PFKFB3 regulates breast cancer tumorigenesis and Fulvestrant sensitivity by affecting ERα stability.

Estrogen receptor alpha (ERα) is expressed in approximately 70% of breast cancer cases and determines the sensitivity and effectiveness of endocrine therapy. 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase3 (PFKFB3) is a glycolytic enzyme that is highly expressed in a great many human tumors, and recent studies have shown that it plays a significant role in improving drug sensitivity. However, the role of PFKFB3 in regulating ERα expression and the underlying mechanism remains unclear. Here, we find by using immunohistochemistry (IHC) that PFKFB3 is elevated in ER-positive breast cancer and high expression of PFKFB3 resulted in a worse prognosis. In vitro and in vivo experiments verify that PFKFB3 promotes ER-positive breast cancer cell proliferation. The overexpression of PFKFB3 promotes the estrogen-independent ER-positive breast cancer growth. In an estrogen-free condition, RNA-sequencing data from MCF7 cells treated with siPFKFB3 showed enrichment of the estrogen signaling pathway, and a luciferase assay demonstrated that knockdown of PFKFB3 inhibited the ERα transcriptional activity. Mechanistically, down-regulation of PFKFB3 promotes STUB1 binding to ERα, which accelerates ERα degradation by K48-based ubiquitin linkage. Finally, growth of ER-positive breast cancer cells in vivo was more potently inhibited by fulvestrant combined with the PFKFB3 inhibitor PFK158 than for each drug alone. In conclusion, these data suggest that PFKFB3 is identified as an adverse prognosis factor for ER-positive breast cancer and plays a previously unrecognized role in the regulation of ERα stability and activity. Our results further explores an effective approach to improve fulvestrant sensitivity through the early combination with a PFKFB3 inhibitor.

ImmunoPET/CT imaging of clear cell renal cell carcinoma with [18F]RCCB6: a first-in-human study.

PURPOSE: The cluster of differentiation (CD70) is a potential biomarker of clear cell renal cell carcinoma (ccRCC). This study aims to develop CD70-targeted immuno-positron emission tomography/computed tomography (immunoPET/CT) imaging tracers and explore the diagnostic value in preclinical studies and the potential value in detecting metastases in ccRCC patients. METHODS: Four novel CD70-specific single-domain antibodies (sdAbs) were produced and labelled with 18F by the aluminium fluoride restrained complexing agent (AlF-RESCA) method to develop radiotracers. The visualisation properties of the tracers were evaluated in a subcutaneous ccRCC patient-derived xenograft (PDX) model. In a registered prospective clinical trial (NCT06148220), six patients with pathologically confirmed RCC were included and underwent immunoPET/CT examination exploiting one of the developed tracers (i.e., [18F]RCCB6). RESULTS: We engineered four sdAbs (His-tagged RCCB3 and RCCB6, His-tag-free RB3 and RB6) specifically targeting recombinant human CD70 without cross-reactivity to murine CD70. ImmunoPET/CT imaging with [18F]RCCB3 and [18F]RCCB6 demonstrated a high tumour-to-background ratio in a subcutaneous ccRCC PDX model, with the latter showing better diagnostic potential supported by higher tumour uptake and lower bone accumulation. In comparison, [18F]RB6, developed by sequence optimisation, has significantly lower kidney accumulation than that of [18F]RCCB6. In a pilot translational study, [18F]RCCB6 immunoPET/CT displayed ccRCC metastases in multiple patients and demonstrated improved imaging contrast and diagnostic value than 18F-FDG PET/CT in a patient with ccRCC. CONCLUSION: The work successfully developed a series of CD70-targeted immunoPET/CT imaging tracers. Of them, [18F]RCCB6 clearly and specifically identified inoculated ccRCCs in preclinical studies. Clinical translation of [18F]RCCB6 suggests potential for identifying recurrence and/or metastasis in ccRCC patients.

ImmunoPET imaging of Trop2 expression in solid tumors with nanobody tracers.

