Growth And Differentiation Factors Research Articles

Association of Incident Stroke Risk With an IL-18-Centered Inflammatory Network Biomarker Composite.

A coordinated network of circulating inflammatory molecules centered on the pleotropic pro-atherogenic cytokine interleukin-18 (IL-18) is linked to cerebral small vessel disease. We sought to validate the association of this inflammatory biomarker network with incident stroke risk, cognitive impairment, and imaging metrics in a sample of the Framingham Offspring Cohort. Using available baseline measurements of serum levels of IL-18, GDF (growth and differentiation factor)-15, soluble form of receptor for advanced glycation end products, myeloperoxidase, and MCP-1 (monocyte chemoattractant protein-1) from Exam 7 of the Framingham Offspring Cohort (1998-2001), we constructed a population-normalized, equally weighted log-transformed mean Z-score value representing the average level of each serum analyte to create an inflammatory composite score (ICS5). Multivariable regression models were used to determine the association of ICS5 with incident stroke, brain magnetic resonance imaging features, and cognitive testing performance. We found a significant association between ICS5 score and increased risk for incident all-cause stroke (hazard ratio, 1.48 [95% CI, 1.05-2.08]; P=0.024) and ischemic stroke (hazard ratio, 1.51 [95% CI, 1.03-2.21]; P=0.033) in the Exam 7 cohort of 2201 subjects (mean age 62±9 years; 54% female) aged 45+ years with an all-cause incident stroke rate of 6.1% (135/2201) and ischemic stroke rate of 4.9% (108/2201). ICS5 and its component serum markers are all associated with the Framingham Stroke Risk Profile score (β±SE, 0.19±0.02; P<0.0001). In addition, we found a significant inverse association of ICS5 with a global cognitive score, derived from a principal components analysis of the neuropsychological battery used in the Framingham cohort (-0.08±0.03; P=0.019). No association of ICS5 with magnetic resonance imaging metrics of cerebral small vessel disease was observed. Circulating serum levels of inflammatory biomarkers centered on IL-18 are associated with an increased risk of stroke and cognitive impairment in the Framingham Offspring Cohort. Linking specific inflammatory pathways to cerebral small vessel disease may enhance individualized quantitative risk assessment for future stroke and vascular cognitive impairment.

Rker-050, a Modified Activin Receptor Type Iia Ligand Trap, Promoted Erythropoiesis in a Murine Model of Myelofibrosis

Myelofibrosis (MF) is one of several myeloproliferative neoplasms most often associated with anemia due to ineffective hematopoiesis, inflammation, aberrant bone metabolism and progressive fibrosis in the bone marrow (BM). As a compensatory mechanism, extramedullary hematopoiesis is initiated in the spleen, resulting in splenomegaly. Megakaryocyte hyperplasia/dysplasia are thought to be one of the main drivers of MF disease progression. Evidence also suggests that dysregulated TGF-β superfamily activity contributes to ineffective hematopoiesis. KER-050 and its research form, RKER-050, are investigational modified activin receptor type IIA ligand traps designed to inhibit specific TGF-β superfamily ligands, including activin A, activin B, growth and differentiation factor (GDF) 8 and GDF11, to promote erythropoiesis and thrombopoiesis. Additionally, the KER-050 target ligands promoted fibrosis and bone resorption in preclinical studies. Therefore, by inhibiting these ligands, KER-050 could potentially rebalance the bone marrow microenvironment, including reducing fibrosis, allowing restoration of hematopoiesis and alleviating extramedullary hematopoiesis and associated splenomegaly. To investigate the potential of RKER-050 to reverse ineffective hematopoiesis in MF, a hypomorphic Gata1 MF mouse model (Gata1Low; MF mice) was utilized which presents similar characteristics to human MF, including ineffective hematopoiesis, cytopenias, extramedullary hematopoiesis, defective bone deposition and BM fibrosis. this study, we also observed aberrant bone growth in the cortex of the hind limb long bones which inappropriately extended into the bone marrow, resulting in limited BM compartment space and demonstrating a severe disease state in these mice. Anemia status of MF mice was confirmed at the start of the treatment. MF mice showed a 16% reduction in hemoglobin (Hgb) compared to WT control mice. After 12 weeks of treatment, MF+VEH mice continued to exhibit a significant or trending decrease in red blood cells (RBCs; -19%), Hgb (-20%), and hematocrit (Hct; -10%) compared to WT mice. In contrast, MF+050 mice had a significant recovery of RBCs (+31%), Hgb (+24%) and Hct (+20%), compared to MF+VEH mice, demonstrating that RKER-050 reversed anemia in this advanced disease MF model. To assess the mechanism of action of RKER-050, we evaluated erythroid precursor populations in the BM. While MF+VEH mice showed a significant reduction in erythroid progenitors compared to WT mice, These data support increased BM erythropoiesis with RKER-050 treatment. In addition, we evaluated the effect of RKER-050 on thrombopoiesis. MF+VEH mice were severely thrombocytopenic and had significantly increased megakaryocyte progenitors (MkP; +591%) compared to WT mice. Although RKER-050 significantly reduced MkP (-33%; MF+050), suggesting RKER-050 may positively influence the megakaryocyte lineage, this did not translate to improvements in thrombocytopenia, and platelet counts remained similar to MF+VEH. Additional data will be presented that investigates the potential of RKER-050 treatment in (6-month vs 10-month-old mice, where disease is less severe) to further evaluate the potential to impact cytopenias, extramedullary hematopoiesis and BM fibrosis. Overall, in the context of severe disease, our results suggest RKER-050 can promote erythropoiesis and reverse anemia in the BM in by rebalancing hematopoiesis in the BM niche. Reestablishing BM hematopoiesis could obviate the need for compensatory extramedullary hematopoiesis in the spleen, the major driver of splenomegaly in MF patients. In conclusion, KER-050 represents a potentially promising approach for patients with MF and other hematological diseases where ineffective hematopoiesis occurs.

