Biology subjects

Jansson, D.

Publications and source records attributed to Jansson, D..

4 recordsLinked to original sources

bioRxiv2026

Trastuzumab deruxtecan kills skin and uveal melanoma in vivo by HER2-independent payload release

Background: HER2-directed CAR-T cells can eradicate melanoma despite low HER2 expression. We therefore asked whether melanoma would also respond to trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate targeting HER2. Patients and methods: T-DXd was evaluated in several patient-derived xenograft (PDX) models and as a compassionate use in one patient with metastatic uveal melanoma. We compared T-DXd with another ADC, trastuzumab emtansine (T-DM1), and examined ADC sensitivity and trastuzumab uptake in vitro, and expression of HER2 and cathepsin L (CTSL) in xenografts. Results: T-DXd inhibited all subcutaneous PDXs, while liver models were less sensitive. T-DM1 had limited activity. Unexpectedly, parental and ERBB2-knockout melanoma xenografts showed similar initial responses to T-DXd, although knockout tumors regrew earlier. Tumor-derived CTSL was detected outside melanoma cells in the xenografts. Melanoma cells were largely resistant to both ADCs in vitro and showed little trastuzumab uptake compared to HER2-amplified breast cancer cells. Conclusions: T-DXd has a substantial HER2-independent component of activity in the tested melanoma xenografts. Presence of extracellular CTSL, an enzyme known to cleave T-Dxd, provide a possibility that linker cleavage and payload release can occur outside of the tumor cells.

cancer biology↗

bioRxiv2025

Multi-modal choroid plexus pathology in aging and Alzheimer's disease

Brain barriers, cerebrospinal fluid (CSF) dynamics, and peripheral factors are implicated as significant contributors to Alzheimers disease (AD). The choroid plexus (ChP) is a blood-brain interface that produces CSF and forms the blood-CSF barrier. However, how ChP pathology develops across the lifespan and contributes to AD has not been systematically characterized. Here, we report a multi-modal ChP atlas integrating single-nucleus transcriptomics from 49 individuals, AI-assisted quantitative histopathology across >500 postmortem samples age 16 to 105, spatial transcriptomics, and functional studies in 5xFAD mice. We identify fibrosis, calcification, and macrophage abnormalities as hallmarks of ChP aging, with AD pathology conferring additional effects, including expansion of a pro-inflammatory fibroblast-macrophage signaling niche. In 5xFAD mice, macrophage dysfunction is associated with impaired epithelial barrier maintenance and repair. Together, these data provide a foundational resource for understanding ChP dysfunction in aging and AD and propose the macrophage-fibroblast-epithelial barrier axis as a driver of ChP pathology.

neuroscience↗

bioRxiv2024

Behaviour-based movement cut-off points in 3-year old children comparing wrist- with hip-worn actigraphs MW8 and GT3X

IntroductionBehaviour-based physical intensities have not undergone rigorous calibration in long-term recordings of 3-year-old childrens sleep/activity patterns. This study aimed at (i) calibrating activity counts of motor behaviour measured simultaneously with MotionWatch 8 (MW8) and ActiGraph (GT3X) in 3-year-old children, (ii) documenting movement intensities in 30s-epochs at wrist/hip positions, and (iii) evaluating the accuracy of cut-off agreements between different behavioural activities. MethodsThirty 3-year-old children of the NorthPop cohort performed six directed behavioural activities individually, each for 8-10 minutes while wearing two pairs of devices at hip and wrist position. Directly observed naturally-occurring behaviours included: watching cartoons, recumbent story listening, sit and handcraft, floor play with toys, engaging in a walk and a sprinting game. Receiver-Operating-Curve classification was applied to determine activity count thresholds and to assign context-guided, physical activity composite classes. ResultsActivity counts of MW8 and GT3X pairs of wrist-worn (r = 0.94) and hip-worn (r = 0.79) devices correlated significantly (p < 0.001). Activity counts at hip position were significantly lower compared to those at the wrist position (p < 0.001), irrespective of device type. Sprinting, floorball/walk and floorplay assigned as physically mobile classes achieved outstanding accuracy (AUC >0.9) and two sedentary and a motionless activities assigned into physically stationary classes achieved excellent accuracy (AUC >0.8). ConclusionThis study provides useful cut-offs for physical activity levels of preschool children using two different devices. Contextual information of behaviour is advantageous over intensity classifications only, because interventions reallocate time among behaviours, which allows to establish dose-response relationships between behavioural changes and health outcomes. Our comparative calibration is one step forward to inform behaviour-based public health guidelines for 3-year-old children.

neuroscience↗

bioRxiv2020

Recycling old drugs: cardiac glycosides as therapeutics to target barrier inflammation of the vasculature, meninges and choroid plexus

Neuroinflammation is a key component of virtually all neurodegenerative diseases; preceding neuronal loss and associating directly with cognitive impairment. Neuroinflammatory signals can originate and be amplified at barrier tissues such as brain vasculature, surrounding meninges and the choroid plexus. We designed a high-throughput screening system to target inflammation in cells of the blood-brain barrier (primary human pericytes and endothelia) and microglia enabling us to target human disease-specific inflammatory modifiers. Screening an FDA-approved drug library we identified digoxin and lanatoside C, members of the cardiac glycoside family as inflammatory modulating drugs that work in blood-brain barrier cells. A novel ex vivo assay of leptomeningeal and choroid plexus explants further confirmed that these drugs maintain their function in 3D cultures of brain border tissues. While current therapeutic strategies for the treatment of neurodegenerative diseases are missing the mark in terms of targets, efficacy and translatability, our innovative approach using in vitro and ex vivo human barrier cells and tissues to target neuroinflammatory pathways is a step forward in drug development and testing, and brings us closer to translatable treatments for human neurodegenerative disease. One Sentence SummaryWe have identified cardiac glycosides as powerful regulators of neuroinflammatory pathways in brain-barrier tissues such as vasculature, meninges and choroid plexus.

neuroscience↗