PURPOSE: The high expression of the transmembrane glycoprotein trophoblast cell-surface antigen 2 (Trop2) was strongly associated with the progression of solid tumors, including pancreatic and gastric cancers. Our study aimed to construct Trop2-specific immuno-positron emission tomography (immunoPET) probes and assess the diagnostic abilities in preclinical pancreatic and gastric cancer models. METHODS: The expression of Trop2 in pancreatic cancer was determined by single-cell sequencing and immunohistochemistry on tissue microarray (TMA). Flow cytometry was used to screen the expression of Trop2 in pancreatic cancer cell lines. Two nanobodies (i.e., RTD98 and RTD01) targeting Trop2 were developed and labeled with gallium-68 (68Ga, T1/2 = 1.1 h) to construct immunoPET imaging probes. The agents were researched in cell-derived pancreatic and patient-derived gastric cancer models expressing varying Trop2. RESULTS: Single-cell sequencing results showed high expression of Trop2 in pancreatic ductal cells as well as acinar cells and immunohistochemical staining of TMA from pancreatic cancers showed significantly higher expression of Trop2 in cancerous than in paracancerous tissues. ImmunoPET utilizing [68Ga]Ga-NOTA-RTD98 could clearly delineate subcutaneous tumors, both in cell-derived pancreatic cancer models and patient-derived gastric cancer models, superior to imaging using [18F]-FDG or a non-specific probe [68Ga]Ga-NOTA-RTD161. Another probe with improved pharmacokinetics targeting Trop2, [68Ga]Ga-NOTA-RTD01, was further prepared and showed advantageous diagnostic capabilities in preclinical pancreatic cancer models. CONCLUSION: In the work, we reported two nanobody tracers targeting human Trop2 which may facilitate better use of Trop2-targeted therapeutics by noninvasively displaying expression dynamics of the target.

ImmunoPET Imaging of CD47 with VHH-Derived Tracers in Pancreatic Cancers.

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with insidious onset, rapid progression, and a very poor prognosis. CD47 is a transmembrane protein associated with the development and poor prognosis of pancreatic cancer. The aim of this study was to evaluate the diagnostic value of novel immunoPET tracers targeting CD47 in preclinical pancreatic cancer models. The association of CD47 expression with pancreatic cancer was analyzed using the Gene Expression Profiling Interactive Analysis platform. Immunohistochemical analysis of tissue microarrays was performed to detect CD47 expression in PDAC. CD47 expression levels on BxPC-3 and AsPC-1 cell membranes were compared using flow cytometry. A VHH (C2)-targeting human CD47 and its albumin-binding derivative (ABDC2) were labeled with 68Ga or 89Zr, respectively. The developed tracers were evaluated by immuno-positron emission tomography (immunoPET) imaging in tumor-bearing nude and CD47-humanized mice. [68Ga]Ga-NOTA-C2 effectively detected tumor lesions in nude mice models and further showed confirmative imaging capacity in CD47-humanized PDAC models. Compared with [68Ga]Ga-NOTA-C2, [89Zr]Zr-DFO-ABDC2 had a significantly prolonged circulation time, increased tumor uptake, and reduced accumulation in the kidneys. Finally, biodistribution and histological staining confirmed the results of the immunoPET imaging studies. In this study, we validated that two novel VHH-derived molecular imaging tracers for immunoPET imaging ([68Ga]Ga-NOTA-C2 and [89Zr]Zr-DFO-ABDC2) can effectively annotate CD47 expression and diagnose PDAC in a target-specific manner. Clinical application of the imaging strategies may help select patients for CD47-targeted therapies and assess the response thereafter.

Systematical analysis of underlying markers associated with Marfan syndrome via integrated bioinformatics and machine learning strategies.

