Unfavorable Prognosis In Patients Research Articles

Relationship between the severity of functional mitral regurgitation at admission and one-year outcomes in patients hospitalized for acute heart failure with mildly reduced ejection fraction

BackgroundThe epidemiological distribution of functional mitral regurgitation (FMR) in heart failure (HF) and mildly reduced ejection fraction (HFmrEF) patients and its impact on outcomes remains unclear. We attempt to investigate the prognosis of FMR in patients with HFmrEF.MethodsThe HF center registry study is a prospective, single, observational study conducted at the Second Affiliated Hospital of Shenzhen University, where 2330 patients with acute HF (AHF) were enrolled and 890 HFmrEF patients were included in the analysis. The patients were stratified into three categories based on the severity of FMR: none/mild, moderate, and moderate-to-severe/severe groups. Subsequently, a comparison of the clinical characteristics among these groups was conducted, along with an assessment of the incidence of the primary endpoint (comprising all-cause mortality and readmission for HF) during a one-year follow-up period.ResultsThe one-year follow-up results indicated that the primary composite endpoint occurrence rates in the three groups were 23.5%, 32.9%, and 36.5%, respectively. The all-cause mortality rates in the three groups were 9.3%, 13.7%, and 16.4% respectively. Survival analysis demonstrated a statistically significant difference in the occurrence rates of the primary composite endpoint and all-cause mortality among the three groups (P < 0.05). Multifactor Cox regression revealed that moderate FMR and moderate-to-severe/severe FMR were independent risk factors for adverse clinical prognosis in HFmrEF patients, with hazard ratios and 95% confidence intervals of 1.382 (1.020–1.872, P = 0.037) and 1.546 (1.092–2.190, P = 0.014) respectively.ConclusionsModerate FMR and moderate-to-severe/severe FMR independently predict an unfavorable prognosis in patients with HFmrEF.

Frailty as an Independent Predictor of Adverse Outcomes in Patients Undergoing Direct Myocardial Revascularization.

The study included 387 patients admitted to the clinic for a scheduled primary CABG. A seven-item questionnaire, "PRISMA-7", was used to identify frail elderly patients before the procedure. We divided the study sample into two groups, taking into account the results of the survey: patients without frailty, n0 = 300 (77.5%), and patients with frailty, n1 = 87 (22.5%). The anamnestic and laboratory data, outcome of the surgical intervention, perioperative and early complications, and adverse outcomes were analyzed. We detected frailty in 22.5% of the patients with CAD before the procedure. According to the anamnestic data and paraclinical and intraoperative findings, the groups of patients with and without frailty were comparable. The differences were revealed in the intraoperative and early postoperative periods of CABG. Thus, postoperative rhythm disturbances (19.5% vs. 10.5%, p = 0.025, V = 0.115, respectively) and transient ischemic attacks/stroke (5.7% vs. 1.3%, p = 0.031, V = 0.122, respectively) occurred significantly more often among the frail patients. There were no significant differences between the groups in the frequency of other intraoperative and early postoperative complications. In the group of frail patients, four fatal outcomes due to early postoperative ischemia were recorded, and among patients without frailty, one fatal outcome was recorded (4.5% vs. 0.3%, p = 0.010, V = 0.156, respectively). At the 1-year follow-up visit, the presence of frailty in history served as a predictor of mortality (11.5% vs. 0.6%, p ˂ 0.001, V = 0.290, respectively). The presence of frailty can be used as an independent predictor of an unfavorable prognosis in patients with CAD, both in the perioperative and early survival period after CABG. It should be taken into account during surgical risk assessment.

Early Hydrogen–Oxygen Gas Mixture Inhalation in Patients with Aneurysmal Subarachnoid Hemorrhage (HOMA): study protocol for a randomized controlled trial

BackgroundAneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening neurosurgical emergency with a high mortality rate. Delayed cerebral ischemia (DCI) and cerebral vasospasm (CVS) are delayed products of early brain injury (EBI), which may constitute the principal determinant of an unfavorable patient prognosis. Consequently, the mitigation of DCI and CVS assumes paramount significance in the pursuit of enhanced patient outcomes. However, except for oral nimodipine, there is no effective therapy available in the current guideline. Hence, the exigency arises to proffer novel treatment paradigms. The diversity of hydrogen therapeutic targets has been largely reported in basic research, unveiling its latent capacity to ameliorate EBI in aSAH patients.MethodsEarly Hydrogen–Oxygen Gas Mixture Inhalation in Patients with Aneurysmal Subarachnoid Hemorrhage (HOMA), a single-center, prospective, open-labeled, randomized controlled clinical trial, endeavors to evaluate the efficacy and safety of hydrogen–oxygen gas mixture inhalation therapy in aSAH patients. A cohort of 206 patients will be randomized to either hydrogen–oxygen gas mixture inhalation group (8 h per day, 3 L/min, hydrogen concentration of 67%, oxygen concentration of 33%) or oxygen inhalation group (8 h per day, 3 L/min, oxygen concentration of 33%) within 72 h after aSAH and treated for 7 days in the ICU ward. The primary outcomes are the incidence of DCI and CVS during hospitalization.DiscussionThe HOMA aims to evaluate the effectiveness of hydrogen–oxygen gas mixture inhalation therapy in preventing DCI or CVS and improving outcomes in aSAH patients. Notably, this is the first large-scale trial of hydrogen therapy in aSAH patients. Given that the Chinese population represents a significant portion of the global population and the increasing incidence of stroke due to aging, optimizing patient care is vital. Given the current challenges in aSAH patient outcomes, initiating more prospective clinical trials is essential. Recent research has shown hydrogen’s therapeutic potential, aligning with EBI in aSAH, driving our exploration of hydrogen therapy’s mechanisms in post-aneurysm rupture damage.Ethics and disseminationThe protocol for the HOMA study was approved by the Ethics Committee of Beijing Tiantan Hospital, Capital Medical University (KY 2022–020-02). All results of the present study will be published in peer-reviewed journals and presented at relevant conferences.Trial registrationClinicalTrials.gov NCT05282836. Registered on March 16, 2022.

SAT-111 Lower levels of Insulin-like growth factor 1 are independently associated with unfavorable prognosis in patients with advanced chronic liver disease

SAT-111 Lower levels of Insulin-like growth factor 1 are independently associated with unfavorable prognosis in patients with advanced chronic liver disease

Factors of unfavorable prognosis in patients with non-high risk pulmonary embolism

Abstract Introduction Pulmonary embolism (PE) nowadays is the third leading cause of death in the structure of cardiovascular mortality after myocardial infarction and stroke. Most of patients (pts) with PE are with non-high risk. According to the latest guidelines PESI and sPESI scores are used to predict 30-day outcome of non-high-risk pts. Nevertheless, the question of additional factors which are not included in PESI and sPESI scores and which may be associated with prognosis in such pts remains poorly understood. Purpose To identify factors associated with in-hospital mortality in non-high-risk PE pts. Methods A retrospective analysis of 635 medical cards of pts with diagnosis "PE" hospitalized in our clinical hospital during 2017 – 2023 period. The diagnosis was verified by multispiral computed tomography angiography (CTPA) of pulmonary arteries and/or by autopsy. There were 530 non-high-risk pts (83,4%). Pts were divided into groups: І group - pts who were discharged from hospital with improved status (479 – 90,4%), II group - pts who died in hospital (51 – 9,6%). Clinical, anamnestic, laboratory and instrumental parameters were measured. Statistical analysis was performed. Results According to multivariate analysis of variance, independent factors, which were associated with in-hospital mortality in pts with non-high-risk PE, were: the presence of atrial fibrillation, obesity, age, history of venous thromboembolism, lower levels of O2 saturation, systolic blood pressure (SBP) and higher pulmonary artery pressure (PAP). ROC analysis was performed to determine the thresholds of factors that were associated with in-hospital mortality: SBP ≤124 mmHg, HR≥110 bpm, PAP ≥54 mmHg, age&amp;gt;54 yo. Conclusions The factors which were associated with in-hospital mortality in pts with non-high-risk PE were: age, SBP, history of VTE, obesity, AF; blood saturation level, pulmonary artery pressure level.

Augmentation of hepatocellular carcinoma malignancy by annexin A5 through modulation of invasion and angiogenesis