Effects of Ker-050 on Iron Metabolism: Exploratory Analyses from an Ongoing Phase 2 Study in Patients with Myelodysplastic Syndromes

Background: Iron overload (IO) is an important clinical consequence of transfusion-dependent myelodysplastic syndromes (MDS). For patients with high transfusion burden (HTB), limited treatment options are available to effectively treat anemia and reduce transfusion dependence. Transfusion dependence is an independent predictor of poor prognosis in MDS. It is associated with IO and elevated ferritin, a marker of intracellular iron storage that also predicts poor prognosis in MDS. When adjusting for transfusion burden, each 500 µg/L increase in ferritin above 1000 µg/L is associated with a 30% greater risk of death (Malcovati et al. 2006). IO also disrupts osteoprogenitors and erythroid precursors within the osteohematopoietic niche, leading to abnormal bone turnover and ineffective erythropoiesis (Bulycheva 2015). While iron chelators have shown some efficacy in managing IO, they introduce toxicities and have little effect on transfusion burden. Unmet need remains for treatments that effectively address anemia, IO, and reduce transfusion dependence in patients with MDS, especially those with HTB. KER-050 is designed to alter signaling of TGF-β superfamily ligands, restoring balance to the osteohematopoietic niche, and promoting differentiation of erythroid and megakaryocytic precursors. It is a modified activin receptor type IIA ligand trap that inhibits TGF-β superfamily ligands, including activins A and B and growth and differentiation factors (GDFs) 8 and 11. To date, clinical data indicate that KER-050 induces sustained increases in reticulocytes and hemoglobin. Preliminary findings also show potential for KER-050 to induce erythroid response and reduce transfusion burden in patients with MDS, including those with HTB (Tan et al., 2022). KER-050 may also impact iron metabolism and this presentation explores the effects of KER-050 on indices of IO. Methods: This Phase 2 study is evaluating KER-050 in participants with very low- to intermediate-risk MDS. Data presented are from Part 1 Dose Escalation which included 16 weeks of KER-050 treatment across 5 cohorts (0.75 to 5 mg/kg). Iron chelator therapy was permitted at the discretion of the investigator provided patients had been on a stable dose for 8 weeks prior to C1D1. Markers of IO and hematopoiesis were assessed as exploratory endpoints over the 16-week treatment period. Analyses presented evaluate the effect of KER-050 on these markers. Baseline markers of bone turnover were also assessed. Results: A total of 31 patients were enrolled in Part 1 Dose Escalation; 26 were transfusion dependent, 18 with HTB (≥ 4 RBC units in 8 weeks prior to day 1). Seven HTB patients (38.9%) received iron chelator therapy. Baseline differences were noted in measures of iron status, erythropoiesis and bone turnover for non-transfused (NT), low transfusion burden (LTB), and HTB patients (Table 1). HTB patients had the highest baseline serum iron and ferritin levels. Preliminary findings indicate that KER-050 treatment was associated with decreases in serum ferritin for patients both with and without iron chelator therapy. Patients achieving transfusion independence (TI) experienced a 39.5% reduction (mean change: -619.4 ng/ml, range: -2118.4 to +243 ng/mL) in serum ferritin at Week 12 that was generally sustained at Week 16 and 20 (Figure 1). Similarly, over the same time period, serum iron and transferrin saturation (TSAT) decreased by 4.03 µmol/L (8.38%) and 5.3%, respectively, in patients achieving TI. Soluble transferrin receptor (sTfR) increased by 32.2% and remained elevated at subsequent visits. Summary: Preliminary data from the 16-week Dose Escalation in this ongoing phase 2 study reveal differences in baseline iron biomarkers indicative of increasing iron overload with increasing transfusion burden. While nearly half of HTB patients received iron chelator therapy, this group had markedly elevated ferritin compared to NT and LTB patients at baseline. KER-050 treatment was associated with reductions in serum ferritin, irrespective of the use of iron chelation. Patients achieving TI experienced decreases in ferritin, iron and TSAT concurrent with increases in sTfR that were generally maintained through follow-up. The data suggest that, in addition to improving hematopoiesis and transfusion burden in MDS patients, KER-050 may reduce iron overload, a serious clinical complication impacting the survival of these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Modulation of TGF-β Superfamily Signaling to Treat Myelofibrosis and Mitigate JAK Inhibitor Toxicity: A Report on the Phase 2 Study of Ker-050 in Participants with Myelofibrosis

