly associated with outcomes, and the hazard ratio (per standard deviation increase) of the final model was 0.402. Conclusion: In patients with CTEPH, baseline RV-PA coupling measured as the TAPSE/PASP ratio is associated with disease severity and adverse outcomes. A low TAPSE/PASP identifies patients with a high risk of clinical deterioration, and this novel metric could be applicable for risk stratification in CTEPH.

Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a severely progressive disease that leads to right heart failure and death. Previous studies have shown that diabetes and insulin resistance (IR) are closely related to pulmonary hypertension, but the role of IR in patients with CTEPH remains unexplored. In this study, we investigated the relationship between four insulin resistance indices and disease severity, hemodynamic parameters, and adverse outcomes in patients with CTEPH. Methods We conducted a multicenter, retrospective cohort study involving 516 patients diagnosed with CTEPH between January 2013 and December 2022. The metabolic score for IR (METS-IR), triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, triglyceride and glucose (TyG) index, and triglyceride-glucose-body mass (TyG-BMI) index were used to quantify IR levels in patients with CTEPH. The primary endpoint events were clinical worsening. Multivariable Cox regression, restricted cubic splines, and receiver operating characteristic analyses were used to evaluate the predictive value of surrogates for IR. Results Compared with in low to intermediate-low risk patients, the METS-IR (36.2 ± 6.7 vs. 37.7 ± 8.7, p  = 0.038) and TyG-BMI index (204.0 ± 36.2 vs. 212.6 ± 46.5, p  = 0.022) were significantly increased in high to intermediate-high risk patients. METS-IR correlated with markers of disease severity, such as World Health Organization functional class, 6-minute walk distance, and N-terminal pro-brain natriuretic peptide levels. During a mean of 2.5 years’ follow-up, 110 participants experienced all-cause death or worsening condition. METS-IR independently predicted clinical worsening (hazard ratio: 1.27; 95% confidence interval 1.06–1.53 per 1.0-standard deviation increment, p  = 0.009) after fully adjusting for covariates. Adding METS-IR to the COMPERA 2.0 risk score significantly improved its predictive ability, reclassification and discrimination ability. Conclusions METS-IR is an independent predictor of clinical worsening in patients with CTEPH. It offers a convenient marker for assessing disease severity and long-term outcomes in clinical risk assessment.

Background Insulin resistance (IR) plays an important role in the pathophysiology of cardiovascular disease. Recent studies have shown that diabetes mellitus and impaired lipid metabolism are associated with the severity and prognosis of idiopathic pulmonary arterial hypertension (IPAH). However, the relationship between IR and pulmonary hypertension is poorly understood. This study explored the association between four IR indices and IPAH using data from a multicenter cohort. Methods A total of 602 consecutive participants with IPAH were included in this study between January 2015 and December 2022. The metabolic score for IR (METS-IR), triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, triglyceride and glucose (TyG) index, and triglyceride-glucose-body mass index (TyG-BMI) were used to quantify IR levels in patients with IPAH. The correlation between non-insulin-based IR indices and long-term adverse outcomes was determined using multivariate Cox regression models and restricted cubic splines. Results During a mean of 3.6 years’ follow-up, 214 participants experienced all-cause death or worsening condition. Compared with in low to intermediate-low risk patients, the TG/HDL-C ratio (2.9 ± 1.7 vs. 3.3 ± 2.1, P = 0.003) and METS-IR (34.5 ± 6.7 vs. 36.4 ± 7.5, P < 0.001) were significantly increased in high to intermediate-high risk patients. IR indices correlated with well-validated variables that reflected the severity of IPAH, such as the cardiac index and stroke volume index. Multivariate Cox regression analyses indicated that the TyG-BMI index (hazard ratio [HR] 1.179, 95% confidence interval [CI] 1.020, 1.363 per 1.0-standard deviation [SD] increment, P = 0.026) and METS-IR (HR 1.169, 95% CI 1.016, 1.345 per 1.0-SD increment, P = 0.030) independently predicted adverse outcomes. Addition of the TG/HDL-C ratio and METS-IR significantly improved the reclassification and discrimination ability beyond the European Society of Cardiology (ESC) risk score. Conclusions IR is associated with the severity and long-term prognosis of IPAH. TyG-BMI and METS-IR can independently predict clinical worsening events, while METS-IR also provide incremental predictive performance beyond the ESC risk stratification.

