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BACKGROUND: Interstitial lung disease is characterized by exertion dyspnea, exercise limitation and reduced quality of life. The role of exercise training in this diverse patient group is unclear. The growth differentiation factor 15 (GDF15) is a stress-sensitive circulating factor that regulates systemic energy balance and could be a possible biomarker in interstitial lung disease. OBJECTIVE: To evaluate the effect of supervised exercise (endurance and resistance) training (SET) on exercise capacity, pulmonary function parameters and GDF15 levels in patients with interstitial lung disease (PwILD). METHODS: In this non-randomized case-control trial, the experimental group comprised of 10 PwILD (7 women and 3 men) while the control group consisted of of 18 apparently healthy participants s 11 women and 7 men). All subjects completed an 8-week supervised exercise training program, at a rate of twice a week. Dyspnea was evaluated using the Shortness of Breath Respiratory Questionnaire. Exercise capacity was measured using the 6-min walk test while the heart rate (HR) was monitored before and after the exercise training. GDF15 levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: PwILD had significantly shorter 6-min walk distance than the control subjects at both the 1st and the 15th visit. However, both groups improved significantly in this test. The change (pre to post-exercise) in HR value was smaller in PwILD compared to the controls. Moreover, PwILD had higher Shortness of Breath Respiratory Questionnaire score than controls. The mean pre and post GDF15 values in both groups remained statistically unchanged. However the GDF15 values of the PwILD patients were significantly higher compared to the controls with respect to pre and post exercise training respectively. CONCLUSION: Supervised exercise training did not affect GDF15 levels in both patient and control groups but its values in PwILD were significantly higher compared to those of controls (p⩽0.05). The exercise capacity and dyspnea in these patients improved after exercise training program.

Early prediction of significant morbidity or mortality in patients with acute ST-segment elevation myocardial infarction (STEMI) represents an unmet clinical need. In phenotypically matched population of 139 STEMI patients (72 cases, 67 controls) treated with primary percutaneous coronary intervention, we explored associations between a 24-h relative change from baseline in the concentration of 91 novel biomarkers and the composite outcome of death, heart failure, or shock within 90 days. Additionally, we used random forest models to predict the 90-day outcomes. After adjustment for false discovery rate, the 90-day composite was significantly associated with concentration changes in 14 biomarkers involved in various pathophysiologic processes including: myocardial fibrosis/remodeling (collagen alpha-1, cathepsin Z, metalloproteinase inhibitor 4, protein tyrosine phosphatase subunits), inflammation, angiogenesis and signaling (interleukin 1 and 2 subunits, growth differentiation factor 15, galectin 4, trefoil factor 3), bone/mineral metabolism (osteoprotegerin, matrix extracellular phosphoglycoprotein and tartrate-resistant acid phosphatase), thrombosis (tissue factor pathway inhibitor) and cholesterol metabolism (LDL-receptor). Random forest models suggested an independent association when inflammatory markers are included in models predicting the outcomes within 90 days. Substantial heterogeneity is apparent in the early proteomic responses among patients with acutely reperfused STEMI patients who develop death, heart failure or shock within 90 days. These findings suggest the need to consider synergistic multi-biomarker strategies for risk stratification and to inform future development of novel post-myocardial infarction therapies.

Growth differentiation factor 15 or macrophage inhibitory cytokine-1 (GDF15/MIC-1) is a divergent member of the transforming growth factor β superfamily and has a diverse pathophysiological role in cancers, cardiometabolic disorder, and other diseases. GDF15 can control hematopoietic growth, energy homeostasis, adipose tissue metabolism, body growth, bone remodeling, and response to stress signals. The role of GDF15 in cancer development and progression is complicated and depends on the specific cancer type, stage, and tumor microenvironment. Recently, research on GDF15 and GDF15-associated signaling has accelerated due to the identification of the GDF15 receptor: glial cell line-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL). Therapeutic interventions to target GDF15 and/or GFRAL revealed the mechanisms that drive its activity and might improve overall outcomes of patients with metabolic disorders or cancer. The present review highlights the structure and functions of GDF15 and its receptor, emphasizing the pleiotropic role of GDF15 in obesity, tumorigenesis, metastasis, immunomodulation, and cachexia.

Mitochondrial transcription factor A (TFAM) controls the transcription of core proteins required for mitochondrial homeostasis. This study was undertaken to investigate changes in TFAM expression in systemic sclerosis (SSc), to analyze mitochondrial function, and to evaluate the consequences for fibroblast activation.TFAM expression was analyzed by immunofluorescence and Western blotting. The effects of TFAM knockout were investigated in cultured fibroblasts and in murine models of bleomycin-induced skin fibrosis, bleomycin-induced lung fibrosis, and skin fibrosis induced by overexpression of constitutively active transforming growth factor β type I receptor (TGFβRΙ).TFAM expression was down-regulated in fibroblasts in SSc skin and in cultured SSc fibroblasts. The down-regulation of TFAM was associated with decreased mitochondrial number and accumulation of damaged mitochondria with release of mitochondrial DNA (mtDNA), accumulation of deletions in mtDNA, metabolic alterations with impaired oxidative phosphorylation, and release of the mitokine GDF15. Normal fibroblasts subjected to long-term, but not acute, exposure to TGFβ mimicked SSc fibroblasts, with down-regulation of TFAM and accumulation of mitochondrial damage. Down-regulation of TFAM promoted fibroblast activation with up-regulation of fibrosis-relevant Gene Ontology terms in RNA-Seq, partially in a reactive oxygen species-dependent manner. Mice with fibroblast-specific knockout of Tfam were prone to fibrotic tissue remodeling, with fibrotic responses even to NaCl instillation and enhanced sensitivity to bleomycin injection and overexpression of constitutively active TGFβRI. TFAM knockout fostered Smad3 signaling to promote fibroblast activation.Alterations in the key mitochondrial transcription factor TFAM in response to prolonged activation of TGFβ and associated mitochondrial damage induce transcriptional programs that promote fibroblast-to-myofibroblast transition and drive tissue fibrosis.

Nonalcoholic fatty liver disease (NAFLD) is accompanied by a complex and multifactorial pathogenesis with sequential progressions from inflammation to fibrosis and then to cancer. This heterogeneity interferes with the development of precise diagnostic and prognostic strategies for NAFLD. The current approach for the diagnosis of simple steatosis, steatohepatitis, and cirrhosis mainly consists of ultrasonography, magnetic resonance imaging, elastography, and various serological analyses. However, individual dry and wet biomarkers have limitations demanding an integrative approach for the assessment of disease progression. Here, we review diagnostic strategies for simple steatosis, steatohepatitis and hepatic fibrosis, followed by potential biomarkers associated with fat accumulation and mitochondrial stress. For mitochondrial stress indicators, we focused on fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), angiopoietin-related growth factor and mitochondrial-derived peptides. Each biomarker may not strongly indicate the severity of steatosis or steatohepatitis. Instead, multidimensional analysis of different groups of biomarkers based on pathogenic mechanisms may provide decisive diagnostic/prognostic information to develop a therapeutic plan for patients with NAFLD. For this purpose, mitochondrial stress indicators, such as FGF21 or GDF15, could be an important component in the multiplexed and contextual interpretation of NAFLD. Further validation of the integrative evaluation of mitochondrial stress indicators combined with other biomarkers is needed in the diagnosis/prognosis of NAFLD.

Aging is one of the primary factors influencing development of osteoarthritis, and the TGF-β pathway plays an important role in age-related osteoarthritis. Specifically, GDF15 phosphorylates SMAD2/3 in the TGF-β pathway to inhibit cardiomyocyte hypertrophy, and promote proliferation of chondrocytes. However, age-dependent changes in the level of GDF15 are unclear, as is whether GDF15 phosphorylates SMAD2/3 in the TGF-β pathway to promote proliferation of old chondrocytes. This study, therefore, sought to examine the effect of various GDF15 concentrations on old chondrocyte proliferation.Serum and cartilage specimens of young adults and older adults were collected, and GDF15 expression was quantified. Human chondrocytes were then cultured following routine protocols, and different concentrations of recombinant human GDF15 or pSMAD2 inhibitor were added into the culture medium. After 48 h of culturing, the proliferation of chondrocytes was detected by EdU, and the expression MMP13, SMAD2, and pSMAD2 was detected in chondrocytes via western blot and qRT-PCR analysis.The GDF15 content in serum and cartilage of young adults was higher than that of older adults (p 0.05). The number of EdU-positive cells in the experimental group (containing recombinant human GDF15) was higher than that in the control group (medium only) (p 0.05). Compared with the control group, chondrocytes in the experimental group showed increased pSMAD2 and type II collagen content (p 0.05) and decreased MMP13 (p 0.05), with no significant difference in SMAD2 content (p 0.05). Moreover, no significant differences were observed between the control group and the TGF-β signaling inhibitor group. The gene expression level of each index was consistent with the protein expression level.The GDF15 content of serum and cartilage in young adults is higher than in older adults, and GDF15 functions to promote the proliferation of chondrocytes by phosphorylating SMAD2 in older individuals.