Background: Myelofibrosis (MF) is a disorder characterized by unrestrained proliferation of myeloid precursors and dysfunctional Janus kinase (JAK) signaling. Hyperplastic and dysplastic megakaryocyte expansion in MF releases inflammatory cytokines. These cytokines promote fibroblast proliferation, bone remodeling, and marrow fibrosis, disrupting the osteohematopoietic niche and leading to ineffective and extramedullary hematopoiesis (Vainchenker et al. 2017). Clinical manifestations include splenomegaly, anemia, and often disabling constitutional symptoms. JAK inhibitors, such as ruxolitinib, have been shown to improve spleen size and symptoms, but are associated with dose-limiting anemia and thrombocytopenia, reducing their utility for many patients (Verstovsek et al. 2012). KER-050 is an investigational product designed to alter signaling of TGF-β superfamily ligands, restoring balance to the osteohematopoietic niche and promoting differentiation of erythroid and megakaryocytic precursors. It is a modified activin receptor type IIA ligand trap that inhibits TGF-β superfamily ligands, including activins A and B and growth and differentiation factors (GDFs) 8 and 11. Preclinical studies have demonstrated that KER-050 induces erythropoiesis, increases platelet counts, improves bone mass, and prevents fibrosis. A preclinical study previously presented demonstrated that RKER-050 can reverse ruxolitinib-associated reductions in hemoglobin, hematocrit, and red blood cell count, indicating potential for KER-050 to mitigate ruxolitinib toxicity. In two clinical studies, including an ongoing study in participants with myelodysplastic syndromes (MDS), KER-050 has been well-tolerated. Accumulated clinical data demonstrate that KER-050 can stimulate erythropoiesis and thrombopoiesis in both healthy post-menopausal women and MDS participants with ineffective hematopoiesis. Here we present data from the first clinical study of KER-050 in participants with MF (NCT05037760). The objective of this study is to evaluate the potential of KER-050 as monotherapy and in combination with ruxolitinib to treat the underlying pathology of MF and mitigate JAK inhibitor-associated cytopenias. Methods: This ongoing Phase 2 open-label study is evaluating the safety, tolerability, pharmacokinetics PK), pharmacodynamics (PD), and efficacy of KER-050 administered with or without ruxolitinib in participants with primary myelofibrosis (PMF), post-essential thrombocythemia myelofibrosis (post-ET MF), and post-polycythemia vera myelofibrosis (post-PV MF) who have anemia (hemoglobin ≤ 10 g/dL or receiving transfusions). Part 1 involves parallel dose escalation arms (1A: monotherapy, 1B: combination with ruxolitinib) to evaluate the safety and tolerability of KER-050 and identify the dose(s) of KER-050 to be evaluated in Part 2 (Figure 1). Changes in hemoglobin, transfusion burden, spleen size, the Myelofibrosis Symptom Assessment Form Total Symptom Score (MF-SAF-TSS), PK and incidence of accelerated MF and acute myeloid leukemia are assessed as secondary endpoints. This study is also evaluating markers of multilineage hematopoiesis, bone remodeling, iron metabolism, inflammation, and marrow fibrosis. Frequency of ruxolitinib dose modification and quality of life will be explored. Results: Preliminary results from Part 1 will be presented. At the time of this writing, 5 patients have received KER-050 on study, 3 in Arm 1A and 2 in Arm 1B. Three participants have completed the dose-limiting toxicity (DLT) assessment period and no DLTs have been experienced. Data evaluated to date indicate a PD effect consistent with previous preclinical and clinical studies of KER-050. Summary: KER-050 is designed to alter TGF-β superfamily signaling, restoring balance to the osteohematopoietic niche and promoting multilineage hematopoietic differentiation. Here we present data from the first study of KER-050 in participants with MF evaluating the potential for KER-050 to impact key aspects of the MF disease state (anemia, spleen size, symptoms, progression), as monotherapy and in combination with ruxolitinib. The potential for KER-050 to mitigate ruxolitinib toxicity and related dose-reductions is being investigated. Exploratory analyses of the KER-050 impact on inflammation, bone remodeling, iron metabolism, and marrow fibrosis, as available, will be shared. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Bone morphogenetic proteins, activins, and growth and differentiation factors in tumor immunology and immunotherapy resistance.

The TGF-β superfamily is a group of secreted polypeptides with key roles in exerting and regulating a variety of physiologic effects, especially those related to cell signaling, growth, development, and differentiation. Although its central member, TGF-β, has been extensively reviewed, other members of the family-namely bone morphogenetic proteins (BMPs), activins, and growth and differentiation factors (GDFs)-have not been as thoroughly investigated. Moreover, although the specific roles of TGF-β signaling in cancer immunology and immunotherapy resistance have been extensively reported, little is known of the roles of BMPs, activins, and GDFs in these domains. This review focuses on how these superfamily members influence key immune cells in cancer progression and resistance to treatment.

