Levels Of Activin Research Articles

P0414 Serum Activin-A level as a new biomarker in active Ulcerative Colitis patients

Abstract Background Ulcerative colitis is a lifelong inflammatory disease affecting the rectum and colon to varying degrees. Multiple scoring-classification methods, including endoscopic, clinical, and combined methods, have been used to assess disease severity. Various biomarkers are used for diagnosis and subtyping in ulcerative colitis, including fecal calprotectin, C-reactive protein, p-ANCA, ESR, anti-integrin αvβ6, and serum trefoil factor 3. In this study, we investigated whether there was a significant difference in serum activin-A levels, considered an indicator of intestinal inflammation, between symptomatic active ulcerative colitis patients and a control group. Methods The study included 34 patients and 18 controls, Patients were analyzed for serum Activin-A levels, symptomatic assessment, endoscopic evaluation, and laboratory parameters. Results Serum Activin-A levels in the patient group were significantly higher than those in the control group (p=0.034). Accordingly, with a sensitivity of 55.9% and a specificity of 72.2%, the cut-off value for Activin-A was found to be 486.925 pg/mL. Conclusion Serum activin A level has been associated with active ulcerative colitis References Namwanje M, Brown CW. Activins and inhibins: roles in development, physiology, and disease. Cold Spring Harb Perspect Biol. 2016;8(7):a021881. https://www.doi.org/10.1101/cshperspect.a021881 Sonoyama K, Rutatip S, Kasai T. Gene expression of activin, activin receptors, and follistatin in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2000;278(1):G89-97. https://www.doi.org/10.1152/ajpgi.2000.278.1.G89 Dignass AU, Jung S, Harder-d’Heureuse J, Wiedenmann B. Functional relevance of activin A in the intestinal epithelium. Scand J Gastroenterol. 2002;37(8):936-943. https://doi.org/10.1080/003655202760230900 Ogihara, R., Kurumi, H., Kanda, T., Yashima, K., Isomoto, H., & Yamaguchi, N. (2023). Serum Activin A Is a Novel Biomarker of Endoscopic Activity in Ulcerative Colitis. Gastroenterology research, 16(6), 334–341. https://doi.org/10.14740/gr1677

Oral biofluid levels of Activin-A and interleukin-1beta in stage III periodontitis.

Activin-A belongs to the transforming growth factor-beta superfamily and is a multifunctional cytokine that plays a role in inflammation, immune response, tissue repair and regeneration. Proinflammatory cytokine interleukin-1beta (IL-1β) can increase Activin-A expression in various cell types. This study aims to evaluate gingival crevicular fluid (GCF) and salivary Activin-A and IL-β levels in stage III periodontitis. 23 patients with stage III periodontitis, 26 with gingivitis and 26 periodontally healthy individuals were included. Full-mouth clinical periodontal indices were recorded, unstimulated whole saliva and GCF samples were obtained, Activin-A and IL-1β total amounts were determined by ELISA. Statistical comparisons were performed using non-parametric tests. Receiver operating characteristics curve was used for estimating the area under the curve (AUC). Periodontitis group exhibited significantly lower GCF Activin-A levels but higher IL-1β levels than the periodontally healthy group (p < 0.05). Gingivitis group had similar GCF Activin-A and IL-1β levels to the periodontitis and periodontally healthy groups (p > 0.05). Salivary Activin-A and IL-1β concentrations were similar among study groups (p > 0.05). GCF Activin-A level showed an excellent diagnostic performance (an AUC value of 0.82 with 87% sensitivity) to discriminate periodontitis from periodontal health. For the first time, this study demonstrated oral biofluid levels of Activin-A in periodontal health and diseases. Within the limits of the study, it might be suggested that diseased sites in periodontitis are associated with reduced Activin-A and increased IL-1β levels in GCF. Reduced GCF Activin-A levels and the accompanying increase in IL-1β might be associated with diseased sites in stage III periodontitis.

