Biology subjects

Leenders, W. P. J.

Publications and source records attributed to Leenders, W. P. J..

3 recordsLinked to original sources

bioRxiv2023

Temporal composition of the cervicovaginal microbiome associates with hrHPV infection outcomes in a longitudinal study

Persistent infections with high-risk human papillomavirus (hrHPV) can cause cervical squamous intraepithelial lesions (SIL) that may progress to cancer. The cervicovaginal microbiome (CVM) correlates with SIL, but the temporal composition of the CVM after hrHPV infections has not been fully clarified. To determine the association between the CVM composition and infection outcome, we applied high-resolution microbiome profiling using the circular probes-based RNA sequencing technology on a longitudinal cohort of cervical smears obtained from 141 hrHPV DNA-positive women with normal cytology at first visit, of whom 51 were diagnosed by cytology with SIL six months later. Here we show that women with a microbial community characterized by low diversity and high Lactobacillus crispatus abundance exhibit low risk to SIL development at both visits, while women with a microbial community characterized by high diversity and Lactobacillus depletion at first visit have a higher risk of developing SIL. At the level of individual species we observed that an increased abundance for Gardnerella vaginalis and Atopobium vaginae associate with SIL outcomes at both visits. These species together with Dialister micraerophilus showed a moderate discriminatory power for hrHPV infection progression. Our results suggest that the CVM can potentially be used as a biomarker for cervical disease and SIL development after hrHPV infection diagnosis with implications on cervical cancer prevention strategies and treatment of SIL.

microbiology↗

bioRxiv2019

Monotherapy efficacy of BBB-permeable small molecule activators of PP2A in glioblastoma

Glioblastoma (GB) is a fatal disease in which most targeted therapies have clinically failed. However, pharmacological reactivation of tumor suppressors has not been thoroughly studied as yet as a GB therapeutic strategy. Tumor suppressor Protein Phosphatase 2A (PP2A), is inhibited by non-genetic mechanisms in GB, and thus it would be potentially amendable for therapeutic reactivation. Here we demonstrate, that small molecule activators of PP2A (SMAPs), NZ-8-061 and DBK-1154, effectively cross the in vitro model of blood-brain barrier (BBB), and in vivo partition to mouse brain tissue after oral dosing. In vitro, SMAPs exhibit robust cell killing activity against five established GB cell lines, and nine patient-derived primary glioma cell lines. Collectively these cell lines have heterogenous genetic background, kinase inhibitor resistance profile, and stemness properties; and they represent different clinical GB subtypes. Oral dosing of either of the SMAPs significantly reduced growth of infiltrative intracranial GB tumors. DBK-1154, with both higher degree of brain/blood distribution, and more potent in vitro activity against all tested GB cell lines, also significantly increased survival of mice bearing orthotopic GB xenografts. In summary, this report presents a proof-of-principle data for BBB-permeable tumor suppressor reactivation therapy for glioblastoma cells of heterogenous molecular background.

cancer biology↗

bioRxiv2018

Targeted RNA NextGenSeq profiling in oncology using single molecule molecular inversion probes.

Hundreds of biology-based precision drugs are available that neutralize aberrant molecular pathways in cancer. Molecular heterogeneity and the lack of reliable companion diagnostic biomarkers for many drugs makes targeted treatment of cancer inaccurate for many individuals, leading to futile overtreatment. To acquire a comprehensive insight in aberrant actionable biological pathways in individual cancers we applied a cost-effective targeted RNA next generation sequencing (NGS) technique. The test allows NGS-based measurement of transcript levels and splice variants of hundreds of genes with established roles in the biological behavior in many cancer types. We here present proof of concept that the technique generates a correct molecular diagnosis and a prognosis for glioma patients. The test not only confirmed known brain cancer-associated molecular aberrations but also identified aberrant expression levels of actionable genes and mutations that are associated with other cancer types. Targeted RNA-NGS is therefore a highly attractive method to guide precision therapy for the individual patient based on pathway analysis.

cancer biology↗