Marfan syndrome (MFS) is a hereditary disease with high mortality. This study aimed to explore peripheral blood potential markers and underlying mechanisms in MFS via a series bioinformatics and machine learning analysis. First, we downloaded two MFS datasets from the GEO database. A total of 215 differentially expressed genes (DEGs) and 78 differentially expressed miRNAs (DEMs) were identified via "Limma" package. 60 DEGs, mainly enriched in abnormal transportation of structure and energy substances, were selected after protein-protein interaction (PPI) network construction, of which 20 were chosen for machine learning after three algorithms (betweenness, closeness, and degree) filtration using Cytoscape. Four overlapping DEGs (ACTN1, CFTR, GCKR, LAMA3) were finally selected as the candidate markers based on three machine-learning approaches (Lasso, random forest, and support vector machine-recursive feature elimination). Furthermore, we collected peripheral blood from MFS patients and healthy control to validate the findings and the results showed that compared with the control, the expression of the four DEGs was all statistically different in MFS patients validated by qRT-PCR. Besides, the area under the receiver operating characteristics curve was greater than 0.8 for each DEG. Single-sample gene-set enrichment analysis showed that the four DEGs were strongly associated with inflammation and myogenesis pathway. Finally, we constructed the mRNA-miRNA network based on the intersection of DEMs and predicted miRNAs targeting DEGs. In conclusion, our study partially provided four potential markers for MFS pathogenesis.Communicated by Ramaswamy H. Sarma.

Antibody theranostics in precision medicine.

With the increasing use of antibody therapeutics, clinicians are faced with challenges of precisely stratifying patients and promptly assessing response to treatment. Antibody theranostics combines the advantages of radionuclides and antibodies (or antibody derivatives) to systematically integrate targeted diagnostics and therapeutics and will play important roles in precision medicine.

Development and Characterization of Novel FAP-Targeted Theranostic Pairs: A Bench-to-Bedside Study.

Fibroblast activation protein (FAP) is among the most popular targets in nuclear medicine imaging and cancer theranostics. Several small-molecule moieties (FAPI-04, FAPI-46, etc.) are used for developing FAP-targeted theranostic agents. Nonetheless, the circulation time of FAP inhibitors is relatively short, resulting in rapid clearance via kidneys, low tumor uptake, and associated unsatisfactory treatment efficacy. To address the existing drawbacks, we engineered 3 peptides named FD1, FD2, and FD3 with different circulation times through solid-phase peptide synthesis. All the 3 reported peptides bind to human and murine FAP with single-digit nanomolar affinity measured by surface plasmon resonance. The diagnostic and therapeutic potential of the agents labeled with 68Ga and 177Lu was assessed in several tumor models exhibiting different levels of FAP expression. While radiolabeled FD1 was rapidly excreted from kidneys, radiolabeled FD2/FD3 have significantly prolonged circulation, increased tumor uptake, and decreased kidney accumulation. Our findings indicated that [68Ga]Ga-DOTA-FD1 positron emission tomography (PET) effectively detected FAP dynamics, whereas [177Lu]Lu-DOTA-FD2 and [177Lu]Lu-DOTA-FD3 exhibited remarkable therapeutic efficacy in FAP-overexpressing tumor models, including pancreatic cancer cell models characterized by abundant stroma. Moreover, a pilot translational investigation demonstrated that [68Ga]Ga-DOTA-FD1 had the capability to identify both primary and metastatic tumors with precision and distinction. In summary, we developed [68Ga]Ga-DOTA-FD1 for same-day PET imaging of FAP dynamics and [177Lu]Lu-DOTA-FD2 and [177Lu]Lu-DOTA-FD3 for effective radioligand therapy of FAP-overexpressing tumors.

Immune-associated pivotal biomarkers identification and competing endogenous RNA network construction in post-operative atrial fibrillation by comprehensive bioinformatics and machine learning strategies.