Stepwise release of Activin-A from its inhibitory prodomain is modulated by cysteines and requires furin coexpression to promote melanoma growth

The Activin-A precursor dimer can be cleaved by furin, but how this proteolytic maturation is regulated in vivo and how it facilitates access to signaling receptors is unclear. Here, analysis in a syngeneic melanoma grafting model shows that without furin coexpression, Activin-A failed to accelerate tumor growth, correlating with failure of one or both subunits to undergo cleavage in signal-sending cells, even though compensatory processing by host cells nonetheless sustained elevated circulating Activin-A levels. In reporter assays, furin-independent cleavage of one subunit enabled juxtacrine Activin-A signaling, whereas completion of proteolytic maturation by coexpressed furin or by recipient cells stimulated contact-independent activity, crosstalk with BMP receptors, and signal inhibition by follistatin. Mechanistically, Activin-A processing was modulated by allosteric disulfide bonds flanking the furin site. Disruption of these disulfide linkages with the prodomain enabled Activin-A binding to cognate type II receptors independently of proteolytic maturation. Stepwise proteolytic maturation is a novel mechanism to control Activin-A protein interactions and signaling.

Abstract P194: Metabolic effects of GDF15 and Activin A on trophoblasts

Preeclampsia (PE), a pregnancy-related complication, is a major cause of maternal and fetal morbidity and mortality. The pathophysiology is not fully elucidated. Activin A and GDF15 are part of the TGFβ superfamily and markers for trophoblast differentiation. Both are senescence associated secretory phenotype (SASP) factors that have been associated with cardiovascular disease. Mitochondrial dysfunction is associated with SASP and both have been described in PE. Serum levels of GDF15 and Activin A, were elevated in the maternal blood prior to the onset of PE and found to be elevated in placental tissue of women with PE. BeWo cells were metabolically reprogrammed to a physiological glucose-environment by cultivating them for 10-15 passages in a cell culture medium with 5.5 mM glucose as opposed to the standard high-glucose environment at 17.1mM. Next, BeWo cells were differentiated into multinucleated syncytiotrophoblasts with Forskolin, and with DMSO as solvent control to model cytotrophoblasts. Subsequently, these two trophoblast differentiation states were treated with GDF15 (20 ng/ml) and Activin A (20ng/ml) and the cell metabolic profile was analyzed. Additionally, a single cell human trophoblast organoid transcriptomics dataset from Shannon et al. was investigated for expression patterns of GDF15 and INHBA (Activin A) together with the overall metabolic profile of trophoblast cells. Treating BeWo cells with Activin A and GDF15 leads to an increase in mitochondrial activity, shown by elevated ATP levels in syncytiotrophoblast and an increase in mitochondrial membrane potential in cytotrophoblasts. Additionally, the oxygen consumption rate is significantly higher in syncytiotrophoblasts after Activin A and GDF15 treatment. In human trophoblast organoids, syncytiotrophoblasts showed the lowest metabolic activity measured by the expression of genes related to glycolysis and mitochondrial respiratory chain. Furthermore, GDF15 and INHBA (Activin A) were strongly expressed in syncytiotrophoblasts. Together, Activin A and GDF15 stimulation increases the metabolic activity in BeWo cells. As preeclampsia is associated with mitochondrial dysfunction as well as with senescence, our data indicate a potential role of Activin A and GDF15 in preeclampsia development.

Activin levels correlate with lymphocytic infiltration in epithelial ovarian cancer.

