Biology subjects

Haddad, E.

Publications and source records attributed to Haddad, E..

At least 19 recordsLinked to original sources

bioRxiv2026

The ENIGMA-PD-WML Pipeline: A Containerized, User-Friendly Approach for Accurate, Standardized Segmentation of White Matter Lesions in Multi-Site MRI Data

Understanding vascular contributions to disease is a major unmet need. White matter lesions (WML) are an accepted imaging marker of cerebral small vessel disease, giving insights into its related pathologies. A unified approach for WML analyses in large multi-site data is lacking despite the need for pooling of data to overcome the limitations of often small heterogenous MRI studies which make subtyping and identifying patterns within disease groups difficult. Our ENIGMA-PD-WML pipeline is an open-source containerized pipeline containing all the code and packages required for pre-processing, processing and post-processing of T1-weighted and FLAIR data, outputting accurate and reproducible binary WML maps using a UNet approach. The pipeline provides a standardized image analysis approach for WML and outputs data in both native and MNI space to allow for sharing and pooling of data from multiple sites for large-data analysis. In addition to a reliable standardized approach for WML segmentation, key priorities when developing the pipeline included: usability, i.e., requiring minimal manual input and technical expertise to use, and suitability to run on various MRI scanners and acquisition parameters as is common in multi-site data. This paper describes the pipeline in detail, with rationale for each step, providing transparency and facilitating its usage to overcome reproducibility issues in large-scale WML analyses.

neuroscience↗

bioRxiv2026

A Multi-Omics Processing Pipeline (MOPP) for Extracting Taxonomic and Functional Insights from Metaribosome Profiling (metaRibo-Seq) data

Metaribosome profiling (metaRibo-Seq) enables genome-wide measurement of translation across complex microbial communities by sequencing ribosome-protected mRNA fragments, but the short length of these footprints creates substantial nonspecific mapping against large reference genome collections, leading to spurious taxonomic and functional assignments. Here we present MOPP (Multi-Omics Processing Pipeline), a modular reference-based workflow that denoises metaRibo-Seq data by leveraging matched metagenomic coverage breadth to identify genomes likely to be truly present in a sample before aligning metatranslatomic and optional metatranscriptomic reads. MOPP generates taxon-by-gene count tables across genomic, transcriptional and translational layers, enabling integrated downstream analyses of microbial function. We evaluated MOPP using a defined 79-member synthetic human gut community profiled by metagenomics and metaRibo-Seq. Coverage breadth filtering markedly improved detection accuracy relative to a standard baseline workflow, with performance remaining robust across a broad intermediate threshold range and peaking at 92-95% coverage breadth. At a 92% threshold, MOPP reduced the number of distinct detected operational genomic units by 99.4% while retaining 87.8% of aligned metaRibo-Seq reads on average, and increased the F1 score from 0.02 to 0.61. Residual false positives were predominantly attributable to genomes with extremely high nucleotide similarity to true community members, whereas false negatives were enriched among low-abundance taxa, indicating that remaining errors are driven primarily by biological similarity and detection limits rather than widespread nonspecific mapping. Together, these results establish MOPP as a high-throughput workflow for robust processing of metaRibo-Seq in the context of matched metagenomics and position it as a scalable framework for integrated taxonomic and functional analysis of microbial communities across genomic, transcriptional and translational layers.

bioinformatics↗

bioRxiv2025

Therapeutic Inducers of NK cell Killing (ThINKK)-induced NK cell cytotoxicity against childhood acute lymphoblastic leukemia: unraveling the dual role of TRAIL leads to the establishment of an efficacy biomarker

