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Roos, Martin. "Innovation gegen GDF-15." Im Focus Onkologie 16, no. 1-2 (February 2013): 9. http://dx.doi.org/10.1007/s15015-013-0005-1.
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Havránek, Štěpán, and Josef Marek. "Biomarker GDF-15 in cardiology." Vnitřní lékařství 67, no. 3 (May 26, 2021): e11-e14. http://dx.doi.org/10.36290/vnl.2021.045.
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Huang, Hong, Zhongli Chen, Yan Li, Kunmei Gong, Le Xiao, Hao Fu, Jingjing Yang, Xianying Wang, and Qiang Meng. "GDF-15 Suppresses Atherosclerosis by Inhibiting oxLDL-Induced Lipid Accumulation and Inflammation in Macrophages." Evidence-Based Complementary and Alternative Medicine 2021 (September 7, 2021): 1–13. http://dx.doi.org/10.1155/2021/6497568.
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The growth differentiation factor-15 (GDF-15) may be involved in atherosclerosis. However, the role of GDF-15 in atherosclerosis remains unclear. The main goal of this study was to verify the role and mechanism of GDF-15 in atherogenesis. We first compared the serum GDF-15 level between patients with coronary atherosclerosis and healthy people. And then one ApoE−/− mouse model of atherosclerosis was used to explore the effects of GDF-15 on oxidized low-density lipoprotein (oxLDL) accumulation, atherosclerosis-related gene expression, and lipid accumulation-related protein expression in mouse macrophages. As a result, the level of serum GDF-15 in patients with coronary atherosclerosis was significantly higher than that in healthy people. In the mouse model, GDF-15 expression was elevated in the core of plaque, and it was secreted mainly by the macrophages. In addition, GDF-15 decreased oxLDL-induced lipid accumulation and inflammation activation in macrophages. GDF-15 decreased the mRNA expressions of CD36, LOX1, and TLR4 that are associated with lipoprotein accumulation in macrophages. Further study showed that GDF-15 might suppress oxLDL-induced lipoprotein accumulation via inhibiting CD36 and LOX1 and decrease inflammation in macrophages by inhibiting TLR4. Thus, GDF-15 may suppress atherosclerosis and plaque formation by inhibiting lipoprotein accumulation and inflammation activation.
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Wischhusen, Joerg, Markus Haake, Neha Vashist, Sabrina Genßler, Kilian Wistuba-Hamprecht, Patrick Harter, Alexander Martens, et al. "Tumor-derived GDF-15 to suppress t-lymphocyte recruitment to the tumor microenvironment resulting in resistance to ANTI-PD-1 treatment." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e14532-e14532. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e14532.
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e14532 Background: Growth and differentiation factor 15 (GDF-15) is a divergent member of the TGF-β superfamily with low to absent expression in healthy tissue. GDF-15 has been linked to feto-maternal immune tolerance, to prevention of excessive immune cell infiltration during tissue damage, and to anorexia. Various major tumor types secrete high levels of GDF-15. In cancer patients, elevated GDF-15 serum levels correlate with poor prognosis and reduced overall survival (OS). Methods: Impact of a proprietary GDF-15 neutralizing antibody (CTL-002) regarding T cell trafficking was analyzed by whole blood adhesion assays, a HV18-MK melanoma-bearing humanized mouse model and a GDF-15-transgenic MC38 model. Additionally, patient GDF-15 serum levels were correlated with clinical response and overall survival in oropharyngeal squamous cell carcinoma (OPSCC) and melanoma brain metastases. Results: In whole blood cell adhesion assays GDF-15 impairs adhesion of T and NK cells to activated endothelial cells. Neutralization of GDF-15 by CTL-002 rescued T cell adhesion. In HV18-MK-bearing humanized mice CTL-002 induced a strong increase in TIL numbers. Subset analysis revealed an overproportional enrichment of T cells, in particular CD8+ T cells. As immune cell exclusion is detrimental for checkpoint inhibitor (CPI) therapy, a GDF-15-transgenic MC38 model was tested for anti-PD-1 therapy efficacy. In GDF-15 overexpressing MC38 tumors response to anti PD-1 therapy was reduced by 90% compared to wtMC38 tumors. Combining aPD-1 with CTL-002 resulted in 50% of the mice rejecting their GDF-15 overexpressing tumors. Clinically, inverse correlations of GDF-15 levels with CD8+ T cell infiltration were shown for HPV+ OPSCC and for melanoma brain metastases. GDF-15 serum levels were significantly higher in HPV- than in HPV+ OPSCC patient (p < 0.0001). Low GDF-15 levels corresponded to longer OS in both HPV- and HPV+ OPSCC. In two independent melanoma patient cohorts treated with nivolumab or pembrolizumab low baseline serum GDF-15 levels were predictive for clinical response to anti-PD1 treatment and superior OS. Bivariate analysis including LDH indicates that GDF-15 independently predicts poor survival in aPD-1 treated melanoma patients. Conclusions: Taken together our in vitro and in vivo data show that elevated GDF-15 levels block T-cell infiltration into tumor tissues. Neutralizing GDF-15 with CTL-002 restores the ability of T cells to extravasate blood vessels and enter tumor tissue both in vitro and in vivo. In melanoma, patients with higher GDF-15 levels have significantly shorter survival and are less likely to respond to anti-PD1 therapy. GDF-15 may thus serve as a new predictive biomarker for anti-PD1 response, but most importantly also represents a novel target for cancer immunotherapy to improve tumor immune cell infiltration and response to anti-PD1 therapy.
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Chen, Jingfei, Fei Luo, Zhenfei Fang, and Weishe Zhang. "GDF-15 levels and atherosclerosis." International Journal of Cardiology 257 (April 2018): 36. http://dx.doi.org/10.1016/j.ijcard.2017.10.037.
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Wu, Guojin, Jinming Liang, Feng He, Meng Zhang, Zhengcheng Guo, and Jinying Ning. "Abstract 5301: GDF-15 neutralizing antibody restores cancer-induced cachexia." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5301. http://dx.doi.org/10.1158/1538-7445.am2022-5301.
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Abstract Growth and differentiation factor 15 (GDF-15) is a member of the transforming growth factor β superfamily. Elevated GDF-15 level was often the result of pathological conditions, including autoimmune disease and cancer. Increased GDF-15 caused metabiotic disorders such as anorexia and cachexia, and GDF-15 became an attractive target for metabolic intervention. Here, we developed a humanized GDF-15 neutralizing antibody (H53E5-8V2) from hybridoma of mice immunized with GDF-15-mFc. H53E5-8V2 had high affinity to GDF-15 (Kd=0.05nM), and demonstrated a stronger binding to coated GDF-15-HIS than Ponsegnomab (Pfizer Inc.) with ELISA assay (EC50=0.33nM vs 0.73nM). H53E5-8V2 also had strong binding to cynoGDF15 (EC50=0.3nM). In ELISA blocking assay, H53E5-8V2 disrupted the interaction of GDF-15 and GFRAL with a lower concentration than Ponsegnomab (EC50=0.25nM vs. 0.5nM). In addition, H53E5-8V2 neutralized GDF-15 in the culture medium and blocked GDF-15 induced GFRAL signaling more efficiently than Ponsegnomab in reporter cell assay (EC50=0.13nM vs. 0.27nM). H53E5-8V2 was stable and had a serum half-life of 9 days in mice with a single antibody injection. And it prevented body weight decrease of the mouse with HT1080 xenograft tumor, MC38 overexpressing GDF-15, or subcutaneous injection of protein GDF-15 fused with mouse Fc at C terminal. These results suggested that H53E5-8V2 was a good candidate drug for the treatment of cachexia. Citation Format: Guojin Wu, Jinming Liang, Feng He, Meng Zhang, Zhengcheng Guo, Jinying Ning. GDF-15 neutralizing antibody restores cancer-induced cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5301.
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Xie, Baikang, Wenjing Tang, Shuang Wen, Fen Chen, Chao Yang, Min Wang, Yong Yang, and Wei Liang. "GDF-15 Inhibits ADP-Induced Human Platelet Aggregation through the GFRAL/RET Signaling Complex." Biomolecules 14, no. 1 (December 27, 2023): 38. http://dx.doi.org/10.3390/biom14010038.
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Growth differentiation factor-15 (GDF-15) is proposed to be strongly associated with several cardiovascular diseases, such as heart failure and atherosclerosis. Moreover, some recent studies have reported an association between GDF-15 and platelet activation. In this study, we isolated peripheral blood platelets from healthy volunteers and evaluated the effect of GDF-15 on adenosine diphosphate (ADP)-induced platelet activation using the platelet aggregation assay. Subsequently, we detected the expression of GDF-15-related receptors on platelets, including the epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 3 (HER3), transforming growth factor-beta receptor I (TGF-βRI), transforming growth factor-beta receptor II (TGF-βRII), glial-cell-line-derived neurotrophic factor family receptor α-like (GFRAL), and those rearranged during transfection (RET). Then, we screened for GDF-15 receptors using the GDF-15-related receptor microarray comprising these recombinant proteins. We also performed the immunoprecipitation assay to investigate the interaction between GDF-15 and the receptors on platelets. For the further exploration of signaling pathways, we investigated the effects of GDF-15 on the extracellular signal-regulated kinase (ERK), protein kinase B (AKT), and Janus kinase 2 (JAK2) pathways. We also investigated the effects of GDF-15 on the ERK and AKT pathways and platelet aggregation in the presence or absence of RET agonists or inhibition. Our study revealed that GDF-15 can dose-independently inhibit ADP-induced human platelet aggregation and that the binding partner of GDF-15 on platelets is GFRAL. We also found that GDF-15 inhibits ADP-induced AKT and ERK activation in platelets. Meanwhile, our results revealed that the inhibitory effects of GDF-15 can be mediated by the GFRAL/RET complex. These findings reveal the novel inhibitory mechanism of ADP-induced platelet activation by GDF-15.
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Breen, Danna, Donald Bennett, Srinath Jagarlapudi, Stephanie Joaquim, Chang Zou, Anita Patel, Zhidan Wu, Randy Seeley, Bei Betty Zhang, and Olivier Bezy. "Effect of growth differentiation factor 15 (GDF-15) inhibition on energy balance in cancer cachexia and in lipopolysaccharide (LPS)-induced sepsis mouse models." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e24153-e24153. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e24153.
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e24153 Background: Growth differentiation factor 15 (GDF-15) is a cytokine that induces anorexia, weight loss and has been reported to be associated with cachexia and poor survival in illnesses characterized by inflammation such as cancer cachexia and heart failure. In preclinical cancer cachexia models, GDF-15 inhibition has been demonstrated to reverse cachexia and improve survival. Circulating GDF-15 is also elevated in patients with sepsis and is associated with increased complications and poor survival. However, the role of infection- and sepsis-induced GDF-15 in mouse models is controversial based on published reports. Methods: In this study, we examined the effect of GDF-15 inhibition on tumor and lipopolysaccharide (LPS)-induced anorexia, weight loss, and survival using a GDF-15 neutralizing antibody (mAB2) and GDF-15 knockout mice. Results: mAB2 efficacy was confirmed by reversing AAV-GDF-15-induced weight loss in wildtype mice. A cachectic (anorexia and weight loss) mouse tumor model was established with subcutaneous implantation of mouse renal cell carcinoma (RENCA) cells. The chemotherapy sorafenib was administered to slow tumor progression. Plasma GDF-15 was increased to ~2 ng/mL, similar to levels in cancer patients. Treatment with mAB2 rapidly reversed both anorexia and weight loss in the tumor-bearing mice. LPS injection (intraperitoneal, 5 mg/kg) increased circulating GDF-15 in wildtype mice reaching concentrations like that reported in septic patients within 90 minutes and remaining elevated after 48 hours (~1 ng/mL). LPS decreased food intake, body weight, and increased mortality (~20%). Different from the tumor model, GDF-15 neutralization with mAB2 did not prevent or exacerbate any of the effects of LPS. There were no observed detrimental effects of mAB2 treatment in either model. Similarly, in GDF-15 knockout mice the LPS effect on energy balance and survival was comparable to that observed in wildtype controls. Plasma GDF-15 was undetectable in the GDF-15 knockout mice. Conclusions: Taken together, these data suggest that GDF-15 is a critical regulator of energy balance and survival in selective pathophysiological states associated with weight loss.