ABSTRUCT Background Hepatocellular carcinoma (HCC) continues to play a substantial role in cancer-related morbidity and mortality, largely owing to its pronounced tumor heterogeneity and propensity for recurrence. This underscores the pressing need for in-depth examination of its highly malignant mechanisms. Annexin A5 (ANXA5), recognized as a hallmark tumor protein, has emerged as a focal point of interest because of its ambiguous function and mechanism in HCC prognosis. This study aimed to provide a comprehensive understanding of the role of ANXA5 in the malignant progression of human HCC cells by employing an integrative approach that combines conventional experimental methods with RNA sequencing. Methods Differences in ANXA5 expression between HCC tissues and corresponding nontumor tissues were evaluated using immunofluorescence (n = 25). Correlation analysis was subsequently performed to assess the association between ANXA5 expression and clinicopathological features (n = 65). The role of ANXA5 in human HCC cell lines with ANXA5 gene knockout and overexpression was explored in vitro using migration and invasion assays and Ki-67 indices and in vivo based on node mice xenograft model. A tube formation assay using human umbilical vein endothelial cells (HUVECs) was conducted to demonstrate the angiogenic effects of ANXA5 in HCC. Single-cell and bulk RNA sequencing was used to further investigate the underlying mechanisms involved. Results This study revealed that ANXA5 is highly expressed in patients with HCC and correlates with poor prognosis. Assays for migration, invasion, and proliferation based on ANXA5 gene knockout and overexpression systems in human HCC cell lines have demonstrated that ANXA5 enhances HCC malignancy in vitro and in vivo. Tube formation assays of HUVECs indicated that ANXA5 facilitates angiogenesis and recruits endothelial cells to HCC cells. Single-cell and bulk RNA sequencing data analysis further confirmed that ANXA5 expression in HCC is associated with hepatocyte metabolism, immune response activation, and various oncogenic signaling pathways. Conclusions This study revealed a meaningful association between elevated ANXA5 expression in tumor tissues and an unfavorable prognosis in patients with HCC. In addition, ANXA5 promotes HCC malignancy by promoting invasion and angiogenesis. Thus, ANXA5 has emerged as a promising therapeutic target for HCC and has the potential to improve patient outcomes.

Risk factors and clinical prediction models for prolonged mechanical ventilation after heart valve surgery

ObjectivesProlonged mechanical ventilation (PMV) is a common complication following cardiac surgery linked to unfavorable patient prognosis and increased mortality. This study aimed to search for the factors associated with the occurrence of PMV after valve surgery and to develop a risk prediction model.MethodsThe patient cohort was divided into two groups based on the presence or absence of PMV post-surgery. Comprehensive preoperative and intraoperative clinical data were collected. Univariate and multivariate logistic regression analyses were employed to identify risk factors contributing to the incidence of PMV. Based on the logistic regression results, a clinical nomogram was developed.ResultsThe study included 550 patients who underwent valve surgery, among whom 62 (11.27%) developed PMV. Multivariate logistic regression analysis revealed that age (odds ratio [OR] = 1.082, 95% confidence interval [CI] = 1.042–1.125; P < 0.000), current smokers (OR = 1.953, 95% CI = 1.007–3.787; P = 0.047), left atrial internal diameter index (OR = 1.04, 95% CI = 1.002–1.081; P = 0.041), red blood cell count (OR = 0.49, 95% CI = 0.275–0.876; P = 0.016), and aortic clamping time (OR = 1.031, 95% CI = 1.005–1.057; P < 0.017) independently influenced the occurrence of PMV. A nomogram was constructed based on these factors. In addition, a receiver operating characteristic (ROC) curve was plotted, with an area under the curve (AUC) of 0.782 and an accuracy of 0.884.ConclusionAge, current smokers, left atrial diameter index, red blood cell count, and aortic clamping time are independent risk factors for PMV in patients undergoing valve surgery. Furthermore, the nomogram based on these factors demonstrates the potential for predicting the risk of PMV in patients following valve surgery.

Hyperuricemia and acute decompensation of heart failure: is there a causative link? A review

The relevance and importance of the problem of acute decompensation of heart failure for the health care system not only in Russia, but also in the whole world is caused by a significant increase in the number of hospitalizations, associated increase in financial costs and extremely unfavorable prognosis in this group of patients. The article is devoted to the pathogenesis of acute decompensation of heart failure and the place of asymptomatic hyperuricemia in the development of this condition. Hyperuricemia is considered as a prognostic marker of unfavorable prognosis in patients with both cardiovascular diseases in general and acute decompensation of heart failure in particular. Special emphasis is made on approaches to drug therapy, tactics of xanthine oxidase inhibitor allopurinol use, doses are analyzed in terms of efficacy, influence on prognosis, methods of achieving and controlling target values of hyperuricemia are discussed.

Hemodynamic Changes in Intrarenal Blood Flow are Associated With Poor Prognosis in Patients With Acute Decompensated Heart Failure.