BackgroundTherapeutic Inducers of Natural Killer cell Killing (ThINKK) represent a novel class of immunotherapy designed to enhance the graft-versus-leukemia effect of hematopoietic stem cell transplantation in pediatric patients with high-risk or relapse leukemia. Our previous work identified high expression of TRAIL as a key signature of Natural Killer (NK) cell stimulation by ThINKK. In this study, we aim to elucidate the mechanisms underlying acute lymphoblastic leukemia (ALL) killing by ThINNK-stimulated NK cells and to identify predictive sensitivity markers of this innovative approach. MethodsWe performed NK cell cytotoxic assays using a panel of genetically diverse ALL cell lines and patients samples. Gene deletion and gene enforced expression in sensitive or resistant cell lines were performed to demonstrate the role of TRAIL-receptors expression and death receptor signaling pathway in ALL cell death induced by ThINKK-stimulated NK cells. These findings were further validated through the analysis of primary patients samples and transcriptomic profiling of a cohort of 320 ALL patients from the CHU Sainte-Justine. ResultsWe found that ALL sensitivity to ThINKK-stimulated NK cell killing was independent of their genetic background or their HLA expression. In addition, our data revealed the dual role of TRAIL: first, a strong NK cell activating receptor that induced rapid killing of ALL expressing TRAIL-R2, and second, a death-receptor ligand inducing ALL apoptosis following sustained engagement with its receptors. The transcriptomic analysis of ALL patients samples indicated that TRAIL-R2 and TRAIL-R1 are widely expressed across ALL subtypes and are not downregulated at relapse. ConclusionThese findings support the use of TRAIL receptor expression as a biomarker of sensitivity to ThINKK immunotherapy and establish a mechanistic framework to guide patient stratification and therapeutic optimization.

immunology↗

bioRxiv2025

Off-the-Shelf Engineered Liver Tissue Reverses Acute Liver Failure Without Immunosuppression

There is an urgent need for effective solutions to replace liver functions in patients with acute liver failure (ALF). We describe here a human engineered liver tissue composed of induced pluripotent stem cell (iPSC)-derived liver organoids encapsulated within a non-degradable biomaterial. Unlike most stem cell-derived products, this encapsulated liver tissue (ELT) achieves functional maturation during manufacturing. When transiently implanted into the peritoneal cavity of immunocompetent mice with ALF, the human ELT improves survival, treats hepatic encephalopathy and promotes liver regeneration, without requiring immunosuppression. Based on robust processes and designed to overcome challenges such as foreign body reaction, loss of function and cryopreservation, the ELT does not require vascularization and provides immediate and long-lasting functional replacement. Once the liver regenerated, the ELT is explanted, leaving the subjects cured. Macroencapsulation prevents rejection by shielding the organoids from the host immune system, and minimizes the risk of tumorigenicity. The data shown demonstrate the ELTs potential to be developed into a safe and effective off-the-shelf treatment that, if validated in upcoming clinical trials, could replace liver transplantation for many patients with ALF.

bioengineering↗

bioRxiv2025

Characterization of a Novel Transmembrane Activating STING Agonist using Genetically Humanized Mice

STING is a pattern recognition receptor that activates type I interferon and proinflammatory responses in addition to unrelated molecular processes following exposure of DNA to the cytosol. Its pharmacologic stimulation enhances vaccine potency and generates effective antitumor responses but clinical trials evaluating STING agonists have not led to approval for human use. STING activation can occur through ligand engagement of either cytosolic or transmembrane protein domains, processes to which distinct cellular phenotypes are attributed. However, the only transmembrane STING agonist identified is human selective and in vivo testing in conventional models is not feasible. Here we describe synthesis of novel STING agonists efficacious against allelic variants of the protein. We also describe genetically humanized STING mice and demonstrate their suitability as a model to evaluate in vivo responses following exogenous administration of human-selective agonists. Experiments demonstrate that the lead molecule (termed INI3069) functions through binding to the STING transmembrane region and its comparison with conventional agonists reveals significant differences in molecular and immune effects. INI3069 can also enhance antibody responses to co-administered antigens and antitumor responses. This work both represents the first in vivo examination of the effects of transmembrane STING agonism and demonstrates efficacy of a potential novel vaccine adjuvant and oncological therapeutic.

immunology↗

bioRxiv2025

Inhibition of IL2Rβ-dependent STAT5 activity supports T-cell stemness and augments antitumor efficacy of CD8+ T cells by preventing T-cell exhaustion

