SD 093 / J&J - LARVOL DELTA

[VIRTUAL] THE ROLE OF X-LINKED INHIBITOR OF APOPTOSIS PROTEIN (XIAP) IN SYSTEMIC SCLEROSIS (EULAR 2020) - "TGFβ induces the expression of XIAP in vitro and in vivo and treatment with the TGFβ1 receptor antagonist SD208 reverses the TGFβ induced expression of XIAP...In vivo, inhibition of XIAP reduced skin fibrosis in the models of bleomycin induced skin fibrosis and in TopoI-induced skin and lung fibrosis as demonstrated by analysis of dermal thickening, dermal hydroxyproline content and by analysis of myofibroblast differentiation... XIAP is upregulated in SSc fibroblasts and murine SSc models in a TGFβ-dependent manner and promotes fibroblast activation by fostering canonical WNT signaling. Our data suggest that XIAP mediates an amplification loop between TGFβ and WNT/β-catenin signaling. Inhibition of XIAP may thus be a novel approach to target aberrant WNT/β-catenin signaling in fibrotic diseases."

Fibrosis • Graft versus Host Disease • Immunology • Scleroderma • Systemic Sclerosis • CTNNB1 • TOP1

Myofibroblast modulation of cardiac myocyte structure and function. (PubMed, Sci Rep) - "Fbs were treated to maintain an undifferentiated state (SD-208) or to attain full differentiation to MyoFb (TGF-β1). MyoFbs, but not Fbs, are likely to electrically connect to CMs and thereby modulate the CM membrane potential. These data provide further support for an active role of MyoFbs in the arrhythmogenic substrate after cardiac remodelling."

Journal • Cardiovascular • Fibrosis • Immunology • Myocardial Infarction

Willingness-to-Pay and Benefit-Cost Analysis of IPL for Rosacea Treatment: A Cross-Sectional Study in China. (PubMed, Patient Prefer Adherence) - "The average cost of a single IPL treatment for rosacea was USD 208.04 in Changsha, China. IPL is an acceptable treatment for rosacea with moderate to severe erythema. For patients with relatively high income or severely impaired quality of life, IPL is an economically feasible therapy and deserves to be recommended."

HEOR • Journal • Observational data • Dermatology • Rosacea

Structure-Based Virtual Screening, Molecular Dynamics and Binding Free Energy Calculations of Hit Candidates as ALK-5 Inhibitors. (PubMed, Molecules) - "ALK-5 inhibitors, such as SB505154, GW6604, SD208, and LY2157299, have recently been reported to inhibit ALK-5 autophosphorylation and induce the transcription of matrix genes. From a lead-like subset of purchasable compounds, five molecules were identified as putative ALK-5 inhibitors. In addition, molecular dynamics and binding free energy calculations combined with pharmacokinetics and toxicity profiling demonstrated the suitability of these compounds to be further investigated as novel ALK-5 inhibitors."

Journal • Cervical Cancer • Gastrointestinal Cancer • Gynecologic Cancers • Hepatocellular Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

TGF-β1 sustains germ cell cyst reservoir via restraining follicle formation in the chicken. (PubMed, Cell Biol Int) - "However, the negative effect of TGF-β1 on early ovary development was rescued by treatment with a TGF-βR1 inhibitor SD208, resulting in increased expresion of steroidogenic enzymes and cell cycle-regulating proteins. In conclusion, TGF-β1 could maintain the germ cell reservior by restraining follicle activation involving reduced cell proliferation and steroidogenic enzymes gene expression at the early stage of ovarian development."

Journal

TGFβ inhibition stimulates collagen maturation to enhance bone repair and fracture resistance in a murine myeloma model. (PubMed, J Bone Miner Res) - "Using in vivo μCT we show substantial and rapid bone lesion repair (and prevention) driven by SD-208 (TGFβ receptor I kinase inhibitor) and chemotherapy (bortezomib and lenalidomide) in mice with human U266-GFP-luc myeloma. We also discovered that SD-208 promoted osteoblastic differentiation (and overcame the TGF?-induced block in osteoblastogenesis) in myeloma patient bone marrow stromal cells in vitro, comparable to normal donors. The improved bone quality and fracture-resistance with SD-208 provides incentive for clinical translation to improve myeloma patient quality of life by reducing fracture risk and fatality."