The TGF-β superfamily member activin, a dimer of the gene products of INHBA and/or INHBB, has been implicated in immune cell maturation and recruitment, but its immune impact within epithelial ovarian cancer (EOC) is not well characterized. We sought to explore differences in activin (INHBA/ Inhibin-βA and INHBB/ Inhibin-βB) between malignant and ovarian tissues at the RNA and protein level and assess the relationship between activin and immune cells in EOC. Publicly available RNA sequencing data were accessed from GEO (#GSE143897) with normalization and quantification performed via DESeq2. Immune gene expression profile was further explored within the TCGA-OV cohort derived from The Cancer Genome Atlas (TCGA). Immunohistochemical analysis was performed to evaluate activin A and T-cell markers CD8 and FoxP3 at the protein level. ELISA to activin-A was used to assess levels in the ascites of advanced EOC patients. Kaplan-Meier curves were generated to visualize survival outcomes. Gene expression levels of components of the activin signaling pathway were elevated within EOC when compared to a benign cohort, with differences in activin type I/II receptor gene profiles identified. Additionally, INHBA gene expression was linked to lymphocytic immune markers in EOC samples. Immunohistochemistry analysis revealed a positive correlation of CD8 and FOXP3 staining with activin A at the protein level in both primary and metastatic epithelial ovarian cancer samples. Furthermore, Activin-A (inhibin-βA) is significantly elevated in EOC patient ascites. INHBA expression is elevated within EOC, correlating with worse survival, with activin protein levels correlating with specific immune infiltration. Our findings suggest that activin-A may play a role in suppressing anti-tumor immunity in EOC, highlighting its potential as a therapeutic target.

Comparison of Levels of Activin A and Follistatin in Ectopic Pregnancies and Missed Abortions Patients

Comparison of Levels of Activin A and Follistatin in Ectopic Pregnancies and Missed Abortions Patients

Activin A as a potential biomarker for preserved ratio impaired spirometry (PRISm) and clinical outcomes in community-dwelling adults

IntroductionThis study endeavors to decipher the association between Activin A and PRISm, thereby addressing the potential of Activin A as a serum biomarker for early detection and long-term clinical outcome prediction of PRISm and subsequent all-cause mortality. MethodsThe study sample comprised middle-aged and older adults from the I-Lan Longitudinal Aging Study. Pulmonary function including forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were measured. Demographic data and laboratory data (including serum Activin A levels) were also collected. Multivariate logistic regression and Cox proportional hazards models were used to identify independent predictors of PRISm and all-cause mortality, respectively. ResultsAmong 711 eligible participants, 34 % had PRISm. The risk of PRISm elevated with Activin A levels in group quartiles (adjusted odds ratio (aOR), Q2: 1.606 [95 % CI 0.972–2.652], p = 0.064, Q3: 2.666 [1.635–4.348], p < 0.001, Q4: 3.225 [1.965–5.293], p < 0.001). On the other hand, lower hemoglobin (aOR: 1.122, p = 0.041) and higher blood urea nitrogen (BUN) levels (aOR: 1.033, p = 0.048) were associated with increased risk of PRISm. In addition, the PRISm group had a higher all-cause mortality rate (non-PRISm 4.5% vs. PRISm 8.3 %, p = 0.038). Multivariate Cox models also identify a higher level of Activin A as a risk factor of all-cause mortality (aHR: 1.001 [1.000–1.003], p = 0.042). ConclusionsHigher Activin A quartiles were linked to increased risk of PRISm, along with lower hemoglobin and higher BUN levels. Additonally, elevated Activin A was a significant risk factor of all-cause mortality.

#1688 Association of baseline serum activin levels with left atrial diameter at 5 years post-kidney transplantation: results from the KNOW-KT