GDF11 ameliorates severe acute pancreatitis through modulating macrophage M1 and M2 polarization by targeting the TGFβR1/SMAD-2 pathway

Severe acute pancreatitis (SAP), as a typical acute inflammatory injury disease, is one of the acute gastrointestinal diseases with a remarkable mortality rate. Macrophages, typical inflammatory cells involved in SAP, play an important role in the pathogenesis of SAP, which are separated into proinflammation M1 and antiinflammation M2. Growth and differentiation factor 11 (GDF11), as a member of the TGF-β family also called BMP-11, has been discovered to suppress inflammation. However, the mechanism by which GDF11 inhibits inflammation and whether it can ameliorate SAP are still elusive. The present research aimed to investigate the roles of GDF11 in SAP and the potential immunomodulatory effect of macrophage polarization. The mouse and rat SAP model were constructed by caerulein and retrograde injection of sodium taurocholate respectively. The effects of GDF11 on SAP were observed by serology, histopathology and tissue inflammation, and the effects of GDF11 on the polarization of macrophages in vivo were observed. Raw264.7 and THP1 crells were used to study the effect of GDF11 on macrophage polarization in vitro. To further investigate the causal link underneath, our team first completed RNA and proteome sequencing, and utilized specific suppressor to determine the implicated signal paths. Herein, we discovered that GDF11 alleviated the damage of pancreatic tissues in cerulein induced SAP mice and SAP rats induced by retrograde injection of sodium taurocholate, and further found that GDF11 facilitated M2 macrophage polarization and diminished M1 macrophage polarization in vivo and in vitro. Subsequently, we further found that the regulation of GDF11 on macrophage polarization through TGFβR1/smad2 pathway. Our results revealed that GDF11 ameliorated SAP and diminished M1 macrophage polarization and facilitated M2 macrophage polarization. The Role of GDF11 in modulating macrophage polarization might be one of the mechanisms by which GDF11 played a protective role in pancreatic tissues during SAP.

Effects of Soy Milk in Conjunction With Resistance Training on Physical Performance and Skeletal Muscle Regulatory Markers in Older Men.

Purpose: We aimed to determine the effects of 12weeks of soy milk consumption combined with resistance training (RT) on body composition, physical performance, and skeletal muscle regulatory markers in older men. Methods: In this randomized clinical trial study, 60 healthy elderly men (age = 65.63 ± 3.16years) were randomly assigned to four groups: resistance training (RT; n = 15), soy milk consumption (SMC; n = 15), resistance training + soy milk (RSM; n = 15), and control (CON; n = 15) groups. The study was double-blind for the soy milk/placebo. Participants in RT and RSM groups performed resistance training (3 times/week) for 12weeks. Participants in the SMC and RSM groups consumed 240mL of soy milk daily. Body composition [body mass (BM), body fat percent (BFP), waist-hip ratio (WHR), and fat mass (FM)], physical performance [upper body strength (UBS), lower body strength (LBS), VO2max, upper anaerobic power, lower anaerobic power, and handgrip strength], and serum markers [follistatin, myostatin, myostatin-follistatin ratio (MFR), and growth and differentiation factor 11 (GDF11)] were evaluated before and after interventions. Results: All 3 interventions significantly (p < 0.05) increased serum follistatin concentrations (RT = 1.7%, SMC = 2.9%, RSM = 7.8%) and decreased serum myostatin (RT = -1.3% SMC = -5.4%, RSM = -0.5%) and GDF11 concentrations (RT = -1.4%, SMC = -1.4%, RSM = -9.0%), and MFR (RT = -2.6%, SMC = -3.2%, RSM = -12%). In addition, we observed significant reduction in all 3 intervention groups in BFP (RT = -3.6%, SMC = -1.4%, RSM = -6.0%), WHR (RT = -2.2%, SMC = -2.1%, RSM = -4.3%), and FM (RT = -9.6%, SMC = -3.8%, RSM = -11.0%). Moreover, results found significant increase only in RT and RSM groups for muscle mass (RT = 3.8% and RSM = 11.8%), UBS (RT = 10.9% and RSM = 21.8%), LBS (RT = 4.3% and RSM = 7.8%), upper anaerobic power (RT = 7.8% and RSM = 10.3%), and lower anaerobic power (RT = 4.6% and RSM = 8.9%). Handgrip strength were significantly increased in all 3 intervention groups (RT = 7.0%, SMC = 6.9%, RSM = 43.0%). VO2max significantly increased only in RSM (1.7%) after 12weeks of intervention. Additionally, significant differences were observed between the changes for all variables in the RSM group compared to RT, SMC, and CON groups (p < 0.05). Conclusions: There were synergistic effects of soy milk and RT for skeletal muscle regulatory markers, body composition, and physical performance. Results of the present study support the importance of soy milk in conjunction with RT for older men.

