Publications by authors named "R M De La Rue"
The Bi-Steric Inhibitor RMC-5552 Reduces mTORC1 Signaling and Growth in Lymphangioleiomyomatosis.
Am J Respir Cell Mol Biol
November 2024
Article Synopsis
- * The only approved treatment, Rapamycin, offers limited benefits as lung function declines after stopping the drug, with LAM cancer stem-like cells displaying high levels of cancer-promoting protein synthesis.
- * A new compound, RMC-5552, shows promise by effectively inhibiting LAM-associated cell growth and providing longer-lasting effects than Rapamycin, suggesting it could be a potential therapy for LAM and other conditions with mTORC1 hyperactivity.
Article Synopsis
- Lymphangioleiomyomatosis (LAM) is a rare genetic lung disease, and the current treatment with Rapamycin only slows its progression, emphasizing the need for new therapeutic options.
- Nitazoxanide (NTZ), a safe and approved drug for treating diarrhea, shows promise due to its mTORC1 inhibitory effect and potential for repurposing in LAM treatment.
- In experiments, NTZ effectively reduced cell growth at specific doses but did not inhibit mTORC1 as expected; it lowered pAkt levels, and while it showed some benefits in reducing lung lesions in mouse models, results need further analysis.
Recurrent infections are a hallmark of STAT3 dominant-negative hyper-IgE syndrome (STAT3 HIES), a rare immunodeficiency syndrome previously known as Jobs syndrome, along with elevated IgE levels and impaired neutrophil function. We have been developing nanoparticles with neutrophil trophism that home to the sites of infection via these first-responder leukocytes, named neutrophil-avid nanocarriers (NANs). Here, we demonstrate that human neutrophils can phagocytose nanogels (NGs), a type of NAN, with enhanced uptake after particle serum opsonization, comparing neutrophils from healthy individuals to those with STAT3 HIES, where both groups exhibit NG uptake; however, the patient group showed reduced phagocytosis efficiency with serum-opsonized NANs.
View Article and Find Full Text PDFLymphangioleiomyomatosis (LAM) is a progressive cystic lung disease caused by tuberous sclerosis complex 1/2 (TSC1/2) gene mutations in pulmonary mesenchymal cells, resulting in activation of the mechanistic target of rapamycin complex 1 (mTORC1). A subset of patients with LAM develop pulmonary vascular remodeling and pulmonary hypertension. Little, however, is known regarding how LAM cells communicate with endothelial cells (ECs) to trigger vascular remodeling.
View Article and Find Full Text PDFRecent studies have demonstrated that regulatory T cells (T) develop in the thymus via two pathways involving distinct T progenitors (TP): CD25FOXP3 (CD25 TP) and CD25FOXP3 (FOXP3 TP) T progenitors. To examine this process in more detail, we carried out single-cell RNA sequencing (scRNA-Seq) and TCR-Seq on sorted murine CD4CD8 double-positive (DP) thymocytes, CD4 single-positive (CD4SP) thymocytes, CD25FOXP3CD73 TP, CD25FOXP3CD73 TP, newly generated mature CD25FOXP3CD73 T, and FOXP3CD73 recirculating/long-term resident T (RT-T). Sorted populations were individually hashtagged and then combined into one scRNA-Seq/TCR-Seq library before sequencing and subsequent analysis.
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