Gallbladder carcinoma (GBC) is the most common biliary tract malignancy with the lowest survival rate, primarily arising from chronic inflammation. To better characterize the progression from inflammation to cancer to metastasis, we performed single-cell RNA sequencing across samples of 6 chronic cholecystitis, 12 treatment-naive GBCs, and 6 matched metastases. Benign epithelial cells from inflamed gallbladders displayed resting, immune-regulating, and gastrointestinal metaplastic phenotypes. A small amount of PLA2G2A+ epithelial cells with copy number variation were identified from a histologically benign sample. We validated significant overexpression of PLA2G2A across in situ GBCs, together with increased proliferation and cancer stemness in PLA2G2A-overexpressing GBC cells, indicating an important role for PLA2G2A during early carcinogenesis. Malignant epithelial cells displayed pervasive cancer hallmarks and cellular plasticity, differentiating into metaplastic, inflammatory, and mesenchymal subtypes with distinct transcriptomic, genomic, and prognostic patterns. Chronic cholecystitis led to an adapted microenvironment characterized by MDSC-like macrophages, CD8+ TRM cells, and CCL2+ immunity-regulating fibroblasts. By contrast, GBC instigated an aggressive and immunosuppressive microenvironment, featured by tumor-associated macrophages, Treg cells, CD8+ TEX cells, and STMN1+ tumor-promoting fibroblasts. Single-cell and bulk RNA-seq profiles consistently showed a more suppressive immune milieu for GBCs with inflammatory epithelial signatures, coupled with strengthened epithelial-immune crosstalk. We further pinpointed a subset of senescence-like fibroblasts (FN1+TGM2+) preferentially enriched in metastatic lesions, which promoted GBC migration and invasion via their secretory phenotype. Collectively, this study provides comprehensive insights into epithelial and microenvironmental reprogramming throughout cholecystitis-propelled carcinogenesis and metastasis, laying a new foundation for the precision therapy of GBC.

Background The COMPERA 2.0 4-stratum (4-S) risk score has been demonstrated superior over the 3-stratum (3-S) one in patients with pulmonary arterial hypertension and medically managed patients with chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to determine the prognostic value of the original 4-S and 3-S COMPERA 2.0 risk score and two new derivative versions in CTEPH patients who underwent balloon pulmonary angioplasty (BPA). Methods We retrospectively enrolled 175 BPA-treated patients with CTEPH. We assessed the risk stratification before and after each BPA session of CTEPH patients by the original 4-S and 3-S COMPERA 2.0 risk score (by rounding decimal to the nearest integer) and two new proposed derivative versions: the modified version (by rounding decimal to the next integer) and a hybrid version that fuses the original and modified versions. The primary endpoint was clinical worsening events. The secondary outcomes were achieving low-risk profile and mean pulmonary arterial pressure (mPAP) < 30 mmHg at follow-up. We used the Kaplan–Meier curve analysis to assess the survival differences between stratified patients. The comparative model’s performance was evaluated in terms of discrimination by Harrell’s C-index. Results All versions of COMPERA 2.0 4-S model outperformed the 3-S one in discriminating the differences in echocardiographic and hemodynamic parameters and clinical worsening-free survival rates. The original and hybrid 4-S model could independently predict the primary and secondary endpoints, and the hybrid version seemed to perform better. The first BPA session could significantly improve risk profiles, and these changes were associated with the likelihood of experiencing clinical worsening events, achieving a low-risk profile and mPAP < 30 mmHg at follow-up. The number of BPA sessions required to achieve low risk/mPAP < 30 mmHg increased as the baseline risk score escalated. Conclusions The COMPERA 2.0 4-S model outperformed the 3-S one in BPA-treated patients with CTEPH. The 4-S model, especially its hybrid version, could be used to predict clinical outcome before the initiation of BPA and monitor treatment response.