Follistatin dysregulation impaired trophoblast biological functions by GDF11-Smad2/3 axis in preeclampsia placentas

IntroductionPreeclampsia (PE) is one of the main causes of maternal, fetal, and neonatal mortality. So far, the underlying mechanism of this pregnancy-specific syndrome remains unelucidated. The expression of Follistatin (FST) decreased in maternal serum (especially early onset severe PE) and placental trophoblasts of PE patients. However, whether FST-deficiency in preeclamptic placentas alters trophoblast function remains to be determined. MethodsTrophoblast cell lines were cultured in vitro and LV3 short hairpin RNA (shRNA) was used to silence FST. Growth and differentiation factor 11 (GDF11) expression level in placentas and serum were detected by immunohistochemistry and enzyme-linked immune-sorbent assay, respectively. To verify the effect of reduced FST expression on trophoblasts, microRNA-24-3p, which was predicted to target the 3′-untranslated region (3′-UTR) of FST, was screened out, and miR-24-3p mimic, inhibitor was used to regulate FST expression in trophoblasts. ResultsDownregulation of FST significantly enhanced the apoptosis and impaired migration and invasion of trophoblast. Reduced FST caused the upregulation of GDF11 in trophoblasts. Interestingly, GDF11 reduced in preeclamptic placental microvascular endothelial cells. Dysregulation of FST-GDF11-Smad2/3 signaling pathway, leading to increased apoptosis of trophoblast. Expression levels of miR-24-3p, was significantly elevated in preeclamptic placentas. Trophoblast cells transfected with miR-24-3p mimics displayed impaired migration and invasion and increased apoptosis. Treated by miR-24-3p inhibitor, trophoblast cells exhibited rescued function. DiscussionFST-deficiency impaired trophoblast function by upregulating GDF11 levels in trophoblasts. The regulation of FST-GDF11-Smad2/3 axis by microRNAs mimic or inhibitor may be critical to trophoblast function regulation and helps to deepen our understanding of the molecular mechanism of PE.

GDF11 knockdown downregulates SMURF1 to inhibit breast cancer progression by activation of p53 and inactivation of ERα signaling.

Breast cancer (BC) is a prevalent neoplasm that occurs in women all over the world. Growth and differentiation factor 11 (GDF11) plays an essential role in cancer progression. This study focused on investigating the biological role and underlying mechanisms of GDF11 in BC. We detected the expression of GDF11 in 27 patients with BC and BC cell lines. Kaplan-Meier plotter was employed to analyze the relationship between GDF11 expression and overall survival (OS) of BC patients. The proliferative, migratory, invasive, and apoptotic abilities of T47D cells were examined. Correlation analysis of GDF11 with Smad ubiquitination regulatory factor 1 (SMURF1) was conducted. The association between GDF11 and the p53 pathway was analyzed by western blot and PFT-α (a p53 inhibitor)-mediated rescue assays. A brief analysis of the role of estrogen receptor alpha (ERα) signaling in BC progression was performed. The results showed that GDF11 was increased in BC tissues and cell lines, and the high expression of GDF11 was associated with the poor OS of BC patients. GDF11 knockdown inhibited the proliferation, migration, and invasion of T47D cells, but promoted cell apoptosis. Meanwhile, the GDF11 knockdown reduced the SMURF1 expression and invoked the p53 pathway activation. SMURF1 overexpression and PFT-α partially blocked the effects of GDF11 knockdown. In addition, GDF11 knockdown and SMURF1 silencing inhibited the activation of the ERα signaling pathway. In summary, GDF11 was involved in the progression of BC by regulating SMURF1-mediated p53 and ERα pathways, opening up a new way for BC treatment.

Growth differentiation factor 1-induced tumour plasticity provides a therapeutic window for immunotherapy in hepatocellular carcinoma

Tumour lineage plasticity is an emerging hallmark of aggressive tumours. Tumour cells usually hijack developmental signalling pathways to gain cellular plasticity and evade therapeutic targeting. In the present study, the secreted protein growth and differentiation factor 1 (GDF1) is found to be closely associated with poor tumour differentiation. Overexpression of GDF1 suppresses cell proliferation but strongly enhances tumour dissemination and metastasis. Ectopic expression of GDF1 can induce the dedifferentiation of hepatocellular carcinoma (HCC) cells into their ancestral lineages and reactivate a broad panel of cancer testis antigens (CTAs), which further stimulate the immunogenicity of HCC cells to immune-based therapies. Mechanistic studies reveal that GDF1 functions through the Activin receptor-like kinase 7 (ALK7)-Mothers against decapentaplegic homolog 2/3 (SMAD2/3) signalling cascade and suppresses the epigenetic regulator Lysine specific demethylase 1 (LSD1) to boost CTA expression. GDF1-induced tumour lineage plasticity might be an Achilles heel for HCC immunotherapy. Inhibition of LSD1 based on GDF1 biomarker prescreening might widen the therapeutic window for immune checkpoint inhibitors in the clinic.

