Identification of diagnostic biomarkers used in the diagnosis of cardiovascular diseases and diabetes mellitus: A systematic review of quantitative studies.

AIMS: To perform a systematic review of studies that sought to identify diagnostic biomarkers for the diagnosis of cardiovascular diseases (CVDs) and diabetes mellitus (DM), which could be used in low- and middle-income countries (LMICs) where there is a lack of diagnostic equipment, treatments and training. MATERIALS AND METHODS: Papers were sourced from six databases: the British Nursing Index, Google Scholar, PubMed, Sage, Science Direct and Scopus. Articles published between January 2002 and January 2023 were systematically reviewed by three reviewers and appropriate search terms and inclusion/exclusion criteria were applied. RESULTS: A total of 18 studies were yielded, as well as 234 diagnostic biomarkers (74 for CVD and 160 for DM). Primary biomarkers for the diagnosis of CVDs included growth differentiation factor 15 and neurogenic locus notch homologue protein 1 (Notch1). For the diagnosis of DM, alpha-2-macroglobulin, C-peptides, isoleucine, glucose, tyrosine, linoleic acid and valine were frequently reported across the included studies. Advanced analytical techniques, such as liquid chromatography mass spectrometry, enzyme-linked immunosorbent assays and vibrational spectroscopy, were also repeatedly reported in the included studies and were utilized in combination with traditional and alternative matrices such as fingernails, hair and saliva. CONCLUSIONS: While advanced analytical techniques are expensive, laboratories in LMICs should carry out a cost-benefit analysis of their use. Alternatively, laboratories may want to explore emerging techniques such as infrared, Fourier transform-infrared and near-infrared spectroscopy, which allow sensitive noninvasive analysis.

Growth Differentiation Factor 15 Provides Prognostic Information Superior to Established Cardiovascular and Inflammatory Biomarkers in Unselected Patients Hospitalized With COVID-19.

BACKGROUND: Growth differentiation factor 15 (GDF-15) is a strong prognostic marker in sepsis and cardiovascular disease (CVD). The prognostic value of GDF-15 in coronavirus disease 2019 (COVID-19) is unknown. METHODS: Consecutive, hospitalized patients with laboratory-confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and symptoms of COVID-19 were enrolled in the prospective, observational COVID Mechanisms Study. Biobank samples were collected at baseline, day 3 and day 9. The primary end point was admission to the intensive care unit or death during hospitalization, and the prognostic performance of baseline and serial GDF-15 concentrations were compared with that of established infectious disease and cardiovascular biomarkers. RESULTS: Of the 123 patients enrolled, 35 (28%) reached the primary end point; these patients were older, more often had diabetes, and had lower oxygen saturations and higher National Early Warning Scores on baseline. Baseline GDF-15 concentrations were elevated (>95th percentile in age-stratified healthy individuals) in 97 (79%), and higher concentrations were associated with detectable SARS-CoV-2 viremia and hypoxemia (both P<0.001). Patients reaching the primary end point had higher concentrations of GDF-15 (median, 4225 [IQR, 3197-5972] pg/mL versus median, 2187 [IQR, 1344-3620] pg/mL, P<0.001). The area under the receiver operating curve was 0.78 (95% CI, 0.70-0.86). The association between GDF-15 and the primary end point persisted after adjusting for age, sex, race, body mass index, estimated glomerular filtration rate, previous myocardial infarction, heart failure, and atrial fibrillation (P<0.001) and was superior and incremental to interleukin-6, C-reactive protein, procalcitonin, ferritin, D-dimer, cardiac troponin T, and N-terminal pro-B-type natriuretic peptide. Increase in GDF-15 from baseline to day 3 was also greater in patients reaching the primary end point (median, 1208 [IQR, 0-4305] pg/mL versus median, -86 [IQR, -322 to 491] pg/mL, P<0.001). CONCLUSIONS: GDF-15 is elevated in the majority of patients hospitalized with COVID-19, and higher concentrations are associated with SARS-CoV-2 viremia, hypoxemia, and worse outcome. The prognostic value of GDF-15 was additional and superior to established cardiovascular and inflammatory biomarkers. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04314232.

Screening of biomarkers for prediction of multisite artery disease in patients with recent myocardial infarction.

