- |||||||||| BMP9 Regulates Endothelial Expression of Mediators of Pulmonary Vascular Remodeling (San Diego Convention Center, Room 29A-D (Upper Level)) - Feb 20, 2024 - Abstract #ATS2024ATS_7996;
In contrast to broad strategies that inhibit BMP9 and BMP10 associated with HHT mimicry in clinical trials and rodent PH models, treatment with anti-BMP9 was well-tolerated. Selective antagonism of BMP9 represents a potential therapeutic strategy for human PAH.
- |||||||||| Journal: Activin A induces apoptosis of human lung adenocarcinoma A549 cells through endoplasmic reticulum stress pathway. (Pubmed Central) - Dec 26, 2023
Additionally, activin A increased intracellular calcium flux in A549 cells, and the calcium ion chelator BAPTA acetoxymethyl ester (BAPTA?AM) inhibited activin A?induced A549 cell apoptosis, whereas the calcium agonist ionomycin significantly increased apoptosis of A549 cells induced by activin A. These findings indicated that the activation of the ER stress pathway resulting in apoptosis of A549 cells triggered by activin A is facilitated by the ActRIIA?ERK1/2 signaling and calcium signaling. The present findings suggest that the agonists of ERK and calcium signaling exhibit promising clinical therapeutic potential for the induction of apoptosis in lung adenocarcinoma.
- |||||||||| Review, Journal: Reconstruction of the TGF-? signaling pathway of Fasciola gigantica. (Pubmed Central) - Dec 18, 2023
signaling pathway in F. gigantica. In addition, this study helps to illustrate the complex mechanisms involved in developmental processes and F. gigantica - host interaction and paves the way for further characterization of the signaling pathway in trematodes.
- |||||||||| Journal: Genetic variants in myostatin and its receptors promote elite athlete status. (Pubmed Central) - Dec 17, 2023
We showed that the specific genotypes of the MSTN rs11333758 and ACVR2A rs3764955, either individually or in gene?gene combination, are significantly associated with athletes' competition level in the Polish population, especially in the mixed-sports athlete group. Thus, although further research is required, these polymorphisms, alone or in combination with other polymorphisms, are among the numerous candidates that could explain individual variations in muscle phenotypes.
- |||||||||| Characterization of the cachexia pathway in pancreatic ductal adenocarcinoma. (Poster Bd # N8) - Dec 6, 2023 - Abstract #ASCOGI2024ASCO_GI_613;
Our data show that increased activation of the myostatin-activin pathway is associated with immune mediators, lipid metabolism, and inflammatory gene activation. Activators and repressors are significant predictors of survival in PDAC, suggesting possible novel therapeutic targets.
- |||||||||| Journal: Loss of chromosome 9p21 is associated with a poor prognosis in adenosquamous carcinoma of the pancreas. (Pubmed Central) - Nov 30, 2023
The mutation rates of ACVR2A (6.25% vs 0%), FANCA (6.25% vs 0%), RBM10 (6.25% vs 0%), and SPTA1 (8.33% vs 1.02%) were significantly higher in ASCP than in PDAC. In conclusion, we have comprehensively described the genomic landscape of the largest cohort of ASCP patients to date and highlight that 9p21 loss may be a promising prognostic biomarker for ASCP, which provides a molecular basis for prognosis prediction and new therapeutic strategies for ASCP.
- |||||||||| Journal: Comprehensive Analysis of the Transcriptome-Wide mA Methylome in Shaziling Pig Testicular Development. (Pubmed Central) - Nov 3, 2023
Furthermore, we proposed a novel mechanism of mA modification during testicular development: ALKBH5 regulated the RNA methylation level and gene expression of SOX9 mRNA. In addition to serving as a potential target for improving boar reproduction, our findings contributed to the further understanding of the regulation of mA modifications in male reproduction.
- |||||||||| Genome-Wide CRISPR/Cas9 Knock-out Screen Identifies Apoptosis-Relevant Genes in Multiple Myeloma (SDCC - Halls G-H) - Nov 3, 2023 - Abstract #ASH2023ASH_6111;
The screen confirmed the importance of the PI3K/AKT/mTOR pathway for positive apoptosis regulation and transcriptional factors affecting TP53 for negative apoptosis regulation. Hits from this screen can be promising targets for future therapies and precision medicine targeting the apoptotic machinery in multiple myeloma cells.
- |||||||||| sotatercept (MK-7962) / BMS, Merck (MSD)
Review, Journal: From bench to bedside: The promise of sotatercept in hematologic disorders. (Pubmed Central) - Aug 17, 2023
pathways in physiological and hematologic disorder contexts, outline the potential mechanism of sotatercept, and delve into its pharmacokinetics and clinical research advancements in various hematologic diseases. A particular emphasis is given to the relationship between sotatercept dosage and its efficacy or associated adverse reactions.