Journal • Preclinical • Hematological Malignancies • Multiple Myeloma • Musculoskeletal Diseases • Oncology • Orthopedics

TGF-β1 enhances the activity of acid-sensing ion channel in rat primary sensory neurons. (PubMed, J Neurosci Res) - "This sustained enhancement by TGF-β1 could be blocked by extracellular treatment of selective TGF-β receptor I antagonist SD-208, and abolished by blockade of intracellular several non-Smad-signaling pathways. Moreover, peripheral pre-treatment with TGF-β1 dose-dependently exacerbated nociceptive behaviors evoked by intraplantar injection of acetic acid through TGF-β receptor I in rats. These results suggested that TGF-β1 potentiated ASIC-mediated electrophysiological activity and nociceptive behaviors, which revealed a novel mechanism underlying TGF-β1 implicated in peripheral pain signaling by sensitizing ASICs."

Journal • Preclinical • Pain

Inhibition of Migration, Invasion and Drug Resistance of Pancreatic Adenocarcinoma Cells - Role of Snail, Slug and Twist and Small Molecule Inhibitors. (PubMed, Onco Targets Ther) - "Additionally, the contribution of small molecule inhibitors of EMT (SD-208 and CX4945) to the effects of gene silencing was evaluated. Both small molecule inhibitors enhanced the outcomes of EMT-ATF silencing. Overall it was found that EMT-ATF silencing, either by EMT-ATF silencing or with the enhancement by small molecules, is a good candidate to treat pancreatic cancer since it simultaneously minimizes metastasis, stem cell properties, and drug resistance."

Journal • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

TGFβ signaling underlies hematopoietic dysfunction and bone marrow failure in Shwachman-Diamond Syndrome. (PubMed, J Clin Invest) - "TGFβ inhibitors (AVID200 and SD208) increased hematopoietic colony formation of SDS patient BM. Finally, TGFβ3 and other TGFβ pathway members were elevated in SDS patient blood plasma. These data establish the TGFβ pathway as a novel candidate biomarker and therapeutic target in SDS and translate insights from single cell biology into a potential therapy."

Biomarker • Journal • Aplastic Anemia

Activated Cardiac Fibroblasts Control Contraction of Human Fibrotic Cardiac Microtissues by a β-Adrenoreceptor-Dependent Mechanism. (PubMed, Cells) - "Fibrotic phenotype of cardiac microtissues was inhibited by treatment with TGF-β-receptor type 1 inhibitor SD208 in a dose-dependent manner...However, in the absence of exogenous agonists, the β-adrenoreceptor blocker nadolol decreased beating rate of fibrotic cardiac microtissues by prolonging relaxation time. Thus, our data suggest that in fibrosis, activated cardiac fibroblasts could promote cardiac contraction rate by a direct stimulation of β-adrenoreceptor signalling. In conclusion, a model of fibrotic cardiac microtissues can be used as a high-throughput model for drug testing and to study cellular and molecular mechanisms of cardiac fibrosis."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology

Induction of SPARC on Oxidative Stress, Inflammatory Phenotype Transformation, and Apoptosis of Human Brain Smooth Muscle Cells Via TGF-β1-NOX4 Pathway. (PubMed, J Mol Neurosci) - "The mechanism was explored by intervention with reactive oxygen scavengers N-acetylcysteine (NAC), TGF-β1 inhibitor (SD-208), and siRNA knockout. The results showed that SPARC upregulated the expression of NOX4 through the TGF-β1-dependent signaling pathway, leading to oxidative stress and pro-inflammatory matrix behavior and apoptosis in HBVSMCs. These findings demonstrated that SPARC may promote the progression of IAs."

Journal • Immunology

TGFβRI antagonist inhibits HIV-1 Nef-induced CC chemokine family ligand 2 (CCL2) in the brain and prevents spatial learning impairment. (PubMed, J Neuroinflammation) - "Consistent with our previous findings, rats treated with Nef showed deficits in spatial learning and memory in the novel location recognition task. In contrast, rats treated with Nef + SD208 showed better spatial learning suggesting that Nef disrupts memory formation in a TGFβ-1-dependent manner. The TGFβRI inhibitor further reduced the induction of inflammation by Nef which was concomitant with decreased TGFβ signaling. Our findings suggest that TGFβ-1 signaling is an intriguing target to reduce neuroHIV."

Journal • Alzheimer's Disease • CNS Disorders • Gene Therapies • Immunology • Infectious Disease • Solid Tumor

Effect of a monocyte chemoattractant protein-1 synthesis inhibitor on fibroblasts from patients with carpal tunnel syndrome. (PubMed, J Orthop Sci) - "These results suggest that Bindarit in combination with SD208 may be beneficial as medical therapy for the SSCT fibrosis associated with CTS."

Clinical • Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • Scleroderma • Systemic Sclerosis • CCL2 • CD61 • CTGF • EDN1

Inhibition of TGF-β-receptor signaling augments the antitumor function of ROR1-specific CAR T-cells against triple-negative breast cancer. (PubMed, J Immunother Cancer) - "We demonstrate the TGF-β suppresses the antitumor function of ROR1-CAR T-cells against TNBC in preclinical models. Our study supports the continued preclinical development and the clinical evaluation of combination treatments that shield CAR T-cells from TGF-β, as exemplified by the TGF-β-receptor kinase inhibitor SD-208 in this study."