A few studies have examined biomarkers in patients with myocardial infarction (MI) and peripheral artery disease (PAD), i.e. multisite artery disease (MSAD). The aim of the study was firstly, to associate biomarkers with the occurrence of PAD/MSAD and secondly, if those can, in addition to clinical characteristics, identify MI patients with MSAD.In two prospectively observational studies including unselected patients with recent MI, PAD was defined as an abnormal ankle-brachial index (ABI) score (<0.9 or >1.4). The proximity extension assay (PEA) technique was used, simultaneously analyzing 92 biomarkers with association to cardiovascular disease. Biomarkers were tested for univariate associations with PAD. Random forest was used to identify biomarkers with a higher association to PAD. The additional discriminatory accuracy of adding biomarkers to clinical characteristics was analyzed by the c-statistics. Nine biomarkers were identified as significantly associated with MSAD/PAD in the primary patient cohort, analyzed early after the MI. In the prediction analysis, six biomarkers were identified associated with PAD. Three of these; Tumor necrosis factor receptor (TNFR-1), Tumor necrosis factor receptor 2 (TNFR-2) and Growth Differentiation Factor 15 (GDF-15) improved c-statistics when added to clinical characteristics from 0.683 (95% CI 0.610-0.756) to 0.715 (95% CI 0.645-0.784) in the primary patient cohort with a similar result, 0.729 (95% CI 0.687-0.770) to 0.752 (95% CI 0.771-0.792) in the secondary patient cohort. Biomarkers associated with inflammatory pathways are associated with MSAD in MI patients. Three biomarkers of 92; TNFR-1, TNFR-2 and GDF-15, in this exploratory added information in the prediction of MSAD and emphasis the importance of further studies.

The clinical potential of GDF15 as a "ready-to-feed indicator" for critically ill adults.

BACKGROUND: Circulating growth-differentiation factor-15 (GDF15), a cellular stress marker, abruptly increases during critical illness, but its later time course remains unclear. GDF15 physiologically controls oral intake by driving aversive responses to nutrition. Early parenteral nutrition (PN) in ICU patients has overall been shown not beneficial. We hypothesized that low GDF15 can identify patients who benefit from early PN, tolerate enteral nutrition (EN), and resume spontaneous oral intake. METHODS: In secondary analyses of the EPaNIC-RCT on timing of PN initiation (early PN versus late PN) and the prospective observational DAS study, we documented the time course of circulating GDF15 in ICU (N = 1128) and 1 week post-ICU (N = 72), compared with healthy subjects (N = 65), and the impact hereon of randomization to early PN versus late PN in propensity score-matched groups (N = 564/group). Interaction between upon-admission GDF15 and randomization for its outcome effects was investigated (N = 4393). Finally, association between GDF15 and EN tolerance in ICU (N = 1383) and oral intake beyond ICU discharge (N = 72) was studied. RESULTS: GDF15 was elevated throughout ICU stay, similarly in early PN and late PN patients, and remained high beyond ICU discharge (p < 0.0001). Upon-admission GDF15 did not interact with randomization to early PN versus late PN for its outcome effects, but higher GDF15 independently related to worse outcomes (p ≤ 0.002). Lower GDF15 was only weakly related to gastrointestinal tolerance (p < 0.0001) and a steeper drop in GDF15 with more oral intake after ICU discharge (p = 0.05). CONCLUSION: In critically ill patients, high GDF15 reflected poor prognosis and may contribute to aversive responses to nutrition. However, the potential of GDF15 as "ready-to-feed indicator" appears limited. TRIAL REGISTRATION: ClinicalTrials.gov , NCT00512122, registered 31 July 2007, https://www.clinicaltrials.gov/ct2/show/NCT00512122 (EPaNIC trial) and ISRCTN, ISRCTN 98806770, registered 11 November 2014, http://www.isrctn.com/ISRCTN98806770 (DAS trial).

Consolidation Chemotherapy Prevents Relapse by Indirectly Regulating Bone Marrow Adipogenesis in Patients with Acute Myeloid Leukemia.

BACKGROUND/AIMS: Chemotherapy is still the main strategy used to prevent the relapse of acute myeloid leukaemia (AML). As the most abundant stromal component in bone marrow (BM), marrow adipocytes have been previously shown to promote leukaemogenesis. The present study was designed to further validate whether marrow adipocytes exert synergistic effects on strengthening chemotherapeutic efficacy and evaluate the underlying mechanism. METHODS: A retrospective study of BM biopsies from 80 patients with AML in remission and 71 control subjects was applied to quantitatively analyse the marrow adipocyte volume. Toxicity tests were used to assess the effect of chemotherapy drugs on BM cells. The possible mechanisms by which chemotherapy regulated the reduced marrow adipocyte content were investigated using antibody neutralization experiments, with an emphasis on growth differentiation factor 15 (GDF15). RESULTS: In our study, the marrow adipocyte content was obviously reduced in the AML- complete remission (CR) group compared with the control group (P<0.001). Moreover, patients with a reduced adipocyte content exhibited longer relapse-free survival (RFS) (P<0.001). We also confirmed that GDF15 was overexpressed in mononuclear cells (MNCs) after treatment with chemotherapy drugs and partially blocked mesenchymal stem cells (MSCs) adipogenesis. Intriguingly, this inhibitory effect on adipogenesis was rescued by treatment with a neutralizing anti-GDF15 antibody. CONCLUSION: Chemotherapy indirectly inhibited adipogenesis by promoting GDF15 secretion from BM MNCs, subsequently strengthening the efficacy of consolidation chemotherapy in patients with AML during CR.

