Increased Growth Differentiation Factor 15 in Patients with Hypoleptinemia-Associated Lipodystrophy

Objective. Similar to obesity, lipodystrophy (LD) causes adipose tissue dysfunction and severe metabolic complications. Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor β superfamily and is dysregulated in metabolic disease including obesity and diabetes mellitus. Circulating levels in LD and the impact of leptin treatment have not been investigated so far. Material and Methods. GDF15 serum levels were quantified in 60 LD patients without human immunodeficiency virus infection and 60 controls matched for age, gender, and body mass index. The impact of metreleptin treatment on circulating GDF15 was assessed in a subgroup of patients. GDF15 mRNA expression was determined in metabolic tissues of leptin-deficient lipodystrophic aP2-nSREBP1c-Tg mice, obese ob/ob mice, and control C57Bl6 mice. Results. Median GDF15 serum concentrations were significantly higher in LD patients (819 ng/L) as compared to the control group (415 ng/L) (p < 0.001). In multiple linear regression analysis, an independent and positive association remained between GDF15 on one hand and age, patient group, hemoglobin A1c, triglycerides, and C-reactive protein on the other hand. Moreover, there was an independent negative association between GFD15 and estimated glomerular filtration rate. Circulating GDF15 was not significantly affected by metreleptin treatment in LD patients. Gdf15 was upregulated in leptin-deficient lipodystrophic mice as compared to controls. Moreover, Gdf15 mRNA expression was downregulated by leptin treatment in lipodystrophic and obese animals. Conclusions. Serum concentrations of GDF15 are elevated in LD patients and independently associated with markers of metabolic dysfunction. Gdf15 expression is higher in lipodystrophic mice and downregulated by leptin treatment.

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Abstract 13423: Impact of Anemia on Growth Differentiation Factor 15 and Mortality in Patients With Stable Coronary Artery Disease: The ANOX Study

Circulation ◽

10.1161/circ.142.suppl_3.13423 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Moritake Iguchi ◽

masahiro suzuki ◽

Morihiro Matsuda ◽

Yoichi Ajiro ◽

Tsuyoshi Shinozaki ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Transforming Growth Factor ◽

Stable Coronary Artery Disease ◽

Linear Regression Analysis ◽

Growth Differentiation Factor 15 ◽

Differentiation Factor ◽

Artery Disease ◽

Stable Cad ◽

The Impact

Background: Growth differentiation factor 15 (GDF-15) is a stress responsive cytokine of the transforming growth factor superfamily. Circulating levels of GDF-15 are elevated in various conditions including anemia and stable coronary artery disease (CAD), and associated with the risk of mortality in patients with stable CAD. However, whether anemia modifies the relationship between GDF-15 and mortality in patients with stable CAD is unknown. Methods: Using data from a multicenter, prospective cohort of 1460 patients with stable CAD, we assessed the association between anemic status and GDF-15 and the impact of anemia on the association between GDF-15 levels and the risk of all-cause death. GDF-15 was measured in 564 anemic and 896 non-anemic patients enrolled in the ANOX Study. Results: The mean age (standard deviation [SD]) of the patients was 71.7 (9.4) years; 74.4% were men. Patients with anemia exhibited significantly higher levels of GDF-15 compared to those without anemia (median [interquartile range], 1953 [1302-3110] vs. 1175 [838-1579] pg/mL, respectively; P <0.001). Stepwise multiple linear regression analysis revealed that the log-transformed (Ln-) GDF-15 level was independently associated with higher age, diabetes, current smoking, lower estimated glomerular filtration rate, anemia, no use of aspirin, Ln-N-terminal pro-natriuretic peptide, and Ln-high-sensitivity C-reactive protein ( P <0.005 for all). In the entire patient cohort, the GDF-15 level was significantly associated with all-cause death after adjusting for potential clinical confounders (hazard ratio per 1-SD increase [HR], 1.51; 95% confidence interval [CI], 1.33-1.71). This association was still significant in patients with anemia (HR, 1.71; 95% CI, 1.44-2.05) and in those without anemia (HR, 1.44; 95% CI, 1.21-1.71). However, GDF-15 provided incremental prognostic information to the model with potential clinical confounders and the established cardiovascular biomarkers in the entire cohort and in patients with anemia, but not in those without anemia. Conclusions: Higher levels of GDF-15 were independently associated with anemia in patients with stable CAD. The prognostic value of GDF-15 on mortality was pronounced in patients with anemia.