Background: Atrial fibrillation (AF) is the most common arrhythmia. Previous studies mainly focused on identifying potential diagnostic biomarkers and treatment strategies for AF, while few studies concentrated on post-operative AF (POAF), particularly using bioinformatics analysis and machine learning algorithms. Therefore, our study aimed to identify immune-associated genes and provide the competing endogenous RNA (ceRNA) network for POAF. Methods: Three GSE datasets were downloaded from the GEO database, and we used a variety of bioinformatics strategies and machine learning algorithms to discover candidate hub genes. These techniques included identifying differentially expressed genes (DEGs) and circRNAs (DECs), building protein-protein interaction networks, selecting common genes, and filtering candidate hub genes via three machine learning algorithms. To assess the diagnostic value, we then created the nomogram and receiver operating curve (ROC). MiRNAs targeting DEGs and DECs were predicted using five tools and the competing endogenous RNA (ceRNA) network was built. Moreover, we performed the immune cell infiltration analysis to better elucidate the regulation of immune cells in POAF. Results: We identified 234 DEGs (82 up-regulated and 152 down-regulated) of POAF via Limma, 75 node genes were visualized via PPI network, which were mainly enriched in immune regulation. 15 common genes were selected using three CytoHubba algorithms. Following machine learning selection, the nomogram was created based on the four candidate hub genes. The area under curve (AUC) of the nomogram and individual gene were all over 0.75, showing the ideal diagnostic value. The dysregulation of macrophages may be critical in POAF pathogenesis. A novel circ_0007738 was discovered in POAF and the ceRNA network was eventually built. Conclusion: We identified four immune-associated candidate hub genes (C1QA, C1R, MET, and SDC4) for POAF diagnosis through the creation of a nomogram and evaluation of its diagnostic value. The modulation of macrophages and the ceRNA network may represent further therapy methods.

Efficacy and Safety of Remimazolam Besylate versus Dexmedetomidine for Sedation in Non-Intubated Older Patients with Agitated Delirium After Orthopedic Surgery: A Randomized Controlled Trial.

Purpose: The purpose of the present study was to investigate the efficacy and safety of remimazolam besylate compared with dexmedetomidine for the relief of agitated delirium in non-intubated older patients after orthopedic surgery. Patients and methods: Seventy-five patients were randomly divided into two groups. Patients assigned to the remimazolam group received a loading dose of 0.075 mg/kg remimazolam besylate over 1 minute, followed by a continuous infusion of 0.1 to 0.3 mg/kg/h. Subjects randomized to the dexmedetomidine group received a loading infusion of 0.5 µg/kg dexmedetomidine over 10 minutes, followed by a maintenance dose of 0.2 to 0.7 µg/kg/h. Meanwhile, RASS score-guided dose titration was followed. To assess the efficacy of the study drugs in terms of time to resolution of agitation, time to first achievement of target sedation, percentage of time within the target sedation range, and time to delirium resolution. Safety of the sedatives was evaluated by adverse events during hospitalization. Results: Time to resolution of agitation did not differ between the two groups. The time to first achievement of target sedation was 19.0 (9.5 to 31.0) minutes for remimazolam besylate vs 43.5 (15.0 to 142.5) minutes for dexmedetomidine (P < 0.001). Percentage of time within the target sedation range was 77.8% for remimazolam besylate-treated patients and 67.4% for dexmedetomidine-treated patients (P = 0.001). Patients in the remimazolam group had longer time to delirium resolution (29.5 [21.3 to 32.5] hours) than those in the dexmedetomidine group (22.8 [18.9 to 28.5] hours) (P = 0.042). Patients sedated with remimazolam besylate had more oversedation (P = 0.036) but less hypotension (P = 0.007). Conclusion: Compared with dexmedetomidine, remimazolam besylate was equally effective in relieving agitation, and resulted in earlier achievement of sedation goal and more controllable sedation. Remimazolam may be an ideal agent for obtaining rapid tranquillisation.

Molecular Imaging of Renal Cell Carcinoma in Precision Medicine.

Renal cell carcinoma (RCC) is the sixth most common cancer among men and the ninth among women, and its prognosis is closely correlated with metastasis. Targeted therapy and immunotherapy are the main adjuvant treatments for advanced RCC and require early diagnosis, precise assessment, and prediction of the therapeutic responses. Current conventional imaging methods of RCC only provide structural information rather than biological processes. Noninvasive diagnostic tools are therefore needed to image RCC early and accurately at the molecular level. Nuclear medicine imaging combines the high sensitivity of radionuclides with the high resolution of structural imaging to visualize the metabolic processes and specific targets of RCC for more accurate and reliable diagnosis, staging, prognosis prediction, and response assessment. This review summarizes the most recent applications of nuclear medicine receptor imaging and metabolic imaging in RCC and highlights future development perspectives in the field.

Classification of endogenous and exogenous bursts in collective emotions based on Weibo comments during COVID-19.

