Biology subjects

Calvo, R.

Publications and source records attributed to Calvo, R..

4 recordsLinked to original sources

bioRxiv2026

SETD5 dysfunction in human astrocytes drives IL-6-mediated neuronal impairments via the JAK/STAT signaling pathway

Intellectual disability (ID) and autism spectrum disorder (ASD) are neurodevelopmental conditions marked by lifelong impairments in cognitive, motor, and social functions. Hundreds of genetic variants have been linked to these disorders, including mutations in chromatin regulators such as the SET-domain-containing protein 5 (SETD5) gene. Most studies linking SETD5 loss-of-function to ASD/ID have focused primarily on neurons. However, while SETD5 is highly expressed in astrocytes, its role in glia cells remains poorly understood. Here, we examine how dysfunction of SETD5 in human-induced pluripotent stem cell (hiPSC)-derived astrocytes affects neuronal physiology. We show that SETD5-deficient astrocytes have increased levels of extracellular reactive oxygen species (ROS), glutamate, and interleukins-6 and 8 (IL-6 and IL-8). Elevated astrocytic IL-6 exerts a non-cell autonomous harmful effect on healthy neurons. Using SETD5-deficient astrocytes as a screening platform, we identify the JAK/STAT pathway as an upstream regulator of abnormal IL-6 accumulation associated with SETD5 dysfunction. Accordingly, pharmacological inhibition of JAK-STAT signaling restores extracellular IL-6 to basal levels and partially rescues astrocyte morphology and neuronal deficits. Collectively, these findings highlight the JAK/STAT pathway as a key regulator of SETD5-mediated astrocytic function and suggest its potential as a therapeutic target for astrocytic-driven neuronal impairments in ASD and ID.

neuroscience↗

bioRxiv2024

Overcoming brain-derived therapeutic resistance in HER2+ breast cancer brain metastasis

Brain metastasis of HER2+ breast cancer occurs in about 50% of all women with metastatic HER2+ breast cancer and confers poor prognosis for patients. Despite effective HER2-targeted treatments of peripheral HER2+ breast cancer with Trastuzumab +/-HER2 inhibitors, limited brain permeability renders these treatments inefficient for HER2+ breast cancer brain metastasis (BCBM). The scarcity of suitable patient-derived in-vivo models for HER2+ BCBM has compromised the study of molecular mechanisms that promote growth and therapeutic resistance in brain metastasis. We have generated and characterized new HER2+ BCBM cells (BCBM94) isolated from a patient HER2+ brain metastasis. Repeated hematogenic xenografting of BCBM94 consistently generated BCBM in mice. The clinically used receptor tyrosine kinase inhibitor (RTKi) Lapatinib blocked phosphorylation of all ErbB1-4 receptors and induced the intrinsic apoptosis pathway in BCBM94. Neuregulin-1 (NRG1), a ligand for ErbB3 and ErbB4 that is abundantly expressed in the brain, was able to rescue Lapatinib-induced apoptosis and clonogenic ability in BCBM94 and in HER2+ BT474. ErbB3 was essential to mediate the NRG1-induced survival pathway that involved PI3K-AKT signalling and the phosphorylation of BAD at serine 136 to prevent apoptosis. High throughput RTKi screening identified the brain penetrable Poziotinib as highly potent compound to reduce cell viability in HER2+ BCBM in the presence of NRG1. Successful in-vivo ablation of BCBM94- and BT474-derived HER2+ brain tumors was achieved upon two weeks of treatment with Poziotinib. MRI revealed BCBM remission upon poziotinib, but not with Lapatinib treatment. In conclusion, we have established a new patient-derived HER2+ BCBM in-vivo model and identified Poziotinib as highly efficacious RTKi with excellent brain penetrability that abrogated HER2+ BCBM brain tumors in our mouse models.

cancer biology↗

bioRxiv2021

Subtly altered topological asymmetry of brain structural covariance networks in autism spectrum disorder across 43 datasets from the ENIGMA consortium

Small average differences in the left-right asymmetry of cerebral cortical thickness have been reported in individuals with autism spectrum disorder (ASD) compared to typically developing controls. Although these alterations affect multiple and widespread cortical regional asymmetries, the extent to which specific structural networks might be affected remains unknown. Inter-regional morphological covariance analysis can capture network connectivity relations between different cortical areas at the macroscale level. Here, we used cortical thickness data from 1,455 individuals with ASD and 1,560 controls, across 43 independent datasets of the ENIGMA consortiums ASD Working Group, to assess hemispheric asymmetries of intra-individual structural covariance networks, using graph theory-based topological metrics. Compared with typical features of small-world architecture in controls, the ASD sample showed significantly altered asymmetry of hemispheric networks involving the fusiform, rostral middle frontal, and medial orbitofrontal cortex, driven by shifts toward higher randomization of the corresponding right-hemispheric networks in ASD. A network involving the superior frontal cortex showed decreased right-hemisphere randomization. Based on comparisons with meta-analyzed functional neuroimaging data, the altered connectivity asymmetry particularly affected networks that subserve working memory, executive functions, language, reading, and sensorimotor processes. Taken together, these findings provide new insights into how altered brain left-right asymmetry in ASD affects specific structural and functional brain networks. Altered asymmetrical brain development in ASD may be partly propagated among spatially distant regions through structural connectivity.

neuroscience↗

bioRxiv2019

Altered structural brain asymmetry in autism spectrum disorder: large-scale analysis via the ENIGMA Consortium

BackgroundLeft-right asymmetry is an important organizing feature of the healthy brain. Various studies have reported altered structural brain asymmetry in autism spectrum disorder (ASD). However, findings have been inconsistent, likely due to limited sample sizes and low statistical power.\n\nMethodsWe investigated 1,774 subjects with ASD and 1,809 controls, from 54 datasets, for differences in the asymmetry of thickness and surface area of 34 cerebral cortical regions. We also examined global hemispheric measures of cortical thickness and area asymmetry, and volumetric asymmetries of subcortical structures. Data were obtained via the ASD Working Group of the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. T1-weighted MRI data were processed with a single protocol using FreeSurfer and the Desikan-Killiany atlas.\n\nResultsASD was significantly associated with reduced leftward asymmetry of total hemispheric average cortical thickness, compared to controls. Eight regional thickness asymmetries, distributed over the cortex, also showed significant associations with diagnosis after correction for multiple comparisons, for which asymmetry was again generally lower in ASD versus controls. In addition, the medial orbitofrontal surface area was less rightward asymmetric in ASD than controls, and the putamen volume was more leftward asymmetric in ASD than controls. The largest effect size had Cohens d = 0.15. Most effects did not depend on age, sex, IQ, or disorder severity.\n\nConclusionAltered lateralized neurodevelopment is suggested in ASD, affecting widespread cortical regions with diverse functions. Large-scale analysis was necessary to reliably detect, and accurately describe, subtle alterations of structural brain asymmetry in this disorder.

neuroscience↗