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Lin, Wei, Wen-Wen Zhang, Ning Lyu, Hong Cao, Wen-Dong Xu, and Yu-Qiu Zhang. "Growth Differentiation Factor-15 Produces Analgesia by Inhibiting Tetrodotoxin-Resistant Nav1.8 Sodium Channel Activity in Rat Primary Sensory Neurons." Neuroscience Bulletin 37, no. 9 (June 2, 2021): 1289–302. http://dx.doi.org/10.1007/s12264-021-00709-5.
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AbstractGrowth differentiation factor 15 (GDF-15) is a member of the transforming growth factor-β superfamily. It is widely distributed in the central and peripheral nervous systems. Whether and how GDF-15 modulates nociceptive signaling remains unclear. Behaviorally, we found that peripheral GDF-15 significantly elevated nociceptive response thresholds to mechanical and thermal stimuli in naïve and arthritic rats. Electrophysiologically, we demonstrated that GDF-15 decreased the excitability of small-diameter dorsal root ganglia (DRG) neurons. Furthermore, GDF-15 concentration-dependently suppressed tetrodotoxin-resistant sodium channel Nav1.8 currents, and shifted the steady-state inactivation curves of Nav1.8 in a hyperpolarizing direction. GDF-15 also reduced window currents and slowed down the recovery rate of Nav1.8 channels, suggesting that GDF-15 accelerated inactivation and slowed recovery of the channel. Immunohistochemistry results showed that activin receptor-like kinase-2 (ALK2) was widely expressed in DRG medium- and small-diameter neurons, and some of them were Nav1.8-positive. Blockade of ALK2 prevented the GDF-15-induced inhibition of Nav1.8 currents and nociceptive behaviors. Inhibition of PKA and ERK, but not PKC, blocked the inhibitory effect of GDF-15 on Nav1.8 currents. These results suggest a functional link between GDF-15 and Nav1.8 in DRG neurons via ALK2 receptors and PKA associated with MEK/ERK, which mediate the peripheral analgesia of GDF-15.
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Haake, Markus, Tina Schäfer, Beatrice Haack, Neha Vashist, Sabrina Genßler, Patrick Harter, Alexander Martens, et al. "568 Tumor-derived GDF-15 prevents therapy success of checkpoint inhibitors by blocking T-lymphocyte recruitment." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A597. http://dx.doi.org/10.1136/jitc-2021-sitc2021.568.
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BackgroundImmune checkpoint blockade (ICB) can achieve durable responses in a subgroup of patients with metastatic cancer, only. Poor immune effector cell infiltration into the tumor microenvironment is a major obstacle to successful therapy. Growth and differentiation factor 15 (GDF-15) is a divergent member of the TGF-β superfamily and has been linked to feto-maternal tolerance, anorexia but recently also to potent local immunosuppression under physiologic and pathophysiologic conditions. GDF-15 is overexpressed in a wide variety of tumors and may be key factor produced by tumors to prevent effective immune cell infiltration into the tumor and to potently block checkpoint inhibitor activity.MethodsEffects of recombinant GDF-15 and a proprietary GDF-15 neutralizing antibody (CTL-002) on immune cell trafficking and activation were analyzed by adhesion and interaction assays and in melanoma-bearing humanized mouse models. The impact of GDF-15 overexpression was tested in subcutaneously implanted, GDF-15-transgenic MC38 cells. Additionally, patient GDF-15 serum levels were correlated with immune infiltration and OS in cutaneous melanoma. Associations between GDF-15 serum levels, response to PD-1-based ICB and corresponding OS were assessed in two independent cohorts of melanoma patients.ResultsGDF-15 impairs adhesion of T and NK cells on activated endothelia. In HV18-MK bearing humanized mice, inhibition of GDF-15 strongly enhances infiltration of activated myeloid and lymphoid cells. In MC38 tumors, GDF-15 overexpression can abrogate tumor rejection upon anti-PD-1 therapy. 50% of the mice with GDF-15 overexpressing tumors were, however, rescued when anti-PD-1 was combined with anti-GDF-15 (CTL-002). Likewise, anti-GDF-15 improved responses to anti-CD40 + poly(I:C) in the same tumor model. Clinically, inverse correlations of GDF-15 levels with CD8+ T cell infiltration were shown for melanoma brain metastases. In two independent melanoma patient cohorts, low baseline serum GDF-15 levels predicted clinical response to anti-PD1 treatment and superior OS. Bivariate analysis including LDH indicates that GDF-15 is an independently predictor for poor survival in anti-PD-1 treated melanoma patients.ConclusionsTumor-derived GDF-15 blocks the infiltration of immune effector cells into tumor tissues. Neutralizing GDF-15 with CTL-002 restores the ability of immune cells to extravasate blood vessels and enter the tumor microenvironment in vivo. GDF-15 thus represents a promising target for cancer immunotherapy. Antibodies against GDF-15 may support treatments with anti-PD-1 and other immunotherapeutic agents. A clinical trial combining anti-GDF-15 (CTL002) with anti-PD-1 (NCT04725474, submitted Abstract ID 15073) is ongoing.Ethics ApprovalUse of patient samples for this study had been approved by the institutional ethics committee Tübingen (ethic vote 125/2015BO2). Use of surplus sera collected in the University of Zurich Hospital (USZ) Biobank during routine blood draws from consenting metastatic melanoma patients was performed according to IRB approval (KEK.Zh- 647/800) and followed the Declaration of Helsinki on Human Rights.ConsentAll patients had given written informed consent to have clinical data recorded by the Central Malignant Melanoma Registry (CMMR) database.
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Haake, Markus, Beatrice Haack, Sabrina Genßler, Julia Weigandt, Marlene Auer, Vincent Thiemann, Wahid M. Haq, et al. "Abstract 6118: Tumor-derived GDF-15 promotes immune escape of tumors by functional alteration of the myeloid compartment." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6118. http://dx.doi.org/10.1158/1538-7445.am2022-6118.
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Abstract Background: Growth and differentiation factor 15 (GDF-15), a divergent member of the TGF-β protein superfamily, shows low physiological baseline expression. GDF-15 is, however, strongly upregulated during pregnancy. It is further induced in stressed and damaged tissues, where it limits immune infiltration and inflammation. In solid tumors, GDF-15 was shown to be a key inhibitor of T-cell infiltration. While this might already explain the strong correlation between GDF-15 overexpression and poor survival with or without checkpoint-based immunotherapy, effects of GDF-15 on dendritic cells and monocytes may further shape the tumor microenvironment. Methods: To analyze the impact of GDF-15 in murine tumor models, GDF-15 was either deleted by CRISPR/CAS9 gene editing or neutralized by administration of a blocking antibody. Effects on tumor growth were recorded and the composition of the tumor microenvironment was characterized by flow cytometry. More detailed insight into tumor-immune interactions was obtained via the CrownBio Mouse I/O RNA-Seq Panel. Specific effects on polarization of innate and on antigen-specific priming of adaptive immune cells were confirmed in cellular assays in vitro. Results: Tumor-derived GDF-15 modulates the tumor microenvironment by inhibiting infiltration and activation of myeloid cells. GDF-15 thereby impairs the induction of antitumoral immune responses. Deletion of GDF-15 enhances infiltration of innate cells into immune-excluded tumors, supports the priming of naïve T cells by dendritic cells and generates a pro-inflammatory tumor microenvironment. In vitro, GDF-15 inhibits DC maturation and synapse formation, thus preventing successful T-cell activation. Moreover, GDF-15 interferes with M1 polarization of macrophages. Conclusion: GDF-15 secretion helps tumors to generate a microenvironment that is poorly infiltrated by immune cells. GDF-15 further polarizes myeloid cells towards a tumor-promoting, anti-inflammatory phenotype. By inducing a more pro-inflammatory tumor phenotype, anti-GDF-15 antibodies may synergize with other immunotherapeutic agents. A clinical trial combining anti-GDF-15 (CTL002) with anti-PD-1 (NCT04725474) is ongoing. Citation Format: Markus Haake, Beatrice Haack, Sabrina Genßler, Julia Weigandt, Marlene Auer, Vincent Thiemann, Wahid M. Haq, Melanie Haag, Florian Wedekink, Birgitt Fischer, Kathrin Klar, Matthias Wölfl, Christine Schuberth-Wagner, Jorg Wischhusen. Tumor-derived GDF-15 promotes immune escape of tumors by functional alteration of the myeloid compartment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6118.
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Krintus, Magdalena, Federica Braga, Marek Kozinski, Simona Borille, Jacek Kubica, Grazyna Sypniewska, and Mauro Panteghini. "A study of biological and lifestyle factors, including within-subject variation, affecting concentrations of growth differentiation factor 15 in serum." Clinical Chemistry and Laboratory Medicine (CCLM) 57, no. 7 (June 26, 2019): 1035–43. http://dx.doi.org/10.1515/cclm-2018-0908.
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Abstract Background Growth differentiation factor 15 (GDF-15) is an emerging cardiovascular biomarker, and a fully automated immunoassay has recently become available. The objectives of the study were to identify biological and lifestyle factors affecting serum GDF-15 concentrations and derive robust reference intervals, and to estimate GDF-15 within-subject biological variation and derived indices. Methods A presumably healthy population of 533 questionnaire-screened adults was used to identify the biological and lifestyle determinants of serum GDF-15. Following stringent exclusion criteria, a final group of 173 individuals was selected to establish GDF-15 reference interval. Twenty-six healthy volunteers were enrolled in the biological variation substudy. Results Using a multiple regression model, age, B-type natriuretic peptide and C-reactive protein as well as smoking status were significantly related to serum GDF-15 concentrations. The upper reference limit (URL) for serum GDF-15 concentrations (90% confidence interval [CI]) was 866 ng/L (733–999 ng/L), with no sex-related difference. Although GDF-15 tended to increase with age, the weak dependence of marker from age does not justify age-related URL. The within-subject CV was 6.3% (95% CI, 4.5%–8.5%), with no sex difference in intraindividual variances. The reference change value (RCV) for GDF-15 was 23%, and two are the specimens required to ensure that the mean GDF-15 result is within ±10% of the individual’s homeostatic set point. Conclusions By identifying the main factors influencing serum GDF-15 concentrations, we robustly established the URL to be applied in adult population. As intraindividual variation of GDF-15 is relatively low, monitoring longitudinal changes in its concentrations over time using RCV can be a good alternative for interpreting GDF-15 in clinical setting.
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Vila, Greisa, Michaela Riedl, Christian Anderwald, Michael Resl, Ammon Handisurya, Martin Clodi, Gerhard Prager, Bernhard Ludvik, Michael Krebs, and Anton Luger. "The Relationship between Insulin Resistance and the Cardiovascular Biomarker Growth Differentiation Factor-15 in Obese Patients." Clinical Chemistry 57, no. 2 (February 1, 2011): 309–16. http://dx.doi.org/10.1373/clinchem.2010.153726.