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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 ◽

10.5604/01.3001.0009.5108 ◽

2016 ◽

Vol 6 (1) ◽

pp. 40-48

Author(s):

K. Jakubowska ◽

A. Pryczynicz ◽

V. Dymicka-Piekarska ◽

D. Cepowicz ◽

D. Jagodzińska ◽

...

Keyword(s):

Colorectal Cancer ◽

Transforming Growth Factor ◽

Distant Metastases ◽

Transforming Growth Factor Β ◽

Mean Value ◽

Immunohistochemical Method ◽

Control Group ◽

Growth Differentiation Factor 15 ◽

Differentiation Factor ◽

Colorectal Cancer Patients

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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Impact of Smoking Status on Growth Differentiation Factor 15 and Mortality in Patients With Suspected or Known Coronary Artery Disease: The ANOX Study

Journal of the American Heart Association ◽

10.1161/jaha.120.018217 ◽

2020 ◽

Vol 9 (22) ◽

Author(s):

Hiromichi Wada ◽

Masahiro Suzuki ◽

Morihiro Matsuda ◽

Yoichi Ajiro ◽

Tsuyoshi Shinozaki ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Smoking Status ◽

Linear Regression Analysis ◽

Growth Differentiation Factor 15 ◽

Differentiation Factor ◽

Former Smokers ◽

Artery Disease ◽

Never Smokers ◽

The Impact

Background Whether circulating growth differentiation factor 15 (GDF‐15) levels differ according to smoking status and whether smoking modifies the relationship between GDF‐15 and mortality in patients with coronary artery disease are unclear. Methods and Results Using data from a multicenter, prospective cohort of 2418 patients with suspected or known coronary artery disease, we assessed the association between smoking status and GDF‐15 and the impact of smoking status on the association between GDF‐15 and all‐cause death. GDF‐15 was measured in 955 never smokers, 1035 former smokers, and 428 current smokers enrolled in the ANOX Study (Development of Novel Biomarkers Related to Angiogenesis or Oxidative Stress to Predict Cardiovascular Events). Patients were followed up during 3 years. The age of the patients ranged from 19 to 94 years; 67.2% were men. Never smokers exhibited significantly lower levels of GDF‐15 compared with former smokers and current smokers. Stepwise multiple linear regression analysis revealed that the log‐transformed GDF‐15 level was independently associated with both current smoking and former smoking. In the entire patient cohort, the GDF‐15 level was significantly associated with all‐cause death after adjusting for potential clinical confounders. This association was still significant in never smokers, former smokers, and current smokers. However, GDF‐15 provided incremental prognostic information to the model with potential clinical confounders and the established cardiovascular biomarkers in never smokers, but not in current smokers or in former smokers. Conclusions Not only current, but also former smoking was independently associated with higher levels of GDF‐15. The prognostic value of GDF‐15 on mortality was most pronounced in never smokers among patients with suspected or known coronary artery disease.

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5949Interleukin-6 and growth differentiation factor-15 in hypertensive heart failure

European Heart Journal ◽

10.1093/eurheartj/ehz746.0099 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

C Fernandez ◽

J Rysa ◽

J Nilsson ◽

G Engstrom ◽

M Orho-Melander ◽

...

Keyword(s):