Background Hyperglycemia upon admission is associated with poor prognosis of many cardiovascular diseases. However, the relationship of stress hyperglycemia ratio (SHR), admission blood glucose (ABG), and hemoglobin A1c (HbA1c) with pulmonary hypertension has not been reported. This study aimed to explore the association of hyperglycemia indices with disease severity and long-term adverse outcomes in patients with idiopathic pulmonary arterial hypertension (IPAH). Methods This multi-center cohort study included 625 consecutive patients diagnosed with or treated for IPAH between January 2015 and June 2023. SHR was calculated using the followings: ABG (mmol/L)/(1.59 × HbA1c [%] − 2.59). The primary endpoint was defined as clinical worsening events. Multivariable Cox regression and restricted cubic spline analyses were employed to evaluate the association of SHR, ABG, and HbA1c with endpoint events. The mediating effect of pulmonary hemodynamics was evaluated to investigate the potential mechanism between hyperglycemia and clinical outcomes. Results During a mean follow-up period of 3.8 years, 219 (35.0%) patients experienced all-cause death or clinical worsening events. Hyperglycemia indices correlated with well-validated variables that reflected the severity of IPAH, such as the World Health Organization functional class, 6-min walk distance, and N-terminal pro-brain natriuretic peptide levels. Multivariable Cox regression analyses indicated that SHR (hazard ratio [HR] 1.328, 95% confidence intervals [CI]: 1.185, 1.489 per 0.1-unit increment, P  < 0.001) and ABG (HR 1.317, 95% CI: 1.134, 1.529 per 1.0-unit increment, P  < 0.001) were independent predictors of primary endpoint events. Mediation analysis indicated that pulmonary vascular resistance mediated 5.65% and 14.62% of the associations between SHR and ABG and clinical worsening events, respectively. The addition of SHR significantly improved reclassification, discrimination ability, and model fit beyond the clinical risk prediction model. Conclusions SHR is positively associated with clinical worsening in patients with IPAH. The association appeared to be partially mediated through the pathway of pulmonary vascular remodeling, indicating that SHR may serve as a valuable indicator for providing additional risk information.

Background: Balloon pulmonary angioplasty (BPA) is typically performed in a sequential manner. Objectives: This study aimed to determine the lowest frequency of BPA for patients who could not reach treatment goals in a short period. Design: Retrospective cohort. Methods: We retrospectively enrolled 186 BPA-treated patients diagnosed with chronic thromboembolic pulmonary hypertension. According to the accumulative number of performed BPA sessions or treated pulmonary vessels or the ratio of the number of treated pulmonary vessels/the number of baseline lesions (T/P) prior to the initial occurrence of clinical outcome or censored date, we divided patients into different groups. The principal outcome was clinical worsening. Results: After stratifying patients by the number of performed BPA sessions, most baseline parameters were comparable among groups. During follow-up, 31 (16.7%) of 186 patients experienced clinical worsening. The 6-month cumulative clinical worsening-free survival rates of ⩾2 performed sessions group were significantly higher than that of 1 performed session group. The 12-month cumulative rates of clinical worsening-free survival exhibited a declining pattern in the subsequent sequence: ⩾3, 2, and 1 performed BPA sessions, and this trend persisted when follow-up time exceeded 12 months. The 6-, 12-, and 24-month cumulative clinical worsening-free survival rates were comparable between patients with 3 and ⩾4 performed BPA sessions. Similar results were also observed when stratifying patients by the accumulative number of treated pulmonary vessels (⩽8, 9–16, ⩾17) and T/P (⩽0.789, 0.790–1.263, ⩾1.264). Conclusion: To achieve optimal short-term outcomes, patients might need to undergo ⩾2 BPA sessions or have ⩾9 pulmonary vessels treated or have T/P ⩾0.790 within 6 months, and undergo ⩾3 BPA sessions or have ⩾17 pulmonary vessels treated or have T/P ⩾1.264 within 12 months. Plain language summary The least number of BPA session to reach a favorable outcome Why was the study done? Balloon pulmonary angioplasty (BPA) has been recommended for patients with chronic thromboembolic pulmonary hypertension, which can significantly improve patients’ hemodynamics. However, BPA is typically performed in a stepwise manner, and the duration from the initial session to the final session could extend over a year. If patients could not quickly undergo adequate number of BPA sessions and reach hemodynamic target due to various reasons, what is the best frequency of BPA for them? What did the researchers do? We retrospectively enrolled 186 BPA-treated patients diagnosed with chronic thromboembolic pulmonary hypertension. According to the accumulative number of BPA sessions, we divided patients into different groups to identify the best frequency of BPA to improve prognosis. What did the researchers find? Patients who received at least two BPA sessions within six months had significantly better prognosis than those with one BPA session. Patients who received at least three BPA sessions within a year had significantly better prognosis than those with two BPA sessions. What do the findings mean? To achieve optimal short-term outcome, patients might need to undergo at least two BPA sessions within six months, and undergo at least three BPA sessions within a year.