Stromal Growth Differentiation Factor 15 and Its Association with Ovarian Cancer.

BACKGROUND/AIMS: Growth differentiation factor 15 (GDF-15) is induced by pro-inflammatory cytokines. Higher levels of GDF-15 have been associated with malignancy. The aim of the study was to evaluate both tissue and serum levels of GDF-15 in ovarian neoplasms. METHODS: A cohort study evaluated 31 patients with benign ovarian tumors and 34 patients with ovarian cancer were evaluated in 2 years. The inclusion criterion was histopathological diagnosis of ovarian epithelial neoplasia. Exclusion criteria were secondary malignant ovarian neoplasia and preoperative treatment. Serum and tissue levels of GDF-15 were assessed by enzyme-linked immunosorbent assay and immunohistochemistry, respectively. Chi-square test and unpaired t test were performed. RESULTS: Serum levels were higher in the patients with malignant neoplasms than in the patients with benign tumors, yet the difference was not statistically significant. GDF-15 immunostaining was significantly more frequent in the stroma of the malignant tumors than in the stroma of the benign tumors (p = 0.0034). CONCLUSION: GDF-15 staining is elevated in the stroma of ovarian cancer, demonstrating that it may be a potential diagnostic and therapeutic target.

NSAID-activated gene 1 and its implications for mucosal integrity and intervention beyond NSAIDs.

In spite of the beneficial actions of non-steroid anti-inflammatory drugs (NSAIDs) in epithelial inflammation and cancers, their use is limited because of their cyclooxygenase-dependent or independent gastrointestinal toxicity. As an eicosanoid-independent mediator, NSAID-activated gene 1 (NAG-1) has been assessed for its involvement in cellular integrity and pathogenesis in mucosal inflammation and carcinogenesis. At the cellular levels, NAG-1 is involved in the cell growth regulation (cell death, cell cycle arrest, or proliferation) in epithelial and mesenchymal tissues. Moreover, NAG-1 can modulate inflammatory responses in either direct or indirect manner, which ultimately affects fibrogenic and tumorigenic processes in various disease states. Finally, NAG-1 has been assessed for its contribution to cellular behavior, such as the mobility of epithelial and malignant cells in response to the external insults or oncogenic stimulation in the mucosa. This review on the "Yin-Yang" nature of NAG-1-mediated responses provides comprehensive insights into therapeutic and diagnostic interventions for mucosal health and integrity in the human body.

Preoperative plasma growth-differentiation factor-15 for prediction of acute kidney injury in patients undergoing cardiac surgery.

BACKGROUND: Growth-differentiation factor-15 (GDF-15) is an emerging humoral marker for risk stratification in cardiovascular disease. Cardiac-surgery-associated acute kidney injury (CSA-AKI), an important complication in patients undergoing cardiac surgery, is associated with poor prognosis. The present secondary analysis of an observational cohort study aimed to determine the role of GDF-15 in predicting CSA-AKI compared with the Cleveland-Clinic Acute Renal Failure (CC-ARF) score and a logistic regression model including variables associated with renal dysfunction. METHODS: Preoperative plasma GDF-15 was determined in 1176 consecutive patients undergoing elective cardiac surgery. Patients with chronic kidney disease stage 5 were excluded. AKI was defined according to Kidney-Disease-Improving-Global-Outcomes (KDIGO) - creatinine criteria. The following variables were screened for association with development of postoperative AKI: age, gender, additive Euroscore, serum creatinine, duration of cardiopulmonary bypass, duration of surgery, type of surgery, total circulatory arrest, preoperative hemoglobin, preoperative oxygen-supplemented cerebral oxygen saturation, diabetes mellitus, hemofiltration during ECC, plasma GDF-15, high sensitivity troponin T (hsTNT), and N-terminal prohormone of B-type natriuretic peptide (NTproBNP). RESULTS: There were 258 patients (21.9 %) with AKI (AKI stage 1 (AKI-1), n = 175 (14.9 %); AKI-2, n = 6 (0.5 %); AKI-3, n = 77 (6.5 %)). The incidence of AKI-1 and AKI-3 increased significantly from the lowest to the highest tertiles of GDF-15. In logistic regression, preoperative GDF-15, additive Euroscore, age, plasma creatinine, diabetes mellitus, and duration of cardiopulmonary bypass were independently associated with AKI. Inclusion of GDF-15 in a logistic regression model comprising these variables significantly increased the area under the curve (AUC 0.738 without and 0.750 with GDF-15 included) and the net reclassification ability to predict AKI. Comparably, in receiver operating characteristic analysis the predictive capacity of the CC-ARF score (AUC 0.628) was improved by adding GDF-15 (AUC 0.684) but this score also had lower predictability than the logistic regression model. In random forest analyses the predictive capacity of GDF-15 was especially pronounced in patients with normal plasma creatinine. CONCLUSION: This suggests that preoperative plasma GDF-15 independently predicts postoperative AKI in patients undergoing elective cardiac surgery and is particularly helpful for risk stratification in patients with normal creatinine. TRIAL REGISTRATION: NCT01166360 on July 20, 2010.