Background & Aims Patients with acute-on-chronic liver failure (ACLF) present a systemic hyperinflammatory response associated with increased circulating levels of small-molecule metabolites. To investigate whether these alterations reflect inadequate cell energy output, we assessed mitochondrial morphology and central metabolic pathways with emphasis on the tricarboxylic acid (TCA) cycle in peripheral leukocytes from patients with acutely decompensated (AD) cirrhosis, with and without ACLF. Methods The study included samples from patients with AD cirrhosis (108 without and 128 with ACLF) and 41 healthy individuals. Leukocyte mitochondrial ultrastructure was visualized by transmission electron microscopy and cytosolic and mitochondrial metabolic fluxes were determined by assessing NADH/FADH2 production from various substrates. Plasma GDF15 and FGF21 were determined by Luminex and acylcarnitines by LC-MS/MS. Gene expression was analyzed by RNA-sequencing and PCR-based glucose metabolism profiler array. Results Mitochondrial ultrastructure in patients with advanced cirrhosis was distinguished by cristae rarefication and swelling. The number of mitochondria per leukocyte was higher in patients, accompanied by a reduction in their size. Increased FGF21 and C6:0- and C8:0-carnitine predicted mortality whereas GDF15 strongly correlated with a gene set signature related to leukocyte activation. Metabolic flux analyses revealed increased energy production in mononuclear leukocytes from patients with preferential involvement of extra-mitochondrial pathways, supported by upregulated expression of genes encoding enzymes of the glycolytic and pentose phosphate pathways. In patients with ACLF, mitochondrial function analysis uncovered break-points in the TCA cycle at the isocitrate dehydrogenase and succinate dehydrogenase level, which were bridged by anaplerotic reactions involving glutaminolysis and nucleoside metabolism. Conclusions Our findings provide evidence at the cellular, organelle and biochemical levels that severe mitochondrial dysfunction governs immunometabolism in leukocytes from patients with AD cirrhosis and ACLF. Lay summary Patients at advanced stages of liver disease have dismal prognosis due to vital organ failures and the lack of treatment options. In this study, we report that the functioning of mitochondria, which are known as the cell powerhouse, is severely impaired in leukocytes of these patients, probably as a consequence of intense inflammation. Mitochondrial dysfunction is therefore a hallmark of advanced liver disease.

BACKGROUND After hepatitis C virus (HCV) elimination, patients should be followed up due to risk of hepatocellular carcinoma (HCC). Growth differentiation factor 15 (GDF15) is a cytokine induced by mitochondrial dysfunction or oxidative stress. Aim To evaluate the prognostic value of GDF15 for HCC occurrence after HCV elimination. METHODS We measured GDF15 levels in stored serum from patients with chronic HCV infection without a history of HCC who had achieved sustained virological response with direct-acting antiviral agents (DAAs). The patients were randomly divided into derivation (n = 964) and validation (n = 642) cohorts. RESULTS In the derivation cohort, serum GDF15 levels were higher in those with HCC occurrence after DAA treatment than in those without. Multivariate Cox proportional hazards analysis revealed baseline GDF15 (>1350 pg/mL, HR 2.54), AFP (>5 ng/mL, HR 2.00), and the FIB-4 index (>3.25, HR 2.69) to be independent risk factors for HCC. Scoring based on GDF15, AFP and the FIB-4 index stratified HCC occurrence risk. In the validation cohort, the cumulative HCC occurrence rate at 3 years was 0.64%, 3.27% and 15.3% in low-score (N = 171), medium-score (N = 300) and high-score (N = 166) groups, respectively. In the total cohort, scoring divided patients with a FIB-4 index ≤3.25, whose HCC occurrence rate was 2.0% at 3 years, into medium-score and low-score groups with HCC occurrence rates at 3 years of 3.76% and 0.24%, respectively. CONCLUSIONS Serum GDF15 predicts de novo HCC occurrence. Scoring using GDF15, AFP, and the FIB-4 index can predict de novo HCC occurrence risk after HCV elimination.

Background and aims Non-alcoholic fatty liver disease (NAFLD) has become a common chronic liver disease in the world. Simple steatosis (SS) is the early phase of NAFLD. However, the molecular mechanisms underlying the development of steatosis have not yet been fully elucidated. Methods Two public datasets (GSE48452 and GSE89632) through the Gene Expression Omnibus (GEO) database were used to identify differentially expressed genes (DEGs) in the development of steatosis. A total of 72 participants including 38 normal histological controls and 34 SS patients were included in this study. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein–protein interaction (PPI) network analysis were performed to explore the function of DEGs. The results were further confirmed in high-fat diet (HFD)-fed mice and oleate-treated HepG2 cells. Results Total 57 DEGs including 31 up- and 26 down-regulated genes between SS patients and healthy controls were determined. GO and KEGG analysis showed that most of the DEGs were enriched in the ligand–receptor signaling pathways. PPI network construction was used to identify the hub genes of the DEGs. MYC, ANXA2, GDF15, AGTR1, NAMPT, LEPR, IGFBP-2, IL1RN, MMP7, and APLNR were identified as hub genes, and IGFBP-2 expression was found to be reversely associated with hepatic steatosis, fasting insulin, HOMA-IR index, and ALT levels. In HFD-fed mice, hepatic IGFBP-2 was also downregulated and negatively associated with hepatic triglyceride (TG) levels. Moreover, overexpression of IGFBP-2 ameliorated the oleate induced accumulation of TGs in hepatocytes. Conclusions This study identified novel gene signatures in the hepatic steatosis and will provide new understanding and molecular clues of hepatic steatosis.

Background: Colorectal Cancer (CRC) is considered the third most deadly and fourth most commonly diagnosed cancer in the world. Objective: The aim of the present study was to compare serum levels ofgrowth differentiation factor-15(GDF-15) in patients with CRC and in those healthy control subjects. Patients and methods: The study included 60 subjects that were divided in two groups: Group Ι included 30 patients diagnosed with colorectal cancer and group ΙΙ that included 30 healthy volunteers as control group. They didn`t have any acute or chronic diseases. All subjects of this study were subjected to full history taking, clinical examination and laboratory investigations. The study was conducted at Internal Medicine Department (gastroenterology and endoscopy unit), Faculty of Medicine, Zagazig University. Results: The study comprised 35 males (58.3%) and 25 females (41.7%), with a mean age of 61 ± 9 years. Twenty-six participants were from urban areas (43.3%) and 34 from rural areas (56.7%). Thirteen participants had a suspicious occupational exposure (21.7%) and 27 were smokers (45%). Mean BMI of all participants was 31 ± 6 kg/m2 with no statistically significant differences between the studied groups. Regarding Hb level and GDF-15, there were statistically significant differences between CRC group and control group where Hb was higher in the control group, while GDF-15 was higher in CRC group. Conclusion: Growth differentiation factor 15 (GDF-15) could be used as a valuable independent biomarker for screening CRC.

Growth and differentiation factor 15 (GDF-15) is associated with muscle, fat, and bone metabolism; however, this association has not been well characterized. Plasma GDF-15, appendicular skeletal muscle mass (ASM), fat mass (FM), and bone mineral density (BMD) were measured in 146 postmenopausal women. GDF-15 levels were higher in subjects with low Body Mass Index (BMI)-adjusted ASM than in those without (median [interquartile range] 831.3 [635.4-1011.4] vs. 583.8 [455.8-771.1] pg/mL, p = 0.018). The GDF-15 level was inversely correlated with BMI-adjusted ASM (r = - 0.377, p 0.001) and BMD at femur neck (FN-BMD; r = - 0.201, p = 0.015), and positively correlated with percent FM (pFM; r = 0.328, p 0.001). After adjusting for confounders, the GDF-15 level was inversely associated with BMI-adjusted ASM (β = -0.250, p = 0.006) and positively associated with pFM (β = 0.272, p = 0.004), and tended to be inversely associated with FN-BMD (β = - 0.176, p = 0.076). The area under the receiver-operating characteristic curve of GDF-15 level 618.4 pg/mL for sarcopenia was 0.706 (95% confidence interval (CI) 0.625-0.779) with a sensitivity of 83.3% and a specificity of 54.5%. Using a GDF-15 level of 618.4 pg/mL as a cut-off, the GDF-15 level was associated with a significantly greater likelihood of sarcopenia (odds ratio [OR] 2.35; 95% CI 1.00-5.51; p = 0.049), obesity (OR 3.28; 95% CI 1.48-7.27; p = 0.001), osteopenic obesity (OR 3.10; 95% CI 1.31-7.30; p = 0.010), and sarcopenic or osteosarcopenic obesity (OR 4.84; 95% CI 0.88-26.69; p = 0.070). These findings support the potential of GDF-15 as a biomarker for age-related changes in muscle, fat, and bone.