CD8+ T-cell exhaustion is a leading cause of adoptive cell therapy (ACT) failure. In contrast, maintaining a stem-like state correlates with better expansion, persistence, and anti-tumor activity of infused T-cell products. IL-2 is extensively used in ACT protocols given its ability to expand T-cell populations. Yet, IL-2 drives more differentiated and exhausted states, diminishing the quality of T-cell products. Understanding how cytokines of the IL2R family drive T-cell differentiation is essential to ultimately design optimal ACT protocols, safeguarding stem-like programs while ensuring sufficient T-cell expansion. Here, we show that cytokine signaling through IL2R{beta} supports more differentiated exhausted T cells in chronic lymphocytic choriomeningitis infection. Similarly, high levels of IL-2 and IL-15 in vitro foster heightened differentiation and exhaustion of cells for adoptive cell therapy. In contrast, absence of IL2R{beta} in vivo or transient inhibition of Janus kinase 3 (JAK3) or signal transducer and activator of transcription 5 (STAT5) in vitro favors features of T-cell stemness. Transcriptional analyses of in vitro expanded T cells further reveal that inhibition of STAT5 sustains a stemness program, which correlates with better antitumor activity in a mouse melanoma model. When applied to a human CAR T expansion model, inhibition of STAT5 supports memory progenitor differentiation and limit inhibitory receptor expression. These results demonstrate that continuous exposure to high levels of cytokines, such as IL-2 and IL-15, constrain CD8+ T cells towards more advanced states of exhaustion. In contrast, limiting cytokine signaling using specific kinase inhibitors preserves stem-like T-cell programs and enhance the quality of ACT products. One Sentence SummarySustained IL-2/IL-15 signaling drives CD8+ T-cell exhaustion while JAK3/STAT5 inhibition preserves stemness, boosting adoptive cell therapy efficacy.

immunology↗

bioRxiv2025

Humanized Bone Marrow-Liver-Thymus Mice for Studying HIV-1 Persistence in Liver and Lung CD4+ T and Myeloid Cell Subsets during Antiretroviral Therapy

BackgroundWhile the role of CD4+ T-cells in HIV-1 reservoir persistence during antiretroviral therapy (ART) is well-established, studies on tissue-resident macrophages (M{Phi}) in people with HIV-1 (PWH) are restricted by difficulties in accessing deep tissue samples. Investigations in myeloid-only humanized mouse models demonstrated the contribution of M{Phi} to viral rebound upon ART interruption. Two distinct M{Phi} subsets exist in mice and humans: one of embryonic origin and self-renewal capacity generating long-lived tissue-resident M{Phi} (LL-TRM), and another one of short-lived M{Phi} (SL-M{Phi}), constantly replenished by bone marrow monocytes. The relative contribution of LL-TRM versus SL-M{Phi} to tissue HIV-1 reservoir persistence during ART remains understudied. Here, we used a humanized BM-liver-thymus (hu-BLT) mouse model to quantify integrative HIV-1 infection in liver/lung M{Phi} versus CD4+ T-cells before/after ART and document their expression of LL-TRM/SL-M{Phi} markers. ResultsLung/liver immune cells were extracted from ART-naive (ART-) and ART-treated (ART+) HIV-infected (HIV+) hu-BLT mice, as well as HIV-uninfected mice (HIV-). M{Phi} were identified as cells expressing the myeloid markers CD33/HLA-DR and/or CD68 and flow-cytometry sorted based on their differential expression of CD14 and/or CCR2. Matched CD3+CD4+ T-cells were sorted in parallel and used as controls. HIV-DNA integration was measured by nested real-time PCR. In contrast to CD4+ T-cells that carried the highest levels of proviral HIV-DNA before and after ART, integrative infection in liver/lung M{Phi} was detected before ART, but was drastically reduced in HIV+ART+ hu-BLT mice, regardless of CD14 or CCR2 expression on M{Phi}. Markers of LL-TRM (CD163/CX3CR1/Ki67/c-Kit) were expressed on a small fraction of liver but not lung M{Phi}, indicative of a deficient LL-TRM development in this hu-BLT model. ConclusionsTogether our results demonstrate that lung/liver M{Phi} in hu-BLT mice support integrative HIV-1 infection in vivo, but their contribution to viral reservoir persistence during ART is minor when compared to CD4+ T-cells. This is consistent with the deficient development of LL-TRM we observed in hu-BLT mice. However, HIV-1 permissive M{Phi} present in this model likely contribute to viral rebound upon ART interruption. Therefore, HIV-1 cure interventions that are tested in such preclinical models should consider targeting HIV-1 replication in both M{Phi} and CD4+ T-cells.