Longitudinal Changes in Multiple Biomarkers Are Associated with Cardiotoxicity in Breast Cancer Patients Treated with Doxorubicin, Taxanes, and Trastuzumab.

BACKGROUND: Biomarkers may play an important role in identifying patients at risk for cancer therapy cardiotoxicity. Our objectives were to define the patterns of change in biomarkers with cancer therapy and their associations with cardiotoxicity. METHODS: In a multicenter cohort of 78 breast cancer patients undergoing doxorubicin and trastuzumab therapy, 8 biomarkers were evaluated at baseline and every 3 months over a maximum follow-up of 15 months. These biomarkers, hypothesized to be mechanistically relevant to cardiotoxicity, included high-sensitivity cardiac troponin I (hs-cTnI), high-sensitivity C-reactive protein (hsCRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor-1 (sFlt-1), and galectin 3 (gal-3). We determined if biomarker increases were associated with cardiotoxicity at the same visit and the subsequent visit over the entire course of therapy. Cardiotoxicity was defined by the Cardiac Review and Evaluation Criteria; alternative definitions were also considered. RESULTS: Across the entire cohort, all biomarkers except NT-proBNP and gal-3 demonstrated increases by 3 months; these increases persisted for GDF-15, PlGF, and hs-cTnI at 15 months. Increases in MPO, PlGF, and GDF-15 were associated with cardiotoxicity at the same visit [MPO hazard ratio 1.38 (95% CI 1.10-1.71), P = 0.02; PlGF 3.78 (1.30-11.0), P = 0.047; GDF-15 1.71 (1.15-2.55), P = 0.01] and the subsequent visit. MPO was robust to alternative outcome definitions. CONCLUSIONS: Increases in MPO are associated with cardiotoxicity over the entire course of doxorubicin and trastuzumab therapy. Assessment with PlGF and GDF-15 may also be of value. These findings motivate validation studies in additional cohorts.

Candidate biomarkers in heart failure with reduced and preserved ejection fraction.

CONTEXT: Patients presenting with heart failure symptoms are categorized into heart failure (HF) with reduced and preserved ejection fraction. OBJECTIVE: Aim is to investigate the additional use of candidate biomarkers to characterize patients with either sub-type of HF. METHODS: Literature search was conducted in the electronic databases MEDLINE and Cochrane Central Register of Controlled Trials from inception through November 2014. RESULTS: The results of 47 diseased and general population cohorts were included. CONCLUSION: Current studies could outline the additional use of candidate biomarkers especially GDF-15, MR-proADM and high-sensitive determined troponin, although major outcome studies are still missing.

The role of cardiac biomarkers in cardiovascular disease risk assessment.

PURPOSE OF REVIEW: A range of cardiovascular biomarkers have come into the routine clinical use for the diagnosis and assessment of patients with symptomatic coronary disease. The review will consider the current evidence base for the role of measurement of a number of these biomarkers in asymptomatic patients. RECENT FINDINGS: Measurement of the cardiac troponins, cardiac troponin T and cardiac troponin I, using sensitive methods, defines a true reference population, and has demonstrated risk of cardiovascular events with small elevations above the reference interval and a gradient of risk across the reference range even in normal healthy individuals. Similar results can be seen for the measurement of the ventricular stress marker B-type natriuretic peptide. In an asymptomatic population, there is occult cardiovascular disease which can be detected by cardiovascular biomarker measurement. Novel markers of myocardial inflammation and fibrosis, such as growth differentiation factor 15, are also powerful predictors of mortality. Measurement of these cardiovascular biomarkers provides additional risk prediction when added to risk prediction models based on the conventional risk factors. SUMMARY: The measurement of cardiovascular biomarkers has the potential to provide additional risk stratification beyond conventional risk factors. The challenge is to translate biomarker measurements to treatment strategies which will reduce long-term cardiovascular risk.