Background In ineffective erythropoiesis, hepcidin synthesis is suppressed by erythroid regulators, namely erythroferrone and growth differentiation factor-15. For the first time, the hypothesis that iron overload in megaloblastic anemia may be related to ineffective erythropoiesis is explored by describing the kinetics of hepcidin, erythroferrone, and growth differentiation factor-15 levels in a patient diagnosed with megaloblastic anemia associated with iron overload. Case presentation An 81-year-old Caucasian male was admitted for fatigue. He had type-2 diabetes previously treated with metformin, ischemic cardiac insufficiency, and stage-3 chronic kidney disease. Vitiligo was observed on both hands. Biological tests revealed normocytic non-regenerative anemia associated with hemolysis, thrombocytopenia, and elevated sideremia, ferritin, and transferrin saturation levels. Megaloblastic anemia was confirmed with undetectable blood vitamin B12 and typical cytological findings like hyper-segmented neutrophils in blood and megaloblasts in bone marrow. The patient received vitamin B12 supplementation. At 3 months, biological parameters reached normal values. Hepcidin kinetics from diagnosis to 3 months inversely correlated with those of erythroferrone and growth differentiation factor-15. Conclusions This case suggests that iron-overload mechanisms of dyserythropoietic anemias may apply to megaloblastic anemias.

AIMS Recent studies suggest an association between cardiovascular disease (CVD) and cancer incidence/mortality, but the pathophysiological mechanisms underlying these associations are unclear. We aimed to examine biomarkers previously associated with CVD and study their association with incident cancer and cancer-related death in a prospective cohort study. METHODS AND RESULTS We used a proteomic platform to measure 71 cardiovascular biomarkers among 5,032 participants in the Framingham Heart Study who were free of cancer at baseline. We used multivariable-adjusted Cox models to examine the association of circulating protein biomarkers with risk of cancer incidence and mortality. To account for multiple testing, we set a 2-sided false discovery rate (FDR Q-value)

Mitochondrial disorders are often difficult to diagnose because of diverse clinical phenotypes. FGF-21 and GDF-15 are metabolic hormones and promising biomarkers for the diagnosis of these disorders. This study has systematically evaluated serum FGF-21 and GDF-15 levels by ELISA in a well-defined cohort of patients with definite mitochondrial disorders (n = 30), neuromuscular disease controls (n = 36) and healthy controls (n = 36) and aimed to ascertain their utility in the diagnosis of mitochondrial disorders. Both serum FGF-21 and GDF-15 were significantly elevated in patients with mitochondrial disorders, especially in those with muscle involvement. The levels were higher in patients with mitochondrial deletions (both single and multiple) and translation disorders compared to respiratory chain subunit or assembly factor defects.

Background/aim Growth differentiation factor (GDF)-15 is related to inflammation and mortality in many conditions. We aimed to determine if an elevated serum GDF-15 level is related to nutritional status of patients on hemodialysis (HD) and mortality. Materials and methods Routine HD patients (n = 158) were included in the study and followed for 18 months. Some malnutrition/ inflammation scoring indexes (malnutrition/inflammation score (MIS), controlling nutritional status (CONUT) score, and prognostic nutritional index (PNI)), biochemical parameters, and GDF-15 were used to build Cox regression multivariate models to study the association with mortality. Results Among the patients, 90 (57 %) had a high MIS (≥8), which associates with worse status. The serum GDF-15 level was higher in the same group (p = 0.003). The serum GDF-15 level differentiated malnutrition/inflammation according to the MIS (p = 0.031). Age, GDF15, and C-reactive protein (CRP) were significantly associated with higher all-cause mortality risk. Patients with both age and GDF-15 above the mean had a hazard ratio of 2.76 (p = 0.006) when compared with those both Conclusion In HD patients, the GDF-15 level is increased in worse nutritional status. Beyond the MIS, age, GDF-15 and CRP would be used together to estimate the worse clinical outcome in these patients.

Aims This study aimed to examine (i) whether circulating growth differentiation factor‐15 (GDF‐15) is associated with acute cellular cardiac allograft rejection (ACR); (ii) a longitudinal trend of GDF‐15 after heart transplantation; and (iii) the prognostic value of GDF‐15 in predicting a composite outcome of severe primary graft dysfunction (PGD) and 30 day mortality post‐transplant. Methods and results Serum samples were collected before heart transplantation and at every endomyocardial biopsy (EMB) post‐heart transplantation in de novo transplant patients. A total of 60 post‐transplant serum samples were matched to the corresponding EMBs. Seven (12%) were considered International Society for Heart Lung Transplantation Grade 1R ACR, and one (2%) was identified as Grade 2R ACR. GDF‐15 levels in patients with ACR were not different from those in the non‐rejection group (6230 vs. 6125 pg/mL, P = 0.27). GDF‐15 concentration gradually decreased from 8757 pg/mL pre‐transplant to 5203 pg/mL at 4 weeks post‐transplant. The composite adverse outcome of PGD and 30 day mortality was significantly associated with increased post‐operative GDF‐15 (odds ratio: 40; 95% confidence interval: 2.01–794.27; P = 0.005) and high inotrope score post‐transplant (odds ratio: 18; 95% confidence interval: 1.22–250.35; P = 0.01). Conclusions Circulating GDF‐15 concentration was markedly elevated in patients with end‐stage heart failure and decreased after heart transplantation. GDF‐15 was significantly associated with post‐transplant PGD and mortality. A lack of association between ACR and GDF‐15 did not support routine use of GDF‐15 as a biomarker to detect ACR. However, GDF‐15 may be potentially useful to determine heart transplant recipients at high risk for adverse post‐transplant outcomes. We suggest that GDF‐15 levels in recipient serum can provide risk stratification for severe PGD including death during post‐operative period. This novel biomarker may serve to inform and guide timely interventions against severe PGD and adverse outcomes during the first 4 weeks after transplantation. Further studies to support the utility of GDF‐15 in heart transplantation are required.

Aims To explore the relationship between serum growth differentiation factor 15 (GDF15) and metabolic abnormalities in Chinese pregnant women. Materials and Methods We recruited 200 patients with gestational diabetes mellitus (GDM) and 211 matched normal control within 24–28 weeks of pregnancy. Enzyme‐linked immunosorbent assay (ELISA) was used to determine the serum GDF15 levels of all participants. Then we grouped participants according to the number of metabolic abnormalities (including blood glucose, blood lipids and blood pressure), divided them into a normal metabolic group, one metabolic abnormality group, two or more metabolic abnormalities group. Finally, multinomial logistic regression analysis was used to estimate the odds radio (OR) and 95% CIs expressing the association between GDF15 and metabolic abnormalities in pregnant women. Results Through bivariate correlation analysis, we found that serum GDF15 is linearly correlated with glucose metabolism indices, such as 1h‐PG, 2h‐PG, HbA1c (all P 1), and the risk of multiple metabolic abnormalities was higher. As the number of metabolic abnormalities increased, serum GDF15 levels also were elevated (P, Our results found that the serum growth differentiation factor 15 plays an important role in metabolic abnormalities in the pregnant population and it may provide new ideas for the prevention and diagnosis of metabolic abnormalities during pregnancy. We believe this work is scientifically valid.

Aims Risk stratification in acute heart failure (HF) patients can help to decide therapies and time for discharge. The potential of growth differentiation factor 15 (GDF‐15) in HF has been previously shown. We aimed to study the importance of GDF‐15‐level variations in acute HF patients. Methods and results We retrospectively evaluated a cohort of patients hospitalized due to acute HF. GDF‐15 was measured both at admission and on the discharge day. Patients were followed‐up during a 3 year period. The endpoint under analysis was all‐cause mortality. GDF‐15 variation is equal to [(admission GDF‐15 − discharge GDF‐15)∕admission GDF‐15] × 100. Variation was categorized in levels of increase or decrease of GDF‐15. Patients were cross‐classified according to admission and discharge GDF‐15 cut‐off points. A Cox regression analysis was used to assess the prognostic impact of GDF‐15 variation and the impact of both admission and discharge GDF‐15 according to the cross‐classification. We studied a group of 249 patients with high co‐morbidity burden. Eighty‐one patients died at 1 year and 147 within 3 years. There was a modest decrease in GDF‐15 during hospitalization from a median value of 4087 to 3671 ng/mL (P = 0.02). No association existed between GDF‐15 variation and mortality. In multivariate analysis, patients with admission GDF‐15 ≥ 3500 ng/mL and discharge GDF‐15 ≥ 3000 ng/mL had a significantly higher 1 year death risk when compared with the remaining—hazard ratio = 2.59 (95% confidence interval: 1.41–4.76)—and a 3 year 1.76 (95% confidence interval: 1.08–2.87) higher death risk compared with those with both values below the cut‐off. Conclusions Growth differentiation factor 15 decreased during an acute HF hospitalization, but its variation had no prognostic implications. The knowledge of both admission and discharge GDF‐15 added meaningful information to patients' risk stratification.