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BACKGROUND Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine linked to obesity comorbidities such as cardiovascular disease, inflammation, and cancer. GDF-15 also has adipokine properties and recently emerged as a prognostic biomarker for cardiovascular events. METHODS We evaluated the relationship of plasma GDF-15 concentrations with parameters of obesity, inflammation, and glucose and lipid metabolism in a cohort of 118 morbidly obese patients [mean (SD) age 37.2 (12) years, 89 females, 29 males] and 30 age- and sex-matched healthy lean individuals. All study participants underwent a 75-g oral glucose tolerance test; 28 patients were studied before and 1 year after Roux-en-Y gastric bypass surgery. RESULTS Obese individuals displayed increased plasma GDF-15 concentrations (P < 0.001), with highest concentrations observed in patients with type 2 diabetes. GDF-15 was positively correlated with age, waist-to-height ratio, mean arterial blood pressure, triglycerides, creatinine, glucose, insulin, C-peptide, hemoglobin A1c, and homeostatic model assessment insulin resistance index and negatively correlated with oral glucose insulin sensitivity. Age, homeostatic model assessment index, oral glucose insulin sensitivity, and creatinine were independent predictors of GDF-15 concentrations. Roux-en-Y gastric bypass led to a significant reduction in weight, leptin, insulin, and insulin resistance, but further increased GDF-15 concentrations (P < 0.001). CONCLUSIONS The associations between circulating GDF-15 concentrations and age, insulin resistance, and creatinine might account for the additional cardiovascular predictive information of GDF-15 compared to traditional risk factors. Nevertheless, GDF-15 changes following bariatric surgery suggest an indirect relationship between GDF-15 and insulin resistance. The clinical utility of GDF-15 as a biomarker might be limited until the pathways directly controlling GDF-15 concentrations are better understood.
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Bonaterra, Gabriel A., Alexander Schleper, Maximilian Skowronek, Lucia S. Kilian, Theresa Rink, Hans Schwarzbach, Hendrik Heers, et al. "Increased Density of Growth Differentiation Factor-15+ Immunoreactive M1/M2 Macrophages in Prostate Cancer of Different Gleason Scores Compared with Benign Prostate Hyperplasia." Cancers 14, no. 19 (September 22, 2022): 4591. http://dx.doi.org/10.3390/cancers14194591.
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Although growth differentiation factor-15 (GDF-15) is highly expressed in PCa, its role in the development and progression of PCa is unclear. The present study aims to determine the density of GDF-15+ cells and immune cells (M1-/M2 macrophages [MΦ], lymphocytes) in PCa of different Gleason scores (GS) compared to BPH. Immunohistochemistry and double immunofluorescence were performed on paraffin-embedded human PCa and BPH biopsies with antibodies directed against GDF-15, CD68 (M1 MΦ), CD163 (M2 MΦ), CD4, CD8, CD19 (T /B lymphocytes), or PD-L1. PGP9.5 served as a marker for innervation and neuroendocrine cells. GDF-15+ cell density was higher in all GS than in BPH. CD68+ MΦ density in GS9 and CD163+ MΦ exceeded that in BPH. GDF-15+ cell density correlated significantly positively with CD68+ or CD163+ MΦ density in extratumoral areas. Double immunoreactive GDF-15+/CD68+ cells were found as transepithelial migrating MΦ. Stromal CD68+ MΦ lacked GDF-15+. The area of PGP9.5+ innervation was higher in GS9 than in BPH. PGP9.5+ cells, occasionally copositive for GDF-15+, also occurred in the glandular epithelium. In GS6, but not in BPH, GDF-15+, PD-L1+, and CD68+ cells were found in epithelium within luminal excrescences. The degree of extra-/intra-tumoral GDF-15 increases in M1/M2Φ is proposed to be useful to stratify progredient malignancy of PCa. GDF-15 is a potential target for anti-tumor therapy.
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de Jager, Saskia C. A., Beatriz Bermúdez, Ilze Bot, Rory R. Koenen, Martine Bot, Annemieke Kavelaars, Vivian de Waard, et al. "Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis." Journal of Experimental Medicine 208, no. 2 (January 17, 2011): 217–25. http://dx.doi.org/10.1084/jem.20100370.
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Growth differentiation factor (GDF) 15 is a member of the transforming growth factor β (TGF-β) superfamily, which operates in acute phase responses through a currently unknown receptor. Elevated GDF-15 serum levels were recently identified as a risk factor for acute coronary syndromes. We show that GDF-15 expression is up-regulated as disease progresses in murine atherosclerosis and primarily colocalizes with plaque macrophages. Hematopoietic GDF-15 deficiency in low density lipoprotein receptor−/− mice led to impaired initial lesion formation and increased collagen in later lesions. Although lesion burden in GDF-15−/− chimeras was unaltered, plaques had reduced macrophage infiltrates and decreased necrotic core formation, all features of improved plaque stability. In vitro studies pointed to a TGFβRII-dependent regulatory role of GDF-15 in cell death regulation. Importantly, GDF-15−/− macrophages displayed reduced CCR2 expression, whereas GDF-15 promoted macrophage chemotaxis in a strictly CCR2- and TGFβRII-dependent manner, a phenomenon which was not observed in G protein–coupled receptor kinase 2+/− macrophages. In conclusion, GDF-15 deletion has a beneficial effect both in early and later atherosclerosis by inhibition of CCR2-mediated chemotaxis and by modulating cell death. Our study is the first to identify GDF-15 as an acute phase modifier of CCR2/TGFβRII-dependent inflammatory responses to vascular injury.
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Sari, Kamran, Huseyin Ede, Zeliha Kapusuz Gencer, Mahmut Ozkiris, Ayse Yesim Gocmen, and Yavuz Selim Intepe. "The Correlation of Serum Growth Differentiation Factor-15 Level in Patients with Obstructive Sleep Apnea." BioMed Research International 2015 (2015): 1–5. http://dx.doi.org/10.1155/2015/807683.
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Purpose. Growth differentiation factor-(GDF-) is a prognostic biomarker in cardiovascular disorders (CVD). GDF-15 level was not studied in patients with obstructive sleep apnea syndrome (OSAS) before. In this study, we investigated serum GDF-15 levels in OSAS patients and compared them with healthy controls.Material and Methods. Polysomnographically, confirmed forty consecutive OSAS patients (20 men and 20 women) and forty consecutive healthy controls (23 men and 17 women) were enrolled in the study. The samples in each group had similar demographic characteristics and body mass index (BMI) values.Results. In the study, no significant correlation was found about GDF-15 levels of OSAS group and healthy controls. However, there was a significant statistical correlation between age and GDF-15 level. In correlation analysis, there was not any significant correlation between age and BMI.Conclusion. Although various developing biomarkers have been studied in cardiovascular disorders, GDF-15 levels have attracted a widespread interest as predictors of cardiovascular risk. GDF-15 level has not been evaluated previously in patients with OSAS. A significant statistical correlation was found between age and GDF-15 level. To reveal close relation between OSAS and GDF-15, further studies are needed with combination of GDF-15 and other biomarkers in OSAS.
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Adela, Ramu, and Sanjay K. Banerjee. "GDF-15 as a Target and Biomarker for Diabetes and Cardiovascular Diseases: A Translational Prospective." Journal of Diabetes Research 2015 (2015): 1–14. http://dx.doi.org/10.1155/2015/490842.
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Growth differentiation factor-15 (GDF-15) is a stress responsive cytokine. It is highly expressed in cardiomyocytes, adipocytes, macrophages, endothelial cells, and vascular smooth muscle cells in normal and pathological condition. GDF-15 increases during tissue injury and inflammatory states and is associated with cardiometabolic risk. Increased GDF-15 levels are associated with cardiovascular diseases such as hypertrophy, heart failure, atherosclerosis, endothelial dysfunction, obesity, insulin resistance, diabetes, and chronic kidney diseases in diabetes. Increased GDF-15 level is linked with the progression and prognosis of the disease condition. Age, smoking, and environmental factors are other risk factors that may increase GDF-15 level. Most of the scientific studies reported that GDF-15 plays a protective role in different tissues. However, few reports show that the deficiency of GDF-15 is beneficial against vascular injury and inflammation. GDF-15 protects heart, adipose tissue, and endothelial cells by inhibiting JNK (c-Jun N-terminal kinase), Bad (Bcl-2-associated death promoter), and EGFR (epidermal growth factor receptor) and activating Smad, eNOS, PI3K, and AKT signaling pathways. The present review describes the different animal and clinical studies and patent updates of GDF-15 in diabetes and cardiovascular diseases. It is a challenge for the scientific community to use GDF-15 information for patient monitoring, clinical decision-making, and replacement of current treatment strategies for diabetic and cardiovascular diseases.
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Heduschke, Aline, Kathrin Ackermann, Beate Wilhelm, Lilli Mey, Gabriel Alejandro Bonaterra, Ralf Kinscherf, and Anja Schwarz. "GDF-15 Deficiency Reduces Autophagic Activity in Human Macrophages In Vitro and Decreases p62-Accumulation in Atherosclerotic Lesions in Mice." Cells 10, no. 9 (September 7, 2021): 2346. http://dx.doi.org/10.3390/cells10092346.
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(1) Background: Growth differentiation factor-15 (GDF-15) is associated with cardiovascular diseases and autophagy in human macrophages (MΦ). Thus, we are interested in investigating autophagic mechanisms with special respect to the role of GDF-15. (2) Methods: Recombinant (r)GDF-15 and siRNA GDF-15 were used to investigate the effects of GDF-15 on autophagic and lysosomal activity, as well as autophagosome formation by transmission electron microscopy (TEM) in MΦ. To ascertain the effects of GDF-15−/− on the progression of atherosclerotic lesions, we used GDF-15−/−/ApoE−/− and ApoE−/− mice under a cholesterol-enriched diet (CED). Body weight, body mass index (BMI), blood lipid levels and lumen stenosis in the brachiocephalic trunk (BT) were analyzed. Identification of different cell types and localization of autophagy-relevant proteins in atherosclerotic plaques were performed by immunofluorescence. (3) Results: siGDF-15 reduced and, conversely, rGDF-15 increased the autophagic activity in MΦ, whereas lysosomal activity was unaffected. Autophagic degradation after starvation and rGDF-15 treatment was observed by TEM. GDF-15−/−/ApoE−/− mice, after CED, showed reduced lumen stenosis in the BT, while body weight, BMI and triglycerides were increased compared with ApoE−/− mice. GDF-15−/− decreased p62-accumulation in atherosclerotic lesions, especially in endothelial cells (ECs). (4) Conclusion: GDF-15 seems to be an important factor in the regulation of autophagy, especially in ECs of atherosclerotic lesions, indicating its crucial pathophysiological function during atherosclerosis development.
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Wollert, Kai C., Tibor Kempf, and Lars Wallentin. "Growth Differentiation Factor 15 as a Biomarker in Cardiovascular Disease." Clinical Chemistry 63, no. 1 (January 1, 2017): 140–51. http://dx.doi.org/10.1373/clinchem.2016.255174.
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Abstract BACKGROUND Growth differentiation factor 15 (GDF-15) is expressed and secreted in response to inflammation, oxidative stress, hypoxia, telomere erosion, and oncogene activation. Cardiovascular (CV) disease is a major driver of GDF-15 production. GDF-15 has favorable preanalytic characteristics and can be measured in serum and plasma by immunoassay. CONTENT In community-dwelling individuals higher concentrations of GDF-15 are associated with increased risks of developing CV disease, chronic kidney disease, and cancer, independent of traditional CV risk factors, renal function, and other biomarkers (C-reactive protein, B-type natriuretic peptide, cardiac troponin). Low concentrations of GDF-15 are closely associated with longevity. GDF-15 is as an independent marker of all-cause mortality and CV events in patients with coronary artery disease, and may help select patients with non–ST-elevation acute coronary syndrome for early revascularization and more intensive medical therapies. GDF-15 is independently associated with mortality and nonfatal events in atrial fibrillation and heart failure (HF) with preserved or reduced ejection fraction. GDF-15 reflects chronic disease burden and acute perturbations in HF and responds to improvements in hemodynamic status. GDF-15 is independently associated with major bleeding in patients receiving antithrombotic therapies and has been included in a new bleeding risk score, which may become useful for decision support. SUMMARY GDF-15 captures distinct aspects of CV disease development, progression, and prognosis, which are not represented by clinical risk predictors and other biomarkers. The usefulness of GDF-15 to guide management decisions and discover new treatment targets should be further explored.
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Breen, Danna, Kevin Beaumont, Donald Bennett, Julia Brosnan, Roberto A. Calle, Jeffrey Chabot, Susie Collins, et al. "Growth differentiation factor 15 (GDF-15) as a key regulator of cachexia induced by platinum-based chemotherapy." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e24162-e24162. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e24162.