Serum growth differentiation factor-15 (GDF-15) is a biomarker of cardiac manifestations in children with COVID-19.

BACKGROUND: COVID-19 leads to severe overwhelming inflammation in some patients mediated by various cytokines (cytokine storm) that usually leads to severe illness accompanied by cardiovascular manifestations. Growth differentiation factor-15 is a cytokine induced by stress and is associated with inflammatory processes in the lung and heart. This study aimed to measure the level of serum growth differentiation factor (GDF-15) in children with COVID-19 and to correlate it with the disease severity, cardiac affection, and the outcome of COVID-19. METHODS: A cross-sectional study was conducted on 144 children; 72 children diagnosed with COVID-19, and 72 healthy children. The severity of COVID-19 was assessed clinically, laboratory, and radiologically. Echocardiography was done within 48 h of admission for COVID-19 patients. Serum GDF-15 was measured by ELISA for both patients and controls. RESULTS: Serum GDF-15 level was significantly higher in patients with COVID-19 than in controls (p < 0.01). In COVID-19 patients with severe clinical grading, those who were hospitalized in the PICU, and those who died, serum GDF-15 levels were greater. individuals with cardiac manifestations exhibited significantly higher serum GDF-15 levels than individuals without them. In children with COVID-19, increased GDF-15 was correlated to poorer ejection fraction and higher INR using multivariate linear regression analysis. CONCLUSION: Serum GDF-15 is a promising biomarker of COVID-19, it can be used as a predictor of cardiac manifestations in children with COVID-19 and severe disease.

Emerging biomarkers in heart failure.

BACKGROUND: Until recently, biomarker testing in heart failure (HF) syndromes has been viewed as an elective supplement to diagnostic evaluation of patients suspected to suffer from this condition. This approach to the use of biomarker testing contrasts with other cardiovascular diagnoses such as acute myocardial infarction, for which biomarkers are integral to disease process definition, risk stratification, and in some cases treatment decision making. CONTENT: In this review we consider various perspectives on the evaluation of biomarkers in HF. In addition, we examine recent advances in the understanding of established biomarkers in HF (such as the natriuretic peptides), the elucidation of novel biomarkers potentially useful for the evaluation and management of patients with HF, and the growing understanding of important and relevant comorbidities in HF. We also review candidate biomarkers from a number of classes: (a) myocyte stretch, (b) myocyte necrosis, (c) systemic inflammation, (d) oxidative stress, (e) extracellular matrix turnover, (f) neurohormones, and (g) biomarkers of extracardiac processes, such as renal function. SUMMARY: Novel applications of established biomarkers of HF as well as elucidation and validation of emerging assays for HF syndromes have collectively led to a growing interest in the more widespread use of such testing in patients affected by the diagnosis.

Low AZGP1 expression predicts for recurrence in margin-positive, localized prostate cancer.

BACKGROUND: Men with positive margins after radical prostatectomy (RP) for localized prostate cancer (PC) have a 40-50% biochemical relapse rate at 5 years. Adjuvant radiotherapy improves biochemical progression-free and overall survival in men with positive margins, but is associated with increased toxicity. There is an urgent need to identify new prognostic markers to define the group of patients who would benefit from multimodality therapy. METHODS: Nuclear ß-catenin, membranous secreted frizzled-related protein 4 (sFRP4), zinc-alpha 2-glycoprotein (AZGP1), and macrophage inhibitory cytokine-1 (MIC-1) have previously been identified as molecular markers of outcome in localized PC. From these published studies, we identified a subset of patients with positive margins. The aim of this study was to assess the association between these four molecular markers and outcome in men with margin-positive, localized PC. RESULTS: We identified 186 men with positive margins from 330 men with localized PC; 53% had preoperative PSA >10 ng/ml, 72% extraprostatic extension (EPE), 24% seminal vesicles involvement (SVI), and 57% RP Gleason score ≥ 7. AZGP1 (P = 0.009), membranous sFRP4 (P = 0.03) and MIC-1 (P = 0.04) expression predicted for biochemical relapse on univariate analysis. Only absent/low AZGP1 expression (P = 0.01) was an independent predictor of recurrence in margin-positive, localized PC when modeled with preoperative PSA (P = 0.2), EPE (P = 0.2), SVI (P = 0.4), Gleason score ≥ 7 (P = 0.5) and adjuvant treatment (P = 0.4). Furthermore, there was an association between absent/low AZGP1 expression and clinical recurrence (P = 0.007). CONCLUSIONS: AZGP1 is a potential molecular marker for biochemical relapse in men with margin-positive, localized PC. Routine assessment of this biomarker may lead to better selection of patients who will benefit from post-RP radiotherapy.

