Biology subjects

Lee, L. H.

Publications and source records attributed to Lee, L. H..

3 recordsLinked to original sources

bioRxiv2025

Sample-level modeling of single-cell data at scale with tinydenseR

Single-cell studies now routinely encompass hundreds of samples and millions of cells, offering unprecedented opportunities to link sample-level phenotypes with cellular and molecular states. However, current workflows often depend on cell-level inference and rigid clustering, which can distort significance and obscure subtle, continuous variation, in particular for complex experimental designs. Here, we present tinydenseR, a clustering-independent framework that enables robust, scalable, and statistically sensitive detection of differential cell state density, outperforming existing workflows in speed and memory usage. Technology-agnostic at its core, tinydenseR works seamlessly on scRNA-seq, flow, mass and spectral cytometry. Across synthetic benchmarks, a preclinical xenograft model, a publicly available COVID-19 study, two immuno-oncology trials and a multi-study atlas, tinydenseR uncovers disease and treatment history-associated effects, including subtle cell state heterogeneity, while embedding samples in a quantitative manner. Designed to accelerate discovery in clinical, preclinical, and translational research, the open-source package is available at GitHub.com/Novartis/tinydenseR.

bioinformatics↗

bioRxiv2024

Pharmacodynamic evaluation of AUM001/tinodasertib, an oral inhibitor of mitogen-activated protein kinase (MAPK)-interacting protein kinase 1, 2 (MNK1/2) in preclinical models and tissues from a Phase 1 clinical study

Mitogen-activated protein kinase (MAPK) interacting kinase (MNK) inhibitors affect cap-dependent mRNA translation by blocking the phosphorylation of RNA-binding proteins such as the eukaryotic initiation factor 4E (eIF4E). Phosphorylation on serine (Ser) 209 of eIF4E causes hyperactivation and dysregulation of mRNA translation, which is a hallmark of numerous malignancies. AUM001/Tinodasertib (ETC-206) is a selective and potent oral kinase inhibitor of MNK1 and MNK2 (IC50 of 64 and 86 nM, respectively), inducing dose-dependent inhibition of eIF4E phosphorylation on Ser209 (p-eIF4E) with an IC50 of 0.8 {micro}M in K562-eIF4E cells. In mice, single oral doses of [~]12.5 mg/kg led to rapid (1-2 h post-dose) [~]70% inhibition of p-eIF4E in different normal or tumor tissues at a plasma concentration of 8.6 M. However, in peripheral blood mononuclear cells (PBMCs), obtained from human healthy volunteers (HVs) in a Ph1 study, single oral doses of 10 or 20 mg ETC-206 did not show inhibitory activity up to 12 h post-dose, instead ETC-206 caused a statistically significant (p=0.0037) p-eIF4E inhibition in PBMCs of 24% at 24 h post-dose with 10 mg, and an inhibition of [≥]27 % up to 52% was seen in 11/14 subjects in the 20 mg group where ETC-206 plasma concentrations remained above the IC50 for p-eIF4E (1.7 {micro}M) for 30 h. While in mouse pharmacodynamic (PD) activity was also shown in tumor, skin, and hair follicles (HFs), in human tissues, PBMCs showed a trend for delayed PD inhibition and skin was not a suitable surrogate. Analysis of pharmacokinetic (PK) and PD relationships shown herein demonstrate excellent pharmaceutical properties of ETC-206 which has now advanced to Ph2 clinical trials (NCT05462236).

cancer biology↗

bioRxiv2020

Vascular calcification has a role in acute non-renal phosphate clearance

RationaleNon-renal extravasation of phosphate from the circulation and transient accumulation into tissues and extracellular fluid is a regulated process of acute phosphate homeostasis that is not well understood. Following oral consumption of phosphate, circulating levels normalize long before urinary excretion has been completed. This process is especially relevant in the setting of chronic kidney disease (CKD), where phosphate exposure is prolonged due to inefficient kidney excretion. Furthermore, CKD-associated dysregulation of mineral metabolism exacerbates pathological accumulation of phosphate causing vascular calcification (VC). ObjectiveDetermine whether the systemic response to acute phosphate challenges is altered by the development and progression of VC. Methods/ResultsAcute circulating and tissue deposition of an acute phosphate challenge was assessed in two rat models of VC using radio-labelled phosphate tracer. In an adenine-induced model of CKD with VC, animals with VC had a blunted elevation of circulating 33PO4 following oral phosphate administration and the discordant deposition could be traced to the calcifying vasculature. In a non-CKD model of VC, VC was induced with 0.5ug/kg calcitriol and then withdrawn. The radio-labelled phosphate challenge was given to assess for vascular preference for phosphate uptake with and without the presence of an active calcification stimulus. The new transport to the calcifying vasculature correlates to the pre-existing burden of calcification, and can be substantially attenuated by removing the stimulus for calcification. The accrual is stimulated by a phosphate challenge, and not present in the same degree during passive disposition of circulating phosphate. ConclusionsOur data indicate that calcifying arteries alter the systemic disposition of a phosphate challenge and acutely deposit substantial phosphate. This study supports the importance of diet as it relates to acute fluctuations of circulating phosphate and the importance of bioavailability and meal-to-meal management in CKD patients as a mediator of cardiovascular risk.

pathology↗