Aims/hypothesis Metabolic effects of intermittent unhealthy lifestyle in young adults are poorly studied. We investigated the gluco-metabolic and hepatic effects of participation in Roskilde Festival (1 week of binge drinking and junk food consumption) in young, healthy males. Methods Fourteen festival participants (FP) were studied before, during and after 1 week’s participation in Roskilde Festival. Fourteen matched controls (CTRL) who did not participate in Roskilde Festival or change their lifestyle in other ways were investigated along a similar timeline. Results The FP group consumed more alcohol compared to their standard living conditions (2.0 ± 3.9 vs 16.3 ± 8.3 units/day, P < 0.001). CTRLs did not change their alcohol consumption. AUC for glucose during OGTT did not change in either group. C-peptide responses increased in the FP group (206 ± 24 vs 236 ± 17 min × nmol/L, P = 0.052) and the Matsuda index of insulin sensitivity decreased (6.2 ± 2.4 vs 4.7 ± 1.4, P = 0.054). AUC for glucagon during oral glucose tolerance test (OGTT) increased in the FP group (1037 ± 90 vs 1562 ± 195 min × pmol/L, P = 0.003) together with fasting fibroblast growth factor 21 (FGF21) (62 ± 30 vs 132 ± 72 pmol/L, P < 0.001), growth differentiation factor 15 (GDF5) (276 ± 78 vs 330 ± 83 pg/mL, P = 0.009) and aspartate aminotransferase (AST) levels (37.6 ± 6.8 vs 42.4 ± 11 U/L, P = 0.043). Four participants (29%) developed ultrasound-detectable steatosis and a mean strain elastography-assessed liver stiffness increased (P = 0.026) in the FP group. Conclusions/Interpretation Participation in Roskilde Festival did not affect oral glucose tolerance but was associated with a reduction in insulin sensitivity, increases in glucagon, FGF21, GDF15 and AST and lead to increased liver stiffness and, in 29% of the participants, ultrasound-detectable hepatic steatosis.

Aim of the work: This study was conducted to assess serum level of growth differentiation factor-15(GDF-15) in Behcet’s disease (BD) patients and its relationship with clinical characteristics, ultrasound findings and disease activity. Patients and methods: Study included 30 BD patients and 20 matched healthy controls. Visual analog scale (VAS)-pain of affected joints and Behcet’s disease current activity form (BDCAF) were assessed. The most affected joints and surrounding soft tissues were assessed by musculoskeletal ultrasound (MSUS).Serum GDF-15 level was measured. Results: Patients were 23 males and 7 females (M:F 3.3:1) with a mean age of 34.6 ± 8.6 years and mean disease duration of 6.6 ± 4.5 years. 18(60%) had arthritis and arthralgia. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were 26.2 ± 21.2 mm/1sthr and 50.4 ± 37 mg/dl respectively. There was significant increase of GDF-15 levels in patients with articular affection (3492.3 ± 4618.8 ng/ml) compared to those without (338.9 ± 90.3 ng/ml) and controls (322 ± 78.8 ng/ml) (p

Rui Peng, Di Li, Si-Qing Mei, Yan Li Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, People’s Republic of ChinaCorrespondence: Yan LiDepartment of Clinical Laboratory, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, People’s Republic of ChinaTel +86 27 88071553Email pengruiwec@163.comBackground: Elevated levels of growth differentiation factor (GDF)-15 and reduced levels of testosterone have been linked to depressive disorder, but whether they are also linked to suicidal ideation in patients with depression is unclear.Methods: This retrospective study involved 301 patients ≥ 22 years old hospitalized for depression between July 2018 and November 2020 at Renmin Hospital of Wuhan University, of whom 120 had suicidal ideation. Serum levels of GDF-15 and testosterone were compared between patients with or without suicidal ideation.Results: GDF-15 levels were significantly higher among patients with suicidal ideation than among those without, regardless of whether testosterone levels were above or below the median of 314 ng/dL. In multivariate logistic regression involving all patients, serum GDF-15 level was associated with low testosterone level (P=0.001). Among patients with testosterone < 314 ng/dL, an increase of 1 standard deviation in serum GDF-15 level translated to a 1.3-fold increase in the risk of suicidal ideation (P=0.007). This relationship was not observed in all population or patients with testosterone levels ≥ 314 ng/dL.Conclusion: High serum GDF-15 level may be associated with an increased risk of suicidal ideation in patients with depression, and this association appears to be partly mediated by low testosterone levels.Keywords: growth differentiation factor-15, testosterone, suicidal ideation, major depressive disorder

Rationale: The association between aging and idiopathic pulmonary fibrosis has been established. The associations between aging-related biomarkers and interstitial lung abnormalities (ILA) have not...

To conduct a proof-of-principle study to identify subtypes of propionic acidemia (PA) and associated biomarkers. Data from a clinically diverse PA patient population ( https://clinicaltrials.gov/ct2/show/NCT02890342 ) were used to train and test machine learning models, identify PA-relevant biomarkers, and perform validation analysis using data from liver-transplanted participants. k-Means clustering was used to test for the existence of PA subtypes. Expert knowledge was used to define PA subtypes (mild and severe). Given expert classification, supervised machine learning (support vector machine with a polynomial kernel, svmPoly) performed dimensional reduction to define relevant features of each PA subtype. Forty participants enrolled in the study; five underwent liver transplant. Analysis with k-means clustering indicated that several PA subtypes may exist on the biochemical continuum. The conventional PA biomarkers, plasma total 2-methylctirate and propionylcarnitine, were not statistically significantly different between nontransplanted and transplanted participants motivating us to search for other biomarkers. Unbiased dimensional reduction using svmPoly revealed that plasma transthyretin, alanine:serine ratio, GDF15, FGF21, and in vivo 1-13C-propionate oxidation, play roles in defining PA subtypes. Support vector machine prioritized biomarkers that helped classify propionic acidemia patients according to severity subtypes, with important ramifications for future clinical trials and management of PA.

In recent years, biomarkers have taken a central place in the assessment of cardiovascular diseases – from prediction to management and prognosis. On the other hand, enough evidence exists to assume that hypertensive disorders of pregnancy share a certain connection with cardiovascular diseases – from common risk factors and underlying mechanisms to the presence of a higher risk for women for the development of a great number of cardiovascular diseases, such as arterial hypertension, coronary atherosclerosis, stroke, peripheral artery disease, venous thromboembolism, and even a higher cardiovascular mortality. The key to a better understanding of the unfavorable cardiovascular profile of women with a hypertensive disorder of pregnancy may lie in their assessment with biomarkers, typically used in the field of cardiology. In this review, we have included studies investigating the use of cardiovascular biomarkers during or after a hypertensive pregnancy, namely, natriuretic peptides, high-sensitivity cardiac troponins, growth/differentiation factor 15 (GDF15), soluble suppression of tumorigenicity-2 (sST2), and galectin-3.

Growth Differentiation Factor-15 (GDF15) is a member of the TGF-β superfamily. Increased serum GDF15 has been associated with increased risk of chronic kidney disease (CKD) progression. However, no prior studies have addressed the significance of urinary GDF15 in adult CKD. We measured serum and urinary GDF15 in a prospective cohort of 84 patients who underwent kidney biopsy and assessed their association with outcomes (survival, kidney replacement therapy) during a follow-up of 29 ± 17 months. There was a statistically significant correlation between serum and urine GDF15 values. However, while serum GDF15 values increased with decreasing glomerular filtration rate, urinary GDF15 did not. Immunohistochemistry located kidney GDF15 expression mainly in tubular cells, and kidney GDF15 staining correlated with urinary GDF15 values. Urine GDF15 was significantly higher in patients with a histologic diagnosis of diabetic nephropathy than in diabetic patients without diabetic nephropathy. This was not the case for serum GDF15. Both serum and urine GDF15 were negatively associated with patient survival in multivariate models. However, when both urine and serum GDF15 were present in the model, lower urine GDF15 predicted patient survival [B coefficient (SEM) − 0.395 (0.182) p 0.03], and higher urine GDF15 predicted a composite of mortality or kidney replacement therapy [0.191 (0.06) p 0.002], while serum GDF15 was not predictive. Decision tree analysis yielded similar results. The area under the curve (AUC) of the receiver operating curve (ROC) for urine GDF15 as a predictor of mortality was 0.95 (95% CI 0.89–1.00, p

Determining the prognosis of a disease and risk stratification are significant issues in practical medicine. Aim.The aim of the study was to estimate the prognostic value of growth differentiation factor 15 (GDF-15) in myocardial infarction according to the literature.