Value of Growth/Differentiation Factor 15 in Diagnosis and the Evaluation of Chemotherapeutic Response in Lung Cancer.

PURPOSE: There is a need for efficient, convenient, and inexpensive methods to accurately diagnose the clinical stage of lung cancer and evaluate the efficacy of chemotherapy in patients with lung cancer. Although growth/differentiation factor 15 (GDF)-15 has great potential as a tumor marker, supporting clinical evidence is still lacking. In this study, we aimed to analyze the relationship between serum GDF15 concentration and the clinical characteristics of patients with lung cancer, and to assess the value of GDF15 in the diagnosis and curative effect of chemotherapy. METHODS: The study comprised 160 participants in total, of whom 88 had lung cancer, 31 had pneumonia, and 41 were control subjects. Among the 88 patients with lung cancer, 64 were willing to participate in follow-up chemotherapy-related studies and meet the inclusion criteria. The serum GDF15 concentration in 288 samples (31 cases, pneumonia group samples; 41 cases, control samples; 88 cases, lung cancer group samples; 64 cases, after 1 chemotherapy cycle; and 64 cases, after 2 chemotherapy cycles) with advanced lung cancer were detected by ELISA. The possible correlations between serum GDF15 level and sex, age, height, weight, body mass index, smoking history, diabetes status, and laboratory findings (hemoglobin, prealbumin, and lactate dehydrogenase) were analyzed using parametric and nonparametric tests. Thereafter, the sensitivity of GDF15 in diagnosing lung cancer was calculated. The serum levels of GDF15, carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and cytokeratin 19 fragment (CYFRA) 21-1 were determined in 64 patients with lung cancer, before and after chemotherapy reception. For the evaluation of the efficacy of chemotherapy, receiver operating characteristic curves were plotted. FINDINGS: Serum GDF15 concentration at baseline was significantly higher in the lung cancer group than were those in the pneumonia and control groups (both, P < 0.001). An increased expression of serum GDF15 was significantly correlated with diabetes, anemia, and clinical stage (tumor size, nodal involvement, and presence/absence of metastasis). After 2 cycles of chemotherapy among the 64 patients who received it, serum GDF15 concentrations were significantly different from baseline in those who had progressive disease (P = 0.003), stable disease (P < 0.001), or partial response (P = 0.039). The AUC of GDF15 was greater than those of CEA, NSE, and CYFRA 21-1 (0.851 vs 0.630, 0.720, and 0.654, respectively). IMPLICATIONS: GDF15 is complementary to CEA, NSE, and CYFRA 21-1 in diagnosing lung cancer and, when used in combination, it could be of great diagnostic value and may facilitate correct predictions of the efficacy of chemotherapy. Therefore, serum GDF15 concentration is valuable in lung cancer diagnosis and in the evaluation of the efficacy of chemotherapy.

Elevated peritoneal soluble endoglin and GDF-15 in infertile women with severe endometriosis and pelvic adhesion.

OBJECTIVES: Chronic inflammation and pelvic adhesion play a critical role in endometriosis-related infertility. Research studies suggest that TGF-ß superfamily members, such as soluble endoglin (sEng), growth differentiation factor 15 (GDF-15) and tumor growth factor-beta (TGF-ß1) contribute to the regulation of inflammation, angiogenesis and cell adhesion. The objective of this study is to investigate the association between the concentrations of these TGF-ß-related members and the clinical parameters of infertile women with endometriosis. MATERIALS AND METHODS: Sixty-five infertile women who underwent laparoscopy were divided into two groups in this study: those who had endometriosis (n = 33) and control subjects with benign gynecologic disorders (n = 32). The levels of TGF-ß- related members in peritoneal fluid and serum were evaluated by the enzyme-linked immunosorbent assay (ELISA). Clinical and hematological parameters were documented and analyzed. RESULTS: Endometriosis cases had significantly higher levels of sEng, GDF-15 and TGF-ß1 in peritoneal fluid (p<0.0005) compared to control subjects, but not in serum. Moreover, serum GDF-15 level was significantly elevated in the late-stage endometriosis compared to the early-stage group. The levels of three TGF-ß related molecules in peritoneal fluid showed positive correlations with rASRM score. Blood neutrophil counts have correlation with the peritoneal sEng concentration. CONCLUSION: Our novel evidence on the elevated concentration of peritoneal sEng and GDF-15 in endometriosis, specifically in the late-stage, may indicate the essential role of TGF-ß-dependent signaling in endometriosis. Serum GDF-15 might serve as a candidate biomarker for endometriosis severity. Further studies are warranted to investigate the role and regulation of these molecules in endometriosis.