Growth and differentiation factor-15 as a potential prognostic biomarker for status-epilepticus-associated-with-fever: A pilot study

ObjectiveBiomarkers predicting poor outcomes of status-epilepticus-associated-with-fever (SEF) at an early stage may contribute to treatment guidance. However, none have been reported thus far. We investigated the dynamics of serum growth and differentiation factor (GDF)-15 after seizure onset in patients with SEF and determined whether GDF-15 can predict poor outcomes, particularly in the first 6 h after seizure onset. MethodsWe enrolled 37 pediatric patients with SEF and eight patients with simple febrile seizures (SFS) and collected their blood samples within 24 h of seizure onset and eight febrile control patients between March 1, 2017 and September 30, 2020. All patients were aged ≤15 years. ResultsIn the SEF group, the median post-seizure serum GDF-15 values were 1,065 (<6h), 2,720 (6–12 h), and 2,411 (12–24 h) pg/mL. The median serum GDF-15 in the first 6 h was measured in patients with SEF without a significant past medical history (n = 21) and was found to be statistically significantly higher (1,587 pg/mL) than in the febrile control (551 pg/mL) and SFS (411 pg/mL) groups. The median serum GDF-15 was statistically significantly higher in patients with SEF with sequelae (n = 5) and patients with acute encephalopathy with biphasic seizures/reduced diffusion/hemorrhagic shock and encephalopathy syndrome (n = 6) than in patients with SEF without sequelae (n = 16) (15,898 vs 756 pg/mL) and patients with prolonged FS (n = 15) (9,448 vs 796 pg/mL). ConclusionsThis study demonstrates the dynamics of serum GDF-15 in patients with SEF and indicates the potential of GDF-15 as an early predictor of poor outcomes.

Sotatercept (ACE-011) Alone and in Combination with Ruxolitinib in Patients (pts) with Myeloproliferative Neoplasm (MPN)-Associated Myelofibrosis (MF) and Anemia

Sotatercept (ACE-011) Alone and in Combination with Ruxolitinib in Patients (pts) with Myeloproliferative Neoplasm (MPN)-Associated Myelofibrosis (MF) and Anemia

Myostatin Gene as a Genetic Marker for Growth and Carcass Traits in Beef Cattle

&lt;p&gt;Growth and carcass traits are of economic importances in livestock breeding, because they affect the profitability of animal production. The phenotypic expression of these traits is controlled by multiple genes (polygenes), such as myostatin (MSTN) gene. This paper aims to discuss the expression, polymorphism and potential application of MSTN gene as a marker-assisted selection (MAS) for growth and carcass traits in beef cattle based on data from published studies. MSTN gene or known as growth and differentiation factor 8 (GDF8) is a member of the transforming growth factor-β (TGF-β) superfamily, which acts as a negative regulator of skeletal muscle mass deposition. Several published studies showed that mutations in the MSTN gene can inhibit the activation of myostatin, which leads to an increased muscle mass (hypertrophy). Several &lt;em&gt;MSTN&lt;/em&gt; gene polymorphisms were reported to be associated with growth and carcass traits in local cattle in several countries, including Indonesia, namely Bali cattle. Based on several assumptions: 1) there is MTSN gene polymorphisms in a population, 2) there is a significant association between MSTN gene polymorphisms and growth and carcass traits, as reported in several beef cattle populations and 3) those cattle with superior genotype have better growth performances, we expect that there will be improvement in growth performances in the future if those cattle are selected. Understanding MSTN gene polymorphisms would be useful to make strategies for the genetic improvement for growth and carcass traits of local cattle.&lt;/p&gt;

Elevated cytokine, chemokine, and growth and differentiation factor-15 levels in hemorrhagic shock and encephalopathy syndrome: A retrospective observational study

Patients with hemorrhagic shock and encephalopathy syndrome (HSES) have a high early mortality rate, which may be caused by a ‘cytokine storm’. However, there is little information on how cytokines and chemokines change over time in these patients. We aimed to describe the characteristics of HSES by examining changes in serum biomarker levels over time. Six patients with HSES were included. We retrospectively evaluated their clinical course and imaging/laboratory data. We measured serum levels of multiple cytokines [interleukin 1β (IL-1β), IL-2, IL-4, IL-6, IL-10, IL-17, interferon-gamma, and tumor necrosis factor alpha], chemokines (IL-8, monocyte chemoattractant protein-1, interferon-inducible protein-10), and growth and differentiation factor (GDF)-15. The highest cytokine and chemokine levels were noted in the first 24 h, and decreased thereafter. The GDF-15 level was markedly high. Cytokine, chemokine, and GDF-15 levels were significantly higher in patients with HSES than in controls in the first 24 h, except for IL-2 and IL-4. Patients with HSES have high inflammatory cytokine and chemokine levels, a high GDF-15 level in the first 24 h, and high lactate levels. Our study provides new insights on the pathophysiology of HSES, a detailed clinical picture of patients with HSES, and potential biomarkers.