Bursts and collective emotion have been widely studied in social physics field where researchers use mathematical models to understand human social dynamics. However, few researches recognize and separately analyze the internal and external influence on burst behaviors. To bridge this gap, we introduce a non-parametric approach to classify an interevent time series into five scenarios: random arrival, endogenous burst, endogenous non-burst, exogenous burst and exogenous non-burst. In order to process large-scale social media data, we first segment the interevent time series into sections by detecting change points. Then we use the rule-based algorithm to classify the time series based on its distribution. To validate our model, we analyze 27.2 million COVID-19 related comments collected from Chinese social media between January to October 2020. We adopt the emotion category called Profile of Mood States which consists of six emotions: Anger, Depression, Fatigue, Vigor, Tension and Confusion. This enables us to compare the burst features of different collective emotions during the COVID-19 period. The burst detection and classification approach introduced in this paper can also be applied to analyzing other complex systems, including but not limited to social media, financial market and signal processing.

Prognostic values of ALDOB expression and 18F-FDG PET/CT in hepatocellular carcinoma.

Purpose: The glycolytic enzyme fructose 1,6-bisphosphate aldolase B (ALDOB) is aberrantly expressed and impacts the prognosis in hepatocellular carcinoma (HCC). Hepatic ALDOB loss leads to paradoxical upregulation of glucose metabolism, favoring hepatocellular carcinogenesis. Nevertheless, the relationship between ALDOB expression and 18F-fluorodeoxyglucose (18F-FDG) uptake, and their effects on HCC prognosis remain unclear. We evaluated whether ALDOB expression is associated with 18F-FDG uptake and their impacts on HCC prognosis prediction. Methods: Changes in ALDOB expression levels and the prognostic values in HCC were analyzed using data from The Cancer Genome Atlas (TCGA) database. Ultimately, 34 patients with HCC who underwent 18F-FDG positron emission tomography/computed tomography (PET/CT) preoperatively were enrolled in this retrospective study. ALDOB expression was determined using immunohistochemistry (IHC) staining, and the maximum standardized uptake value (SUVmax) of HCC was calculated from the 18F-FDG PET/CT scans. The relationship between ALDOB expression and SUVmax was examined, and their impacts on overall survival were evaluated using Cox proportional hazards models and Kaplan-Meier survival analysis. ALDOB overexpression in HUH7 and 7721 cells was used to analyze its role in tumor metabolism. Results: According to TCGA database, the ALDOB mRNA level was downregulated in HCC compared to normal tissue, and significantly shortened overall survival in HCC patients. ALDOB protein expression was similarly decreased in IHC findings in HCC than that in adjacent normal tissues (P<0.05) and was significantly associated with tumor size (P<0.001), high tumor-node-metastasis stage (P=0.022), and elevated SUVmax (P=0.009). ALDOB expression in HCC was inversely correlated with SUVmax (r=-0.454; P=0.012), and the optimal SUVmax cutoff value for predicting its expression was 4.15. Prognostically, low ALDOB expression or SUVmax ≥3.9 indicated shorter overall survival time in HCC. Moreover, COX regression analysis suggested high SUVmax as an independent prognostic risk factor for HCC (P=0.036). HCC patients with negative ALDOB expression and positive SUVmax (≥3.9) were correlated with worse prognosis. ALDOB overexpression in HCC cells significantly decreases 18F-FDG uptake and lactate production. Conclusion: SUVmax in HCC patients is inversely correlated with ALDOB expression, and 18F-FDG PET/CT may be useful for ALDOB status prediction. The combined use of ALDOB expression and 18F-FDG PET/CT data can provide additional information on disease prognosis in HCC patients.

Mechanical Properties and Damage Evolution of Concrete Materials Considering Sulfate Attack.