[The value of growth differentiation factor-15 and extravascular lung water index in severity grading of acute respiratory distress syndrome patients and their prognosis prediction].

OBJECTIVE: To investigate the value of growth differentiation factor-15 (GDF-15) and extravascular lung water index (EVLWI) in severity grading and prognosis prediction of patients with acute respiratory distress syndrome (ARDS). METHODS: Patients with ARDS aged 18-75 years admitted to the department of respiratory intensive care unit (RICU) of Zhengzhou Central Hospital Affiliated to Zhengzhou University from January 2019 to February 2020 were enrolled. All patients were treated with conventional therapies such as mechanical ventilation, anti-infection, stabilization of water, electrolytes and acid-base environment, blood purification and nutritional support according to their conditions. Besides, the pulse-indicated continuous cardiac output (PiCCO) was performed after admission to the department, and EVLWI before treatment and at 24, 48 and 72 hours of treatment were recorded. Serum GDF-15 level was measured by enzyme linked immunosorbent assay (ELISA) during the same period. Patients were classified as mild, moderate, and severe degree according to the 2012 Berlin Definition of ARDS, and EVLWI and GDF-15 levels in patients with different disease levels before and after treatment were compared. In addition, the length of intensive care unit (ICU) stay, ICU mortality, and 28-day mortality of patients with different GDF-15 or EVLWI levels were analyzed comparatively, with the GDF-15 3 458 ng/L and EVLWI 15 mL/kg as the cut point. RESULTS: A total of 82 patients with ARDS were enrolled, including 22 patients with mild ARDS, 28 patients with moderate ARDS, and 32 patients with severe ARDS. The GDF-15 and EVLWI levels in patients with moderate and severe ARDS at each time point before and after treatment were higher than those in patients with mild ARDS. Both GDF-15 and EVLWI levels in patients with severe ARDS were higher than those in the patients with moderate ARDS. The differences were statistically significant at all the time points except for the difference of GDF-15 levels at 24 hours after treatment (ng/L: 3 900.41±546.43 vs. 3 695.66±604.73, P > 0.05). [GDF-15 (ng/L): 3 786.11±441.45 vs. 3 106.83±605.09 before treatment, 3 895.48±558.96 vs. 3 333.29±559.66 at 48 hours, 3 397.33±539.56 vs. 3 047.53±499.57 at 72 hours; EVLWI (mL/kg): 19.06±1.91 vs. 14.31±1.50 before treatment, 18.56±2.23 vs. 13.26±1.69 at 24 hours, 17.23±1.76 vs. 12.45±1.36 at 48 hours, 15.47±1.81 vs. 11.13±2.19 at 72 hours, all P < 0.05]. According to the cut-off value, there were 23 patients with GDF-15 ≥ 3 458 ng/L and GDF-15 < 3 458 ng/L respectively and there were 23 patients with EVLWI ≥ 15 mL/kg and EVLWI < 15 mL/kg respectively. The length of ICU stay and 28-day mortality in patients with high GDF-15 were significantly higher than those in patients with low GDF-15 [length of ICU stay (days): 21.22±2.69 vs. 15.37±3.14, 28-day mortality: 56.5% vs. 21.7%, both P < 0.05]. The length of ICU stay and 28-day mortality in patients with high EVLWI were also significantly higher than those in patients with low EVLWI [length of ICU stay (days): 18.45±2.61 vs. 14.98±2.75, 28-day mortality: 47.8% vs. 17.4%, both P < 0.05]. CONCLUSIONS: To some extent, GDF-15 and EVLWI levels reflect the severity of patients with ARDS, and high GDF-15 and EVLWI levels are significantly associated with poor prognosis in patients with ARDS.

Accuracy of FGF-21 and GDF-15 for the diagnosis of mitochondrial disorders: A meta-analysis.