To evaluate a potential role of different patterns of intrarenal blood flow using Doppler ultrasound as a part of determining the severity of venous congestion, predicting impairment of renal function and an unfavorable prognosis in patients with acute decompensated chronic heart failure (ADCHF). This prospective observational single-site study included 75 patients admitted in the intensive care unit for ADCHF. Upon admission all patients underwent bedside renal venous Doppler ultrasound to determine the blood flow pattern (continuous, biphasic, monophasic). In one hour after the initiation of intravenous diuretic therapy, sodium concentration was measured in a urine sample. The primary endpoint was the development of acute kidney injury (AKI). The secondary endpoints were the development of diuretic resistance (a need to increase the furosemide daily dose by more than 2 times compared with the baseline), decreased natriuretic response (defined as urine sodium concentration less than 50-70 mmol/l), and in-hospital death. According to the data of Doppler ultrasound, normal renal blood flow was observed in 40 (53%) patients, biphasic in 21 (28%) patients, and monophasic in 14 (19%) patients. The monophasic pattern of intrarenal blood flow was associated with the highest incidence of AKI: among 14 patients in this group, AKI developed in 100% of cases (OR 3.8, 95% CI: 2.5-5.8, p&lt;0.01), while among patients with normal and moderate impairment of renal blood flow, there was no significant increase in the risk of developing AKI. The odds of in-hospital death were increased 25.77 times in patients with monophasic renal blood flow (95% CI: 5.35-123.99, p&lt;0.001). Patients with a monophasic intrarenal blood flow pattern were also more likely to develop diuretic resistance compared to patients with other blood flow patterns (p&lt;0.001) and had a decreased sodium concentration to less than 50 mmol/l (p&lt;0.001) in a spot urine test obtained one hour after the initiation of furosemide administration. Patients with monophasic intrarenal blood flow are at a higher risk of developing AKI, diuretic resistance with decreased natriuretic response, and in-hospital death.

Predictors of Unfavorable Prognosis in Patients with Heart Failure After Cardioverter-Defibrillator Implantation According to the Prospective Part of the Kuzbass Registry.

Identification of clinical and instrumental predictors for non-arrhythmic death in patients with heart failure (HF) and implantable cardioverter-defibrillator (ICD). Through a telephone survey and examination of medical records from hospital and polyclinic databases, data were obtained on the alive/dead status and causes of death for 260 patients with heart failure (HF) and ICD included in the Kuzbass Registry of Patients with ICD. The follow-up period was 1.5 years. Clinical and instrumental parameters entered into the registry before the ICD implantation were included in a univariate and multivariate step-by-step analysis using the logistic (for qualitative variables) and linear (for quantitative variables) regression with calculation of regression coefficients and construction of a prognostic regression model. The quality of the created model was assessed using a ROC analysis. During the observation period, 54 (20.8%) patients died. In 21 (38.8%) patients, death occurred in the hospital and was caused by acute decompensated heart failure in 15 (71.4%) patients, myocardial infarction in 3 (14.3%) patients, stroke in 1 (4.7%) patient, and pneumonia in 2 (9.5%) patients. 33 (61.2%) patients died outside the hospital; the cause of death was stated as the underlying disease associated with acute decompensated heart failure: in 9 (27.2%) patients, dilated cardiomyopathy; in 1 (3.0%) patient, rheumatic mitral disease; and in 23 (69.7%) patients, ischemic cardiomyopathy. According to the univariate regression model, the risk of death in the long-term period was increased by the QT interval prolongation (U 2.41, p = 0.0161); elevated pulmonary artery systolic pressure (U 4.30, p=0.0000) and increased left atrial size according to echocardiography (U 2.98, p=0.0029); stage IIB HF (OR 2.41; 95% CI: 1.26-4.6), NYHA III-IV (OR 3.03; 95% CI: 1.58-5.81); chronic obstructive pulmonary disease (OR 5.24; 95% CI: 2.04-13.45); and lack of optimal drug therapy (ODT) for HF before ICD implantation (OR 2.41; 95% CI: 1.29-4.49). The multivariate analysis identified the most significant factors included in the prognostic regression model: pulmonary artery systolic pressure above 45 mm Hg, social status, chronic obstructive pulmonary disease, and lack of ODT for HF. To ensure a maximum benefit from ICD, the factors that increase the likelihood of non-arrhythmic death should be considered before making a decision on ICD implantation. Particular attention should be paid to mandatory ODT for HF as the main modifiable risk factor for unfavorable prognosis.

