Project description:According to the developmental origins of health and disease (DOHaD) hypothesis, exposure to environmental stressors during early development can cause genetic, epigenetic, or functional changes in tissues that increase disease risk later in life. Atrazine (ATZ) is a commonly used pesticide that frequently contaminates rural and urban water sources at levels above the 3 ppb maximum contaminant level set by the US Environmental Protection Agency. Exposure to ATZ is linked to endocrine disruption, cancer, changes in genome methylation, and alterations in neurochemistry and behavior. This study tests the hypothesis that embryonic exposure to ATZ results in sex-specific changes in behavior, the adult brain transcriptome, and adult body and brain pathology, according to the DOHaD hypothesis. Zebrafish (Danio rerio) embryos were exposed to 0, 0.3, 3, or 30 ppb (ppb; µg/L) ATZ during the period from fertilization through 72 hours post fertilization (hpf), and then were rinsed and raised to maturity with no further exposure. At 9 months post fertilization (mpf), a novel tank test, a light-dark box, and an open field test evaluated adult behavior. Transcriptomic analysis investigated ATZ related differences in gene expression and the brain was evaluated histopathologically for morphometric alterations in the area of the dorsal telencephalon, posterior tuberculum, and raphe populations. At 14 mpf, the body length, weight, and brain weight was measured to evaluate effects of ATZ on mature body and brain size. The 9 mpf adult behavioral tests found non-monotonic, sex-specific behavior changes, with male zebrafish having decreased activity and female zebrafish having increased signs of anxiety. Transcriptomic analysis identified sex-specific alterations, with females having altered expression of genes in pathways related to cancer and organismal injury and males having altered gene expression in organismal development and reproductive system development and function pathways. Morphometric analysis identified a decreased number of cells in male raphe populations and adult zebrafish also had non-monotonic, sex-specific alterations in body length, body weight, and brain weight. This results suggests that developmental exposure to ATZ does cause sex-specific alterations in adult neural function.

Project description:Patients with locally/regionally advanced melanoma were treated with neoadjuvant combination immunotherapy with high-dose interferon α-2b (HDI) and ipilimumab in a phase I clinical trial. Tumor specimens were obtained prior to the initiation of neoadjuvant therapy, at the time of surgery and progression if available. In this study, gene expression profiles of tumor specimens (N = 27) were investigated using the NanoString nCounter® platform to evaluate associations with clinical outcomes (pathologic response, radiologic response, relapse-free survival (RFS), and overall survival (OS)) and define biomarkers associated with tumor response. The Tumor Inflammation Signature (TIS), an 18-gene signature that enriches for response to Programmed cell death protein 1 (PD-1) checkpoint blockade, was also evaluated for association with clinical response and survival. It was observed that neoadjuvant ipilimumab-HDI therapy demonstrated an upregulation of immune-related genes, chemokines, and transcription regulator genes involved in immune cell activation, function, or cell proliferation. Importantly, increased expression of baseline pro-inflammatory genes CCL19, CD3D, CD8A, CD22, LY9, IL12RB1, C1S, C7, AMICA1, TIAM1, TIGIT, THY1 was associated with longer OS (p < 0.05). In addition, multiple genes that encode a component or a regulator of the extracellular matrix such as MMP2 and COL1A2 were identified post-treatment as being associated with longer RFS and OS. In all baseline tissues, high TIS scores were associated with longer OS (p = 0.0166). Also, downregulated expression of cell proliferation-related genes such as CUL1, CCND1 and AAMP at baseline was associated with pathological and radiological response (unadjusted p < 0.01). In conclusion, we identified numerous genes that play roles in multiple biological pathways involved in immune activation, immune suppression and cell proliferation correlating with pathological/radiological responses following neoadjuvant immunotherapy highlighting the complexity of immune responses modulated by immunotherapy. Our observations suggest that TIS may be a useful biomarker for predicting survival outcomes with combination immunotherapy.

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Microplastics induce transcriptional changes, immune response and behavioral alterations in adult zebrafish.

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Microplastics induce transcriptional changes, immune response and behavioral alterations in adult zebrafish.

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