Abstract Background and Aims Serum activin A inhibits muscle growth, promotes apoptosis, and impairs heart function. However, the role of serum activin remains unclear in kidney transplant patients, where cardiovascular complications are a significant cause of morbidity and mortality. In this multicenter, observational cohort study, we investigated a potential association of pre-transplant serum activin levels with the left atrial (LA) diameter, an indicator of diastolic burden and a predictor of cardiovascular complications, to indirectly assess the impact of pre-transplant activin levels on heart function in kidney transplant patients. Method Overall, 602 kidney transplant patients from KNOW-KT (Korean cohort study for outcome in patients with kidney transplantation) were analyzed. Activin levels were measured at baseline immediately before kidney transplantation (KT). The primary outcome was the LA diameter that was measured by transthoracic echocardiography at 5 years after KT. Results The mean age of study population was 45.4 years and 221 (46.7%) patients were men. Pre-transplant serum activin levels were 718.4 ± 363.2 (mean ± standard deviation). When activin levels were divided into categorical variables according to the median value, the ejection fraction of LV showed a lower tendency in the high-activin group (64.3 ± 7.0) compared to the low-activin group (65.3 ± 6.2); however, there was no statistical significance (P=0.069). LV diastolic dimension was significantly higher in the high-activin group (47.3 ± 5.3) compared to the low-activin group (46.3 ± 5.5) (P=0.021). Notably, the post-transplant LA diameter was 37.0 ± 7.0 mm in the low-activin group and 39.1 ± 6.5 mm in the high-activin group, showing a significant difference (P&amp;lt;0.001). The multivariate linear regression coefficient for association between activin groups and LA diameter was 1.08 (95% confidence interval [CI], 0.67-2.10, P=0.037). In an additional logistic regression analysis of LA diameter groups, the high activin group was significantly associated with the high LA diameters compared to the low-activin group in multivariate analysis (adjusted odds ratio [OR], 2.04; 95% CI, 1.34-3.09, P=0.001). When activin levels were used as a continuous variable, adjusted ORs of activin for high LA diameters were 1.29 (95% CI, 1.04-1.60, P=0.018). Conclusion Pre-transplant serum activin levels were independently associated with a higher post-transplant LA diameter, suggesting that activin may negatively affect heart functions in kidney transplant patients. Therefore, activin may be a potential prognostic and therapeutic target in kidney transplant patients.

Activin A: a marker of mineral bone disorder in children with chronic kidney disease?

Activin A has been shown to enhance osteoclast activity and its inhibition results in bone growth. The potential role of activin A as a marker of chronic kidney disease-mineral bone disease(CKD-MBD) and its relationship with other markers has not been studied in children with CKD. A cross sectional study was conducted among 40 children aged 2 to 18years with CKD (Stage 2 to 5; 10 in each stage) and 40 matched controls. Activin A, cathepsin K, FGF-23, PTH, serum calcium, phosphorous and alkaline phosphatase in both groups were measured and compared. The correlation of activin A and markers of CKD-MBD was studied. A p value of < 0.05 was considered significant. The mean age of children with CKD was 9.30 ± 3.64years. Mean levels of activin A in cases were 485.55pg/ml compared to 76.19pg/ml in controls (p < 0.001). FGF-23 levels in cases were 133.18pg/ml while in controls it was 6.93pg/ml (p < 0.001). Mean levels of cathepsin K were also significantly higher in cases as compared to controls. There was a progressive increase in activin A and cathepsin K levels with increasing stage of CKD. Activin A had a significant positive correlation with serum creatinine (r = 0.51; p < 0.001). Activin A levels progressively rise with advancing CKD stage. These findings suggest that activin A can be a potential early marker of CKD-MBD in children.

Increase in activin A may counteract decline in synaptic plasticity with age.

Activin A, a member of the transforming growth factor β (TGF-β) family, is widely recognized for its neurotrophic and neuroprotective function in the developing and injured brain, respectively. Moreover, in the healthy adult brain, activin A has been shown to tune signal processing at excitatory synapses in a fashion that improves cognitive performance. Because its level in human cerebrospinal fluid rises with age, we wondered whether activin A has a role in mitigating the gradual cognitive decline that healthy individuals experience in late-life. To interrogate the role of activin A in synaptic plasticity in the aging brain, we used an established transgenic mouse line, in which expression of a dominant-negative mutant of activin receptor IB (dnActRIB) serves to disrupt activin receptor signaling in a forebrain-specific fashion. In brain slices of young adult dnActRIB mice (2-4 months old), the NMDA receptor-dependent and -independent forms of long-term potentiation (LTP) at the Schaffer collateral-CA1 pyramidal cell synapse of the hippocampus were equally impaired relative to the extent of LTP measured in the wild-type preparation. Unexpectedly, the difference between the genotypes disappeared when the two forms of LTP were re-examined in slices from middle-aged mice (13-16 months old). Since the level of activin A and endogenous ActRIB both displayed a significant elevation in middle-aged hippocampus, we reasoned that with such a rise, the dominant-negative effect of the mutant receptors could be overcome. Substantiating this idea, we found that administration of recombinant activin A was indeed capable of restoring full-blown LTP in slices from young dnActRIB mice. Our data suggest that, beginning in the middle-aged brain, endogenous activin receptor signaling appears to become strengthened in an attempt to stave off cognitive decline. If further corroborated, this concept would also hold promise for new therapeutic venues to preserve cognitive functions in the aged brain.