Levels of cardiac biomarkers and three-year survival rate in hospitalized patients with heart failure and community-acquired pneumonia

Aim. To evaluate the impact of community-acquired pneumonia (CAP) on the levels of cardiac biomarkers and long-term survival rate in patients with heart failure (HF).Material and methods. The prospective observational single-center study included 132 patients (73 men, 59 women); mean age — 72,3±12,1 years, consecutively hospitalized at Clinical Hospital № 4 of the I. M. Sechenov First Moscow State Medical University with decompensated heart failure in the period from March 2018 to December 2019. The main (n=40) and comparison group (n=92) included patients with and without clinical and CT signs of CAP, respectively.Results. Patients with HF and CAP and HF without CAP were comparable in sex, age, and severity of HF. CAP in most patients met the criteria for non-severe pneumonia (average CURB-65 score — 1,55±0,73). The levels of N-terminal probrain natriuretic peptide (NT-proBNP) in patients with HF with CAP (1188,9 [439; 2493] pg/ml) were insignificantly higher than in patients with HF without CAP (839,6 [413; 1900]) pg/ml (p&gt;0,05). A similar pattern was noted for the soluble growth stimulation expressed gene 2 (sST2) (30,85 [12,8; 59,6] ng/ml vs 22,8 [15,2; 44,7] ng/ml, p&gt;0,05). The haptoglobin level in patients with CAP was significantly lower (732 [315; 1312] ng/l), compared to the group without CAP (1270 [902; 2022] ng/l, p=0,0022). No differences in the concentrations of galectin-3, copeptin and hepcidin were detected. The one-year mortality rate of patients who underwent CAP was 27,3%, and without CAP — 7,2% (p&lt;0,001), while the three-year mortality rate was 44,9% and 21,4%, respectively (p=0,0004). Elevated levels of NT-proBNP and sST2, along with age over 75 years and left ventricular ejection fraction &lt;40%, are additional factors of poor prognosis in patients with HF and CAP.Conclusion. CAP in patients with HF does not have a significant effect on most cardiac biomarkers, but significantly worsens the prognosis. Independent factors of unfavorable prognosis in patients with HF and CAP are age over 75 years, left ventricular ejection fraction &lt;40%, increased NT-proBNP and sST2 levels.

CK2α-mediated phosphorylation of GRP94 facilitates the metastatic cascade in triple-negative breast cancer

Distant metastasis is a significant hallmark affecting to the high death rate of patients with triple-negative breast cancer (TNBC). Thus, it is crucial to identify and develop new therapeutic strategies to hinder cancer metastasis. While emerging studies have hinted a pivotal role of glucose-regulated protein 94 (GRP94) in tumorigenesis, the exact biological functions and molecular mechanisms of GRP94 in modulating cancer metastasis remain to be elucidated. Our study demonstrated an increased expression of GRP94 in TNBC correlated with metastatic progression and unfavorable prognosis in patients. Functionally, we identified that GRP94 depletion significantly diminished TNBC tumorigenesis and subsequent lung metastasis. In contrast, GRP94 overexpression exacerbated the invasiveness, migration, and lung metastasis of non-TNBC cells. Mechanistically, we found that casein kinase 2 alpha (CK2α) active in advanced breast cancer phosphorylated GRP94 at a conserved serine 306 (S306) residue. This phosphorylation increased the stability of GRP94 and enhanced its interaction with LRP6, leading to activation of canonical Wnt signaling. From a therapeutic standpoint, we found that benzamidine, a novel CK2α inhibitor, effectively suppressed GRP94 phosphorylation, LRP6 stabilization, and metastasis of TNBC. Our results point to the critical role of CK2α-mediated GRP94 phosphorylation in TNBC metastasis through activation of Wnt signaling, highlighting GRP94 as a therapeutic target to impede TNBC metastasis.

Kinase activities in pancreatic ductal adenocarcinoma with prognostic and therapeutic avenues.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a limited number of known driver mutations but considerable cancer cell heterogeneity. Phosphoproteomics provides a direct read-out of aberrant signaling and the resultant clinically relevant phenotype. Mass spectrometry (MS)-based proteomics and phosphoproteomics were applied to 42 PDAC tumors. Data encompassed over 19 936 phosphoserine or phosphothreonine (pS/T; in 5412 phosphoproteins) and 1208 phosphotyrosine (pY; in 501 phosphoproteins) sites and a total of 3756 proteins. Proteome data identified three distinct subtypes with tumor intrinsic and stromal features. Subsequently, three phospho-subtypes were apparent: two tumor intrinsic (Phos1/2) and one stromal (Phos3), resembling known PDAC molecular subtypes. Kinase activity was analyzed by the Integrative iNferred Kinase Activity (INKA) scoring. Phospho-subtypes displayed differential phosphorylation signals and kinase activity, such as FGR and GSK3 activation in Phos1, SRC kinase family and EPHA2 in Phos2, and EGFR, INSR, MET, ABL1, HIPK1, JAK, and PRKCD in Phos3. Kinase activity analysis of an external PDAC cohort supported our findings and underscored the importance of PI3K/AKT and ERK pathways, among others. Interestingly, unfavorable patient prognosis correlated with higher RTK, PAK2, STK10, and CDK7 activity and high proliferation, whereas long survival was associated with MYLK and PTK6 activity, which was previously unknown. Subtype-associated activity profiles can guide therapeutic combination approaches in tumor and stroma-enriched tissues, and emphasize the critical role of parallel signaling pathways. In addition, kinase activity profiling identifies potential disease markers with prognostic significance.