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e24162 Background: Platinum-based drug use in cancer treatment is restricted by dose-limiting side effects, including nausea/emesis, anorexia and weight loss that reduce patient quality of life and limit treatment adherence. Cisplatin increases GDF-15, a cytokine that induces aversion, anorexia and weight loss in preclinical models. GDF-15 signals through the hindbrain receptor glial cell-derived neurotrophic factor receptor alpha-like (GFRAL) and cisplatin-induced weight loss was attenuated in a GFRAL knockout mouse. Methods: In the current study, using mouse and/or nonhuman primate models, we examined whether GDF-15 inhibition via a potent and selective monoclonal antibody (mAB1) prevents platinum-induced emesis, anorexia, weight loss, with increased survival. Results: Circulating GDF-15 levels in NSCLC and colorectal cancer were higher (~1.5 fold) in patients on platinum therapy compared to non-platinum-based therapy. Higher levels of circulating GDF-15 were also associated with greater weight loss in colorectal cancer patients prior to receiving FOLFOX as part of cancer treatment. In wildtype mice, cisplatin, oxaliplatin and carboplatin each increased circulating GDF-15 (≥ 5-fold) and induced anorexia, skeletal muscle wasting, and weight loss. These effects were prevented in GDF-15 knockout mice, however only a partial blockade of carboplatin was observed. The GDF-15 neutralizing efficacy of mAB1 was confirmed by reversing AAV-GDF-15-induced weight loss in wildtype mice. In nonhuman primates, cisplatin treatment for 5 days (96% of the daily recommended clinical dose) also increased circulating GDF-15 ( > 5-fold), and induced anorexia and emesis. Treatment with mAB1 resulted in no detectable circulating levels of free GDF-15 and attenuated both cisplatin-induced anorexia and emesis. In a mouse cachectic tumor model (subcutaneous; NSCLC patient derived xenograft), cisplatin inhibited tumor growth; however, GDF-15 levels remained elevated and additional weight loss occurred compared to control. When mAB1 was given in combination with cisplatin, weight loss was reversed and tumor growth inhibition was maintained, resulting in greater survival compared to cisplatin alone. Conclusions: Taken together, these data support that GDF-15 inhibition with mAB1 holds the potential as an effective therapeutic approach to alleviate GDF-15 mediated emesis, anorexia and weight loss, with the aim to enable optimal cancer treatment as well as to improve patient quality of life and potentially survival.
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Buendgens, Lukas, Eray Yagmur, Jan Bruensing, Ulf Herbers, Christer Baeck, Christian Trautwein, Alexander Koch, and Frank Tacke. "Growth Differentiation Factor-15 Is a Predictor of Mortality in Critically Ill Patients with Sepsis." Disease Markers 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/5271203.
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Growth differentiation factor-15 (GDF-15) is a member of the transforming growth factor-β superfamily related to inflammation and macrophage activation. Serum concentrations of GDF-15 can predict poor survival in chronic diseases, but its role in sepsis is obscure. Therefore, we investigated GDF-15 as a prognostic biomarker in critically ill patients. We measured GDF-15 levels in 219 critically ill patients (146 with sepsis, 73 without sepsis) upon admission to the intensive care unit (ICU), in comparison to 66 healthy controls. GDF-15 levels were significantly increased in ICU patients compared to controls. GDF-15 was further increased in sepsis and showed a strong association with organ dysfunction (kidney, liver and lactate) and disease severity (APACHE II and SOFA score). High GDF-15 concentrations at admission independently predicted ICU (HR 3.42; 95% CI 1.33–8.78) and overall mortality (HR 2.02, 95% CI 1.02–3.88) in all ICU critically ill patients as well as in a large subgroup of sepsis patients (ICU mortality: HR 3.16; 95% CI 1.10–9.07; overall mortality: HR 2.62; 95% CI 1.14–6.02). Collectively, serum GDF-15 levels are significantly increased in critically ill patients, associated with sepsis, organ failure, and disease severity. High GDF-15 levels at ICU admission predict short- and long-term mortality risk.
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Peloquin, Matthew, Brianna LaCarubba, Stephanie Joaqium, Gregory Weber, John Stansfield, Olivier Bezy, Ja Young Kim-Muller, Danna Breen, Zhidan Wu, and Bei Betty Zhang. "Growth differentiation factor 15 (GDF-15) inhibition to increase muscle mass and function in cancer cachexia." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15633-e15633. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15633.
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e15633 Background: Almost half of cancer deaths are attributed to cancers most frequently associated with cachexia. Cachexia is a complex metabolic disease characterized by anorexia and unintentional weight loss. Skeletal muscle depletion has been recognized as a key feature of the disease, however muscle anabolic therapies have not been successful, suggesting that treatments that target multiple aspects of the disease will be most effective. Growth differentiation factor 15 (GDF-15) is a cytokine that induces anorexia and weight loss and is associated with cachexia in cancer patients. In preclinical cancer cachexia models, GDF-15 inhibition is sufficient to normalize food intake and body weight, including skeletal muscle mass. However, it remains to be determined whether the increased skeletal muscle mass also results in restoration of muscle function. Therefore, we examined the effect of GDF-15 inhibition on muscle mass and function in mouse models of cancer cachexia in comparison with myostatin inhibition, an established muscle anabolic pathway. Methods: Cachectic mouse tumor models were established with subcutaneous implantation of tumor cell lines reported to be GDF-15-dependent; mouse renal cell carcinoma (RENCA) and human ovarian cancer (TOV-21G) cell lines. Mice were treated with anti-GDF-15 (mAB2) or anti-myostatin (RK35) monoclonal antibodies and skeletal muscle function was assessed in vivo via maximum force, maximum rate of contraction and half relax time. In the RENCA tumor model, GDF-15 inhibition fully restored body weight and skeletal muscle mass whereas myostatin inhibition showed only a modest effect. Results: Consistent with the muscle mass improvement, GDF-15 inhibition dramatically increased functional muscle endpoints compared to the partial effect of myostatin inhibition. Interestingly, in the TOV-21G tumor model GDF-15 inhibition only partially restored body weight, however skeletal muscle mass and muscle function were completely normalized. Consistent with the functional assessment, GDF-15 inhibition in the RENCA tumor model decreased the expression of several catabolic genes (i.e. Trim63, Fbxo32, Myh7 and Myh2). The GDF-15 effect is likely to be secondary to the reversal of anorexia since wildtype mice pair-fed to Fc-GDF-15-treated mice demonstrated equivalent muscle mass loss. Conclusions: Taken together these data suggest that GDF-15 inhibition holds potential as an effective therapeutic approach to alleviate multiple aspects of cachexia.
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LIU, Hai-tao, Hai-chang WANG, Ling TAO, Cheng-xiang LI, Fei LI, Yu-yang ZHANG, and Bo-wu LIU. "Stress-induced growth-differentiation factor 15 plays an intriguing role in cardiovascular diseases." Chinese Medical Journal 126, no. 7 (April 5, 2013): 1350–54. http://dx.doi.org/10.3760/cma.j.issn.0366-6999.20121475.
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Objective To provide an overview of the current knowledge of growth-differentiation factor 15 (GDF-15) in heart disease. Data sources To identify relevant publications, we searched PubMED database combining the textual terms of heart, cardiac, cardiovascular disease with GDF-15. Study selection Well-controlled, relatively large-scale, retrospective studies as well as meaningful individual cases were all selected as materials. Results GDF-15 is a distant member of the transforming growth factor-β cytokine superfamily. In myocardium, GDF-15 is weakly expressed under physiological conditions. However, its expression level is increased in response to pathological stress. Growing evidence indicate that elevated levels of GDF-15 is a promising prognostic biomarker in cardiovascular diseases. Moreover, GDF-15 exhibits the properties of endogenous anti-hypertrophy of cardiomyocytes and protecting the heart suffering from ischemia and reperfusion insult. Conclusion Ve GDF-15 may be a promising biomarker for evaluation and management of patient with cardiovascular diseases, and have potential protective properties on myocardium.
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Lungulescu, Cristina, Daniel Sur, Ștefan Răileanu, Ștefania Maria Dumitru, Elena Adriana Mateianu, and Cristian Virgil Lungulescu. ""GDF-15 Signaling Leading to Epithelial-to-Mesenchymal Transition in Colorectal Cancer - a Literature Review"." Journal of Medical and Radiation Oncology 2, no. 1 (July 1, 2022): 1–7. http://dx.doi.org/10.53011/jmro.2022.01.01.
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"Abstract Importance: The epithelial-mesenchymal transition (EMT) is a well-established process leading to metastasis, which is responsible for the majority of cancer-related deaths. EMT represents a critical step in the development of tumors, and is distinguishable through specific characteristics in tumor cells, such as the ability to invade and resist pharmacological treatments. Growth differentiation factor 15 (GDF-15) is a distinct member of the transforming growth factor β (TGF- β) superfamily which increases metastasis of cells both in vitro and in vivo by inducing EMT. Observations: High GDF-15 levels in certain cancers, including endometrial, prostate, pan-creatic, and colorectal cancer (CRC), may be associated with poor clinical outcomes. Higher plasma concentrations of GDF-15 have been linked to an increased risk of developing CRC and colorectal CRC-related mortality prior to a diagnosis of CRC. It has been observed that surgical excision of CRC reduces serum GDF-15, which increases when the tumor progresses, and that monitoring serum levels after surgery may aid in the prediction of cancer recurrence. However, data showed that GDF-15 regulation promoted 5-Fluorouracil (5-FU) resistance in colon cancer and GDF-15 overexpression can re-sensitize 5-FU-resistant tumor cells to chemotherapy, sug-gesting that GDF-15 may function as a tumor suppressor gene in colon cancer. Conclusions: Functional investigations of GDF-15's role in malignancy are scarce and dis-puted; prior findings indicate overexpression of GDF-15 in cancers, which contrasts GDF-15's potential role as a tumor suppressor. A thorough understanding of the regulatory mechanisms of EMT may lead to significant advancements in the treatment and prevention of cancer. Keywords: growth/differentiation factor-15, GDF-15, epithelial–mesenchymal transition, EMT, colorectal cancer, metastasis, prognostic."
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Geenen, Laurie W., Vivan J. M. Baggen, Robert M. Kauling, Thomas Koudstaal, Karin A. Boomars, Eric Boersma, Jolien W. Roos-Hesselink, and Annemien E. van den Bosch. "Growth differentiation factor-15 as candidate predictor for mortality in adults with pulmonary hypertension." Heart 106, no. 6 (September 6, 2019): 467–73. http://dx.doi.org/10.1136/heartjnl-2019-315111.
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ObjectiveDespite its predictive value for mortality in various diseases, the relevance of growth differentiation factor-15 (GDF-15) as prognostic biomarker in pulmonary hypertension (PH) remains unclear. This study investigated the association between GDF-15 and outcomes in adults with PH.MethodsThis is a single-centre prospective observational cohort study. All adults with PH were included at the day of their diagnostic right heart catheterisation between 2012 and 2016. PH due to left heart disease was excluded. Venous blood sampling was performed and included GDF-15 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements. Kaplan-Meier curves and Cox regression analysis were used to investigate the association between GDF-15 and a composite endpoint of death or lung transplantation. We adjusted for age and NT-proBNP in multivariable analysis. Reference values were established by GDF-15 measurements in healthy controls.ResultsGDF-15 was measured in 103 patients (median age 59.2 years, 65% women, 51% pulmonary arterial hypertension). GDF-15 was elevated in 76 patients (74%). After a median follow-up of 3.4 (IQR 2.3–4.6) years, 32 patients (31.1%) reached the primary endpoint. Event-free survival 2 years after diagnosis was 100% in patients with normal GDF-15 versus 72.4% in patients with elevated GDF-15 (p=0.007). A significant association was found between GDF-15 and the primary endpoint (HR per twofold higher value 1.77, 95% CI 1.39 to 2.27, p<0.001), also after adjustment for age and NT-proBNP (HR 1.41, 95% CI 1.02 to 1.94, p=0.038).ConclusionsHigh GDF-15 levels are associated with an increased risk of death or transplant in adults with PH, independent of age and NT-proBNP. As non-specific biomarker, GDF-15 could particularly be useful to detect low-risk patients.