Heart Failure ◽

Transforming Growth Factor ◽

Mechanical Stretch ◽

Neonatal Rat ◽

Chronic Hypertension ◽

Mrna Levels ◽

Growth Differentiation Factor 15 ◽

Hypertrophic Growth ◽

Differentiation Factor ◽

Circulating Levels

Abstract Background Hypertension is the leading cause for the development of heart failure (HF). Increased hemodynamic load, including mechanical stretch and neurohumoral factors, is able to trigger hypertrophic growth of cardiac myocytes. Although hypertensive HF is prevalent, there is no useful biomarker to identify HF due to chronic hypertension. Aims To identify plasma markers associated with incidence of hypertensive HF. Methods Circulating levels of 149 proteins were measured by proximity extension assay at baseline examination in 4469 individuals from the Malmö Diet and Cancer study. Protein levels were compared to stretch-activated gene expression changes in cultured neonatal rat ventricular myocytes (NRVM) in response to 1, 4, 12, 24 or 48 hours of cyclic mechanical stretch. Association between plasma proteins level and HF incidence and hypertension was studied using respectively Cox proportional hazards model and binary logistic regressions. Results After Bonferroni correction, 44 circulating proteins were significantly differentially expressed in individuals who developed HF during follow-up versus controls (P<3.4E-4). Out of these, 5 proteins (Interleukin-6 (IL-6), Growth Differentiation Factor-15 (GDF15), Interleukin-1 Receptor-Like-1 (ST2), Plasminogen Activator Urokinase Receptor (U-PAR), Transforming Growth Factor-α (TGF-α)), corresponding mRNA levels were upregulated by mechanical stretch in NRVM at all time points (P<0.05). Similar upregulation for the 5 proteins was shown in hypertensive versus normotensive individuals (P≤8.05E-4). In a model with all 5 proteins entered simultaneously, GDF15 and IL-6 were predictive of incident HF after adjustment for age, sex and NT-BNP levels (205 events; hazard ratio [HR] per SD increment of protein: HR=1.29, CI=1.05–1.58, P=0.013 and HR=1.16, CI=1.02–1.33, P=0.028). Using the same model, IL-6 but not GDF15 associated with hypertension (Odds ratio [OR] per SD increment of IL-6: OR=1.18, CI=1.09–1.27, P=3.3E-5). In hypertensive individuals GDF15 and IL-6 were individually predictive of future HF after adjustment for age, sex, NT-BNP levels, smoking, BMI and diabetes (183 events; HR=1.36, CI=1.16–1.60, P=1.64E-4 and HR=1.21, CI=1.05–1.40, P=0.008). Furthermore, in these hypertensive individuals, GDF15 and IL-6 were predictive of HF in a model with IL-6, GDF15, ST2 and TGF-α entered simultaneously after adjustment for age, sex and NT-BNP levels (176 events; HR=1.36, CI=1.13–1.64, P=0.001 and HR=1.16, CI=1.01–1.34, P=0.041). Conclusions Circulating levels of IL-6 and GDF15 might be used as NT-BNP independent biomarkers for HF development in hypertensive patients. Acknowledgement/Funding Påhlsson, Crafoord, Lundström, Åke Wiberg, Royal Physiographic Society and the Swedish Foundation for Strategic Research for IRC15-0067

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Growth Differentiation Factor 15 Ameliorates Anti-Glomerular Basement Membrane Glomerulonephritis in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21196978 ◽

2020 ◽

Vol 21 (19) ◽

pp. 6978

Author(s):

Foteini Moschovaki-Filippidou ◽

Stefanie Steiger ◽

Georg Lorenz ◽

Christoph Schmaderer ◽

Andrea Ribeiro ◽

...

Keyword(s):

T Cells ◽

Basement Membrane ◽

Glomerular Basement Membrane ◽

Transforming Growth Factor ◽

Protective Effects ◽

Crescent Formation ◽

Activated T Cells ◽

Growth Differentiation Factor 15 ◽

Differentiation Factor ◽

Deficient Mice

Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor-β (TGF-β) cytokine family and an inflammation-associated protein. Here, we investigated the role of GDF15 in murine anti-glomerular basement membrane (GBM) glomerulonephritis. Glomerulonephritis induction in mice induced systemic expression of GDF15. Moreover, we demonstrate the protective effects for GDF15, as GDF15-deficient mice exhibited increased proteinuria with an aggravated crescent formation and mesangial expansion in anti-GBM nephritis. Herein, GDF15 was required for the regulation of T-cell chemotactic chemokines in the kidney. In addition, we found the upregulation of the CXCR3 receptor in activated T-cells in GDF15-deficient mice. These data indicate that CXCL10/CXCR3-dependent-signaling promotes the infiltration of T cells into the organ during acute inflammation controlled by GDF15. Together, these results reveal a novel mechanism limiting the migration of lymphocytes to the site of inflammation during glomerulonephritis.

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Expression of C-type lectin receptors and Toll-like receptors in decidua of patients with unexplained recurrent spontaneous abortion

Reproduction Fertility and Development ◽

10.1071/rd15489 ◽

2017 ◽

Vol 29 (8) ◽

pp. 1613 ◽

Cited By ~ 5

Author(s):

Liang Xu ◽

Tian Qiu ◽

Yudong Wang ◽

Yan Chen ◽

Weiwei Cheng

Keyword(s):