OBJECTIVE: Given their diverse phenotypes, mitochondrial diseases (MDs) are often difficult to diagnose. Fibroblast growth factor 21 (FGF-21) and growth differentiation factor 15 (GDF-15) represent promising biomarkers for MD diagnosis. Herein we conducted a meta-analysis to compare their diagnostic accuracy for MDs. METHODS: We comprehensively searched PubMed, EMBASE, MEDLINE, the Web of Science, and Cochrane Library up to 1 January 2020. Data were analyzed by two independent reviewers. We obtained the sensitivity and specificity, positive and negative likelihood ratios (LR+ and LR-), diagnostic odds ratios (DORs) and summary receiver operating characteristic (SROC) curves of each diagnostic method. RESULTS: Eight randomized controlled trials (RCTs) including 1563 participants (five encompassing 718 FGF-21 assessments; seven encompassing 845 participants for GDF-15) were included. Pooled sensitivity, specificity, DOR and SROC of FGF-21 were 0.71 (95% CI 0.53, 0.84), 0.88(95% CI 0.82, 0.93), 18 (95% CI 6, 54), 0.90 (95% CI 0.87, 0.92), respectively, which were lower than GDF-15 values; 0.83 (95% CI 0.65, 0.92), 0.92 (95% CI 0.84, 0.96), 52 (95% CI 13, 205), 0.94 (95% CI 0.92, 0.96). INTERPRETATION: FGF-21 and GDF-15 showed acceptable sensitivity and high specificity. Of the biomarkers, GDF-15 had the highest diagnostic accuracy.

Growth differentiation factor 15 production is necessary for normal erythroid differentiation and is increased in refractory anaemia with ring-sideroblasts.

The disturbed erythropoiesis in patients with refractory anaemia with ring-sideroblasts (RARS) is characterized by intramedullary apoptosis of erythroid precursors and increased iron accumulation in mitochondria. To gain insight into these pathophysiological mechanisms we compared the gene expression profile (GEP) of erythroid precursors from RARS patients to the GEP of normal erythroid precursors. Three hundred sixty four probe sets were up-, and 253 probe sets downregulated in RARS cells. Interestingly, Growth Differentiation factor 15 (GDF15), a cytokine from the TGFbeta family, was dramatically upregulated in all RARS patients. Measurement of GDF15 in the sera from twenty RARS patients confirmed this finding by showing significantly, 7.2-fold, increased protein levels (3254 +/- 1400 ng/ml vs. 451 +/- 87 ng/ml in normals). In vitro studies demonstrated erythroid-specific production of GDF15 and dependence on erythropoietin. Induction of apoptosis by arsenic trioxide, a drug which acts via reduction of the mitochondrial membrane potential, also stimulated GDF15 production. Downregulation of endogenous GDF15 production in erythoblasts by specific siRNA led to diminished erythroid differentiation. Taken together, our findings demonstrate a new role for GDF15 in normal erythropoiesis as well as in the ineffective erythropoiesis of RARS patients.

Growth-differentiation factor-15, endoglin and N-terminal pro-brain natriuretic peptide induction in athletes participating in an ultramarathon foot race.

We investigated the actions of growth-differentiation factor (GDF)-15, endoglin and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) in 15 male athletes who participated in the ultradistance foot race of the 246 km 'Sparthathlon'. Measurements were performed before (phase I), at the end of the race (phase II) and 48 h post-race (phase III). GDF-15 and endoglin serum concentrations were determined with enzyme-linked immunosorbent assay and NT-pro-BNP plasma levels by electrochemiluminescence. GDF-15 levels were increased from phase I (563.9 +/- 57.1 pg ml(-1)) to phase II (2311.1 +/- 462.3 pg ml(-1)) and decreased at phase III (862.0 +/- 158.0 pg ml(-1)) (p < 0.0002). NT-pro-BNP levels followed a similar pattern to that of GDF-15 from 38.1 +/- 4.8 pg ml(-1) at phase I to 1280.6 +/- 259.0 pg ml(-1) at phase II and 89.8 +/- 13.6 pg ml(-1) at phase III (p < 0.0001) and at the same time points, endoglin levels were 4.7 +/- 0.2 ng ml(-1) at phase I, 5.8 +/- 0.2 ng ml(-1) at phase II and 4.3 +/- 0.2 ng ml(-1) at phase III (p < 0.002). These findings indicate that circulating GDF-15, endoglin and NT-pro-BNP levels reflect a transient endothelial dysfunction in these athletes who participated in a foot race consisting of continuous, prolonged and brisk exercise.