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Jakubowska, K., A. Pryczynicz, V. Dymicka-Piekarska, D. Cepowicz, D. Jagodzińska, Ł. Lewczuk, A. Lebelt, M. Ozimkiewicz, P. Kiszło, and K. Guzińska-Ustymowicz. "The growth differentiation factor-15 (GDF-15) can be useful in the detection of distant metastases in sera of colorectal cancer patients." Progress in Health Sciences 6, no. 1 (June 30, 2016): 40–48. http://dx.doi.org/10.5604/01.3001.0009.5108.
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Purpose: Growth differentiation factor-15 (GDF- 15) protein belongs to a transforming growth factor-β family which determines the growth and differentiation of cells. In cancers, GDF-15 influences on the proliferation, differentiation, viability, migration and invasiveness of cancer cells. The aim of our study was to evaluate the expression of GDF-15 in the tissue and its levels in sera of patients with colorectal cancer. Materials and methods: The level of GDF-15 in the sera of 55 patients diagnosed with colorectal cancer was determined using the ELISA method whereas expression of this protein was performed by immunohistochemical method. Results: The mean value of GDF-15 levels in the sera of patients with colorectal cancer was significantly higher than in healthy control group (p<0.001). The expression of GDF-15 in the tissue was weak, moderate and strong in 23.6%, 15.7% and 60.7% cases, respectively. Statistical analysis showed that the expression of GDF-15 correlated with patients’ age (p<0.005) and non-mucinous type of cancer (p<0.001). The high GDF-15 levels in the serum was associated with tumor size (p<0.01) and distant metastases (p<0.05). Conclusions: According to our results, we postulate that the level of GDF-15 in serum can be use to assess the metastatic behavior of colorectal cancer
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Ueland, Thor, Lars Gullestad, Lei Kou, James B. Young, Marc A. Pfeffer, Dirk Jan van Veldhuisen, Karl Swedberg, et al. "Growth differentiation factor 15 predicts poor prognosis in patients with heart failure and reduced ejection fraction and anemia: results from RED-HF." Clinical Research in Cardiology 111, no. 4 (October 5, 2021): 440–50. http://dx.doi.org/10.1007/s00392-021-01944-6.
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Abstract Aims We aimed to assess the value of GDF-15, a stress-responsive cytokine, in predicting clinical outcomes in patients with heart failure (HF) with reduced ejection fraction (HFrEF) and anemia Methods and results Serum GDF-15 was assessed in 1582 HFrEF and mild-to-moderate anemia patients who where followed for 28 months in the Reduction of Events by Darbepoetin alfa in Heart Failure (RED-HF) trial, an overall neutral RCT evaluating the effect darbepoetin alfa on clinical outcomes in patients with systolic heart failure and mild-to-moderate anemia. Association between baseline and change in GDF-15 during 6 months follow-up and the primary composite outcome of all-cause death or HF hospitalization were evaluated in multivariable Cox-models adjusted for conventional clinical and biochemical risk factors. The adjusted risk for the primary outcome increased with (i) successive tertiles of baseline GDF-15 (tertile 3 HR 1.56 [1.23–1.98] p < 0.001) as well as with (ii) a 15% increase in GDF-15 levels over 6 months of follow-up (HR 1.68 [1.38–2.06] p < 0.001). Addition of change in GDF-15 to the fully adjusted model improved the C-statistics (p < 0.001). No interaction between treatment and baseline or change in GDF-15 on outcome was observed. GDF-15 was inversely associated with several indices of anemia and correlated positively with ferritin. Conclusions In patients with HF and anemia, both higher baseline serum GDF-15 levels and an increase in GDF-15 during follow-up, were associated with worse clinical outcomes. GDF-15 did not identify subgroups of patients who might benefit from correction of anemia but was associated with several indices of anemia and iron status in the HF patients. Graphic abstract
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Kempf, Tibor, Anja Guba-Quint, Jarl Torgerson, Maria Chiara Magnone, Carolina Haefliger, Maria Bobadilla, and Kai C. Wollert. "Growth differentiation factor 15 predicts future insulin resistance and impaired glucose control in obese nondiabetic individuals: results from the XENDOS trial." European Journal of Endocrinology 167, no. 5 (November 2012): 671–78. http://dx.doi.org/10.1530/eje-12-0466.
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Objective Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine that is increased in obesity and established type 2 diabetes. We assessed whether GDF-15 can predict future insulin resistance and impaired glucose control in obese nondiabetic individuals. Design and methods Plasma GDF-15 concentrations were measured with an automated electrochemiluminescent immunoassay at baseline and after 4 years in 496 obese nondiabetic individuals (52% men, median age 48 years, median body mass index (BMI) 37.6 kg/m2) enrolled in the XENical in the prevention of Diabetes in Obese subjects (XENDOS) trial. Results The median GDF-15 concentration at baseline was 869 ng/l (interquartile range 723–1064 ng/l). GDF-15 was related to body weight, BMI, waist-to-hip ratio, and insulin resistance (homeostasis model assessment of insulin resistance (HOMA-IR)) (all P<0.01). Changes in GDF-15 from baseline to 4 years were related to changes in body weight, BMI, waist-to-hip ratio, and HOMA-IR (all P<0.05). Baseline GDF-15 was associated with the risk to have prediabetes or diabetes at 4 years by univariate analysis (odds ratio (OR) for 1 unit increase in ln GDF-15, 3.2; 95% confidence interval (CI): 1.7–6.1; P<0.001), and after multivariate adjustment for age, gender, treatment allocation (orlistat vs placebo), BMI, waist-to-hip ratio, and glucose control at baseline (OR 2.2; 95% CI: 1.1–4.7; P=0.026). Similarly, baseline GDF-15 was independently associated with HOMA-IR at 4 years (P=0.024). Conclusions This first longitudinal study of GDF-15 in a large cohort of obese individuals indicates that GDF-15 is related to abdominal obesity and insulin resistance and independently associated with future insulin resistance and abnormal glucose control.
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Kim, Jin Sug, Sunyoung Kim, Chang Won Won, and Kyung Hwan Jeong. "Association between Plasma Levels of Growth Differentiation Factor-15 and Renal Function in the Elderly: Korean Frailty and Aging Cohort Study." Kidney and Blood Pressure Research 44, no. 3 (2019): 405–14. http://dx.doi.org/10.1159/000498959.
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Background/Aims: Growth differentiation factor-15 (GDF-15) expression has been reported to increase in response to tissue damage and has recently emerged as a useful biomarker for various diseases. Although emerging evidence supports the clinicopathological value of GDF-15 in renal impairment, few studies have analyzed it in the elderly. Thus, we conducted a cross-sectional study to investigate the association of plasma GDF-15 with renal function and the presence of chronic kidney disease (CKD) in community-dwelling elderly. Materials: The present study was based on the baseline data of the Korean Frailty and Aging Cohort Study (KFACS), a nationwide cohort study that began in 2016. Of the 1,559 participants assessed in the first year, 443 with available plasma GDF-15 data were enrolled in this study. We investigated the association of plasma GDF-15 levels with clinical and biochemical parameters. The study population was divided into two groups according to renal function (CKD and non-CKD groups) to investigate whether GDF-15 can determine the presence of renal dysfunction in the elderly. Plasma GDF-15 was measured by enzyme-linked immunosorbent assay (ELISA) kit. Results: In a simple regression analysis, the levels of plasma GDF-15 were negatively correlated with estimated glomerular filtration rate (eGFR; r = –0.383, p < 0.001). In multiple linear regression analysis, GDF-15 levels were still significantly correlated with eGFR, even after adjusting for other parameters (r = –0.259, p < 0.001). Plasma GDF-15 levels were significantly higher in the elderly with CKD than in those without CKD (2,364.025 ± 1,052.23 ng/L and 1,451.23 ± 835.79 ng/L, respectively; p < 0.001). The optimal cut-off value of plasma GDF-15 for detecting the presence of CKD was 1,699.4 ng/L (76.5% sensitivity and 76.0% specificity), as determined by the receiver operating characteristic curve. The area under the curve was 0.793 ± 0.033 (95% CI 0.729–0.857, p < 0.001). Conclusion: Plasma GDF-15 levels were negatively associated with eGFR and were significantly increased in the elderly with CKD. Our results suggested that plasma GDF-15 might be a useful marker for discriminating renal impairment in the elderly. Further large and prospective outcome studies of extended duration are needed.
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Nakajima, Shibasaki, Sawaguchi, Haruyama, Kaneda, Nakajima, Hasegawa, et al. "Growth Differentiation Factor-15 (GDF-15) is a Biomarker of Muscle Wasting and Renal Dysfunction in Preoperative Cardiovascular Surgery Patients." Journal of Clinical Medicine 8, no. 10 (October 1, 2019): 1576. http://dx.doi.org/10.3390/jcm8101576.
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Frailty and sarcopenia increase the risk of complications and mortality when invasive treatment such as cardiac surgery is performed. Growth differentiation factor-15 (GDF-15) involves various pathophysiological conditions including renal dysfunction, heart failure and cachexia. We investigated the pathophysiological roles of preoperative GDF-15 levels in cardiovascular surgery patients. Preoperative skeletal muscle index (SMI) determined by bioelectrical impedance analysis, hand-grip strength, 4 m gait speed, and anterior thigh muscle thickness (TMth) measured by echocardiography were assessed in 72 patients (average age 69.9 years) who underwent cardiovascular surgery. The preoperative serum GDF-15 concentration was determined by enzyme-linked immunosorbent assay. Circulating GDF-15 level was correlated with age, brain natriuretic peptide, and estimated glomerular filtration rate (eGFR). It was also negatively correlated with SMI, hand-grip strength, and anterior TMth. In multivariate analysis, eGFR and anterior TMth were the independent determinants of GDF-15 concentration even after adjusting for age, sex, and body mass index. Alternatively, the GDF-15 level was an independent determinant of eGFR and anterior TMth. We concluded that preoperative GDF-15 levels reflect muscle wasting as well as renal dysfunction in preoperative cardiovascular surgery patients. GDF-15 may be a novel biomarker for identify high-risk patients with muscle wasting and renal dysfunction before cardiovascular surgery.
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Zelniker, Thomas A., Petr Jarolim, Michael G. Silverman, Erin A. Bohula, Jeong-Gun Park, Marc P. Bonaca, Benjamin M. Scirica, and David A. Morrow. "Prognostic role of GDF-15 across the spectrum of clinical risk in patients with NSTE-ACS." Clinical Chemistry and Laboratory Medicine (CCLM) 57, no. 7 (June 26, 2019): 1084–92. http://dx.doi.org/10.1515/cclm-2018-1081.
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Abstract Background Growth differentiation factor (GDF)-15 has been shown to predict cardiovascular (CV) outcomes in acute coronary syndrome (ACS) using non-commercial assays. We evaluated the prognostic performance of GDF-15 measured with the first clinically available assay. Furthermore, we evaluated whether GDF-15 was associated with CV death or heart failure (HF) across the spectrum of risk in non-ST-segment elevation (NSTE)-ACS. Methods We measured baseline GDF-15 (Roche, Elecsys) in 4330 patients with NSTE-ACS enrolled in MERLIN-TIMI 36. Patients were categorized using a priori thresholds of GDF-15 levels (<1200, 1200–1800, ≥1800 ng/L) and stratified according to estimated clinical risk per TIMI risk score (0–2, 3–4, and ≥5). Cox modeling included age, sex, BMI, smoking, HF, diabetes, renal function, NT-proBNP, hsTnT, and hsCRP. Results There were 2286 (53%), 1104 (25%), and 940 (22%) pts with GDF-15 <1200, 1200–1800, and ≥1800 respectively. GDF-15 was significantly associated after multivariable adjustment with CV death/HF modeled either as a categorical (1200–1800 ng/L: Adj hazard ratios [HR] 1.55 [1.09–2.19]; ≥1800 ng/L: Adj HR 1.94 [1.34–2.79]) or continuous variable (Adj HR 1.36 [1.16–1.60] per 1-unit increase in log2-transformed GDF-15). Notably, there was an interaction (Pinteraction=0.003) between TIMI risk score and GDF-15, with GDF-15 identifying the greatest incremental relative risk in those at lowest risk based on the TIMI risk score alone. Conclusions Using a clinically available assay, GDF-15 can be applied using established cut-off points to independently predict risk of CV death/HF in patients with NSTE-ACS. This incremental risk appears to be particularly robust among individuals traditionally identified as low risk.