immunology↗

bioRxiv2024

A Surface-based deep learning approach for cortical shape analysis

Advances in deep learning hold promise for predicting clinical factors from human brain images. In this study, we applied a spherical harmonics-based convolutional neural network approach (SPHARM-Net) to MRI-derived brain shape metrics to predict age, sex, and Alzheimers disease (AD) diagnosis. MRI-derived brain features included vertex-wise cortical curvature, convexity, thickness, and surface area. SPHARM-Net performs convolutions using the spherical harmonic transforms, eliminating the need to explicitly define neighborhood size, and achieving rotational equivariance. Sex classification and age regression were carried out in a large sample of healthy adults (UK Biobank; N=32,979), and AD classification performance was tested in a large, publicly available sample (ADNI; N=1,213). SPHARM-Net showed strong performance for sex classification (accuracy=0.91; balanced accuracy= 0.91; AUC=0.97), and age regression (average absolute error=2.97 years; R-squared=0.77; Pearsons coefficient=0.9). AD classification also performed well (accuracy=0.86; balanced accuracy=0.83; AUC=0.9). Our experiments demonstrate promising preliminary performance using the SPHARM-Net for two widely studied benchmarking tasks and for AD classification. Future work will include comparisons of shape-based methods and extending these analysis to more challenging tasks such as mood disorder classification.

neuroscience↗

bioRxiv2024

The Genetic Architecture of the Human Corpus Callosum and its Subregions

The corpus callosum (CC) is the largest set of white matter fibers connecting the two hemispheres of the brain. In humans, it is essential for coordinating sensorimotor responses, performing associative/executive functions, and representing information in multiple dimensions. Understanding which genetic variants underpin corpus callosum morphometry, and their shared influence on cortical structure and susceptibility to neuropsychiatric disorders, can provide molecular insights into the CCs role in mediating cortical development and its contribution to neuropsychiatric disease. To characterize the morphometry of the midsagittal corpus callosum, we developed a publicly available artificial intelligence based tool to extract, parcellate, and calculate its total and regional area and thickness. Using the UK Biobank (UKB) and the Adolescent Brain Cognitive Development study (ABCD), we extracted measures of midsagittal corpus callosum morphometry and performed a genome-wide association study (GWAS) meta-analysis of European participants (combined N = 46,685). We then examined evidence for generalization to the non-European participants of the UKB and ABCD cohorts (combined N = 7,040). Post-GWAS analyses implicate prenatal intracellular organization and cell growth patterns, and high heritability in regions of open chromatin, suggesting transcriptional activity regulation in early development. Results suggest programmed cell death mediated by the immune system drives the thinning of the posterior body and isthmus. Global and local genetic overlap, along with causal genetic liability, between the corpus callosum, cerebral cortex, and neuropsychiatric disorders such as attention-deficit/hyperactivity and bipolar disorders were identified. These results provide insight into variability of corpus callosum development, its genetic influence on the cerebral cortex, and biological mechanisms related to neuropsychiatric dysfunction.