In order to study the durability of concrete materials subjected to sulfate attack, in a sulfate attack environment, a series of concrete tests considering different fly ash contents and erosion times were conducted. The mechanical properties and the micro-structure of concrete under sulfate attack were studied based on the following: uniaxial compressive strength test, split tensile test, ultrasonic impulse method, scanning electron microscopy (SEM) and X-ray diffraction (XRD). The mechanical properties were compressive strength, splitting tensile strength, and relative dynamic elastic modulus, respectively. Additionally, according to the damage mechanical theory, experimental results and micro-structure analysis, the damage evolution process of concrete under a sulfate attack environment were studied in detail. Finally, according to the sulfate attack time and fly ash content, a damage model of the sulfate attack of the binary surface was established. The specific results are as follows: under the action of sulfate attack, the change law of the rate of mass change, relative dynamic modulus of elasticity, corrosion resistance coefficient of compressive strength, and the corrosion resistance coefficient of the splitting tensile strength of concrete all increase first and then decrease. Under the same erosion time, concrete mixed with 10% fly ash content has the best sulfate resistance. Through data regression, the damage evolution equation of the sulfate attack was developed and there is an exponential function relationship among the different damage variables. The binary curved surface regression effect of the concrete damage and the erosion time and the amount of fly ash is significant, which can predict deterioration of concrete damage under sulfate attack. During the erosion time, the combined expansion of ettringite and gypsum caused micro cracks. With an increase of corrosion time, micro cracks developed and their numbers increased.

Association Between High-Sensitivity Troponin T on Admission and Organ Dysfunction During Hospitalization in Patients Aged 80 Years and Older with Hip Fracture: A Single-Centered Prospective Cohort Study.

BACKGROUND: Prognostic evaluation of elderly patients with hip fracture is an issue that has been highly concerned by clinicians. Only a few studies have focused on organ dysfunction after hip fracture in the elderly. This study aimed to investigate the association between high-sensitivity troponin T (hs-TnT) at admission and organ dysfunction during hospitalization in elderly patients with hip fracture. METHODS: We enrolled 168 patients with hip fracture who were aged 80 years and older at Geriatric Orthopaedic Center of Sichuan Provincial Orthopedic Hospital between January 2020 and August 2020. Baseline characteristics, perioperative information, and short-term clinical outcomes were analyzed. RESULTS: Of the 208 patients admitted during the study period, 168 met the inclusion criteria; of these, 91 (54.2%) had higher hs-TnT than the 99th percentile in the normal population. After adjustment for confounders, elevated hs-TnT was independently associated with multiple organ dysfunction syndrome in the elderly (MODSE) (adjusted OR, 5.76; 95% CI, 1.74-19.10; P = 0.004), heart dysfunction (adjusted OR, 7.48; 95% CI, 2.17-25.82; P = 0.001), MODS severity score > 3 (adjusted OR, 5.22; 95% CI, 1.32-20.60; P = 0.018), and length of hospital stay > 14 days (adjusted OR, 2.38; 95% CI, 1.05-5.36; P = 0.037). CONCLUSION: Increased hs-TnT on admission is an independent risk factor for MODSE after hip fracture in patients aged 80 years and older. Effective measures should be applied to avoid progression of MODSE from pre-failure stage to failure stage.

Day surgery appointment scheduling with patient preferences and stochastic operation duration.

BACKGROUND: Due to its fast service and high utilization, day surgery is becoming more and more important in the medical system. As a result, an effective day surgery scheduling can reasonably release the supply and demand pressure. OBJECTIVE: This paper aims to investigate the day surgery scheduling problem with patient preferences and limited operation room for the sake of increasing operation efficiency and further decreasing surgery costs. METHODS: A multiple objective stochastic programming model is constructed to seek a satisfactory surgical scheduling for both patients and hospitals under different scenarios. Multi-objective genetic algorithm is designed to solve the model and different scales of scenarios are utilized to test the effectiveness of the algorithm and modeling process. RESULTS: Results show that the proposed model and algorithm can provide a feasible solution for maximizing individual preference of surgeons with surgery date and operation room utilization as well. CONCLUSIONS: Patient preference is proposed to be incorporated into day surgery scheduling, and the variability of surgery duration considered to seek a satisfactory surgery scheduling scheme for both patients and hospitals is more in line with the actual hospital situation.

Prognostic Value of N-Terminal Pro-B-Type Natriuretic Peptide and Glomerular Filtration Rate in Patients With Acute Heart Failure.