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Alserawan, Leticia, Patricia Peñacoba, Sandra Elizabet Orozco Echevarría, Diego Castillo, Esther Ortiz, Laura Martínez-Martínez, Esther Moga Naranjo, et al. "Growth Differentiation Factor 15 (GDF-15): A Novel Biomarker Associated with Poorer Respiratory Function in COVID-19." Diagnostics 11, no. 11 (October 27, 2021): 1998. http://dx.doi.org/10.3390/diagnostics11111998.
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It is essential to find new biomarkers for severity stratification of patients with coronavirus disease (COVID-19). Growth differentiation factor 15 (GDF-15) is upregulated in pathological conditions that involve inflammation and/or oxidative stress. We determined circulating levels of GDF-15 and correlated them with clinical and laboratory parameters reflecting severity in 84 patients with COVID-19, finding that GDF-15 levels were higher in both patients than in 20 healthy controls and were higher in patients with poorer respiratory function. GDF-15 levels also correlated with interleukin-6, C-reactive protein, ferritin and D-dimer levels and with neutrophilia and lymphopenia. Of all the analysed biomarkers, GDF-15 showed the best area under the receiver operating characteristics curve in identifying patients with poor respiratory function. In conclusion, our data support GDF-15 as a biomarker associated with pulmonary impairment in COVID-19 and so can potentially be useful in stratifying COVID-19 cases by severity.
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Hansen, Ellen-Sofie, Kristian Hindberg, Nadezhda Latysheva, Pål Aukrust, Thor Ueland, John-Bjarne Hansen, Sigrid K. Brækkan, and Vânia M. Morelli. "Plasma levels of growth differentiation factor 15 are associated with future risk of venous thromboembolism." Blood 136, no. 16 (October 15, 2020): 1863–70. http://dx.doi.org/10.1182/blood.2019004572.
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Abstract Growth differentiation factor 15 (GDF-15), a marker of inflammation and oxidative stress, has emerged as a biomarker for arterial cardiovascular disease. However, the association between GDF-15 and venous thromboembolism (VTE) remains uncertain. We therefore investigated the association between plasma GDF-15 levels and future risk of incident VTE and explored the potential of a causal association using Mendelian randomization (MR). We conducted a population-based nested case-control study comprising 416 VTE patients and 848 age- and sex-matched controls derived from the Tromsø Study. Logistic regression was used to calculate odds ratios (ORs) for VTE across GDF-15 quartiles. For the MR, we used data from the International Network on Venous Thrombosis (INVENT) consortium to examine whether single nucleotide polymorphisms (SNPs) associated with GDF-15 levels with genome-wide significance were related to VTE. We found that the ORs for VTE increased across GDF-15 quartiles (Ptrend = .002). Participants with GDF-15 values in the highest quartile (≥358 pg/mL) had an OR for VTE of 2.05 (95% confidence interval, 1.37-3.08) compared with those with GDF-15 in the lowest quartile (<200 pg/mL) in the age- and sex-adjusted model. ORs remained essentially the same after further adjustment for body mass index, smoking, hormone therapy, physical activity, and C-reactive protein. Similar results were obtained for provoked/unprovoked events, deep vein thrombosis, and pulmonary embolism. GDF-15 levels, as predicted by the SNPs, were not associated with VTE in MR. Our results indicate that high GDF-15 levels are associated with increased risk of VTE, but MR suggests that this association is not causal.
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Hubens, Wouter H. G., Mariëlle T. Kievit, Tos T. J. M. Berendschot, Irenaeus F. M. de Coo, Hubert J. M. Smeets, Carroll A. B. Webers, and Theo G. M. F. Gorgels. "Plasma GDF-15 concentration is not elevated in open-angle glaucoma." PLOS ONE 16, no. 5 (May 28, 2021): e0252630. http://dx.doi.org/10.1371/journal.pone.0252630.
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Aim Recently, the level of growth differentiation factor 15 (GDF-15) in blood, was proposed as biomarker to detect mitochondrial dysfunction. In the current study, we evaluate this biomarker in open-angle glaucoma (OAG), as there is increasing evidence that mitochondrial dysfunction plays a role in the pathophysiology of this disease. Methods Plasma GDF-15 concentrations were measured with ELISA in 200 OAG patients and 61 age-matched controls (cataract without glaucoma). The OAG patient group consisted of high tension glaucoma (HTG; n = 162) and normal tension glaucoma (NTG; n = 38). Groups were compared using the Kruskal-Wallis nonparametric test with Dunn’s multiple comparison post-hoc correction. GDF-15 concentration was corrected for confounders identified with forward linear regression models. Results Before correcting for confounders, median plasma GDF-15 levels was significantly lower in the combined OAG group (p = 0.04), but not when analysing HTG and NTG patients separately. Forward linear regression analysis showed that age, gender, smoking and systemic hypertension were significant confounders affecting GDF-15 levels. After correction for these confounders, GDF-15 levels in OAG patients were no longer significantly different from controls. Subgroup analysis of the glaucoma patients did not show a correlation between disease severity and plasma GDF-15, but did reveal that for NTG patients, intake of dietary supplements, which potentially improve mitochondrial function, correlated with lower plasma GDF-15. Conclusion The present study suggests that plasma GDF-15 is not suited as biomarker of mitochondrial dysfunction in OAG patients.
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Wu, Xun, Yunting Wang, Ziyu Ren, Linman Li, Wenjie Qian, Yue Chen, and Wei Ren. "Association between Growth Differentiation Factor-15 and Risk of Cardiovascular Diseases in Patients with Adult Growth Hormone Deficiency." International Journal of Endocrinology 2021 (August 6, 2021): 1–7. http://dx.doi.org/10.1155/2021/5921863.
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Objective. Patients with adult growth hormone deficiency (AGHD) confer a heightened risk of cardiovascular disease and increased mortality because of metabolic disorders. Growth differentiation factor-15 (GDF-15) plays an important role in predicting metabolic abnormalities. We sought to investigate the correlation between GDF-15 and cardiovascular risk in AGHD patients. Methods. The study enrolled 80 AGHD patients and 80 healthy subjects. We analyzed the association between GDF-15 and some major biochemical indicators. The potential association between GDF-15 and cardiovascular disease risk was analyzed. Results. The AGHD group exhibited increased waist-hip ratio and high-sensitivity C-reactive protein (hs-CRP) and lipid levels compared with the healthy control group. Serum GDF-15 levels in AGHD group were elevated significantly compared with the control group P < 0.001 . GDF-15 levels were negatively associated with insulin-like growth factor-1 in AGHD group P = 0.006 and positively correlated with waist-to-hip ratio P = 0.018 , triglycerides P = 0.007 , and hs-CRP P = 0.046 . In addition, GDF-15 was positively correlated with Framingham risk score significantly after adjustment for other factors (r = 0.497, P < 0.001 ). Moreover, GDF-15 was an independent risk factor for cardiovascular disease in AGHD patients after adjusting for traditional cardiovascular risk factors. Conclusion. Elevated GDF-15 levels were significantly associated with cardiovascular risk factors and can be considered as a predictive biomarker of cardiovascular risk in AGHD patients.
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Semba, Richard D., Marta Gonzalez-Freire, Toshiko Tanaka, Angelique Biancotto, Pingbo Zhang, Michelle Shardell, Ruin Moaddel, and Luigi Ferrucci. "Elevated Plasma Growth and Differentiation Factor 15 Is Associated With Slower Gait Speed and Lower Physical Performance in Healthy Community-Dwelling Adults." Journals of Gerontology: Series A 75, no. 1 (March 15, 2019): 175–80. http://dx.doi.org/10.1093/gerona/glz071.
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Abstract Background Growth and differentiation factor 15 (GDF-15) has been associated with obesity, muscle wasting, and cachexia. The receptor for GDF-15 was recently identified in the brainstem and regulates food intake and metabolism. The relationship of plasma GDF-15 with the age-associated decline of muscle mass and strength, gait speed, and physical performance in adults has not been well characterized. Methods Plasma GDF-15, grip strength, 6-m gait speed, 400-m walking test time, lower extremity physical performance score, appendicular lean mass, and fat mass were measured in 194 healthy adult participants, aged 22–93 years, of the Baltimore Longitudinal Study of Aging. Results Plasma GDF-15 concentrations increased with age (p < .001) and were higher in whites compared with blacks and Asians (p = .04). Adults with higher plasma GDF-15 had slower 6-m gait speed, longer 400-m walking time, and lower physical performance score in multivariable analyses adjusting for age and race. Plasma GDF-15 was not associated with grip strength, appendicular lean mass, or fat mass. Conclusions Elevated plasma GDF-15 is associated with slower gait speed, higher 400-m walking time, and lower physical performance in very healthy community-dwelling adults. The relationship between plasma GDF-15 and sarcopenia-related outcomes may be stronger in the population not selected to be healthy, and this hypothesis should be tested in a representative population.
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Cheng, Jung-Chien, Hsun-Ming Chang, and Peter C. K. Leung. "Wild-Type p53 Attenuates Cancer Cell Motility by Inducing Growth Differentiation Factor-15 Expression." Endocrinology 152, no. 8 (May 17, 2011): 2987–95. http://dx.doi.org/10.1210/en.2011-0059.
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A major function of the p53 tumor suppressor is the regulation of the cell cycle and apoptosis. In addition to its well-documented functions in malignant cancer cells, p53 can also regulate cell migration and invasion, which contribute to metastasis. Growth differentiation factor-15 (GDF-15), a member of the TGF-β superfamily, has been shown to be a downstream target of p53 and is associated with diverse human diseases and cancer progression. In this study, we examined the potential role of GDF-15 in p53-regulated cancer cell motility. We show that overexpression of wild-type p53 in two highly invasive p53-null human cancer cell lines, SKOV3 and PC3, attenuated cell migration and the movement through Matrigel. Using wild-type p53 and DNA-binding-deficient p53 mutants, we found that the transcriptional activity of p53 is required in the induction of GDF-15 expression. Cell movement through uncoated and Matrigel-coated transwell decreased in response to treatment with recombinant GDF-15, whereas the cell proliferation was not affected by GDF-15 treatment. Moreover, the induction of GDF-15 expression and secretion by p53 and the reduction in cell movement through Matrigel were diminished by treatment with GDF-15 small interfering RNA. This study demonstrates a mechanism by which p53 attenuates cancer cell motility through GDF-15 expression. In addition, our results indicate that GDF-15 mediates the functions of p53 by autocrine/paracrine action.
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Tscharre, Maximilian, Franziska Wittmann, Daniela Kitzmantl, Silvia Lee, Beate Eichelberger, Patricia P. Wadowski, Günther Laufer, et al. "Growth Differentiation Factor-15 Correlates Inversely with Protease-Activated Receptor-1-Mediated Platelet Reactivity in Patients with Left Ventricular Assist Devices." Pharmaceuticals 15, no. 4 (April 15, 2022): 484. http://dx.doi.org/10.3390/ph15040484.