Prognostic Impact of Left Atrial Appendage Patency After Device Closure.

The prognostic impact of left atrial appendage (LAA) patency, including those with and without visible peri-device leak (PDL), post-LAA closure in patients with atrial fibrillation, remains elusive. Patients with atrial fibrillation implanted with the WATCHMAN 2.5 device were prospectively enrolled. The device surveillance by cardiac computed tomography angiography was performed at 3 months post-procedure. Adverse events, including stroke/transient ischemic attack (TIA), major bleeding, cardiovascular death, all-cause death, and the combined major adverse events (MAEs), were compared between patients with complete closure and LAA patency. Among 519 patients with cardiac computed tomography angiography surveillance at 3 months post-LAA closure, 271 (52.2%) showed complete closure, and LAA patency was detected in 248 (47.8%) patients, including 196 (37.8%) with visible PDL and 52 (10.0%) without visible PDL. During a median of 1193 (787-1543) days follow-up, the presence of LAA patency was associated with increased risks of stroke/TIA (adjusted hazard ratio for baseline differences, 3.22 [95% CI, 1.17-8.83]; P=0.023) and MAEs (adjusted hazard ratio, 1.12 [95% CI, 1.06-1.17]; P=0.003). Specifically, LAA patency with visible PDL was associated with increased risks of stroke/TIA (hazard ratio, 3.66 [95% CI, 1.29-10.42]; P=0.015) and MAEs (hazard ratio, 3.71 [95% CI, 1.71-8.07]; P=0.001), although LAA patency without visible PDL showed higher risks of MAEs (hazard ratio, 3.59 [95% CI, 1.28-10.09]; P=0.015). Incidences of stroke/TIA (2.8% versus 3.0% versus 6.7% versus 22.2%; P=0.010), cardiovascular death (0.9% versus 0% versus 1.7% versus 11.1%; P=0.005), and MAEs (4.6% versus 9.0% versus 11.7% versus 22.2%; P=0.017) increased with larger PDL (0, >0 to ≤3, >3 to ≤5, or >5 mm). Older age and discontinuing antiplatelet therapy at 6 months were independent predictors of stroke/TIA and MAEs in patients with LAA patency. LAA patency detected by cardiac computed tomography angiography at 3 months post-LAA closure is associated with unfavorable prognosis in patients with atrial fibrillation implanted with WATCHMAN 2.5 device. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03788941.

Prediction of trends in unfavorable prognosis in patients with acute ischemic stroke according to low left ventricular ejection fraction levels

As few studies have reported the impact of lower left ventricular ejection fraction (LVEF) on the prognosis of acute ischemic stroke (AIS) patients, we aimed to explore this through a retrospective cohort study and a meta-analysis. A total of 283 AIS patients receiving intravenous thrombolysis at the Third Affiliated Hospital of Wenzhou Medical University between 2016 and 2019 were enrolled and divided into three groups based on LVEF tertiles. The logistic regression model estimated the association between LVEF and the three-month AIS prognosis. After adjusting for confounding factors, patients in tertile 3 exhibited an increased risk of poor functional outcome and mortality [odds ratio (OR), 2.656 (95% CI: 1.443–4.889); OR, 7.586 (95% CI: 2.102–27.375)]. A systematic search of PubMed, EMBASE and Cochrane Library was performed. Our meta-analysis revealed that LVEF < 40% was significantly associated with poor functional outcome [OR 1.94 (95% CI: 1.08–3.50)], mortality [OR 3.69 (95% CI: 1.22–11.11)], as well as LVEF < 55% [OR 1.68 (95% CI: 1.22–2.32); 2.27 (95% CI: 1.30–3.96)], respectively. A decreased LVEF could predict an inferior prognosis for AIS; therefore, it could aid in clinical decision-making in this patient population.