O148: Unlocking Enhanced Immunity in Pancreatic Ductal Adenocarcinoma: Activins Interplay with CAF-Stroma Mechanisms

Abstract SMAD4 is a tumour suppressor gene that is mutated in up to 60% of pancreatic ductal adenocarcinoma (PDAC) tumours. Activins are members of the TGF-b signalling superfamily which signal through SMAD4 and are generally associated with an oncogenic process, with differing effects on tumour and stromal cells, such as cancer associated fibroblasts (CAFs). We sought to further elucidate the role of activin within PDAC and perturb activin signalling in vitro and in vivo. Analysis was performed of publicly available human datasets alongside human and murine single-cell RNA-sequencing datasets to study the effect of activin expression on survival and tumourigenesis. We developed anti-activin monoclonal antibodies to perturb activin signalling in PDAC mice, with deep analysis of tumour composition including immune cells and CAFs via a multitude of basic science techniques. We demonstrated that circulating activin levels are higher in PDAC patients than in healthy volunteers, whilst activin overexpression is associated with reduced overall survival in PDAC patients. Activin was shown to be predominantly expressed by contractile (collagen-depositing) CAFs, as opposed to inflammatory CAFs. Activin expression co-localises with fibroblasts, and anti-activin antibodies can reduce the collagen content of dense PDAC tumours. Additionally, anti-activin antibodies led to a statistically significant increase in CD4 and CD8 T-cell infiltration into murine PDAC tumours. We have shown that activin is overexpressed in PDAC, and high expression is associated with a more aggressive disease process. Anti-activin antibodies can alter the composition of desmoplastic PDAC tumours and increase the immune infiltrate of these typically “immune cold” tumours.

Myostatin and Activin A as Biomarkers of Sarcopenia in Inflammatory Bowel Disease Patients.

The prevalence of sarcopenia in inflammatory bowel disease patients has received increasing attention. The aim of this study is to assess the usefulness of determining levels of myostatin (MSTN) and activin A (Act A) as potential markers of disease activity and occurrence of sarcopenia in Crohn's disease and ulcerative colitis patients. The case-control study included 82 patients with Inflammatory Bowel Disease. The control group consisted of 25 healthy volunteers. The serum levels of myostatin and activin A were determined by the quantitative sandwich enzyme-linked immunosorbent assay. Sarcopenia was diagnosed based on the EWGSOP2 criteria. The study found lower levels of myostatin and activin A in the IBD patients. There were significantly lower levels of myostatin (80.6 pg/mL vs. 186.2 pg/mL; p = 0.0364) as well as activin A (32.1 pg/mL vs. 35.2 pg/mL; p = 0.0132) in the IBD patients with sarcopenia compared to those without sarcopenia. Positive correlations were found between MSTN levels and Muscle Mass Index (rho = 0.31; p < 0.005) and hand grip strength (rho = 0.34, p < 0.05) in the IBD patients. The determination of serum levels of MSTN and Act A may be useful in the early diagnosis of sarcopenia in IBD patients.