- |||||||||| Journal: FKBP12 inhibits hepcidin expression by modulating BMP receptors interaction and ligand responsiveness in hepatocytes. (Pubmed Central) - Jul 13, 2023
Interestingly, the activation state of ALK3 modulates its interaction with FKBP12, which may explain the cell-specific activity of FKBP12. Overall, our results identify the mechanism whereby FKBP12 regulates the BMP-SMAD pathway and hepcidin expression in hepatocytes, and suggest that FKBP12-ALK2 interaction is a potential pharmacologic target in disorders caused by defective BMP-SMAD signaling and characterized by low hepcidin and high BMP6 expression.
- |||||||||| sotatercept (MK-7962) / BMS, Merck (MSD)
Sotatercept for the treatment of PAH: an update (Coral 4+5) - Jun 17, 2023 - Abstract #ERS2023ERS_796;
Inhibition of these ligands by sotatercept is proposed to rebalance pulmonary vascular homeostasis toward growth-inhibiting and proapoptotic signaling. Exciting new data showed that sotatercept treatment lead to clinical benefit across multiple efficacy end points with a potential for modifying disease evolution.; Cell and molecular biology; Physiology
- |||||||||| pilocarpine / Generic mfg.
Seizure activity and hypoxia differentially regulate endogenous neurotrophic Activin A and Neuroglobin expression in the immature mouse brain (Foyer 3B, 3rd Floor) - May 29, 2023 - Abstract #EPNS2023EPNS_97;
We analyzed effects of acute pilocarpine-induced seizures in the brain of neonatal C57BL/6 wild-type mice (P10) on age- and region-specific mRNA (real-time RT-PCR) and protein expression (IHC) of Neuroglobin (Ngb), Activin A (AcvA) and its receptors (Activin A receptor type IB, ActRIB; Activin A receptor type IIA, ActRIIA; Activin A receptor type IIB, ActRIIB), after regeneration periods of 6-72 h. Additional, P7-mice were subjected to acute hypoxia (FiO2 8 % O2 for 6 h) using the established mouse model of acute neonatal hypoxic brain injury and the prolyl hydroxylase inhibitor (PHI) FG-4497 (60-100 mg/kg, i.p.) stabilizing cerebral accumulation of HIFs... Present results indicate the differential regulation of Neuroglobin and Activin A in relation to the time and type of injury and their role as potential biomarkers of excitotoxic and hypoxic injury of the developing brain.
- |||||||||| DISSECTING THE ROLE OF THE IMMUNOPHILIN FKBP12 IN HEPCIDIN REGULATION (Harmony 2) - May 12, 2023 - Abstract #EHA2023EHA_2454;
Decreasing the binding of FKBP12 to ALK2 could be a novel approach worth to be explored to increase, at least partially, hepcidin expression in hemochromatosis or in disorders with ineffective erythropoiesis, all conditions characterized by high BMP6 levels. Iron metabolism, Hepcidin
- |||||||||| Journal, BRCA Biomarker, IO biomarker: Differences in DNA damage repair gene mutations between left- and right-sided colorectal cancer. (Pubmed Central) - Apr 25, 2023
Here, we found that stage and grade were statistically significant independent prognostic factors in the left-sided CRC and the right-sided CRC, recommending treatment for these patients stratified by stage. For the future, utilizing DDR gene defects for expanding treatment options and improving prognosis is an issue worth exploring.
- |||||||||| bimagrumab (BYM338) / Novartis, MorphoSys, Versanis Bio
Optimized Weight Loss with Bimagrumab (Ballroom 6CF; [Board No. 370]) - Apr 10, 2023 - Abstract #ADA2023ADA_2695;
P2
Bimagrumab Tx results in decreased fat deposition in tissues and increased muscle mass despite minimal change in caloric intake, which could lead to durable, high quality wt loss. A study of bima in obesity without T2DM is ongoing (NCT05616013).
- |||||||||| HS135 / 35Pharma
HS135, a Novel Activin and GDF Trap, Is Efficacious in Models of Pulmonary Hypertension (PH) and Heart Failure (HF) (Walter E. Washington Convention Center, Area B, Hall C (Lower Level)) - Mar 25, 2023 - Abstract #ATS2023ATS_5746;
The best-in-class target engagement profile of HS135 translates into increased and differentiated efficacy improving the PH and HF phenotype in preclinical models. Collectively, these data support the development of HS135 as a novel agent in cardiometabolic and cardiopulmonary diseases including PAH and PH-associated with left heart disease.
- |||||||||| Genomic alterations associated with early-onset and late-onset colorectal cancer (Section 40; Poster Board #16) - Mar 14, 2023 - Abstract #AACR2023AACR_8161;
Patients with LOCRC were more likely to have pathogenic gene variants and mutations in established pathways of CRC carcinogenesis. Tumors in EOCRC cases harbored unique genomic alterations that varied between the TMB-low/MSS, TMB-H/MSI-H, and TMB-H/MSS subpopulations.