Molecular subtyping and the construction of a predictive model of colorectal cancer based on ion channel genes

PurposeColorectal cancer (CRC) is a highly heterogeneous malignancy with an unfavorable prognosis. The purpose of this study was to address the heterogeneity of CRC by categorizing it into ion channel subtypes, and to develop a predictive modeling based on ion channel genes to predict the survival and immunological states of patients with CRC. The model will provide guidance for personalized immunotherapy and drug treatment.MethodsA consistent clustering method was used to classify 619 CRC samples based on the expression of 279 ion channel genes. Such a method was allowed to investigate the relationship between molecular subtypes, prognosis, and immune infiltration. Furthermore, a predictive modeling was constructed for ion channels to evaluate the ion channel properties of individual tumors using the least absolute shrinkage and selection operator. The expression patterns of the characteristic genes were validated through molecular biology experiments. The effect of potassium channel tetramerization domain containing 9 (KCTD9) on CRC was verified by cellular functional experiments.ResultsFour distinct ion channel subtypes were identified in CRC, each characterized by unique prognosis and immune infiltration patterns. Notably, Ion Cluster3 exhibited high levels of immune infiltration and a favorable prognosis, while Ion Cluster4 showed relatively lower levels of immune infiltration and a poorer prognosis. The ion channel score could predict overall survival, with lower scores correlated with longer survival. This score served as an independent prognostic factor and presented an excellent predictive efficacy in the nomogram. In addition, the score was closely related to immune infiltration, immunotherapy response, and chemotherapy sensitivity. Experimental evidence further confirmed that low expression of KCTD9 in tumor tissues was associated with an unfavorable prognosis in patients with CRC. The cellular functional experiments demonstrated that KCTD9 inhibited the proliferation, migration and invasion capabilities of LOVO cells.ConclusionsIon channel subtyping and scoring can effectively predict the prognosis and evaluate the immune microenvironment, immunotherapy response, and drug sensitivity in patients with CRC.

SEPT3 as a Potential Molecular Target of Triple-Negative Breast Cancer.

The survival rate for triple-negative breast cancer (TNBC) is very low due to its advanced metastatic and aggressive nature, and there is no specific target to improve the survival rate. The expression and clinical signature of neuronal-specific septin-3 (Septin3, SEPT3) in TNBC remain undetermined. SEPT3 differential expression in TNBC was detected with the use of bioinformatic approaches based on TCGA and GEO database, which was verified with immunohistochemistry in TNBC tissues. Next, the effect of SEPT3 on survival and the association between SEPT3 expression and clinical characteristics were assessed for TNBC patients. We performed Cox analysis to evaluate whether SEPT3 is an independent predictor for TNBC patients. SEPT3 was identified as a key differentially expressed gene. SEPT3 was observed to be elevated in 112 TNBC significantly. Increased expression of SEPT3 contributed to an unfavorable prognosis in patients with TNBC. Additionally, SEPT3 was associated with several factors including TNM stage, lymph node metastasis, Ki67 level and histological grade. SEPT3 was determined to be an independent risk factor for TNBC patients through Cox regression analysis. This study demonstrated that SEPT3 could be a potential disease marker for TNBC patients by bioinformatics analysis and validation in clinical samples.

Identification of a prognosis-related gene signature and ceRNA regulatory networks in lung adenocarcinoma

The ceRNA network, consisting of both noncoding RNA and protein-coding RNA, governs the occurrence, progression, metastasis, and infiltration of lung adenocarcinoma. Signatures comprising multiple genes can effectively determine survival stratification and prognosis of patients with lung adenocarcinoma. To explore the mechanisms of lung adenocarcinoma progression and identify potential biological targets, we carried out systematic bioinformatics analyses of the genetic profiles of lung adenocarcinoma, such as weighted gene co-expression network analysis (WGCNA), differential expression (DE) assessment, univariate and multivariate Cox proportional hazard regression models, ceRNA modulatory networks generated using the ENCORI and miRcode databases, nomogram models, ROC curve assessment, and Kaplan-Meier survival curve analysis. The ceRNA network encompassed 37 nodes, comprising 12 mRNAs, 22 lncRNAs, and three miRNAs. Simultaneously, we performed integration analysis using the 12 genes from the ceRNA network. Our findings revealed that the signature established by these 12 genes serves as an adverse element in lung adenocarcinoma, contributing to unfavorable patient prognosis. To ensure the credibility of our results, we used in vitro experiments for further verification. In conclusion, our study delved into the potential mechanisms underlying lung adenocarcinoma via the ceRNA regulatory network, specifically focusing on the PIF1 and has-miR-125a-5p axis. Additionally, a signature comprising 12 genes was identified as a biomarker related to the prognosis of lung adenocarcinoma.