Background: Biomarkers of left atrial (LA) overload are considered factors affecting the efficacy of atrial fibrillation (AF) treatment. Increasing obesity rates contribute to a growing number of obese patients qualified for electrical cardioversion (CVE).Biomarkers of left atrial (LA) overload are considered as factors influencing efficacy of atrial fibrillation (AF) treatment. The increasing rate of obesity contributes to obese patients constituting a significant group of subjects qualified to electrical cardioversion (CVE). Aims: The aim of the study was to evaluate serum concentrations of biomarkers of LA overload and their impact on the efficacy of CVE. Methods: A total of 82 patients with persistent AF who underwent successful CVE were prospectively enrolled in the study. The study population was divided into the obese group (OG) and the nonobese group (NOG). The serum levels of the following biomarkers were measured on the day of admission and at follow‑up: high‑sensitivity C‑reactive protein (hs‑CRP), N‑terminal pro‑B‑type natriuretic peptide, copeptin, galectin 3, growth differentiation factor 15 (GDF‑15), and renalase. Results: Baseline and follow‑up hs‑CRP levels were increased in the OG compared with the NOG. Four‑week CVE efficacy was 38.8% in the OG and 60.6% in the NOG. Time of the observation, allocation to the groups, and CVE outcomes showed no associations with most LA biomarkers during follow‑up. Baseline concentrations of 2 biomarkers of LA overload were associated with clinical characteristics of the study group, that is, log10 serum GDF‑15 and log10 serum renalase levels correlated positively with the CHA2DS2‑VASc score. Conclusions: Although obesity modifies the long‑term efficacy of CVE, the OG and NOG did not differ significantly in most biomarkers of LA overload, except hs‑CRP. The efficacy of CVE seems to be independent of the levels of biomarkers. A favorable procedure outcome did not affect their blood concentrations.

Objective An interplay between thrombo-inflammatory and atherogenic mechanisms is recognized in cardiovascular disease (CVD) pathogenesis in APS. Herein, we examine associations of growth differentiation factor-15 (GDF-15), a pro-inflammatory cytokine identified as a potent CVD risk biomarker in the general population, with subclinical atherosclerosis in APS. Methods We measured plasma GDF-15 levels by an electrochemiluminescence immunoassay (cut-off 1200 pg/ml) and we examined carotid intima-media thickness (IMT) and the presence of carotid and femoral plaques using vascular ultrasound in 80 patients with APS (44 primary, 36 SLE/APS) and 40 healthy controls. We calculated the adjusted Global APS Score for cardiovascular disease (aGAPSSCVD), a revised adjusted Global APS Score (aGAPSS) for predicting CVD, including lupus anticoagulant, anticardiolipin and anti-beta2glycoprotein-I antibodies, and hypertension, dyslipidaemia, obesity, diabetes and smoking. Results GDF-15 levels were higher in APS patients vs controls, after adjusting for age and gender [absolute difference: 281 (95% CI: 141, 421) pg/ml, P Conclusion GDF-15 is independently associated with subclinical atherosclerosis in APS patients, suggesting its potential role in CVD risk stratification in APS.

Lingli Cai,* Cheng Li,* Yufei Wang, Yifei Mo, Jun Yin, Xiaojing Ma Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Clinical Center for Diabetes; Shanghai Diabetes Institute; Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun Yin; Xiaojing MaDepartment of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yishan Road, Shanghai, 200233, People’s Republic of ChinaTel +86-21-64369181Fax +86-21-64368031Email yinjun@sjtu.edu.cn; maxiaojing@sjtu.edu.cnAim: Growth differentiation factor 15 (GDF15) is closely related to obesity. This study aimed to explore the influence of weight loss intervention on serum GDF15 levels and the relationship between GDF15 and metabolism.Materials and Methods: Forty-four overweight and obese adults either adopted a low-carbohydrate diet or performed moderate-to-vigorous exercise for 3 weeks. Weekly follow-ups were conducted to measure body composition, glucose and lipid metabolism and serum GDF15 levels.Results: After 3 weeks of intervention, body weight, fat mass and waist circumference in both groups decreased (P < 0.05). No significant change in GDF15 levels was observed in the two groups. Among all the subjects, 10 of them (22.7%, group of Down) showed a decrease in GDF15 and 34 (77.3%, group of Up) showed an increase in GDF15 after the intervention. We found that GDF15 increased significantly with the follow-up time in the UP group and waist circumference, fasting serum insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR) and triglycerides (TG) decreased (P for trend < 0.05). However, no significant differences in all parameters were detected in Down group. In addition, GDF15 was elevated between 30 mins and 120 mins in a 75-g oral glucose tolerance test. Its trend was negatively correlated with plasma glucose and serum insulin.Conclusion: Increased serum GDF15 was associated with improvement in metabolism by lifestyle intervention among young overweight and obese adults. The increase of GDF15 could be an indicator to evaluate metabolic improvements in overweight and obese people.Clinical Trial Registration: www.chictr.org.cn, registration number ChiCTR1800016786.Keywords: growth differentiation factor 15, obesity, metabolism, low-carbohydrate diet, exercise

A prime concern of young patients with Polycystic Ovary Syndrome (PCOS) is the control of body adiposity, given their tendency to gain weight and/or their difficulty to lose weight. Circulating growth-and-differentiation factor-15 (GDF15) facilitates the control of body weight via receptors in the brainstem. C-reactive protein (CRP) and insulin are endogenous GDF15 secretagogues. We hypothesised that PCOS in non-obese adolescents is characterised by low concentrations of circulating GDF15, when judged by the degree of CRP and insulin drive. GDF15 was added as a post-hoc endpoint of two previously reported, randomised studies in non-obese adolescent girls with PCOS (N = 58; 60% normal weight; 40% overweight) who received either an oral oestroprogestogen contraceptive (OC), or a low-dose combination of spironolactone-pioglitazone-metformin (SPIOMET) for 1 year; subsequently, all girls remained untreated for 1 year. Adolescent girls with regular menses (N = 20) served as healthy controls. Circulating GDF15, CRP and fasting insulin were assessed prior to treatment, and halfway the on- and post-treatment years. Pre-treatment, the absolute GDF15 concentrations were normal in PCOS girls, but their relative levels were markedly low, in view of the augmented CRP and insulin drives. OC treatment was accompanied by a near-doubling of circulating GDF15 (on average, from 296 to 507 pg/mL) and CRP, so that the relative GDF15 levels remained low. SPIOMET treatment was accompanied by a 3.4-fold rise of circulating GDF15 (on average, from 308 to 1045 pg/mL) and by a concomitant lowering of CRP and insulin concentrations towards normal, so that the relative GDF15 levels became markedly abundant. Post-OC, the relatively low GDF15 levels persisted; post-SPIOMET, the circulating concentrations of GDF15, CRP and insulin were all normal. BMI remained stable in both treatment groups. Only SPIOMET was accompanied by a reduction of hepato-visceral fat (by MRI) towards normal. In conclusion, early PCOS was found to be characterised by a relative GDF15 deficit that may partly explain the difficulties that young patients experience to control their body adiposity. This relative GDF15 deficit persisted during and after OC treatment. In contrast, SPIOMET treatment was accompanied by an absolute and a relative abundance of GDF15, and followed by normal GDF15, CRP and insulin concentrations. The present findings strengthen the rationale to raise the concentrations of circulating GDF15 in early PCOS, for example with a SPIOMET-like intervention that attenuates low-grade inflammation, insulin resistance and ectopic adiposity, without necessarily lowering body weight.Clinical trial registries: ISRCTN29234515 and ISRCTN11062950.