Prognostic value of activin A level in patients with advanced lung cancer and sarcopenia

The aim of this work is to determine the prognostic role of activin A in patients with advanced lung cancer and sarcopenia. Materials and methods. Forty patients with advanced pulmonary adenocarcinoma who received treatment in the medical center “ONCOLIFE” from 2020 to 2022 were studied. Computed tomography (CT) was used to measure skeletal muscle index at the third lumbar vertebra level expressed in cm2/m2. The criteria for sarcopenia using CT was &lt;55 cm2/m2 for men and &lt;39 cm2/m2 for women. Determination of activin A (DAC00B, RnD Systems) was carried out by the immunoenzymatic method based on using the “sandwich” variant of solid-phase immunoenzymatic analysis. Results. Overall survival in patients with a high level of activin A was worse than in patients with a low level (22.7 % vs. 64.2 % respectively; p = 0.017 by the log-rank test). Conclusions. A high level of activin A in the blood plasma can contribute to the worsening of the severity of sarcopenia, thereby affecting the survival of cancer patients. Understanding and finding new molecular targets underlying muscle atrophy will help identify new potential for treating patients with advanced cancer.

Activin A levels are raised during human tuberculosis and blockade of the activin signaling axis influences murine responses to M. tuberculosis infection.

Tuberculosis remains the leading cause of death by a bacterial pathogen. The etiologic agent of tuberculosis, Mycobacterium tuberculosis, can remain dormant in the infected host for years before causing disease. Significant effort has been made to identify biomarkers that can discriminate between latently infected and actively diseased individuals. We found that serum levels of the cytokine activin A were associated with increased lung pathology and could discriminate between active tuberculosis and tuberculin skin-test-positive healthy controls. Activin A signals through the ActRIIB receptor, which can be blocked by administration of the ligand trap ActRIIB-Fc, a soluble activin type IIB receptor fused to human IgG1 Fc. In a murine model of tuberculosis, we found that ActRIIB-Fc treatment reduced mycobacterial loads. Strikingly, ActRIIB-Fc treatment significantly increased the number of tissue-resident memory T cells. These results suggest a role for ActRIIB signaling pathways in host responses to Mycobacterium tuberculosis and activin A as a biomarker of ongoing disease.

Monocyte Chemoattractant Protein-1 (MCP-1), Activin-A and Clusterin in Children and Adolescents with Obesity or Type-1 Diabetes Mellitus.

We obtained serum samples from children and adolescents with a history of T1DM or obesity, in order to measure and compare MCP-1, activin-A, and clusterin concentrations. Forty-three subjects were included in each of the three groups (controls, T1DM, and obesity). MCP-1 values were positively correlated to BMI z-score. Activin-A was increased in children with obesity compared to the control group. A trend for higher values was detected in children with T1DM. MCP-1 and activin-A levels were positively correlated. Clusterin levels showed a trend towards lower values in children with T1DM or obesity compared to the control group and were negatively correlated to renal function. The inflammation markers MCP-1, activin-A, and clusterin are not altered in children with T1DM. Conversely, obesity in children is positively correlated to serum MCP-1 values and characterized by higher activin-A levels, which may reflect an already established systematic inflammation with obesity since childhood.

Targeting the activin receptor 1C on CD4+ T cells for cancer immunotherapy

ABSTRACT Activins, members of the TGF-beta superfamily, have been isolated and identified in the endocrine system, but have not been substantially investigated in the context of the immune system and endocrine-unrelated cancers. Here, we demonstrated that tumor-bearing mice had elevated systemic activin levels, which correlated directly with tumor burden. Likewise, cancer patients have elevated plasma activin levels compared to healthy controls. We observed that both tumor and immune cells could be sources of activins. Importantly, our in vitro studies suggest that activins promote differentiation of naïve CD4+ cells into Foxp3-expressing induced regulatory T cells (Tregs), particularly when TGF-beta was limited in the culture medium. Database and qRT-PCR analysis of sorted major immune cell subsets in mice revealed that activin receptor 1c (ActRIC) was uniquely expressed on Tregs and that both ActRIC and ActRIIB (activin receptor 2b) were highly upregulated during iTreg differentiation. ActRIC-deficient naïve CD4+ cells were found to be defective in iTreg generation both in vitro and in vivo. Treg suppression assays were also performed, and ActRIC deficiency did not change the function or stability of iTregs. Mice lacking ActRIC or mice treated with monoclonal anti-ActRIC antibody were more resistant to tumor progression than wild-type controls. This phenotype was correlated with reduced expression of Foxp3 in CD4+ cells in the tumor microenvironment. In light of the information presented above, blocking activin-ActRIC signaling is a promising and disease-specific strategy to impede the accumulation of immunosuppressive iTregs in cancer. Therefore, it is a potential candidate for cancer immunotherapy.

