MS-275 (Entinostat) Promotes Radio-sensitivity in PAX3-FOXO1 Rhabdomyosarcoma cells

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. About 25% of RMS expresses fusion oncoproteins such as PAX3/PAX7‐FOXO1 (fusion‐positive, FP) while fusion‐negative (FN)‐RMS harbors RAS mutations. Radiotherapy (RT) plays a crucial role in local control but metastatic RMS is often radio‐resistant. HDAC inhibitors (HDACi) radio‐sensitize different cancer cells types. Thus, we evaluated MS−275 (Entinostat), a Class I and IV HDACi, in combination with RT on RMS cells in vitro and in vivo. MS−275 reversibly hampered cell survival in vitro in FN‐RMS RD (RASmut) and irreversibly in FP‐RMS RH30 cell lines down‐regulating cyclin A, B, and D1, up‐regulating p21 and p27 and reducing ERKs activity, and c‐Myc expression in RD and PI3K/Akt/mTOR activity and N‐Myc expression in RH30 cells. Further, MS−275 and RT combination reduced colony formation ability of RH30 cells. In both cell lines, co‐treatment increased DNA damage repair inhibition and reactive oxygen species formation, down‐regulated NRF2, SOD, CAT and GPx4 anti‐oxidant genes and improved RT ability to induce G2 growth arrest. MS−275 inhibited in vivo growth of RH30 cells and completely prevented the growth of RT‐unresponsive RH30 xenografts when combined with radiation. Thus, MS−275 could be considered as a radio‐sensitizing agent for the treatment of intrinsically radio‐resistant PAX3‐FOXO1 RMS

Signaling Crosstalks Drive Generation and Regeneration of the Thymus

https://www.frontiersin.org/article/10.3389/fimmu.2022.92030

Eltrombopag in paediatric immune thrombocytopenia: Iron metabolism modulation in mesenchymal stromal cells

Immune thrombocytopenia (ITP) is an autoimmune disease caused by platelet destruction mediated by auto-antibody production. It is characterized by a compromised immune system and alteration of the inflammatory response. Mesenchymal stromal cells (MSCs) play an important role in modulating immune and inflammatory processes, exerting immune-suppressing and anti-inflammatory properties. In ITP-MSCs the activity and survival are strongly impaired. Eltrombopag (ELT) is a thrombopoietin receptor agonist approved in chronic ITP for stimulating platelet production. It has immunomodulating properties by stimulating T and B regulatory cell activity and by promoting a macrophage switch from the pro-inflammatory to the anti-inflammatory phenotype. ELT also exhibits iron-chelating properties. Iron is a crucial element involved in several physiologic processes, but its intracellular accumulation determines cell damages. Therefore, for the first time we analysed the effect of ELT on ITP-MSCs demonstrating its ability to restore survival and activity of MSCs directly and to promote their survival and proliferation indirectly, by iron metabolism modulation

SARS-CoV-2 infection of thymus induces loss of function that correlates with disease severity

Background: Lymphopenia, particularly when restricted to the T-cell compartment, has been described as one of the major clinical hallmarks in patients with coronavirus disease 2019 (COVID-19) and proposed as an indicator of disease severity. Although several mechanisms fostering COVID-19-related lymphopenia have been described, including cell apoptosis and tissue homing, the underlying causes of the decline in T-cell count and function are still not completely understood. Objective: Given that viral infections can directly target thymic microenvironment and impair the process of T-cell generation, we sought to investigate the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on thymic function. Methods: We performed molecular quantification of T-cell receptor excision circles and κ-deleting recombination excision circles to assess, respectively, T- and B-cell neogenesis in SARS-CoV-2-infected patients. We developed a system for in vitro culture of primary human thymic epithelial cells (TECs) to mechanistically investigate the impact of SARS-CoV-2 on TEC function. Results: We showed that patients with COVID-19 had reduced thymic function that was inversely associated with the severity of the disease. We found that angiotensin-converting enzyme 2, through which SARS-CoV-2 enters the host cells, was expressed by thymic epithelium, and in particular by medullary TECs. We also demonstrated that SARS-CoV-2 can target TECs and downregulate critical genes and pathways associated with epithelial cell adhesion and survival. Conclusions: Our data demonstrate that the human thymus is a target of SARS-CoV-2 and thymic function is altered following infection. These findings expand our current knowledge of the effects of SARS-CoV-2 infection on T-cell homeostasis and suggest that monitoring thymic activity may be a useful marker to predict disease severity and progression