Aims: To investigate the relationship between N-terminal pro-B-type natriuretic peptide (NT-proBNP), Glomerular Filtration Rate (GFR), and outcomes in patients hospitalized with acute heart failure (AHF). Methods: The trial was registered at http://www.chictr.org/cn/. (ChiCTR - ONC - 12001944). A total of 493 patients hospitalized for AHF in cardiology department of the First Affiliated Hospital of Nanjing Medical University from March 2012 to October 2016 were enrolled into registry. The end event was the occurrence of all-cause death within an 18-month follow-up. The data collected from the participants in admission were used to calculate the GFR by chronic kidney disease epidemiology collaboration equation (CKD-EPI) and performed the according statistical analysis. Results: There were 74 participants (13.8%) dropped out and 91 (21.7%) passed away within the 18-month follow up. Comparison of clinical indicators between survival and death group were analyzed for the long-term prognosis of patients with AHF. In the single factor analysis, both NT-proBNP and GFR were statistically significant (P < 0.001). Combined NT-proBNP and GFR in multi-factor COX regression analysis showed significant predictive value (P < 0.001). In receiver operator characteristics (ROC) analyses, the area under the curves (AUC) for NT-proBNP was 0.648 [95%CI: 0.598-0.695, P < 0.001] and for GFR was 0.677 [95%CI: 0.627-0.723, P < 0.001]. According to the Youden index, the best prediction point of NT-proBNP was 2,137 pg/ml and GFR was 61.7 ml/(min·1.73 m2). After using the Binary Logistic Regression to combine the two indicators, the AUC was 0.711, which was significantly compared to the AUC of either single factor. The sensitivity of the combined indicators were 0.535, the specificity were 0.853. According to the cut-off point, these two indexes were separated into four groups for further analysis by Kaplan-Meier survival curve comparison (log-rank test), which showed that patients in the group with higher NT-proBNP and lower GFR had the worst prognosis. Conclusions: In patients with NT-proBNP > 2,137 pg/ml and GFR < 61.7 ml/(min·1.73 m2), the risk of death was significantly higher. The combination of GFR and NT-proBNP improved the predictive value for the long-term prognosis of AHF patients.

Growth differentiation factor-15 combined with N-terminal prohormone of brain natriuretic peptide increase 1-year prognosis prediction value for patients with acute heart failure: a prospective cohort study.

BACKGROUND: Clinical assessment and treatment guidance for heart failure depends on a variety of biomarkers. The objective of this study was to investigate the prognostic predictive value of growth differentiation factor-15 (GDF-15) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in assessing hospitalized patients with acute heart failure (AHF). METHODS: In total, 260 patients who were admitted for AHF in the First Affiliated Hospital of Nanjing Medical University were enrolled from April 2012 to May 2016. Medical history and blood samples were collected within 24 h after the admission. The primary endpoint was the all-cause mortality within 1 year. The patients were divided into survival group and death group based on the endpoint. With established mortality risk factors and serum GDF-15 level, receiver-operator characteristic (ROC) analyses were performed. Cox regression analyses were used to further analyze the combination values of NT-proBNP and GDF-15. RESULTS: Baseline GDF-15 and NT-proBNP were significantly higher amongst deceased than those in survivors (P < 0.001). In ROC analyses, area under curve (AUC) for GDF-15 to predict 1-year mortality was 0.707 (95% confidence interval [CI]: 0.648-0.762, P < 0.001), and for NT-proBNP was 0.682 (95% CI: 0.622-0.738, P < 0.001). No statistically significant difference was found between the two markers (P = 0.650). Based on the optimal cut-offs (GDF-15: 4526.0 ng/L; NT-proBNP: 1978.0 ng/L), the combination of GDF-15 and NT-proBNP increased AUC for 1-year mortality prediction (AUC = 0.743, 95% CI: 0.685-0.795, P < 0.001). CONCLUSIONS: GDF-15, as a prognostic marker in patients with AHF, is not inferior to NT-proBNP. Combining the two markers could provide an early recognition of high-risk patients and improve the prediction values of AHF long-term prognosis. CLINICAL TRIAL REGISTRATION: ChiCTR-ONC-12001944, http://www.chictr.org.cn.