Regular Exercise Training Decreases Circulating Myostatin In Older Overweight Women At Rest And In Response To Acute Exercise

Myostatin (growth and differentiation factor (GDF) 8) inhibits skeletal muscle growth, whereas follistatin (FST) can inhibit GDF8 to promote skeletal muscle growth. GDF15 may be a biomarker of stress, and also impact skeletal muscle growth. The PURPOSE of this project was to determine if an acute bout of exercise in older women could positively influence these three circulating biomarkers. METHODS: Overweight, older women (64.0±1.3 years; BMI=32.8±1.0 kg•m-2; n=18) participated in an acute bout of cardiorespiratory and resistance exercise before and after a 12-week training intervention. The training intervention consisted of 3 d/wk of progressive supervised treadmill walking and resistance exercise at a moderate to vigorous intensity. Blood was collected before acute exercise (PRE), immediately after (POST), 1 hour recovery (1HR), and 2 hour recovery (2HR). Serum GDF8, FST, and GDF-15 were measured with commercially available ELISA kits. RESULTS: BMI did not change (p>0.05). GDF8 was higher (p<0.05) at PRE, 1HR, and 2HR before the exercise training intervention. Both before and after the training intervention, an acute bout of exercise increased (p<0.05) GDF8 at POST, 1HR, 2HR compared to PRE. FST increased (p<0.05) from PRE to 1HR and 2HR both before and after the intervention. GDF15 increased (p<0.05) from PRE to POST before the intervention, but PRE to POST, 1HR, and 2HR after the intervention. CONCLUSION: Regular exercise training can reduce the acute exercise effect on circulating GDF8. Further, acute exercise will increase FST before and after an exercise training intervention. These results were independent of a change in BMI. Together, this may be a potential mechanism for exercise to help maintain skeletal muscle mass during aging.

ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension.

Human genetics, biomarker, and animal studies implicate loss of function in bone morphogenetic protein (BMP) signaling and maladaptive transforming growth factor-β (TGFβ) signaling as drivers of pulmonary arterial hypertension (PAH). Although sharing common receptors and effectors with BMP/TGFβ, the function of activin and growth and differentiation factor (GDF) ligands in PAH are less well defined. Increased expression of GDF8, GDF11, and activin A was detected in lung lesions from humans with PAH and experimental rodent models of pulmonary hypertension (PH). ACTRIIA-Fc, a potent GDF8/11 and activin ligand trap, was used to test the roles of these ligands in animal and cellular models of PH. By blocking GDF8/11- and activin-mediated SMAD2/3 activation in vascular cells, ACTRIIA-Fc attenuated proliferation of pulmonary arterial smooth muscle cells and pulmonary microvascular endothelial cells. In several experimental models of PH, prophylactic administration of ACTRIIA-Fc markedly improved hemodynamics, right ventricular (RV) hypertrophy, RV function, and arteriolar remodeling. When administered after the establishment of hemodynamically severe PH in a vasculoproliferative model, ACTRIIA-Fc was more effective than vasodilator in attenuating PH and arteriolar remodeling. Potent antiremodeling effects of ACTRIIA-Fc were associated with inhibition of SMAD2/3 activation and downstream transcriptional activity, inhibition of proliferation, and enhancement of apoptosis in the vascular wall. ACTRIIA-Fc reveals an unexpectedly prominent role of GDF8, GDF11, and activin as drivers of pulmonary vascular disease and represents a therapeutic strategy for restoring the balance between SMAD1/5/9 and SMAD2/3 signaling in PAH.

A 5-bp mutation within MSTN/GDF8 gene was significantly associated with growth traits in Inner Mongolia White Cashmere goats

Myostatin (MSTN) gene, also known as growth and differentiation factor 8 (GDF8) gene, is a negative regulator of skeletal muscle growth and development, especially the number, size and type of muscle fibers. Its mutations contribute to the double-muscling (DBM) phenomenon which significantly increases the muscle mass. Hence, variations within MSTN/GDF8 gene receive so much attention in several kinds of species such as bovines, poultries, goats, sheep, horses. A 5-base pairs (bp) indel in the 5’ untranslated region (5’UTR) of goat MSTN/GDF8 was verified to be significantly associated with growth traits except Inner Mongolia White Cashmere (IMWC) goats. Given that almost all sample sizes were below 150, we enlarged sample sizes to more than 500 to uncover the association between the 5-bp indel and growth traits in IMWC goats. Only two genotypes (deletion/deletion (DD) and insertion/deletion (ID)) were found, and DD genotypes were dominant genotypes. The detected locus displayed low genetic diversity (PIC = 0.090). Interestingly, the association analyses revealed that the 5-bp indel had a significant effect on the chest depth (p = 0.003), and DD genotypes were dominant genotypes. Hinted that the 5-bp indel could act as an effective marker in molecular marker-assisted selection (MAS) processes for selection of excellent goat individuals.