Introduction Laboratory studies suggest an involvement of growth differentiation factor 15 (GDF-15) in metabolic dysregulation. However, the utility of GDF-15 for assessing risk of cardiometabolic outcomes has not been rigorously examined among older adults. Methods We conducted a cross-sectional analysis of older adults who attended visit 6 (2016–2017) of the Atherosclerosis Risk in Communities (ARIC) Study. We used multivariable logistic regression to quantify cross-sectional associations of GDF-15 (in quartiles) with prevalent diabetes, obesity, atherosclerotic cardiovascular disease (ASCVD), subclinical myocardial stress/injury (assessed by NT-proB-type Natriuretic Peptide [NT-proBNP] and high-sensitivity cardiac troponin T [hs-cTnT]), and heart failure (HF). Results Among 3792 ARIC study participants (mean age 80 years, 59% women, 23% Blacks and 77% Whites, mean GDF-15: 2094.9 pg/mL [SD: 1395.6]), higher GDF-15 concentrations (highest vs. lowest quartile) were positively associated with diabetes (adjusted odds ratio [aOR]:] : 2.48, 95% CI : 1.89, 3.26), ASCVD (aOR: 1.57, 95% CI: 1.16, 2.11), increased hscTnT (aOR: 2.27, 95%CI: 1.54, 3.34), increased NT-proBNP (aOR: 1.98, 95%CI: 1.46, 2.70), and HF (aOR: 3.22, 95%CI : 2.13, 4.85), in models adjusted for demographics and traditional cardiovascular risk factors. Conclusions In this sample of older US black and whites, increased GDF-15 was positively associated with diabetes, ASCVD, HF, and markers of subclinical myocardial stress or injury. These results illustrate the diverse aspects of the link between GDF-15 and diseases states, and its potential utility as robust biomarker of adverse cardiometabolic outcomes.

Glioblastoma multiforme (GBM) is the commonest primary malignant brain tumor and has a remarkably weak prognosis. According to the aggressive form of GBM, understanding the accurate molecular mechanism associated with GBM pathogenesis is essential. Growth differentiation factor 15 (GDF-15) belongs to transforming growth factor-β superfamily with important roles to control biological processes. It affects cancer growth and progression, drug resistance, and metastasis. It also can promote stemness in many cancers, and also can stress reactions control, bone generation, hematopoietic growth, adipose tissue performance, and body growth, and contributes to cardiovascular disorders. The role GDF-15 to develop and progress cancer is complicated and remains unclear. GDF-15 possesses tumor suppressor properties, as well as an oncogenic effect. GDF-15 antitumorigenic and protumorigenic impacts on tumor development are linked to the cancer type and stage. However, the GDF-15 signaling and mechanism have not yet been completely identified because of no recognized cognate receptor.

Background and aims: Matrix Gla protein (MGP) is a natural inhibitor of vascular calcification critically dependent on circulating vitamin K status. Growth differentiation factor 15 (GDF-15) is a regulatory cytokine mainly of the inflammatory and angiogenesis pathways, but potentially also involved in bone mineralization. We sought to determine whether these two circulating biomarkers jointly influenced morbidity and mortality risk in patients with chronic coronary heart disease (CHD).Methods and results: 894 patients >= 6 months after myocardial infarction and/or coronary revascularization at baseline were followed in a prospective study. All-cause and cardiovascular mortality, non-fatal cardiovascular events (myocardial infarction, stroke, any revascularization), and hospitalization for heart failure (HF) were followed as outcomes. Desphospho-uncarboxylated MGP (dp-ucMGP) was used as a biomarker of vitamin K status.Both, increased concentrations of dp-ucMGP (>= 884 pmol/L) and GDF-15 (>= 1339 pg/mL) were identified as independent predictors of 5-year all-cause or cardiovascular mortality. However, their coincidence further increased mortality risk. The highest risk was observed in patients with high dp-ucMGP plus high GDF-15, not only when compared with those with "normal" concentrations of both biomarkers [HR 5.51 (95% CI 2.91-10.44), p < 0.0001 and 6.79 (95% CI 3.06 -15.08), p < 0.0001 for all-cause and cardiovascular mortality, respectively], but even when compared with patients with only one factor increased. This pattern was less convincing with non-fatal cardiovascular events or hospitalization for HF.Conclusions: The individual coincidence of low vitamin K status (high dp-ucMGP) and high GDF15 expression predicts poor survival of stable CHD patients. (C) 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Ineffective erythropoiesis and iron overload are common in myelodysplastic syndromes (MDS). Erythroferrone (ERFE) and growth/differentiation factor 15 (GDF15) are two regulators of iron homeostasis produced by erythroid progenitors. Elevated systemic levels of ERFE and GDF15 in MDS are associated with dysregulated iron metabolism and iron overload, which is especially pronounced in MDS with SF3B1 gene mutations. However, the role of ERFE and GDF15 in MDS pathogenesis and their influence on disease progression are largely unknown. Here, we analyzed the expression of ERFE and GDF15 in CD71+ erythroid progenitors of n = 111 MDS patients and assessed their effects on patient survival. The expression of ERFE and GDF15 in MDS was highly aberrant. Unexpectedly, ERFE expression in erythroprogenitors was highly relevant for MDS prognosis and independent of International Prognostic Scoring System (IPSS) stratification. Although ERFE expression was increased in patients with SF3B1 mutations, it predicted overall survival (OS) in both the SF3B1wt and SF3B1mut subgroups. Of note, ERFE overexpression predicted superior OS in the IPSS low/Int-1 subgroup and in patients with normal karyotype. Similar observations were made for GDF15, albeit not reaching statistical significance. In summary, our results revealed a strong association between ERFE expression and MDS outcome, suggesting a possible involvement of ERFE in molecular MDS pathogenesis.

We aimed to evaluate the expression of growth differentiation factor-15 (GDF-15) and lactoferrin (Lf) in tumor and their relationship with the body iron-status and overall survival (OS) outcome of patients with breast cancer. A retrospective cohort study of female patients with primary breast cancer was performed. Clinical tumor samples from the Second Affiliated Hospital of Soochow University between December 2008 and June 2014 were collected. The immuno-expression of GDF-15 and Lf was stratified into positive or negative expression. Kaplan-Meier method and Cox proportional hazards regression model were used for data analysis. 74 breast cancer patients with a mean age of 52 years were included into our study. 14 (18.9%) patients were died by the end of August 1, 2019. The serum iron level of patients with GDF-15 (+)/Lf(-) expression was higher than that of patients with other expression patterns (18.2 ± 5.4 vs. 15.5 ± 5.0 μmol/L, P = 0.038), but was not associated with OS. In univariate Cox analyses, GDF-15(+) and GDF-15(+)/Lf(-) were significantly correlated with high mortality risk (HR = 3.75, 95%CI 1.05-13.48, P = 0.025; HR = 5.00, 95%CI 1.56-16.04, P = 0.004, respectively). After adjusted for age, menopause status and primary tumor grade, the association between GDF-15 and OS disappeared. However, the association between GDF-15/Lf and OS still existed in GDF-15(+)/Lf(-) (HR = 4.50, 95%CI 1.31-15.51, P = 0.017). The combined immuno-expression pattern of GDF-15 and Lf was significant associated with high serum iron level. GDF-15/Lf could be a powerful biomarker to predict survival outcome of patients with breast cancer but still needed to be confirmed by future studies.

Background Growth differentiation factor 15(GDF15) is a distant member of the superfamily of the transforming growth factor beta (TGF-β). It has been established that increased GDF15 levels are associated with an increased risk of cardiovascular disease. However, the detail effect of GDF15 on cardiovascular system in patients with chronic kidney disease (CKD) needs detail analysis. Methods Patients with CKD who did not need dialysis were enrolled in the study. Blood pressure (BP), endothelial function, pulse wave velocity (PWV) and heart rate variability (HRV) were taken in all subjects. Plasma GDF15 concentration was measured by an enzyme-linked immunosorbent assay. Results Among the 355 participants, the mean age was 57.4 (±14.2) years old and the mean estimated glomerular filtration rate (eGFR) was 50.1 (±33.2) mL/min/1.73m2. The average plasma GDF15 level was 1394.7 (±610.1) pg/mL. Higher GDF15 concentrations were significantly associated with decreased eGFR and increased urine protein-to-creatinine ratio (uPCR). In multivariable models, after adjusting for potential confounders, plasma GDF15 has negative concerning with HRV parameters including the standard deviation of the normal-to-normal (NN) interval (SDNN), the square root of the mean of the sum of the squares of differences between adjacent NN intervals (RMSSD) and Triangular Index. Conclusion We observed there was a link between increased plasma of GDF15 and decreased HRV. The mechanisms and prediction of GDF15 in the cardiovascular disease with CKD needs further discussion and study.

Our study aimed to explore potential new diagnostic biomarkers in patients with oral squamous cell carcinoma (OSCC) to find new target molecules involved in the progression of OSCC. Potential novel biomarkers of OSCC were identified using a protein microarray assay. Compared with the healthy control group, there were five proteins (I309, GDF15, AXL, MMP3, and CTACK) in the serum of in situ oral cancer group. However, there were four differentially expressed proteins (MCSF, I309, MMP3, and CTACK) in the serum of the OSCC group. Receiver operating characteristic (ROC) curve analysis results suggested that these six proteins (I309, GDF15, AXL, MMP3, CTACK, and MCSF) had diagnostic value for OSCC. Based on The Cancer Genome Atlas (TCGA) database, we found that only GDF15 expression was associated with the prognosis of OSCC. Subsequently, we verified the expression levels of six proteins in HSC-3 and HaCaT cells, and the results showed that the level of these six proteins was significantly higher in HSC-3 cells than in normal HaCaT cells. Similarly, in the OSCC nude mouse model, the expression levels of these proteins were significantly upregulated in OSCC tumor tissue compared to the normal tissue. GDF15, MMP3, AXL, MCSF, I309, and CTACK may be used as biomarkers for OSCC diagnosis and provide a novel study direction for the treatment of OSCC.

