Biology subjects

Job, A.

Publications and source records attributed to Job, A..

3 recordsLinked to original sources

bioRxiv2026

Early microglial activation in the TME enables FLASH-RT to eradicate medulloblastoma while promoting neuron-astrocyte crosstalk to minimize toxicity in the hippocampus

BackgroundFLASH-RT defines a promising treatment modality against medulloblastoma, as it minimizes treatment-related complications. To support its clinical translation, we dissected the cellular and molecular determinants of the FLASH response in the tumor-microenvironment (TME) and healthy hippocampus using an orthotopic human medulloblastoma mouse model treated with a hypo-fractionated FLASH regimen. MethodsFive cohorts of 4 weeks-old UW228-MB-bearing female nude mice (n=57) were irradiated, or sham-irradiated using 3x10 Gy (BED=60), delivered 48h apart at 0.1 Gy/s (CONV) or 5.5x106 Gy/s (FLASH) using an electron beam (eRT6). Digital spatial profiling (DSP) was performed 24h after radiotherapy in one cohort, while the four other cohorts were followed for long-term tumor response, cognition, and neuroinflammation. ResultsBoth CONV and FLASH-RT induced a complete and long-lasting anti-tumor response in 100% of animals associated with cognitive decline. However, more mice maintained a very good discrimination score after FLASH exposure (38%) than CONV (7%). DSP revealed a sustained microglial activation in the cerebellar tumor micro-environment, where FLASH enhanced expression of genes with phagocytic and proteolytic activity. In the tumor free hippocampus, FLASH exposure induced a preferential neuron/astrocyte transcriptional crosstalk, which manifested over protracted times to minimize neuroinflammation and cognitive complications. ConclusionThe study shows the tumor-ablative efficacy of hypo-fractionated FLASH-RT in a human medulloblastoma mouse model. It is associated with qualitatively distinct transcriptional signatures prone to tumor and debris clearance mediated by microglial cells of the TME. Moreover, in the hippocampus, FLASH mitigates radiation-induced neurotoxicity by enhancing genes involved in synaptic plasticity, attenuating neuroinflammation, and preserving metabolic function. Key PointsO_LIComplete response of medulloblastoma and reduction of neurotoxicity with hypo-fractionated FLASH regimen. C_LIO_LIClearance-prone phagocytic and proteolytic activity in the microglia of the TME. C_LIO_LINeuron/astrocyte transcriptional crosstalk in the hippocampus. C_LI Importance of the studyThis study constitutes a milestone for the future implementation of FLASH-RT in the treatment of children with brain cancer. It shows that FLASH does not protect medulloblastoma and on the contrary can be ablative when delivered in 3 fractions of 10 Gy. FLASH promotes a metabolically active, phagocytosis-prone phenotype in microglial cells consistent with immune activation and tumor surveillance, in contrast to the proliferative and immunosuppressive signaling programs induced by CONV. It also shows how FLASH may differentially shape long-term brain function in patients with brain tumors by modifying the transcriptional program of hippocampal subregions known to be critical for memory encoding, pattern separation, and consolidation. In summary, this study supports the idea that FLASH has the potential to shift treatment paradigms and change the dismal therapeutic outcome in patients with brain cancer.

cancer biology↗

bioRxiv2023

Penetration of Topically Applied Polymeric Nanoparticles across the Epidermis of Thick skin

The natural barrier function of the epidermal skin layer poses a significant challenge to nanoparticle-mediated topical delivery. A key factor in this barrier function is the thickness of the stratum corneum (SC) layer within the epidermis, which varies across different anatomical sites. The epidermis from the palms and soles, for instance, have thicker SC compared to those from other areas. Previous studies have attempted to bypass the SC layer for nanoparticle penetration by using physical disruption; however, these studies have mostly focused on non-thick skin. In this study, we investigate the role of mechano-physical strategies on SC of thick skin for transdermal nanoparticle penetration. We characterize and compare two mechano-physical strategies, namely tape-stripping and microneedle abrasion, for epidermal disruption in both thick and thin skin. Furthermore, we examine the impact of SC disruption in thick and thin skin on the penetration of topically applied 100 nm sized polystyrene nanoparticles using an ex-vivo model. Our findings show that tape-stripping reduced the overall thickness of SC in thick skin by 87%, from 67.4 {+/-} 17.3 {micro}m to 8.2 {+/-} 8.5 {micro}m, whereas it reduced thin skin SC by only 38%, from 9.9 {+/-} 0.6 {micro}m to 6.2 {+/-} 3.2 {micro}m. Compared to non-thick skin, SC disruption in thick skin resulted in higher nanoparticle diffusion. Tape-stripping effectively reduces SC thickness of thick skin and can be potentially utilized for enhanced penetration of topically applied nanoparticles in skin conditions that affect thick skin.

bioengineering↗

bioRxiv2019

Specific connectivity with Operculum 3 (OP3) brain region in acoustic trauma tinnitus: a seed-based resting state fMRI study

Tinnitus mechanisms remain poorly understood. Our previous functional MRI (fMRI) studies demonstrated an abnormal hyperactivity in the right parietal operculum 3 (OP3) in acoustic trauma tinnitus and during provoked phantom sound perceptions without hearing loss, which lead us to propose a new model of tinnitus. This new model is not directly linked with hearing loss and primary auditory cortex abnormalities, but with a proprioceptive disturbance related to middle-ear muscles. In the present study, a seed-based resting-state functional MRI method was used to explore the potential abnormal connectivity of this opercular region between an acoustic trauma tinnitus group presenting slight to mild tinnitus and a control group. Primary auditory cortex seeds were also explored because they were thought to be directly involved in tinnitus in most current models. In such a model, hearing loss and tinnitus handicap were confounding factors and were therefore regressed in our analysis. Between-groups comparisons showed a significant specific connectivity between the right OP3 seeds and the potential human homologue of the premotor ear-eye field (H-PEEF) bilaterally and the inferior parietal lobule (IPL) in the tinnitus group. Our findings suggest the existence of a simultaneous premotor ear-eye disturbance in tinnitus that could lift the veil on unexplained subclinical abnormalities in oculomotor tests found in tinnitus patients with normal vestibular responses. The present work confirms the involvement of the OP3 subregion in acoustic trauma tinnitus and provides some new clues to explain its putative mechanisms.

neuroscience↗