Correlation of serum VEGF-C, ANGPTL4, and activin A levels with frailty

BackgroundSecretory factors linked to lymphogenesis, such as vascular endothelial growth factor C (VEGF-C), angiopoietin like protein 4 (ANGPTL4), and activin A (ACV-A), have been recognized as potential markers of chronic inflammatory status and age-related diseases. Furthermore, these factors may also be linked to frailty. The primary objective of this study was to examine the serum VEGF-C, ANGPTL4, and ACV-A levels in young individuals, healthy older individuals, and older individuals with pre-frailty and frailty, and to determine their association with pro-inflammatory factor levels. MethodsWe conducted an observational study, enrolling a total of 210 older individuals and 20 young healthy volunteers. Participants were divided into four groups based on the Freid frailty phenotype: healthy young group, older patients without frailty group, pre-frail older group, and frail older group. Plasma and peripheral blood mononuclear cells (PBMCs) were collected from all four groups. ELISA was used to measure the serum levels of VEGF-C, ANGPTL4, ACV-A, and pro-inflammatory cytokines, while RT-qPCR was used to measure the transcription level of VEGF-C, ANGPTL4 and ACV-A in PBMCs. ResultsIn comparison to healthy young individuals and older participants without frailty, older participants with frailty exhibited lower renal function, higher serum levels and transcription levels of VEGF-C, ANGPTL4, ACV-A, and elevated levels of pro-inflammatory cytokines (CRP, IL-1β, and TNF-α). Multiple linear regression analysis revealed that serum levels of VEGF-C, ANGPTL4, and ACV-A were positively correlated with the frailty index, independent of age, eGFR, and comorbidities. Furthermore, the receiver operating characteristic (ROC) curve analysis demonstrated that serum levels of VEGF-C, ANGPTL4, and ACV-A have great accuracy in predicting frailty. ConclusionElevated serum levels of VEGF-C, ANGPTL4, and ACV-A are associated with frailty status.

Association of Serum Activin Levels with Allograft Outcomes in Patients with Kidney Transplant: Results from the KNOW-KT.

Serum activin A has been reported to contribute to vascular calcification and kidney fibrosis in chronic kidney disease. We aimed to investigate whether higher serum activin levels were associated with poor allograft outcomes in patients with kidney transplantation (KT). A total of 860 KT patients from KNOW-KT (Korean Cohort Study for Outcome in Patients with Kidney Transplantation) were analyzed. We measured serum activin levels pre-KT and 1 year after KT. The primary outcome was the composite of a ≥50% decline in estimated glomerular filtration rate and graft failure. Multivariable cause-specific hazard model was used to analyze association of 1-year activin levels with the primary outcome. The secondary outcome was coronary artery calcification score (CACS) at 5 years after KT. During the median follow-up of 6.7 years, the primary outcome occurred in 109 (12.7%) patients. The serum activin levels at 1 year were significantly lower than those at pre-KT (488.2 ± 247.3 vs. 704.0 ± 349.6). When patients were grouped based on the median activin level at 1 year, the high-activin group had a 1.91-fold higher risk (95% CI, 1.25-2.91) for the primary outcome compared to the low-activin group. A one-standard deviation increase in activin levels as a continuous variable was associated with a 1.36-fold higher risk (95% CI, 1.16-1.60) for the primary outcome. Moreover, high activin levels were significantly associated with 1.56-fold higher CACS (95% CI, 1.12-2.18). Post-transplant activin levels were independently associated with allograft functions as well as coronary artery calcification in KT patients.