Cachexia is a metabolic mutiny that directly reduces life expectancy in chronic conditions such as cancer. The underlying mechanisms associated with cachexia involve inflammation, metabolism, and anorexia. Therefore, the need to identify cachexia biomarkers is warranted to better understand catabolism change and assess various therapeutic interventions. Among inflammatory proteins, growth differentiation factor-15 (GDF15), an atypical transforming growth factor-beta (TGF-β) superfamily member, emerges as a stress-related hormone. In inflammatory conditions, cardiovascular diseases, and cancer, GDF15 is a biomarker for disease outcome. GDF15 is also implicated in energy homeostasis, body weight regulation, and plays a distinct role in cachexia. The recent discovery of its receptor, glial cell line-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL), sheds light on its metabolic function. Herein, we critically review the mechanisms involving GDF15 in cancer cachexia and discuss therapeutic interventions to improve outcomes in people living with cancer.

Background: Growth differentiation factor 15 (GDF15), induced by tissue inflammation and mitochondrial stress, has received significant attention as a biomarker of mitochondrial dysfunction and has been implicated in various age-related diseases. However, the association between circulating GDF15 and sarcopenia-associated outcomes in older adults remains to be established. Aim: To validate previous experimental data and to investigate the possible role of GDF15 in aging and muscle physiology in humans, this study examined serum GDF15 levels in relation to sarcopenia-related parameters in a cohort of older Asian adults. Methods: Muscle mass and muscle function-related parameters, such as grip strength, gait speed, chair stands, and short physical performance battery score were evaluated by experienced nurses in 125 geriatric participants with or without sarcopenia. Sarcopenia was diagnosed using the Asian-specific cutoff points. Serum GDF15 levels were measured using an enzyme immunoassay kit. Results: Serum GDF15 levels were not significantly different according to sarcopenia status, muscle mass, muscle strength, and physical performance and were not associated with the skeletal muscle index, grip strength, gait speed, time to complete 5 chair stands, and short physical performance battery score, regardless of adjustments for sex, age, and BMI. Conclusions: These findings indicate that the definite role of GDF15 on muscle metabolism observed in animal models might not be evident in humans and that elevated GDF15 levels might not predict the risk for sarcopenia, at least in older Asian adults.

The existence, the functional role and clinical relevance of GDF15 and its signaling through a GFRAL/RET-dependent complex in gastric cancer (GC) and other human tumors remain to be elucidated, despite the widespread recognition of obesity as an important cancer-predisposing factor. Therefore, we aimed to analyze the expression levels of GDF15, GFRAL and RET in GC tissues in relation to each other and clinicopathological features, including patient survival, in order to establish a potential implication of the body-weight signaling pathway in the pathology and clinical outcome of GC. Protein expression was examined by immunohistochemistry on tissue microarrays containing 104 and 30 consecutive GC and normal gastric mucosa samples, whereas gene expression data for The Cancer Genome Atlas cohort of 413 GC patients were obtained from public sources. We found that the protein expression of GDF15, GFRAL and RET was significantly elevated and positively correlated in our set of GC tissues, which was reflected in their tendency to be overexpressed in low-grade and intermediate-grade tumors rather than high-grade ones. No other relationships between the expression status of the examined proteins and clinicopathological characteristics of GC patients were found. Through in silico data analysis, we showed that high GDF15 expression was associated with better overall survival (OS) of GC patients, whereas the opposite was true for high levels of GFRAL or RET. Specifically, GFRAL and RET emerged as independent prognostic factors associated with poor OS. Furthermore, high combined expression of the three markers: GDF15+GFRAL+RET was significantly associated with reduced OS, and it was an independent prognostic factor of borderline significance in terms of OS, when adjusted for covariates. If validated in large-scale studies, the individual and combined expression of GDF15, GFRAL and RET may provide significant clinical implications for the prognosis prediction of GC patients.

Aims Hereditary transthyretin (ATTRv) amyloidosis is the most frequent and representative form of autosomal dominant hereditary systemic amyloidosis. Disease‐modifying treatments of the disease are more effective during the early stages, and we require biomarkers to detect early pathological changes for prompt diagnosis. This study aimed to investigate whether plasma growth differentiation factor 15 (GDF‐15) levels could aid detection of early pathological changes in ATTRv amyloidosis. Methods and results We retrospectively studied 32 patients with ATTRv amyloidosis, eight asymptomatic TTR mutation carriers, and eight healthy volunteers. We evaluated plasma GDF‐15 levels in these subjects as related to levels of brain natriuretic peptide and high‐sensitivity troponin T, echocardiographic features, 99mTc‐pyrophosphate (PYP) scans, and cardiac magnetic resonance imaging findings. Plasma GDF‐15 levels significantly increased even in asymptomatic TTR mutation carriers compared with healthy volunteers (P

Introduction To clarify mechanisms of ineffective erythropoiesis on iron metabolism, studies on erythroid factors that regulating hepcidin suppression have been carried out. The aim of the current study is to identify associations between erythropoiesis and iron homeostasis parameters in β-thalassemias. Materials and methods This study consisted of 83 subjects: 21 thalassemia major (TM), 20 thalassemia intermedia (TI), 20 thalassemia trait (TT), and 22 healthy subjects (HS). Erythroferrone (ERFE), hepcidin, growth differentiation factor-15 (GDF15), erythropoietin (EPO), and iron status parameters were measured. Results Our results showed that TM and TI patients had higher hepcidin than the TT and control groups. The hepcidin/ferritin in TM patients was significantly lower than the other groups. GDF15 in TM and TI patients was significantly higher than in the TT and control groups. Also, TI group had significantly higher ERFE concentration and EPO activity when compared with the TM, TT, and HS groups. EPO activity showed positive correlation with ERFE and GDF15 concentrations. We could not find any correlation between ERFE and hepcidin concentrations. Conclusions ERFE may be one of the parameters used to demonstrate erythropoietic activity level in thalassemias. More detailed studies are needed to clarify the role of ERFE in iron metabolism in the patients with thalassemias.

Aim and Objectives: This study aimed to evaluate the plasma levels of Growth Differentiation Factor-15 (GDF-15) in children with congestive heart failure, also to evaluate the diagnostic and prognostic value of this novel biomarker in pediatric congestive heart failure, by correlation of its levels with the clinical status and the echocardiographic data of these patients. Subjects and Methods: This study was conducted on Thirty (30) children with congestive heart failure (CHF), Patients were selected from those admitted to Pediatric Cardiology Unit, Pediatric Department, Tanta University Hospital, from (August 2018-April 2020), and thirty (30) healthy children, matched for age and sex, were enrolled as a control group. All children in this study were subjected to Plain X-ray chest and heart: Cardiothoracic ratio (CTR) was measured, and Echocardiographic assessment: Doppler and Two-dimensional, M-mode Echocardiographic evaluation of these parameters and Plasma level of Growth Differentiation Factor-15 (GDF-15) was measured. Results: the results revealed that The best cutoff point of GDF-15 to differentiate between cases with CHF and control group was >446.5 ng/l with 93.33% sensitivity, 90% specificity, 90.3% PPV, 93.1% NPV and AUC was 0.992. There was significant decrease of EF% and FS% (systolic dysfunction of LV) in patients with CHF as compared to control group. There was statistically significant positive correlation between plasma level of GDF-15 and Ross clinical stage of CHF. There was statistically significant negative correlation between GDF-15 and EF%, FS % by echocardiography. Conclusion: Plasma levels of GDF-15 were elevated in children with CHF, and these levels were correlated to the Ross staging of CHF and echocardiographic assessment of LV function. Plasma levels of GDF-15 were elevated in patients with bad prognosis, denoting its prognostic value as a novel biomarker in pediatric CHF.