Mrna Expression ◽

Spontaneous Abortion ◽

Transforming Growth Factor ◽

Recurrent Spontaneous Abortion ◽

Intercellular Adhesion Molecule ◽

Control Group ◽

Toll Like Receptors ◽

Lectin Receptors ◽

Unexplained Recurrent Spontaneous Abortion ◽

Normal Controls

In the present study, the mechanisms underlying the pathogenesis of unexplained recurrent spontaneous abortion (URSA) were explored. The protein and mRNA expression of two C-type lectin-like receptors (CLRs), namely dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) and mannose receptor (MR), and two Toll-like receptors (TLRs), namely TLR2 and TLR4, in the decidua and dendritic cells (DCs) was compared between URSA patients and normal controls. URSA patients had significantly lower protein and mRNA expression of DC-SIGN and significantly higher expression of TLR2 and TLR4 in decidual tissues compared with normal controls. In addition, URSA patients had significantly higher levels of the T helper (Th) 1 cytokines interleukin (IL)-2 and interferon-γ, and significantly lower levels of the Th2 cytokines IL-10 and transforming growth factor β1 in decidual tissues compared with the control group. The TLR2 agonist synthetic triacylated lipoprotein (Pam3CSK4) and the TLR4 agonist lipopolysaccharide were used to demonstrate that TLR2 and TLR4 modulate Th1/Th2 cytokine imbalance in DC–T cell cocultures. The results suggest that the balance between CLRs and TLRs was tilted towards a TLR-dominant response in URSA patients, which may disrupt maternal–fetal immune tolerance, resulting in spontaneous abortion.

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Growth differentiation factor-15 upregulates interleukin-6 to promote tumorigenesis of prostate carcinoma PC-3 cells

Journal of Molecular Endocrinology ◽

10.1530/jme-11-0149 ◽

2012 ◽

Vol 49 (2) ◽

pp. 153-163 ◽

Cited By ~ 33

Author(s):

Ke-Hung Tsui ◽

Ying-Ling Chang ◽

Tsui-Hsia Feng ◽

Li-Chuan Chung ◽

Tzu-Yi Lee ◽

...

Keyword(s):

Cell Proliferation ◽

Prostate Carcinoma ◽

Interleukin 6 ◽

Transforming Growth Factor ◽

Lncap Cells ◽

Rt Pcr ◽

Prostate Cell ◽

Growth Differentiation Factor 15 ◽

Matrigel Invasion ◽

Differentiation Factor

Growth differentiation factor-15 (GDF15), a member of the transforming growth factor-β superfamily, is associated with human cancer progress. We evaluated the role GDF15 plays in tumorigenesis of prostate carcinoma PC-3 cells. Results from real-time RT-PCR and ELISA revealed that expression of GDF15 was approximately threefold higher in LNCaP cells than in PC-3 cells. Other prostate cell lines (PZ-HPV-7, CA-HPV-10, and DU145 cells) expressed extremely low levels of GDF15. Stable overexpression of GDF15 in PC-3 cells enhanced the degree of cell proliferation and invasion as shown in the 3H-thymidine incorporation assay and in the Matrigel invasion assay respectively. Soft agar assays and xenograft animal studies indicated that overexpression of GDF15 in PC-3 cells increased tumorigenesis in vitro and in vivo. Results from RT-PCR, immunoblot, and reporter assays revealed that overexpression of GDF15 resulted in decreased expression of maspin and upregulation of interleukin-6 (IL6), matriptase, and N-myc downstream-regulated gene 1 (NDRG1) expression. Further studies revealed that overexpression of IL6 enhanced GDF15 expression in LNCaP cells while knockdown of IL6 blocked the expression of GDF15 in PC-3 cells, suggesting that expression of GDF15 is upregulated by IL6. This study demonstrated that expression of GDF15 induces cell proliferation, invasion, and tumorigenesis of prostate carcinoma PC-3 cells. The enhancement of tumorigenesis and invasiveness of prostate carcinoma cells that stably overexpress GDF15 may be caused by the dysregulation of maspin, matriptase, and IL6 gene expression. The expression of GDF15 and IL6 is controlled via a positive feedback loop in PC-3 cells.

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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 ◽

10.1055/s-0037-1603358 ◽

2017 ◽

Vol 43 (06) ◽

pp. 621-628 ◽

Cited By ~ 1

Author(s):

Gian Salvagno ◽

Elisa Danese ◽

Giorgio Brocco ◽

Matteo Gelati ◽

Martina Montagnana ◽

...