neuroscience↗

bioRxiv2023

Guild and Niche Determination Enable Targeted Alteration of the Microbiome

Microbiome science has greatly contributed to our understanding of microbial life and its essential roles for the environment and human health1-5. However, the nature of microbial interactions and how microbial communities respond to perturbations remains poorly understood, resulting in an often descriptive and correlation-based approach to microbiome research6-8. Achieving causal and predictive microbiome science would require direct functional measurements in complex communities to better understand the metabolic role of each member and its interactions with others. In this study we present a new approach that integrates transcription and translation measurements to predict competition and substrate preferences within microbial communities, consequently enabling the selective manipulation of the microbiome. By performing metatranscriptomic (metaRNA-Seq) and metatranslatomic (metaRibo-Seq) analysis in complex samples, we classified microbes into functional groups (i.e. guilds) and demonstrated that members of the same guild are competitors. Furthermore, we predicted preferred substrates based on importer proteins, which specifically benefited selected microbes in the community (i.e. their niche) and simultaneously impaired their competitors. We demonstrated the scalability of microbial guild and niche determination to natural samples and its ability to successfully manipulate microorganisms in complex microbiomes. Thus, the approach enhances the design of pre- and probiotic interventions to selectively alter members within microbial communities, advances our understanding of microbial interactions, and paves the way for establishing causality in microbiome science.

microbiology↗

bioRxiv2022

Developmental role of macrophages modelled in human pluripotent stem cell derived intestinal tissue

Macrophages populate the embryo early in gestation but their role in the developmental process remains largely unknown. In particular, specification and function of macrophages in intestinal development remain unexplored. To study this event in human developmental context, we derived and combined human intestinal organoid and macrophages from pluripotent stem cells. Macrophages migrated into the organoid, proliferated, and occupied the emerging micro-anatomical niches of epithelial crypts and ganglia. They also acquired a similar transcriptomic profile to fetal intestinal macrophages and displayed tissue macrophage behaviors, such as recruitment to tissue injury. Using this model, we show that macrophages reduce glycolysis in mesenchymal cells and limit tissue growth without affecting tissue architecture, in contrast to the pro-growth effect of enteric neurons. In short, we engineered an intestinal tissue model populated with macrophages, and we suggest that resident macrophages contribute to regulation of metabolism and growth of the developing intestine.

developmental biology↗

bioRxiv2022

Molecular basis for antiviral activity of pediatric neutralizing antibodies targeting SARS-CoV-2 Spike receptor binding domain

Neutralizing antibodies (NAbs) hold great promise for clinical interventions against SARS-CoV- 2 variants of concern (VOCs). Understanding NAb epitope-dependent antiviral mechanisms is crucial for developing vaccines and therapeutics against VOCs. Here we characterized two potent NAbs, EH3 and EH8, isolated from an unvaccinated pediatric patient with exceptional plasma neutralization activity. EH3 and EH8 cross-neutralize the early VOCs and mediate strong Fc-dependent effector activity in vitro. Structural analyses of EH3 and EH8 in complex with the receptor-binding domain (RBD) revealed the molecular determinants of the epitope-driven protection and VOC-evasion. While EH3 represents the prevalent IGHV3-53 NAb whose epitope substantially overlaps with the ACE2 binding site, EH8 recognizes a narrow epitope exposed in both RBD-up and RBD-down conformations. When tested in vivo, a single-dose prophylactic administration of EH3 fully protected stringent K18-hACE2 mice from lethal challenge with Delta VOC. Our study demonstrates that protective NAbs responses converge in pediatric and adult SARS-CoV-2 patients.

microbiology↗

bioRxiv2022

Generation of Functional Human T Cell Development in NOD/SCID/IL2rγnull Humanized Mice Without Using Fetal Tissue: Application as a Model of HIV Infection and Persistence

Generating humanized mice with fully functional T cells currently relies on co-implantation of hematopoietic stem cells from fetal liver and autologous fetal thymic tissue (BLT mouse). However, access to such tissues has ethical and logistical challenges. Herein, we show that NOD/SCID/IL2r{gamma}null mice humanized with cord blood-derived CD34+ cells and implanted in quadriceps with pediatric thymic tissues excised during cardiac surgeries (CCST mice) are an alternative to BLT mice. Our data revealed a strong immune reconstitution in CCST mice, with T cells originating from CD34+ progenitor cells, proliferating efficiently in response to mitogenic stimulation ex vivo and capable of rejecting allogeneic human leukemic cells in vivo. Despite having less T cells than BLT mice, CCST mice were equally susceptible to mucosal or intraperitoneal HIV infection. Importantly, HIV-specific T cell responses were significantly higher in CCST-mice (median: 10.4% vs. 0.7%; p<0.0001 for CD8+cells and 3.9% vs. 0.7%; p<0.01 for CD4+ cells). As well, antiretroviral therapy (ART) robustly suppressed viremia and reduced the frequencies of cells carrying integrated HIV DNA by up to 2 logs in various CCST mouse tissues. As in BLT mice, we observed a complete viral rebound in 67% of the animals by 2-4 weeks following ART interruption, suggesting the presence of HIV reservoirs. In conclusion, CCST mice represent an ethical and practical alternative to BLT mice, broadening the feasibility of utilizing humanized mice for research on HIV and other human diseases. One Sentence SummaryWe herein report a new humanized mouse model implanted with human cord blood hematopoietic stem cells and allogenic pediatric thymic tissue that develops a functional T cell compartment and supports efficient HIV infection and persistence during antiretroviral therapy.

