Biology subjects

Le, H. D.

Publications and source records attributed to Le, H. D..

4 recordsLinked to original sources

bioRxiv2026

Organoids serve as viable in vitro model for functional precision medicine for mesonephric-like adenocarcinoma of the ovary

BackgroundMesonephric-like adenocarcinoma has been recently classified as a rare type of ovarian carcinoma. Description of these tumours have been rare and mostly covered in case reports. In some cases, molecular characterization by sequencing has been employed for guided therapy recommendations, however, functional chemosensitivity testing of targetable pathways using advanced in vitro cellular models such as organoids has not been reported so far. Here, we report on a case of ovarian cancer that was later identified as mesonephric-like adenocarcinoma at an advanced stage. MethodsThe tumour was characterized by molecular techniques including immunohistochemistry and whole-exome sequencing. At the same time, ovarian cancer organoids were established by adapting existing protocols for high-grade serous ovarian carcinoma. The organoids were subsequently used for functional in vitro chemosensitivity testing by treatment with standard-of-care chemotherapeutics cisplatin, paclitaxel, and the Poly (ADP-Ribose) Polymerase 1-inhibitor olaparib. Based on molecular characteristics, we also applied the inhibitor binimetinib, to target Mitogen-Activated Protein Kinase downstream of the KRAS Proto-Oncogene. Additionally, chemotoxicity testing with healthy fallopian tube organoids and high-grade ovarian cancer organoids was applied to determine the therapeutic window. ResultsImmunohistochemical analysis showed characteristic PAX8+, GATA3+, TFF1+, ER-, PR-, WT1- staining while the sequencing revealed mutations in 31 genes of which KRAS G12V and DYNC1H1 G4072S were annotated as (likely) pathogenic. The tumour was mismatch-repair proficient. Tumour-derived organoids proved to be highly resistant to standard-of-care chemotherapeutics cisplatin, paclitaxel, and olaparib, but sensitive to inhibition by binimetinib, which aligned well with the molecular characteristics. Direct comparison to healthy fallopian tube organoids and high-grade ovarian cancer organoids confirmed low cytotoxic potential underlining a feasible therapeutic window for binimetinib. ConclusionsFor the first time, we show that existing protocols for high-grade serous ovarian carcinoma can be used for the generation of organoids derived from mesonephric-like adenocarcinoma. These organoids could be used as an essential tool for functional precision medicine purposes. This functional data could be applied as an additional layer for molecular tumour boards diagnostics by supporting molecular datasets and even identify targetable pathways beyond genetic variations, thus offering novel therapeutic options particularly for rare and aggressive tumours.

cancer biology↗

bioRxiv2025

Nodamuravirus protein B2 boosts self-amplifying mRNA efficacy by overcoming innate immune barriers.

Self-amplifying RNA (sa-RNA) technology is a promising strategy for vaccine design, as its intracellular replication boosts transgene expression and provides self-adjuvanticity. However, sa-RNA efficiency is limited by innate immune responses triggered by the presence of intracellular double-stranded RNA (dsRNA). In vertebrates, differentiated cells mainly use type I interferon (IFN) system for protection against viruses, while stem cells rely on IFN-independent mechanisms such as antiviral RNA interference (RNAi). Here, we found that the efficiency of sa-RNAs based on chikungunya virus (CHIKV) or Venezuelan equine encephalitis virus (VEEV) genomes is enhanced when co-expressed in cis with the Nodamura virus (NoV) B2 protein, a viral suppressor of RNAi. In stem cells, NoV B2 prevents Dicer-mediated processing of dsRNA, while in somatic cells, it blocks the translation shutdown caused by protein kinase R (PKR), a key effector of the IFN system. Notably, NoV B2 does not interfere with IFN induction and signalling, preserving sa-RNAs self-adjuvant properties. Mechanistically, NoV B2 sequesters replication-derived dsRNA at the cell periphery, offering a novel strategy to boost sa-RNA efficiency without compromising its immune stimulatory properties. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/661928v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@4412aforg.highwire.dtl.DTLVardef@126d089org.highwire.dtl.DTLVardef@144dd38org.highwire.dtl.DTLVardef@179bac_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

Profiling Transcription Initiation in Peripheral Leukocytes Reveals Severity-Associated Cis-Regulatory Elements in Critical COVID-19

The contribution of transcription factors (TFs) and gene regulatory programs in the immune response to COVID-19 and their relationship to disease outcome is not fully understood. Analysis of genome-wide changes in transcription at both promoter-proximal and distal cis-regulatory DNA elements, collectively termed the active cistrome, offers an unbiased assessment of TF activity identifying key pathways regulated in homeostasis or disease. Here, we profiled the active cistrome from peripheral leukocytes of critically ill COVID-19 patients to identify major regulatory programs and their dynamics during SARS-CoV-2 associated acute respiratory distress syndrome (ARDS). We identified TF motifs that track the severity of COVID- 19 lung injury, disease resolution, and outcome. We used unbiased clustering to reveal distinct cistrome subsets delineating the regulation of pathways, cell types, and the combinatorial activity of TFs. We found critical roles for regulatory networks driven by stimulus and lineage determining TFs, showing that STAT and E2F/MYB regulatory programs targeting myeloid cells are activated in patients with poor disease outcomes and associated with single nucleotide genetic variants implicated in COVID-19 susceptibility. Integration with single-cell RNA-seq found that STAT and E2F/MYB activation converged in specific neutrophils subset found in patients with severe disease. Collectively we demonstrate that cistrome analysis facilitates insight into disease mechanisms and provides an unbiased approach to evaluate global changes in transcription factor activity and stratify patient disease severity.

genomics↗

bioRxiv2020

Astroglia in lateral habenula is essential for antidepressant efficacy of light

Successful antidepressant (AD) treatments are still difficult to achieve. Recently, bright light stimulation (BLS) was shown effective in non-seasonal depression but its mode of action remains elusive. We demonstrate here, using a new mouse model of depression resistant to ADs including ketamine, that chemogenetic activation of lateral habenula (LHb) astroglia prevented the potentiating effect of BLS on the AD response. Additionally, the beneficial action of BLS was associated with upregulation of a specific part of the prefrontal cortex opioid system. These results show that improved behavioral outcome produced by BLS requires habenular astroglia and endogenous opioids as crucial buffer systems.

neuroscience↗