Objective: Pre-eclampsia (PE) is a significant contributor to adverse maternal and perinatal outcome; however, accurate prediction and early diagnosis of this condition remain a challenge. The aim of this study was to compare serum levels of growth-differentiation factor-15 (GDF-15) at three different gestational ages between asymptomatic women who subsequently developed preterm or term PE and healthy controls. Methods: This was a case–control study drawn from a prospective observational study on adverse pregnancy outcomes in women attending for their routine second- and third-trimester hospital visits. Serum GDF-15 was determined in 300 samples using a commercial GDF-15 enzyme-linked immunosorbent assay: 120 samples at 19–24 weeks of gestation, 120 samples at 30–34 weeks and 60 samples at 35–37 weeks. Multiple linear regression was applied to logarithmically transformed GDF-15 control values to evaluate the influence of gestational age at blood sampling and maternal characteristics on GDF-15 results. GDF-15 multiples of the normal median (MoM) values, adjusted for gestational age and maternal characteristics, were compared between pregnancies that subsequently developed preterm or term PE and healthy controls. Results: Values of GDF-15 increased with gestational age. There were no significant differences in GDF-15 MoM values between cases of preterm or term PE and normotensive pregnancies at 19–24 or 35–37 weeks of gestation. At 30–34 weeks, GDF-15 MoM values were significantly increased in cases of preterm PE, but not in those who later developed term PE. Elevated GDF-15 MoM values were associated significantly with a shorter interval between sampling at 30–34 weeks and delivery with PE (P = 0.005). Conclusion: Serum GDF-15 levels at 19–24 or 35–37 weeks of gestation are not predictive of preterm or term PE. At 30–34 weeks, GDF-15 levels are higher in women who subsequently develop preterm PE; however, this difference is small and GDF-15 is unlikely to be useful in clinical practice when used in isolation. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

ObjectiveTo evaluate the potential diagnostic value of growth differentiation factor 15 (GDF15) alone and its combination with protein induced by vitamin K absence-II (PIVKA-II) and alpha-fetoprotein (AFP) for hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC).MethodsSerum levels of GDF15, PIVKA-II, and AFP were measured in 110 patients with HBV-associated HCC, 70 patients with HBV-related liver cirrhosis (LC), 70 patients with chronic hepatitis B (CHB), and 110 healthy patients.ResultsSerum GDF15 was positively related to the levels of PIVKA-II and AFP in patients with HCC (r = 0.352 and r = 0.378; all P ConclusionWe found that GDF15 is a potent serum marker for the detection of HBV-associated HCC and that PIVKA-II combined with GDF15 can improve diagnostic accuracy for HBV-associated HCC.

The expression of growth differentiation factor 15 (GDF15) is increased in cervical cancer tissues, especially in metastatic cervical cancer tissue, as well as cultivated cells. Knockdown of GDF15 markedly affects epithelial–mesenchymal transformation‐related gene expression and suppresses the migration and invasion abilities of cervical cancer cells through the transforming growth factor‐β/Smad2/3/Snail1 pathway., Growth differentiation factor 15 (GDF15), a member of the transforming growth factor β (TGF‐β) superfamily, is a prognostic biomarker of cervical cancer. In addition, GDF15 has been reported to enhance the migration of colorectal cancer cells and liver cancer stem‐like cells. However, the mechanism by which GDF15 promotes cervical cancer cell migration is not completely understood. Here, we report that GDF15 expression is enhanced in cervical cancer tissues, as well as in cultured cervical cancer cells. ShGDF15 transfection markedly inhibited expression of Vimentin, N‐cadherin and Snail1, and resulted in up‐regulation of E‐cadherin expression in HT‐3 and HeLa cells. Moreover, knockdown of GDF15 suppressed wound healing rate and reduced the number of invasive cells. Furthermore, knockdown of GDF15 significantly suppressed the expression of phosphorylated Smad2 and Smad3. The addition of TGF‐β1 partially abolished the inhibitory effects of GDF15 knockdown on the migration and invasion of cervical cancer cells. In summary, we report here that GDF15 knockdown inhibits migration and invasion of cervical cancer cells in vitro through the TGF‐β/Smad2/3/Snail1 pathway.

Fibroblast Growth Factor 21 (FGF21), Growth Differentiation Factor 15 (GDF15), and Humanin (HN) are mitochondrial stress-related mitokines, whose role in health and disease is still debated. In this study, we confirmed that their plasma levels are positively correlated with age in healthy subjects. However, when looking at patients with type 2 diabetes (T2D) or Alzheimer’s disease (AD), two age-related diseases sharing a mitochondrial impairment, we found that GDF15 is elevated in T2D but not in AD and represents a risk factor for T2D complications, while FGF21 and HN are lower in AD but not in T2D. Moreover, FGF21 reaches the highest levels in centenarian’ offspring, a model of successful aging. As a whole, these data indicate that (i) the adaptive mitokine response observed in healthy aging is lost in age-related diseases, (ii) a common expression pattern of mitokines does not emerge in T2D and AD, suggesting an unpredicted complexity and disease-specificity, and (iii) FGF21 emerges as a candidate marker of healthy aging. Supplementary Information The online version of this article (10.1007/s11357-020-00287-w) contains supplementary material, which is available to authorized users.

Primary biliary cholangitis (PBC) is a common condition that usually shows a progressive course towards cirrhosis without adequate treatment. Growth differentiation factor 15 (GDF15) plays multiple roles in various pathological conditions. The overall role of circulating GDF15 in cirrhotic PBC requires further investigation. Twenty patients with cirrhotic PBC, 26 with non-cirrhotic PBC, and 10 healthy subjects were enrolled between 2014 and 2018, and the serum levels of GDF15 were measured via enzyme immunoassay. The correlations between serum GDF15, weight, biochemical parameters, and the prognosis were analysed. Serum levels of GDF15 were significantly higher in cirrhotic PBC patients than in non-cirrhotic PBC patients or healthy controls ( p = 0.009 and p < 0.001 , respectively). The circulating GDF15 levels strongly correlated with weight changes ( r = − 0.541 , p = 0.0138 ), albumin ( r = − 0.775 , p < 0.0001 ), direct bilirubin ( r = − 0.786 , p < 0.0001 ), total bile acids ( r = 0.585 , p = 0.007 ), and C-reactive protein ( r = 0.718 , p = 0.0005 ). Moreover, circulating GDF15 levels strongly correlated with the Mayo risk score ( r = 0.685 , p = 0.0009 ) and Model for End-stage Liver Disease score ( r = 0.687 , p = 0.0008 ). Determined by the area under the receiver operating characteristic curves, the overall diagnostic accuracies of GDF15 were as follows: cirrhosis = 0.725 (>3646.55 pg/mL, sensitivity: 70.0%, specificity: 69.2%), decompensated cirrhosis = 0.956 (>4073.30 pg/mL, sensitivity: 84.62%, specificity: 100%), and cirrhotic biochemical non-responders = 0.835 (>3479.20 pg/mL, sensitivity: 71.43%, specificity: 92.31%). GDF15 may be a useful and integrated biochemical marker to evaluate not only the disease severity and prognosis but also the nutrition and response to treatment of cirrhotic PBC patients, and its overall performance is satisfactory. Therapy targeting GDF15 is likely to benefit cirrhotic PBC patients and is worth further research.

Background The majority of patients with pancreatic cancer develops cachexia. The mechanisms underlying cancer cachexia development and progression remain elusive, although tumour‐derived factors are considered to play a major role. Pancreatic tumour organoids are in vitro three‐dimensional organ‐like structures that retain many pathophysiological characteristics of the in vivo tumour. We aimed to establish a pancreatic tumour organoid biobank from well‐phenotyped cachectic and non‐cachectic patients to enable identification of tumour‐derived factors driving cancer cachexia. Methods Organoids were generated from tumour tissue of eight pancreatic cancer patients. A comprehensive pre‐operative patient assessment of cachexia‐related parameters including nutritional status, physical performance, body composition, and inflammation was performed. Tumour‐related and cachexia‐related characteristics of the organoids were analysed using histological stainings, targeted sequencing, and real‐time–quantitative PCR. Cachexia‐related factors present in the circulation of the patients and in the tumour organoid secretome were analysed by enzyme‐linked immunosorbent assay. Results The established human pancreatic tumour organoids presented typical features of malignancy corresponding to the primary tumour (i.e. nuclear enlargement, multiple nucleoli, mitosis, apoptosis, and mutated KRAS and/or TP53). These tumour organoids also expressed variable levels of many known cachexia‐related genes including interleukin‐6 (IL‐6), TNF‐α, IL‐8, IL‐1α, IL‐1β, Mcp‐1, GDF15, and LIF. mRNA expression of IL‐1α and IL‐1β was significantly reduced in organoids from cachectic vs. non‐cachectic patients (IL‐1α: −3.8‐fold, P = 0.009, and IL‐1β: −4.7‐fold, P = 0.004). LIF, IL‐8, and GDF15 mRNA expression levels were significantly higher in organoids from cachectic vs. non‐cachectic patients (LIF: 1.6‐fold, P = 0.003; IL‐8: 1.4‐fold, P = 0.01; GDF15: 2.3‐fold, P

Supplemental Digital Content is available in the text., 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