Development of KER-012, a modified ActRIIB ligand trap, for the treatment of pulmonary arterial hypertension

Abstract Background Pulmonary Arterial Hypertension (PAH) is a debilitating disorder characterized by elevated pulmonary vascular resistance (PVR) due to severe constriction obliteration of pulmonary vessels (Tielemans 2019). The pathology of PAH is driven by endothelial dysfunction and vascular remodeling that leads to increased wall thickening and resistance to blood flow. Dysregulated TGF-β, specifically SMAD signaling, is a key molecular defect in proliferative thickening of pulmonary arterioles in PAH leading to increased arterial pressure and compensatory right ventricular hypertrophy, ultimately resulting in decompensated right heart failure. Increased levels of activin A, a TGF-β superfamily ligand, have been found in PAH patients, and in the lungs of hypoxia-induced pulmonary hypertensive mice (Yndestad 2009). KER-012 is an investigational modified ActRIIB ligand trap designed to bind and inhibit activin A, activin B, GDF8 and GDF11 to maximally inhibit SMAD2/3 (pro proliferative), while permitting SMAD1/5/9 (anti-proliferative) signaling. This profile is expected to rebalance defective SMAD signaling in PAH and potentially delay or reverse disease progression. Aim To evaluate safety and tolerability of KER-012 in healthy post-menopausal women (PMW) and present the planned design of a Phase 2 trial in participants with PAH. Methods A two-part Phase 1 study has been conducted with KER-012 in healthy PMW. Participants received either placebo or a single dose of KER-012 ranging between 0.75 and 5.0 mg/kg in Part 1 or multiple doses between 0.75 and 4.5 mg/kg in Part 2 subcutaneously once every 4 weeks over a 12-week period. Safety, PK and biomarkers of activin target engagement were assessed. Results KER-012 was generally well tolerated at dose levels up to 5 mg/kg as a single dose and at dose levels up to 4.5 mg/kg administered Q4W for a total of 3 doses (Table 1). Maximal target engagement of KER-012, as demonstrated by changes in biomarkers of activin inhibition, namely follicle stimulating hormone (FSH) and bone specific alkaline phosphatase (BSAP), was observed in this study. As previous studies with activin receptor type II ligand traps have shown a potentially dose-limiting increase in erythropoiesis, changes in red blood cells (RBC) were closely monitored in this study. KER-012 did not elicit any changes in hemoglobin or RBC count in the Phase 1 study (Figure 1). Summary KER-012 was generally well tolerated in healthy participants. The observed biomarker changes are consistent with inhibition of activins, suggestive of a balance shift in favor of signaling via the anti-proliferative SMAD 1/5/9 pathway. Based on this mechanism, administration of KER-012 could potentially result in reverse vascular remodeling and clinical cardiopulmonary improvements in patients with PAH, without targeting erythropoietic pathways. Given this profile, KER-012 is being advanced for development in patients with PAH in an upcoming Ph2 clinical trial (Figure 2).

Correlation of progesterone and activin A with pregnancy outcome following IVF/ICSI cycle

The association between the two hormones (progesterone and Activin A) in infertile women on the day of ova pick up and their relationship with pregnancy status in assisted reproductive programs are both poorly understood. To determine the correlation of progesterone and activin A on the day of ova pick up with pregnancy status of women undergoing IVF/ICSI cycle .The study was conducted on 80 infertile couples. The serum at day of ova pick up was collected. Serum progesterone and activin A analysis were done for all samples for activin A. Out of eighty infertile females twenty-five became pregnant (Pregnancy rate = 31%). Serum progesterone levels at days of oocytes pick up was significantly higher in pregnant females than nonpregnant (9.22 ± 0.54 vs. 4.47 ± 0.44; p &lt; 0.001). There was a significantly higher serum activin levels at day of oocytes pick up in pregnant women compared to non-pregnant (2.19 ± 0.04 vs. 1.52 ± 0.04; p &lt; 0.001). The cutoff value of serum progesterone at day of oocytes picks up was &gt; 7.5 ng/ml and the cut-off value of serum activin A at day of oocytes pick up was &gt; 1.85 ng/ml .Pregnant women had higher levels of the hormone progesterone and Activin A than non-pregnant women, which is significantly correlated. This result can be utilized to predicate the pregnancy status early in IVF Centers.