immunology↗

bioRxiv2022

Multisite Test-Retest Reliability and Compatibility of Brain Metrics derived from FreeSurfer Versions 7.1, 6.0, and 5.3

Automatic neuroimaging segmentation and parcellation tools provide convenient and systematic methods for extracting numerous features from brain MRI scans, and are becoming standard practice for large-scale coordinated studies. One such tool, FreeSurfer, provides an easy-to-use pipeline to extract metrics describing cortical and subcortical morphometry. Over the past two decades, there have been over 25 stable releases of FreeSurfer, and different versions are used across published works. Despite this, the reliability and compatibility of metrics derived from the most recent major version releases have yet to be assessed empirically. Here, we use test-retest data from three public brain MRI datasets to assess within-version reliability and between-version compatibility across 42 regional outputs from three versions of FreeSurfer: the latest, v7.1, and two previous stable releases - v5.3, and v6.0. We find v7.1 was less compatible with older versions for measuring cortical thickness. In particular, the thickness of the cingulate gyrus had low compatibility (intraclass correlation coefficient (ICC) between 0.37 and 0.61) between versions. Temporal and frontal poles, and the medial orbitofrontal surface area metrics, also showed low to moderate compatibility with v7.1. While our work compares all three versions, our sub-comparisons between the older versions (v5.3 and v6.0) replicates earlier findings of low compatibility of pallidum and putamen volumes. Low between-version compatibility was not always indicative of low within-version reliability - all versions showed good to excellent reliability across most regional measures (ICC>0.8). Age associations, quality control metrics, and Dice coefficients in an independent sample of 106 individual scans, processed with all three versions of FreeSurfer, revealed differences in results of downstream statistical analysis. As neuroimaging studies adopt more recently released software, we provide researchers with a reference to highlight the regions and metrics that may yield findings inconsistent with published works using older FreeSurfer software. An interactive viewer for the results is provided at http://data.brainescience.org/Freesurfer_Reliability/

neuroscience↗

bioRxiv2022

Genome-wide CRISPR Screens Identify Ferroptosis as a Novel Therapeutic Vulnerability in Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most frequent cancer diagnosed in children. Despite the great progress achieved over the last 40 years, with cure rates now exceeding 85%, refractory or relapsed ALL still exhibit a dismal prognosis. This poor outcome reflects the lack of treatment options specifically targeting relapsed or refractory ALL. To address this gap, we have performed whole-genome CRISPR/Cas drop-out screens on a panel of seven B-ALL cell lines. Our results demonstrate that while there was a significant overlap in gene essentiality between ALL cell lines and other cancer types survival of ALL cell lines was dependent on several unique metabolic pathways, including an exquisite sensitivity to GPX4 depletion and ferroptosis induction and GPX4 KO. Detailed molecular analysis of B-ALL cells suggest that they are primed to undergo ferroptosis as they exhibit high steady-state oxidative stress potential, a low buffering capacity, and a disabled GPX-independent secondary lipid peroxidation detoxification pathway. Finally, we validated the sensitivity of B-ALL to ferroptosis induction using patient-derived B-ALL samples.

cancer biology↗

bioRxiv2021

Early Life Adversity in Male Mice Sculpts Reward Circuits.