- |||||||||| sotatercept (MK-7962) / BMS, Merck (MSD)
Journal: Sotatercept analog improves cardiopulmonary remodeling and pulmonary hypertension in experimental left heart failure. (Pubmed Central) - Mar 14, 2023
Our results demonstrate that ActRIIA-Fc broadly corrects cardiopulmonary structure and function in experimental PH-LHD, including models of PH-HFrEF and PH-HFpEF, leading to alleviation of PH under diverse pathophysiological conditions. These findings highlight the important pathogenic contributions of activin-class ligands in multiple forms of experimental PH and support ongoing clinical evaluation of human ActRIIA-Fc (sotatercept) in patients with PH-HFpEF.
- |||||||||| Journal: GWAS of Reproductive Traits in Large White Pigs on Chip and Imputed Whole-Genome Sequencing Data. (Pubmed Central) - Nov 16, 2022
Finally, several genes were detected and regarded as potential candidate genes for each of the traits: for the TNB trait: NOTCH2, KLF3, PLXDC2, NDUFV1, TLR10, CDC14A, EPC2, ORC4, ACVR2A, and GSC; for the NSB trait: NUB1, TGFBR3, ZDHHC14, FGF14, BAIAP2L1, EVI5, TAF1B, and BCAR3; for the GL trait: PPP2R2B, AMBP, MALRD1, HOXA11, and BICC1. In conclusion, expanding the size of the reference population and finding an optimal imputation strategy to ensure that more loci are obtained for GWAS under high imputation accuracy will contribute to the identification of causal mutations in pig breeding.
- |||||||||| sotatercept (MK-7962) / BMS, Merck (MSD), Reblozyl (luspatercept-aamt) / BMS, Merck (MSD)
Journal: Detection of activin receptor type IIA and IIB-Fc fusion proteins by automated capillary immunoassay. (Pubmed Central) - Oct 7, 2022
The recent approval of Luspatercept for the treatment of anemia associated to transfusion-dependent MDS and Beta-thalassemia in afflicted patients means that it can now pose a real threat of being abuse in sport for its ability to stimulate erythropoiesis...The option to use different antibodies allows the possibility to use this method as an initial testing procedure as well as a confirmation procedure. Finally, results coming from an administration study confirm that the method is suitable for routine analysis.
- |||||||||| Journal: Investigation of cell signalings and therapeutic targets in PTPRK-RSPO3 fusion-positive colorectal cancer. (Pubmed Central) - Sep 29, 2022
Among these pathways, the most altered cancer genes (ALK, ACSL3, AXIN, MYC, TP53, GNAQ, ACVR2A, and FAS) specific for P:R fusion and involved in multiple cancer pathways were considered to have a key role in P:R fusion-positive CRC. Based on the drug-target network analysis, crizotinib, alectinib, lorlatinib, brigatinib, ceritinib, erdafitinib, infigratinib and pemigatinib were selected as putative therapeutic candidates, since they were already used in routine clinical practice in other cancer types and target genes of the drugs were involved in multiple cancer-pathways.
- |||||||||| Targeting TGF² pathway dependencies in group 3 medulloblastoma (Ballroom A) - Sep 28, 2022 - Abstract #SNO2022SNO_106;
We postulate that epigenetic remodeling via MYC and recruitment of other MYC-interacting cofactors culminates in transcriptional changes that lead to aggressive disease. Overall, our studies provide insights on identifying new therapeutic avenues for patients with MYC and TGFβ driven G3 MB.
- |||||||||| Journal, Tumor Mutational Burden, Microsatellite instability, MSi-H Biomarker, PD(L)-1 Biomarker, IO biomarker: Genomic landscape of microsatellite instability in Chinese tumors: a comparison of Chinese and TCGA cohorts. (Pubmed Central) - Aug 27, 2022
Mutations in ACVR2A (73% vs 28%, p <0.01) and MMR-related genes (51.4% vs 21.3%, p <0.01) were significantly higher in the Chinese population. Thus, our study suggests the fraction of MSI-H attributable to MMR inactivation mutations were lower in European than in Chinese patients, while the proportion of MSI-H due to other events may be higher.
- |||||||||| Journal: De novo mutations in the BMP signaling pathway in lambdoid craniosynostosis. (Pubmed Central) - Aug 24, 2022
Single cell RNA sequencing analysis of the mouse lambdoid suture identified enrichment of mutations in osteoblast precursors (P = 1.6 × 10), implicating perturbations in the balance between proliferation and differentiation of osteoprogenitor cells in lambdoid CS. The results contribute to the growing knowledge of the genetics of CS, have implications for genetic counseling, and further elucidate the molecular etiology of premature suture fusion.
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