CAR T-Cell Therapy • IO Biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • PD-1 • SMAD4

Dihydroartemisinin inhibits the tumorigenesis and metastasis of breast cancer via downregulating CIZ1 expression associated with TGF-β1 signaling. (PubMed, Life Sci) - "DHA treatment inhibits the proliferation and metastasis of breast cancer, through suppressing TGF-β1/Smad signaling and CIZ1, suggesting the promising potential of DHA as a well-tolerated antitumor TGF-β1 pathway inhibitor."

Journal

Ultrasound melted polymer sleeve for improved primary pedicle screw anchorage: A novel augmentation technique. (PubMed, Clin Biomech (Bristol, Avon)) - "Our findings indicate that polymer-reinforcement significantly enhances pedicle screw anchorage in low quality bone and that its effect is similar in size than that of cement augmentation."

Journal

ALK5 is essential for tooth germ differentiation during tooth development. (PubMed, Biotech Histochem) - "Human recombinant TGFβ3 protein or an ALK5 inhibitor (SD208) was added to the cells. TAK1, P-TAK1, p38 and P-p38 showed greater expression and SMAD4 showed less expression when ALK5 was inhibited. Our findings contribute to understanding the role of TGFβ signaling for the differentiation of mesenchymal stem cells derived from dental germ and suggest possible targets for optimizing the use of stem cells of dental origin for tissue regeneration."

Journal

Oncoplastic surgery and the influence of the surgical clip on breast, heart and lung volumes of patients submitted to boost during the planning of breast cancer radiotherapy after lumpectomy (SABCS 2019) - "The presence of the clip reduced significantly the irradiated boost volume. When controlled by oncoplasty, there was no difference between the two groups. For those who did not undergo oncoplastic surgery, the presence of the clip made it possible to reduce the irradiated volume that received 100% of the prescribed dose of the whole breast and the boost area, and the increased cardiac volume that received 40% of the prescribed dose during the radiotherapy boost planning deserves further analysis.Keywords: breast cancer, radiotherapy, boost, surgical clip tumor bed, oncoplastic techniques"

Clinical

Replication Stress Response and CDKN1A Engagement Constrain Fetal Hematopoietic Stem Cell Pool Size in Fanconi Anemia (ASH 2019) - "To test regulation of p21 in fetal HSC under RS, we first treated WT FL HSC with aphidicolin to experimentally simulate RS and found that SD208, a small molecule TGF-β-R1 inhibitor, completely rescued the p21 nuclear localization. Our experiments suggest a central and p53-independent role for p21 in fetal FA HSC regulation. Detailed knowledge of the physiological role of FA proteins in fetal phenotype HSC has the potential to lead to new therapies that delay or rescue hematopoietic failure in FA patients."

CDKN1A • FANCD2

TGF-β1 as a candidate molecule for the functional inhibition of healthy CD34 + hematopoietic stem and progenitor cells (HSPZ) in acute myeloid leukemia (AML) (DGHO 2019) - "Overall, these data indicate that leukemic blasts mediate direct suppressive effects on important functions of healthy CD34+ HSPC thereby contributing to hematopoietic insufficiency in AML and TGF-β1 may be a potential candidate molecule, which is at least in parts responsible for the observed effects."

Clinical

TGFβ1-mediated functional inhibition of mesenchymal stromal cells in myelodysplastic syndromes and acute myeloid leukemia. (PubMed, Haematologica) - "Blockade of TGFβ signalling by SD-208 also restored the osteogenic differentiation capacity of patient-derived stromal cells, thus confirming the role of TGFβ1 in the bone marrow microenvironment of patients with myelodysplastic syndromes and acute myeloid leukemia. Our findings establish TGFβ1 as a relevant trigger causing functional inhibition of MSC in myelodysplastic syndromes and acute myeloid leukemia and identify SD-208 as candidate to revert these effects."

Journal

INHIBITION OF NEMO-LIKE KINASE IMPROVES ERYTHROPOIESIS IN MODELS OF DIAMOND BLACKFAN ANEMIA (ASPHO 2019) - "The inhibitor screen identified SB431542 and SD208, two known TGF-beta inhibitors, that increased erythroid expansion in murine (3.1- and 5.4-fold) and human (3.2- and 6.3-fold) DBA models with no effect on normal erythropoiesis. Aberrant NLK hyperactivation underlies the erythrocyte expansion defect seen in DBA, and NLK inhibition helps restore normal erythropoiesis. NLK holds promise as a potential treatment target that avoids the side effects seen with current therapies."