Keyword(s):

Renal Function ◽

Serum Concentration ◽

Platelet Function ◽

Healthy Subjects ◽

Cardiovascular Events ◽

Linear Regression Analysis ◽

Univariate Analysis ◽

Plasma Fibrinogen ◽

Growth Differentiation Factor 15 ◽

Differentiation Factor

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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Effects of danshensu on the transforming growth factor-β1/smads signaling pathway in rats with lung injury

Materials Express ◽

10.1166/mex.2020.1824 ◽

2020 ◽

Vol 10 (11) ◽

pp. 1816-1823

Author(s):

Jing Qin ◽

Xiaoqiang Zhang ◽

Shengyan Wang ◽

Yongming Zhang

Keyword(s):

Lung Injury ◽

Mrna Expression ◽

Transforming Growth Factor ◽

Interstitial Fibrosis ◽

Abdominal Cavity ◽

Physiological Saline ◽

Transforming Growth Factor Β1 ◽

Control Group ◽

Sprague Dawley ◽

Sd Rats

Observe the therapeutic effect of Danshensu on lung injury for rats, as well as explore the mechanism of Danshensu in TGF-β1/Smads signaling. Thirty Sprague-Dawley (SD) rats were intratracheally instilled with bleomycin to induce lung injury and interstitial fibrosis. Divided Thirty rats into three groups. DA group (η = 10): Inject 15 mg/kg Danshensu into the abdominal cavity; DXM group (η = 10): Inject 1 mg/kg dexamethasone into the abdominal cavity; BLM group (η = 10): Inject 2 mL physiological saline into the abdominal cavity. Then ten SD rats were intratracheally instilled with physiological saline as normal control group, NC group: Inject 2 mL physiological saline into the abdominal cavity. After a period of 28 days, the degree of pulmonary alveolitis was evaluated using hematoxylin-eosin (HE) staining, and the degree of lung fibrosis was evaluated using Masson?s trichrome (MT) staining. The immunohistochemistry was used to determine the expression of α-SMA. Magnetic nanoparticles+rtQ-PCR was used to determine the mRNA expressions for TGF-β1, Smad3, and Smad7. The alveolitis and pulmonary fibrosis in DA rats were obviously less than those in BLM rats and DXM rats. The expression of α-SMA in DA rats was obviously less than that of in BLM rats and DXM rats; the mRNA expression of TGF-β1 and Smad3 in DA rats were obviously reduced; the Smad7 mRNA expression was obviously up-regulated. DA can alleviate rat lung injury caused by bleomycin. Inhibiting the TGF-β1 and Smad3 mRNA expression, as well as boosting the Smad7 mRNA expression is one of the mechanisms by which Danshensu reduces lung injury.

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Regulation of growth differentiation factor 15 expression by intracellular iron

Blood ◽

10.1182/blood-2008-07-170431 ◽

2009 ◽

Vol 113 (7) ◽

pp. 1555-1563 ◽

Cited By ~ 52

Author(s):

Samira Lakhal ◽

Nick P. Talbot ◽

Alexi Crosby ◽

Chantal Stoepker ◽

Alain R. M. Townsend ◽

...

Keyword(s):

Iron Homeostasis ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Intracellular Iron ◽

Iron Depletion ◽

Iron Regulatory Proteins ◽

Regulatory Pathways ◽

Growth Differentiation Factor 15 ◽

Differentiation Factor ◽

Iron Deficient

Abstract Growth differentiation factor 15 (GDF15) is a divergent member of the transforming growth factor–β superfamily and has been identified in different contexts as a hypoxia-inducible gene product and as a molecule involved in hepcidin regulation. The biology of iron and oxygen is closely related, and known regulatory pathways involving hypoxia-inducible factor (HIF) and iron-regulatory proteins (IRPs) are responsive to both these stimuli. We therefore sought to characterize the regulation of GDF15 by iron and oxygen and to define the involvement or otherwise of HIF and IRP pathways. Here we show that GDF15 is strongly up-regulated by stimuli that deplete cells of iron and that this response is specifically antagonized by the reprovision of iron. GDF15 exhibits greater sensitivity to iron depletion than hypoxia, and responses to hypoxia and iron depletion are independent of HIF and IRP activation, suggesting a novel mechanism of regulation. We also report significant induction of serum GDF15 in iron-deficient subjects and after administration of an iron chelator to normal subjects. These findings indicate that GDF15 can be induced by pathophysiologic changes in iron availability, raising important questions about the mechanism of regulation and its role in iron homeostasis.

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