Early life adversity (ELA) comprises a wide variety of negative experiences during early life and has been linked to cognitive impairments, reduced experiences of pleasure (anhedonia), and other long-term consequences implying that ELA impacts the reward circuitry. In this study, we focused on the projections from the dorsal raphe (DR) to the ventral tegmental area (VTA) and on to the nucleus accumbens (NAcc), an important pathway within the reward circuit. We hypothesized that ELA alters connectivity within the DR-VTA- NAcc pathway, manifested behaviorally as anhedonia in adulthood. We used the limited bedding and nesting model to induce ELA in mice and measured reward-related behaviors in adulthood using the three-chamber social interaction and sucrose preference tests. High resolution ex vivo diffusion tensor imaging (DTI) was acquired and processed for regional DTI metrics, including tractography to assess circuit organization. We found brain-wide changes in radial diffusivity (RD) and altered connectivity of the reward circuit in the ELA group. DR-VTA-NAcc circuit tractography and axial diffusivity (AD) along this tract exhibited dispersed organization where AD was increased in the VTA segment. Behaviorally, ELA elicited an anhedonic phenotype in adulthood with decreased direct social approach and time spent with peer but no overt differences in sucrose preference test. Our findings suggest that reward circuits, assessed using DTI, are altered following ELA and that these changes may drive enduring reward deficits.

neuroscience↗

bioRxiv2021

Autologous humanized mouse models of iPSC-derived tumors allow for the evaluation and modulation of cancer-immune cell interactions

Modeling the tumor-immune cell interactions in humanized mice is complex and limits drug development. Here, we generated easily accessible tumor models by transforming either primary skin fibroblasts or iPSC-derived cell lines injected in immune-deficient mice reconstituted with human autologous immune cells. Our results showed that either fibroblastic, hepatic or neural tumors were all efficiently infiltrated and partially or totally rejected by autologous immune cells in humanized mice. Characterization of tumor immune infiltrates revealed high expression levels of the dysfunction markers Tim3 and PD-1 in T cells and an enrichment in regulatory T cell suggesting rapid establishment of an immunosuppressive microenvironment. Inhibition of PD-1 by Nivolumab in humanized mice resulted in an increased immune cell infiltration and a slight decrease in tumor growth. We expect these versatile and accessible cancer models will facilitate preclinical studies and the evaluation of autologous cancer immunotherapies across a range of different tumor cell types. SIGNIFICANCE STATEMENTPreclinical models capable of providing an environment where human tumors are confronted with autologous immune cells are not easily accessible and limit drug development. As an alternative we generated genetically-defined tumor cell lines from primary and iPSC-derived cells for the evaluation of cancer-immune cell interactions in autologous humanized mice.

cancer biology↗

bioRxiv2020

Exogenous sex hormone effects on brain microstructure in women: a diffusion MRI study in the UK Biobank

Changes in estrogen levels in women have been associated with increased risk for age-related neurodegenerative diseases, including Alzheimers disease, but the impact of exogenous estrogen exposure on the brain is poorly understood. Oral contraceptives (OC) and hormone therapy (HT) and are both common sources of exogenous estrogen for women in reproductive and post-menopausal years, respectively. Here we examined the association of exogenous sex hormone exposure with the brains white matter (WM) aging trajectories in postmenopausal women using and not using OC and HT (HT users: n=3,033, non-users n=5,093; OC users: n=6,964; non-users n=1,156), while also investigating multiple dMRI models. Cross-sectional brain dMRI data was analyzed from the UK Biobank using conventional diffusion tensor imaging (DTI), the tensor distribution function (TDF), and neurite orientation dispersion and density imaging (NODDI). Mean skeletonized diffusivity measures were extracted across the whole brain, and fractional polynomial regressions were used to characterize age-related trajectories for WM microstructural measures. Advanced dMRI model NODDI revealed a steeper WM aging trajectory in HT users relative to non-users, and for those using unopposed estrogens relative to combined estrogens treatment. By contrast, no interaction was detected between OC status and age effects on the diffusivity measures we examined. Exogenous sex hormone exposure may negatively impact WM microstructure aging in postmenopausal women. We also present normative reference curves for white matter microarchitectural parameters in women, to help identify individuals with microstructural anomalies.

neuroscience↗