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Growth differentiation factor (GDF)-15 inhibits platelet activation, prevents thrombus formation, and has been linked to bleeding events. This was a prospective study including 51 left-ventricular assist device (LVAD) patients on aspirin and phenprocoumon. Platelet surface expression of activated glycoprotein (GP) IIb/IIIa was assessed by flow cytometry, and platelet aggregation was measured by multiple electrode aggregometry (MEA) in response to arachidonic acid (AA), adenosine diphosphate (ADP), and thrombin receptor-activating peptide (TRAP), a protease-activated-receptor-1 (PAR-1) agonist. GDF-15 was determined with a commercially-available assay. There was a trend towards an inverse correlation of GDF-15 with activated GPIIb/IIIa in response to TRAP (r = −0.275, p = 0.0532) but not in response to AA and ADP. Moreover, GDF-15 correlated with MEA TRAP (r = −0.326, p = 0.0194), whereas it did not correlate with MEA ADP and MEA AA. In a second step, GDF-15 levels in the fourth quartile were defined as high GDF-15. Patients with high GDF-15 showed significantly lower TRAP-inducible platelet aggregation by MEA compared to patients in the first quartile (63 AU vs. 113 AU, p = 0.0065). In conclusion, in LVAD patients receiving state-of-the-art antithrombotic therapy, GDF-15 correlates inversely with residual platelet reactivity via PAR-1.
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Dogan, Zekeriya, Cigdem Ileri, Esin A. Kay, Murat Sunbul, Emre Y. Gurel, Beste Özben Sadıc, Nurten Sayar, Tulin Ergun, and Kursat M. Tigen. "Evaluation of Arterial Stiffness Parameters and the Growth Differentiation Factor-15 Level in Patients with Premature Myocardial Infarction." Journal of Personalized Medicine 13, no. 10 (October 13, 2023): 1489. http://dx.doi.org/10.3390/jpm13101489.
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Background: Myocardial infarction (MI) is increasing at a younger age. Growth differentiation factor-15 (GDF-15) has been implicated in several key mechanisms of atherogenesis. Arterial stiffness parameters, including pulse wave velocity (PWV) and the augmentation index (AIx), can indicate the presence or progression of atherosclerosis. The aim of this study is to evaluate the GDF-15 level and arterial stiffness parameters in patients with premature MI. Method: Thirty patients aged ≤45 years (mean age: 39 ± 5 years, 23 male) who recovered from a MI and 15 age and sex-matched subjects were consecutively included. The serum GDF-15 concentration levels and arterial stiffness parameters of the patients and controls were measured. Results: GDF-15 levels were significantly higher in patients with premature MI, while there were no significant differences in PWV and AIx between the groups. The GDF-15 level was correlated negatively with high-density lipoprotein (HDL) cholesterol and positively with uric acid levels. Both GDF-15 (p = 0.046, odds ratio: 1.092, 95% confidence interval: 1.003–1.196) and HDL cholesterol (p = 0.037, odds ratio: 0.925, 95% confidence interval: 0.859–0.995) were found as independent factors associated with premature MI. Conclusions: GDF-15 could be a risk factor for premature MI. Further studies are needed to elucidate the central role of GDF-15 in the pathophysiology of early atherosclerosis and MI in the young population.
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Miyaue, Noriyuki, Hayato Yabe, and Masahiro Nagai. "Serum GDF-15 Levels in Patients with Parkinson’s Disease, Progressive Supranuclear Palsy, and Multiple System Atrophy." Neurology International 15, no. 3 (August 30, 2023): 1044–51. http://dx.doi.org/10.3390/neurolint15030066.
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Serum growth differentiation factor 15 (GDF-15) levels are elevated in patients with Parkinson’s disease (PD) and may help differentiate these patients from healthy individuals. We aimed to clarify whether serum GDF-15 levels can help differentiate PD from atypical parkinsonian syndromes and determine the association between serum GDF-15 levels and clinical parameters. We prospectively enrolled 46, 15, and 12 patients with PD, progressive supranuclear palsy (PSP), and multiple system atrophy (MSA), respectively. The serum GDF-15 level in patients with PD (1394.67 ± 558.46 pg/mL) did not differ significantly from that in patients with PSP (1491.27 ± 620.78 pg/mL; p = 0.573) but was significantly higher than that in patients with MSA (978.42 ± 334.66 pg/mL; p = 0.017). Serum GDF-15 levels were positively correlated with age in patients with PD (r = 0.458; p = 0.001); PSP (r = 0.565; p = 0.028); and MSA (r = 0.708; p = 0.010). After accounting for age differences, serum GDF-15 levels did not differ significantly between patients with PD and MSA (p = 0.114). Thus, age has a strong influence on serum GDF-15 levels, which may not differ significantly between patients with PD and atypical parkinsonian syndromes such as PSP and MSA.
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Sabirzyanova, A. A., A. S. Galyavich, L. V. Baleeva, and Z. M. Galeeva. "Predictive value of growth differentiation factor-15 in patients with myocardial infarction." Russian Journal of Cardiology 26, no. 2 (March 28, 2021): 4288. http://dx.doi.org/10.15829/1560-4071-2021-4288.
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Aim. To evaluate the prognostic value of growth differentiation factor-15 (GDF-15) in patients with acute myocardial infarction (MI).Material and methods. The study included 118 patients under the age of 70 with STand non-ST segment elevation myocardial infarction, who, in addition to routine examination, were tested for GDF-15 by enzyme-linked immunosorbent assay in the first 48 hours from the onset. The statistical significance of the differences in quantitative indicators was assessed by the Student’s t-test for a normal distribution and by the nonparametric U Mann-Whitney test for a non-normal distribution, while in qualitative indicators — by Pearson’s chisquared test. Pearson’s correlation coefficient and Spearman’s rank correlation coefficient were used as an indicator of strength of relationship between quantitative indicators.Results. The average GDF-15 level in patients with MI was 2,25±1,0 ng/ml. For 6 months of follow-up, 15,25% of patients were rehospitalized for unstable angina or recurrent myocardial infarction. The GDF-15 level in 82,6% of cases was in the third and fourth quartiles (≥2,07 ng/ml). All patients with recurrent MI had GDF-15 levels in the upper quartile (≥2б73 ng/ml). Patients with GDF-15 levels in the upper quartile had a significantly higher risk of rehospitalization (hazard ratio, 3,3 (95% CI, 1,65-6,76), p<0,05) compared with patients with GDF-15 levels in other quartiles. The potential for the combined use of GDF-15 and N-terminal probrain natriuretic peptide (NT-proBNP) levels to assess the risk of readmission has been evaluated. Patients who had both GDF-15 and NT-proBNP levels in the upper quartiles (GDF-15>2,73 ng/ml, NT-proBNP>1418 pg/ml) had 4,8 times higher risk of rehospitalizations for unstable angina or recurrent myocardial infarction.Conclusion. In patients with MI, the determination of the GDF-15 level has prognostic value and may serve as an additional marker of the risk of recurrent cardiovascular events.
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Ham, Young Rok, Chang Hun Song, Hong Jin Bae, Jin Young Jeong, Min-Kyung Yeo, Dae Eun Choi, Ki-Ryang Na, and Kang Wook Lee. "Growth Differentiation Factor-15 as a Predictor of Idiopathic Membranous Nephropathy Progression: A Retrospective Study." Disease Markers 2018 (2018): 1–9. http://dx.doi.org/10.1155/2018/1463940.
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Idiopathic membranous nephropathy (IMN) is a major cause of nephrotic syndrome. No biomarker to predict the long-term prognosis of IMN is currently available. Growth differentiation factor-15 (GDF-15) is a member of the transforming growth factor-β superfamily and has been associated with chronic inflammatory disease. It has the potential to be a useful prognostic marker in patients with renal diseases, such as diabetic nephropathy and IgA nephropathy. This study examined whether GDF-15 is associated with the clinical parameters in IMN and showed that GDF-15 can predict IMN disease progression. A total of 35 patients with biopsy-proven IMN, treated at Chungnam National University Hospital from January 2010 to December 2015, were included. Patients younger than 18 years, those with secondary membranous nephropathy, and those lost to follow-up before 12 months were excluded. Levels of GDF-15 at the time of biopsy were measured using enzyme-linked immunosorbent assays. Disease progression was defined as a ≥30% decline in estimated glomerular filtration rate (eGFR) or the development of end-stage renal disease. The mean follow-up was 44.1 months (range: 16–72 months). Using receiver operating curve analysis, the best serum GDF-15 cut-off value for predicting disease progression was 2.15 ng/ml (sensitivity: 75.0%, specificity: 82.1%, p=0.007). GDF-15 was significantly related to age and initial renal function. In the Kaplan-Meier analysis, the risk of disease progression increased in patients with GDF-15 ≥ 2.15 ng/ml when compared with those with GDF-15 < 2.15 ng/ml (50.0% versus 9.7%) (p=0.012). In the multivariate Cox regression analysis adjusted for potential confounders, only GDF-15 was significantly associated with disease progression in IMN (p=0.032). In conclusion, the GDF-15 level at the time of diagnosis has a significant negative correlation with initial renal function and is associated with a poor prognosis in IMN. Our results suggest that GDF-15 provides useful prognostic information in patients with IMN.
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Rueda, Ferran, Josep Lupón, Cosme García-García, German Cediel, M. Cruz Aranda Nevado, Judith Serra Gregori, Carlos Labata, et al. "Acute-phase dynamics and prognostic value of growth differentiation factor-15 in ST-elevation myocardial infarction." Clinical Chemistry and Laboratory Medicine (CCLM) 57, no. 7 (June 26, 2019): 1093–101. http://dx.doi.org/10.1515/cclm-2018-1189.
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Abstract Background Growth differentiation factor 15 (GDF-15) in ST-elevation myocardial infarction (STEMI) is prognostic in first-generation radioimmunoassays. We examined GDF-15 temporal dynamics in STEMI and its predictive value using a first fully automated GDF-15 electrochemiluminescence assay. Methods In this prospective study, circulating GDF-15 concentration was measured at admission (0 h), 12 h and 24 h in 1026 consecutive STEMI patients treated between February 2011 and May 2016 with primary percutaneous coronary intervention. GDF-15 dynamics (0 h, 12 h, 24 h) and predictive value (30 days and 3 years) were examined. Results Median GDF-15 concentration was 1443 pg/mL at 0 h, 1731 pg/mL at 12 h and 1510 pg/mL at 24 h (p<0.001). During follow-up, 94 patients died (9.2%) and 154 (15.0%) were hospitalized. GDF-15 was a strong predictor of 30-day mortality (hazard ratio [HR] 1.76, 95% confidence interval [CI], 1.33–2.34 at 0 h; HR 2.99 [95% CI, 2.18–4.09] at 12 h, and HR 1.97 [95% CI, 1.47–2.63] at 24 h) in multivariable Cox proportional hazards models. GDF-15 improved discrimination and reclassification of a clinical risk model. GDF-15 was also associated with 3-year mortality (HR 1.31 [95% CI, 1.04–1.65] at 0 h, HR 1.42 [95% CI, 1.10–1.84] at 12 h, and HR 1.51 [95% CI, 1.16–1.96] at 24 h) and 3-year composite of mortality and cardiovascular hospitalization (HR 1.17 [95% CI, 1.01–1.37] at 0 h, HR 1.20 [95% CI, 1.02–1.42] at 12 h, and HR 1.27 [95% CI, 1.08–1.50] at 24 h). Conclusions GDF-15 peaked at 12 h and remained elevated at 24 h in STEMI. GDF-15 measurement during the first 24 h in STEMI is valuable for predicting especially short- but also long-term outcomes, and may be a useful addition to risk stratification.
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Eggers, Kai M., Tibor Kempf, Lars Wallentin, Kai C. Wollert, and Lars Lind. "Change in Growth Differentiation Factor 15 Concentrations over Time Independently Predicts Mortality in Community-Dwelling Elderly Individuals." Clinical Chemistry 59, no. 7 (July 1, 2013): 1091–98. http://dx.doi.org/10.1373/clinchem.2012.201210.
