Biology subjects

Nguyen, F.

Publications and source records attributed to Nguyen, F..

4 recordsLinked to original sources

bioRxiv2026

Ileitis abolishes tolerogenic functions of the enterohepatic bile acid pool

Bile acids (BAs) regulate lipid uptake, epithelial integrity, and immune responses in the gut. Hepatocytes synthesize primary BAs, which microbiota metabolize into secondary metabolites. Together, these species form a composite pool that circulates enterohepatically between the liver and intestines. Here, we show that immunoregulatory outputs of the enterohepatic BA pools involve competition between multiple BA species for individual nuclear receptors and are dependent on intestinal health. In healthy mice, the primary BA, tauro {beta} muricholic acid (t{beta}MCA) antagonized ROR{gamma}t-mediated Th17 function in the presence of two secondary BAs (tDCA, tLCA) which activated ROR{gamma}t. Conversely, ileitis in Crohns disease patients and Tnf{delta}ARE mice depleted primary BAs by reducing the number and function of BA transporting enterocytes. In mice, ileitis driven t{beta}MCA depletion enhanced tDCA and tLCA mediated ROR{gamma}t activation and supported Th17 cell function. Replenishing t{beta}MCA in Tnf{delta}ARE mice reestablished BA dependent Th17 cell regulation. Thus, intra pool competition underpins BA immunoregulatory functions and reveals new opportunities for precision Crohns disease therapy.

immunology↗

bioRxiv2024

Advantage of the F(ab)'2 fragment over IgG for RIT and PRIT

Radioimmunotherapy (RIT) has proved clinically effective in the treatment of relapsed or consolidating NHL after chemotherapy. However, it is still at the clinical trial stage for the treatment of solid tumors. The efficacy of the treatment on this type of tumor is limited by hematological toxicity, which restricts the activities injected. Pre-targeted radioimmunotherapy (PRIT) enables radiolabeling to be carried out in vivo at a time when the quantities of antigen-targeted vector reach a maximum level in the tumor, but have largely decayed in the bloodstream, thus limiting hematological toxicity. This therapeutic approach would make it possible to use higher radiopharmaceutical activities than those used in RIT, thereby increasing the doses deposited in the tumor and the therapeutic response. Despite encouraging preclinical trials, this approach has failed to live up to expectations in terms of clinical applications. In the context of PRIT using the Inverse Electron Demand Diels Alder (IEDDA) reaction as a method for radiolabeling tumor-targeted vectors, a major research effort has been made to improve the quality of in vivo radiolabeling using tetrazine (Tz) and transcycloctene (TCO) variants whose stability and reactivity have been optimized. Most trials in this field have been carried out using antibodies which, thanks to their long biological half-life, enable prolonged irradiation of tumors. Low-molecular-weight vectors such as affinity proteins or antigen-specific antibody fragments (VHH,scFv, F(ab)) have the advantage of being rapidly eliminated from circulation by renal filtration, but on the other hand, the quantities and residence times of these vectors in the tumor are reduced compared with IgG. F(ab)2 antibody fragments have properties intermediate between those of IgG and low-molecular-weight vectors that could be suitable for PRIT approaches, but they have not yet been evaluated in PRIT using IEDDA. In preparation for a preclinical trial of radioimmunotherapy of triple-negative breast cancer in spontaneously affected dogs, we compared the biodistribution of IgG and its F(ab)2 fragment targeting canine CD138 in a xenogeneic model of canine breast cancer and in a mouse model of colon cancer expressing human ACE antigen. This analysis shows that the use of F(ab)2 fragments improves the therapeutic index compared with IgG. F(ab)2 fragments seem particularly well suited to tumor targeting in PRIT using short-lived isotopes such as 211At.

cancer biology↗

bioRxiv2018

Network-Based Biomarkers Enable Cross-Disease Biomarker Discovery

Biomarkers lie at the heart of precision medicine, biodiversity monitoring, agricultural pathogen detection, amongst others. Surprisingly, while rapid genomic profiling is becoming ubiquitous, the development of biomarkers almost always involves the application of bespoke techniques that cannot be directly applied to other datasets. There is an urgent need for a systematic methodology to create biologically-interpretable molecular models that robustly predict key phenotypes. We therefore created SIMMS: an algorithm that fragments pathways into functional modules and uses these to predict phenotypes. We applied SIMMS to multiple data-types across four diseases, and in each it reproducibly identified subtypes, made superior predictions to the best bespoke approaches, and identified known and novel signaling nodes. To demonstrate its ability on a new dataset, we measured 33 genes/nodes of the PIK3CA pathway in 1,734 FFPE breast tumours and created a four-subnetwork prediction model. This model significantly out-performed existing clinically-used molecular tests in an independent 1,742-patient validation cohort. SIMMS is generic and can work with any molecular data or biological network, and is freely available at: https://cran.r-project.org/web/packages/SIMMS.

bioinformatics↗

bioRxiv2017

BPG: Seamless, Automated and Interactive Visualization of Scientific Data

We introduce BPG, an easy-to-use framework for generating publication-quality, highly-customizable plots in the R statistical environment. This open-source package includes novel methods of displaying high-dimensional datasets and facilitates generation of complex multi-panel figures, making it ideal for complex datasets. A web-based interactive tool allows online figure customization, from which R code can be downloaded for seamless integration with computational pipelines. BPG is available at http://labs.oicr.on.ca/boutros-lab/software/bpg

bioinformatics↗