SPDEF drives pancreatic adenocarcinoma progression via transcriptional upregulation of S100A16 and activation of the PI3K/AKT signaling pathway.

Pancreatic adenocarcinoma (PAAD) is a notably aggressive malignancy with limited treatment options and an unfavorable prognosis for patients. We aimed to investigate molecular mechanisms by which Sam's pointed domain-containing ETS transcription factor (SPDEF) exerts effects on PAAD progression. We analyzed differentially expressed genes (DEGs) and their integration with ETS family members using the The Cancer Genome Atlas (TCGA) database, hence identifying SPDEF as a core gene in PAAD. Kaplan-Meier survival analysis confirmed SPDEF's prognostic potential. In vitro experiments validated the association with cell proliferation and apoptosis, affecting pancreatic cancer cell dynamics. We detected increased SPDEF expression in PAAD tumor samples. Our in vitro studies revealed that SPDEF regulates mRNA and protein expression levels, and significantly affects cell proliferation. Moreover, SPDEF was associated with reduced apoptosis and enhanced cell migration and invasion. In-depth analysis of SPDEF-targeted genes revealed four crucial genes for advanced prognostic model, among which S100A16 was significantly correlated with SPDEF. Mechanistic analysis showed that SPDEF enhances the transcription of S100A16, which in turn enhances PAAD cell migration, proliferation, and invasion by activating the PI3K/AKT signaling pathway. Our study revealed the critical role of SPDEF in promoting PAAD by upregulating S100A16 transcription and stimulating the PI3K/AKT signaling pathway. This knowledge deepened our understanding of pancreatic cancer's molecular progression and unveiled potential therapeutic strategies targeting SPDEF-driven pathways.

Abstract 6524: Single-cell landscape of cancer-associated fibroblasts in immunotherapy resistance of hepatocellular carcinoma

Abstract Introduction: The advent of immune checkpoint blockade (ICB) therapy has revolutionized the treatment approach for hepatocellular carcinoma (HCC). However, the response rate to ICB therapy remains low (below 20%). This limited response rate can be attributed to the considerable heterogeneity observed in HCC cells and the tumor microenvironment (TME). Recent research has highlighted the pivotal role of cancer-associated fibroblasts (CAFs) in orchestrating various components within the TME of HCC. Although the significance of lipid metabolism-associated CAFs in the efficacy of ICB therapy has been demonstrated in HCC murine models [1], the functions and contributions of other CAF subtypes remain largely unknown. Therefore, identifying CAF heterogeneity could advance our comprehension of HCC TME and potentially augment ICB efficacy. Methods: We performed single-cell RNA sequencing on tumor biopsy specimens obtained from patients with advanced HBV-related HCC who had participated in a pembrolizumab (anti-PD1) phase II clinical trial (NCT03419481). Our objective was to examine the dynamic alterations in the HCC TME before and during anti-PD1 treatment (upon 2-cycle). We utilized the Seurat and Cellchat packages for bioinformatics analysis which enabled us to investigate the associations between changes in the proportions of CAF subtypes and the patients' clinical responses, as well as the potential cell-cell interactions involving CAF and other TME components. Results: We identified four CAF subtypes within the TME: cycling, inflammatory, matrix, and vascular CAFs in our anti-PD1 HCC patient cohort. Among the anti-PD1 non-responders, there was a significant increase in the proportions of cycling CAFs (cCAFs) and matrix CAFs (matCAFs) compared to the responders. Notably, matCAFs exhibited a high enrichment of Gene Ontology (GO) Terms related to the extracellular matrix (ECM), whose higher proportion correlated with poor prognosis of patients. Moreover, a distinct collagen pathway signal was found between matCAFs and two immunosuppressive cell types, namely regulatory T cells and M2 macrophages in the non-responders. Discussion and Conclusion: The presence of matCAFs within the HCC tumor may associate with the development of an immunosuppressive TME and unfavorable prognosis for patients. Targeting this specific CAF subtype holds promise as a potential strategy to overcome resistance to ICB therapy. Acknowledgments: The CUHK Strategic Seed Funding for Collaborative Research Scheme and The Li Ka Shing Foundation.