GDF11 promotes osteogenesis as opposed to MSTN, and follistatin, a MSTN/GDF11 inhibitor, increases muscle mass but weakens bone

Growth and differentiation factor 11 (GDF11) and myostatin (MSTN) are closely related transforming growth factor β (TGF-β) family members, but their biological functions are quite distinct. While MSTN has been widely shown to inhibit muscle growth, GDF11 regulates skeletal patterning and organ development during embryogenesis. Postnatal functions of GDF11, however, remain less clear and controversial. Due to the perinatal lethality of Gdf11 null mice, previous studies used recombinant GDF11 protein to prove its postnatal function. However, recombinant GDF11 and MSTN proteins share nearly identical biochemical properties, and most GDF11-binding molecules have also been shown to bind MSTN, generating the possibility that the effects mediated by recombinant GDF11 protein actually reproduce the endogenous functions of MSTN. To clarify the endogenous functions of GDF11, here, we focus on genetic studies and show that Gdf11 null mice, despite significantly down-regulating Mstn expression, exhibit reduced bone mass through impaired osteoblast (OB) and chondrocyte (CH) maturations and increased osteoclastogenesis, while the opposite is observed in Mstn null mice that display enhanced bone mass. Mechanistically, Mstn deletion up-regulates Gdf11 expression, which activates bone morphogenetic protein (BMP) signaling pathway to enhance osteogenesis. Also, mice overexpressing follistatin (FST), a MSTN/GDF11 inhibitor, exhibit increased muscle mass accompanied by bone fractures, unlike Mstn null mice that display increased muscle mass without fractures, indicating that inhibition of GDF11 impairs bone strength. Together, our findings suggest that GDF11 promotes osteogenesis in contrast to MSTN, and these opposing roles of GDF11 and MSTN must be considered to avoid the detrimental effect of GDF11 inhibition when developing MSTN/GDF11 inhibitors for therapeutic purposes.

Specification of BMP Signaling.

Bone Morphogenetic Proteins (BMPs) together with the Growth and Differentiation Factors (GDFs) form the largest subgroup of the Transforming Growth Factor (TGF)β family and represent secreted growth factors, which play an essential role in many aspects of cell communication in higher organisms. As morphogens they exert crucial functions during embryonal development, but are also involved in tissue homeostasis and regeneration in the adult organism. Their involvement in maintenance and repair processes of various tissues and organs made these growth factors highly interesting targets for novel pharmaceutical applications in regenerative medicine. A hallmark of the TGFβ protein family is that all of the more than 30 growth factors identified to date signal by binding and hetero-oligomerization of a very limited set of transmembrane serine-threonine kinase receptors, which can be classified into two subgroups termed type I and type II. Only seven type I and five type II receptors exist for all 30plus TGFβ members suggesting a pronounced ligand-receptor promiscuity. Indeed, many TGFβ ligands can bind the same type I or type II receptor and a particular receptor of either subtype can usually interact with and bind various TGFβ ligands. The possible consequence of this ligand-receptor promiscuity is further aggravated by the finding that canonical TGFβ signaling of all family members seemingly results in the activation of just two distinct signaling pathways, that is either SMAD2/3 or SMAD1/5/8 activation. While this would implicate that different ligands can assemble seemingly identical receptor complexes that activate just either one of two distinct pathways, in vitro and in vivo analyses show that the different TGFβ members exert quite distinct biological functions with high specificity. This discrepancy indicates that our current view of TGFβ signaling initiation just by hetero-oligomerization of two receptor subtypes and transduction via two main pathways in an on-off switch manner is too simplified. Hence, the signals generated by the various TGFβ members are either quantitatively interpreted using the subtle differences in their receptor-binding properties leading to ligand-specific modulation of the downstream signaling cascade or additional components participating in the signaling activation complex allow diversification of the encoded signal in a ligand-dependent manner at all cellular levels. In this review we focus on signal specification of TGFβ members, particularly of BMPs and GDFs addressing the role of binding affinities, specificities, and kinetics of individual ligand-receptor interactions for the assembly of specific receptor complexes with potentially distinct signaling properties.

Polymorphism of Myostatin Gene and its Association with Body Weight of Iraqi Local Ducks

Myostatin, or growth and differentiation factor-8(GDF-8) is a member of the transforming growth factor (TGF)-ß superfamily. The objective of this study was to investigate the association between genetic polymorphism of the myostatin gene with the body-weight of Iraqi local ducks by DNA sequence analysis. The results of DNA sequence showed nitrogen base change (G?A) at 129 base pair sites of the exon1 of MSTN gene. Therefore, two alleles, G and A and two patterns of genotypes, GG, AG were observed. The observed numbers of GG and AG genotypes were 25 and 6, respectively. The G allele was of the highest frequency (0.9) while A allele showed the lowest frequency (0.1). The GG genotype showed the highest frequency (80.65%) and AG genotype showed the lowest frequency (19.35%). Additionally, the percentages of observed and expected heterozygosity were 0.19 and 0.17 respectively. Moreover, the percentages of observed and expected homozygosity were 0.80 and 0.82, respectively. The average heterozygosity was 0.17. The results revealed no significant (P?0.05) effect of the MSTN gene on body weight.