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BACKGROUND Growth differentiation factor 15 (GDF-15) is emerging as a powerful risk indicator in both cardiovascular disease patients and community-dwelling individuals. We investigated GDF-15 concentrations and their changes over 5 years in elderly individuals from the community, together with the underlying conditions and prognostic implications of these measurements. METHODS We analyzed GDF-15 concentrations using a sandwich immunoassay in participants from the PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study. Measurements were performed at both 70 (n = 1004) and 75 (n = 813) years of age. Median follow-up was 8.0 years. RESULTS Over time, GDF-15 concentrations increased by 11.0% (P < 0.001). These changes were related to male sex, hypertension, diabetes, heart failure, renal function, and concentrations of N-terminal pro–B-type natriuretic peptide (NT-proBNP). Significant relationships also emerged between changes in GDF-15 and changes in concentrations of NT-proBNP and C-reactive protein (CRP) and renal function between ages 70 and 75. The R2 value of the model including all covariates was 0.20. GDF-15 concentrations independently predicted all-cause mortality [hazard ratio 4.0 (95% CI 2.7–6.0)] with results obtained at ages 70 and 75 as updated covariates. Baseline GDF-15 concentrations improved prognostic discrimination and reclassification [C statistic 0.06 (P = 0.006); integrated discrimination improvement = 0.030 (P = 0.004); category-free net reclassification improvement = 0.281 (P = 0.006)]. The change in GDF-15 concentrations over time independently predicted even all-cause mortality occurring after age 75 [hazard ratio 3.6 (95% CI 2.2–6.0)]. CONCLUSIONS GDF-15 concentrations and their changes over time are powerful predictors of mortality in elderly community-dwelling individuals. GDF-15 concentrations increase with aging, and these changes are explained only partially by cardiovascular risk factors, indicators of neurohumoral activation and inflammation, and renal function. Thus GDF-15 reflects both cardiovascular and other biological processes closely related to longevity.
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Sökmen, Erdoğan, Cahit Uçar, Serkan Sivri, Mustafa Çelik, Yalçın Boduroğlu, Murat Erer, Alp Yıldırım, and Bilal İlanbey. "Association between Growth Differentiation Factor 15 and Non-Dipping Circadian Pattern in Patients with Newly Diagnosed Essential Hypertension." Medical Principles and Practice 28, no. 6 (2019): 566–72. http://dx.doi.org/10.1159/000501096.
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Objective: Non-dipper hypertension (HT) confers greater risk compared with dipper HT. Growth differentiation factor 15 (GDF-15) recently emerged as a novel and independent marker of cardiovascular disease, both in diagnostic and prognostic scopes. Our aim was to evaluate the relationship of circadian blood pressure (BP) pattern with serum GDF-15 level in newly diagnosed HT patients without left ventricular hypertrophy. Subjects and Methods: Newly diagnosed non-dipper (n = 66) and dipper (n = 60) HT patients were selected according to 24-h ambulatory BP monitoring (ABPM). The controls comprised healthy normotensive subjects (n = 31). Data was collected through physical examination, laboratory analysis, ABPM, and echocardiography. GDF-15 was measured using ELISA. Results: Greater GDF-15 level was found in the non-dippers compared with the dippers and the controls (557.53 ± 91.7, 513.79 ± 62.86, and 494.44 ± 79.30 ng/L, respectively, p < 0.001). In bivariate linear correlation analysis, GDF-15 correlated positively with glomerular filtration rate (r = 0.180, p =0.030), total cholesterol (r = 0.170, p = 0.038), septal E/E′ ratio (r = 0.344, p = 0.001), lateral E/E′ ratio (r = 0.366, p < 0.001), nighttime systolic BP (r = 0.166, p = 0.046), and nighttime diastolic BP (r = 0.188, p = 0.024); however, it correlated negatively with septal and lateral E′ velocities (r = 0.268, p = 0.005 and r = 0.236, p = 0.013, respectively). Furthermore, GDF-15 level and nighttime diastolic BP remained independently associated with non-dipper HT. In ROC analysis, optimal cutoff value for GDF-15 was 524.6 ng/L with 56.7% sensitivity and 72.4% specificity (AUC: 0.676, 95% CI: 0.580–0.772, p < 0.05). Conclusion: Our results showed GDF-15 upregulation in the non-dipper HT group. GDF-15 and nighttime diastolic BP were independently associated with the non-dipping pattern. This study may suggest possible utilization of GDF-15 in the prediction of non-dipper HT.
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Sun, Ting, Rui Peng, Xiaojun Sun, and Yan Li. "Associations between Sex Hormones and Circulating Growth Differentiation Factor-15 in Male Patients with Major Depressive Disorder." Brain Sciences 11, no. 12 (December 7, 2021): 1612. http://dx.doi.org/10.3390/brainsci11121612.
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The interaction between the endocrine system and inflammation is crucial pathogenesis of depression. Our study aimed at exploring the possible relationship between sex hormones and growth differentiation factor-15 (GDF-15), a common indicator of inflammation in male patients with major depressive disorder (MDD). Methods: GDF-15 levels of 121 male MDD patients were compared with 105 healthy subjects with the help of a Cobas 8000 automatic chemiluminescence immunoanalyzer. Results: (1) MDD patients showed higher GDF-15 levels, a lower testosterone (T) level and testosterone/estradiol ratio (T/E2 ratio) than healthy subjects (all p < 0.05). (2) Serum T levels and the T/E2 ratio were inversely associated with GDF-15 serum levels (all p < 0.05). (3) HAMD-24 scores were positively correlated with the levels of GDF-15 (p < 0.01), but not with T levels, estradiol (E2) levels, and the T/E2 ratio (all p > 0.05). Conclusion: The high level of GDF-15 was correlated with a low T/E2 ratio and T deficiency in male MDD patients. The above results demonstrate that up-regulation of serum GDF-15 and down-regulation of T and T/E2 ratio may be correlated with the occurrence and severity of depression. So, changing the level of GDF-15 by regulating the proportion of sex hormones may play a key role in the prognosis and treatment of depression.
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Lim, Jeong-Hoon, Yena Jeon, Ji-Sun Ahn, Sejoong Kim, Dong Ki Kim, Jung Pyo Lee, Dong-Ryeol Ryu, et al. "GDF-15 Predicts In-Hospital Mortality of Critically Ill Patients with Acute Kidney Injury Requiring Continuous Renal Replacement Therapy: A Multicenter Prospective Study." Journal of Clinical Medicine 10, no. 16 (August 18, 2021): 3660. http://dx.doi.org/10.3390/jcm10163660.
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Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine. This study evaluated the association between GDF-15 and in-hospital mortality among patients with severe acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT). Among the multicenter prospective CRRT cohort between 2017 and 2019, 66 patients whose blood sample was available were analyzed. Patients were divided into three groups according to the GDF-15 concentrations. The median GDF-15 level was 7865.5 pg/mL (496.9 pg/mL in the healthy control patients). Baseline characteristics were not different among tertile groups except the severity scores and serum lactate level, which were higher in the third tertile. After adjusting for confounding factors, the patients with higher GDF-15 had significantly increased risk of mortality (second tertile: adjusted hazards ratio [aHR], 3.67; 95% confidence interval [CI], 1.05–12.76; p = 0.041; third tertile: aHR, 6.81; 95% CI, 1.98–23.44; p = 0.002). Furthermore, GDF-15 predicted in-hospital mortality (area under the curve, 0.710; 95% CI, 0.585–0.815) better than APACHE II and SOFA scores. Serum GDF-15 concentration was elevated in AKI patients requiring CRRT, higher in more severe patients. GDF-15 is a better independent predictor for in-hospital mortality of critically ill AKI patients than the traditional risk scoring system such as APACHE II and SOFA scores.
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Salvagno, Gian, Elisa Danese, Giorgio Brocco, Matteo Gelati, Martina Montagnana, Fabian Sanchis-Gomar, Emmanuel Favaloro, and Giuseppe Lippi. "Serum Concentration of Growth Differentiation Factor-15 Is Independently Associated with Global Platelet Function and Higher Fibrinogen Values in Adult Healthy Subjects." Seminars in Thrombosis and Hemostasis 43, no. 06 (June 8, 2017): 621–28. http://dx.doi.org/10.1055/s-0037-1603358.
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AbstractGrowth differentiation factor-15 (GDF-15) has recently emerged as a strong and independent predictor of cardiovascular events and mortality. However, the pathophysiological mechanisms underlying this important association remain speculative. This study was aimed to investigate the potential associations between the serum concentration of GDF-15 and clinical or laboratory parameters in a population of ostensibly healthy subjects. The study population consisted of 44 healthy volunteers enrolled from the laboratory staff (14 males and 30 females; mean age, 47 ± 11 years), who had their blood collected for assessing complete blood cell count, GDF-15, serum creatinine, albumin, cardiac troponin T, galectin-3, routine coagulation tests, D-dimer, von Willebrand factor, and platelet function testing using platelet function analyzer-100. In univariate analysis, serum GDF-15 was found to be positively associated with age and plasma fibrinogen, and negatively associated with renal function and collagen-epinephrine (CEPI). In multiple linear regression analysis, serum GDF-15 remained significantly associated with renal function, CEPI, and plasma fibrinogen. Healthy subjects with GDF-15 above the median value had a twofold probability of displaying shorter CEPI closure times. Taken together, these results suggest that higher serum values of GDF-15 may be associated with overall global platelet hyperactivity and increased plasma fibrinogen, so providing another plausible explanation for the association between GDF-15, cardiovascular events, and mortality.
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Sökmen, Erdoğan, Cahit Uçar, Serkan Sivri, Mustafa Çelik, and Kenan Güçlü. "Relationship of growth differentiation factor-15 with aortic stiffness in essential hypertension." Future Science OA 5, no. 7 (August 2019): FSO406. http://dx.doi.org/10.2144/fsoa-2019-0029.
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Aim: We aimed to assess the relationship between echocardiographic parameters of aortic elasticity, namely aortic strain, aortic distensibility and aortic β-index, and serum growth differentiation factor (GDF)-15 in patients with newly diagnosed essential hypertension (HT). Methods: Grade-1 HT patients (n = 50), grade-2 HT (n = 70) patients and 35 healthy controls were included. Results: GDF-15 was greater in grade-2 HT group compared with the other groups. All aortic elasticity parameters were worse in grade-2 HT group compared with the other groups. GDF-15 correlated positively with E/E′ ratio (the ratio of transmitral E velocity to mean diastolic mitral annular velocity) and β-index; and aortic strain and aortic distensibility correlated negatively with serum GDF-15. β-index, aortic diastolic diameter and diastolic blood pressure were independently associated with GDF-15. Conclusion: GDF-15 may be utilized in the prediction of increased aortic stiffness.
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Liu, Shiqiang, Xu Chen, Hua Wang, Bo Ming, Mingle Wu, Yongjie Wang, and Tao Liu. "Association of GDF-15 and Syntax Score in Patient with Acute Myocardial Infarction." Cardiovascular Therapeutics 2019 (March 5, 2019): 1–6. http://dx.doi.org/10.1155/2019/9820210.
Full textAbstract:
Aims. GDF-15 is considered to be an important biomarker for cardiovascular events, but the differences in serum GDF-15 levels between acute myocardial infarction (AMI) patients and non-AMI patients warrant further investigation. Methods. A cohort of 409 subjects was enrolled in the current study. The Syntax score was calculated from the baseline coronary angiography results by using online methods. Blood samples were obtained at the start of the study for an assessment of GDF-15 by using ELISA methods. Results. Patients with AMI had significantly higher levels of serum GDF-15 (Wilcox test, P < 0.001), Syntax scores (Wilcox test, P = 0.006), and left ventricular ejection fractions (LEVF, Wilcox test, P< 0.001). However, no significant differences were present among the other clinical characteristics. The logistical regression analysis indicated that serum GDF-15 levels (P=0.01534) were independent predictors of non-AMI and AMI after adjusting for age, sex, smoking status, and LVEF. Conclusions. Elevated serum levels of GDF-15 are independently associated with the risk of MI, and GDF-15 may serve as a protective factor for MI in the cardiovascular system.