13 research outputs found
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Systematic genomic and translational efficiency studies of uveal melanoma
To further our understanding of the somatic genetic basis of uveal melanoma, we sequenced the protein-coding regions of 52 primary tumors and 3 liver metastases together with paired normal DNA. Known recurrent mutations were identified in GNAQ, GNA11, BAP1, EIF1AX, and SF3B1. The role of mutated EIF1AX was tested using loss of function approaches including viability and translational efficiency assays. Knockdown of both wild type and mutant EIF1AX was lethal to uveal melanoma cells. We probed the function of N-terminal tail EIF1AX mutations by performing RNA sequencing of polysome-associated transcripts in cells expressing endogenous wild type or mutant EIF1AX. Ribosome occupancy of the global translational apparatus was sensitive to suppression of wild type but not mutant EIF1AX. Together, these studies suggest that cells expressing mutant EIF1AX may exhibit aberrant translational regulation, which may provide clonal selective advantage in the subset of uveal melanoma that harbors this mutation
What\u27s Up With Fat?
Background: Didactic dietetic students felt that dietary fat phobia is an apparent issue at Utah State University that needed to be addressed. Additionally, using a variety of teaching methods such as interactive games, food tasting, and informational pamphlets to reach a variety of individual learning preferences.
Purpose: The purpose of this study was to determine the impact of booths on educating about fat and fat containing foods in Food Day attendees.
Setting: Food Day 2016 at Utah State University in the Taggart Student Center Hub
Methods: Food Day participants (84) completed a pre-survey (including a 27 item food frequency questionnaire (FFQ) and 16 questions on knowledge, self-efficacy and intent to change) before entering and a post-survey before leaving. Participants (47) completed a follow-up survey 4 weeks later. Repeated measures ANOVA was used to evaluate knowledge, self-efficacy, and intent to change questions. Paired t-test found mean differences in pre and follow-up FFQ.
Results: Participants spent an average of 21 minutes at Food Day. Knowledge and self- efficacy showed more of a short-term effect as opposed to a longer-term. At follow-up, participants reported consuming less whole milk, full fat dairy products, nuts, medium and high fat meats (p
Conclusion: Food Day 2016 had a positive effect on students\u27 perception of fat in foods and the effect on health but less impact on food habits related to fat intake
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Neuropathic pain drives anxiety behavior in mice, results consistent with anxiety levels in diabetic neuropathy patients
Abstract Background: Epidemiological studies in patients with neuropathic pain demonstrate a strong association with psychiatric conditions such as anxiety; however, the precipitating pathology between these symptoms remains unclear. To investigate this, we studied the effects of lifelong stress on levels of neuropathic pain–like behavior and conversely, the effects of chronic neuropathic injury on anxiety-like status in male and female mice. In addition, we assayed this link in painful and painless diabetic peripheral neuropathy patients. Methods: Male and female mice were subject to ongoing life-stress or control living conditions. Baseline sensitivity and anxiety tests were measured followed by spared nerve injury (SNI) to the sciatic nerve. Subsequent sensory testing occurred until 3 weeks after SNI followed by anxiety tests between 4 and 6 weeks after SNI. Results: Levels of tactile or cold allodynia did not differ between adult mice subject to lifelong chronic stress, relative to nonstressed controls, for at least 3 weeks after SNI. By contrast, longer-term neuropathic mice of both sexes displayed pronounced anxiety-like behavior, regardless of exposure to stress. If sex differences were present, females usually exhibited more pronounced anxiety-like behavior. These ongoing anxiety behaviors were corroborated with plasma corticosterone levels in distinct animal groups. In addition, data from patients with painful and nonpainful diabetic neuropathy showed a clear relationship between ongoing pain and anxiety, with females generally more affected than males. Discussion: Taken together, these data demonstrate a strong link between chronic neuropathic pain and chronic anxiety, with the driver of this comorbidity being neuropathic pain as opposed to on-going stress
Mechanistic Differences in Neuropathic Pain Modalities Revealed by Correlating Behavior with Global Expression Profiling
SUMMARY Chronic neuropathic pain is a major morbidity of neural injury, yet its mechanisms are incompletely understood. Hypersensitivity to previously non-noxious stimuli (allodynia) is a common symptom. Here, we demonstrate that the onset of cold hypersensitivity precedes tactile allodynia in a model of partial nerve injury, and this temporal divergence was associated with major differences in global gene expression in innervating dorsal root ganglia. Transcripts whose expression change correlates with the onset of cold allodynia were nociceptor related, whereas those correlating with tactile hypersensitivity were immune cell centric. Ablation of TrpV1 lineage nociceptors resulted in mice that did not acquire cold allodynia but developed normal tactile hypersensitivity, whereas depletion of macrophages or T cells reduced neuropathic tactile allodynia but not cold hypersensitivity. We conclude that neuropathic pain incorporates reactive processes of sensory neurons and immune cells, each leading to distinct forms of hypersensitivity, potentially allowing drug development targeted to each pain type
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Pulmonary Fibrosis Stakeholder Summit: A Joint NHLBI, Three Lakes Foundation, and Pulmonary Fibrosis Foundation Workshop Report.
Despite progress in elucidation of disease mechanisms, identification of risk factors, biomarker discovery, and the approval of two medications to slow lung function decline in idiopathic pulmonary fibrosis and one medication to slow lung function decline in progressive pulmonary fibrosis, pulmonary fibrosis remains a disease with a high morbidity and mortality. In recognition of the need to catalyze ongoing advances and collaboration in the field of pulmonary fibrosis, the NHLBI, the Three Lakes Foundation, and the Pulmonary Fibrosis Foundation hosted the Pulmonary Fibrosis Stakeholder Summit on November 8-9, 2022. This workshop was held virtually and was organized into three topic areas: 1) novel models and research tools to better study pulmonary fibrosis and uncover new therapies, 2) early disease risk factors and methods to improve diagnosis, and 3) innovative approaches toward clinical trial design for pulmonary fibrosis. In this workshop report, we summarize the content of the presentations and discussions, enumerating research opportunities for advancing our understanding of the pathogenesis, treatment, and outcomes of pulmonary fibrosis
EIF1AX-regulated growth and translation in uveal melanoma.
<p><b>(A)</b> Distribution of <i>EIF1AX</i> mutations observed in cohort of 52 uveal melanomas in comparison to other cancer types (as reported by <a href="http://www.tumorportal.org" target="_blank">http://www.tumorportal.org</a>). <b>(B)</b> <i>EIF1AX</i> wild type (WT) or mutant (MUT) uveal melanoma cells were infected with <i>EIF1AX</i> or control shRNAs and cell viability was determined after 6 days using MTS. Percent growth is relative to shLuc-expressing cells. Error bars represent SD of mean from 3 independent experiments. <b>(C)</b> Immunoblot analysis of EIF1AX protein levels in shRNA-expressing cells. <b>(D)</b> Polysome profiles of cell lines expressing shRNAs against <i>EIF1AX</i> and <i>Luciferase</i>.</p
Somatic mutations in primary and metastatic uveal melanoma.
<p><b>(A)</b> The number of synonymous and nonsynonymous mutations per megabase of DNA sequence for 52 samples, arranged in columns. <b>(B)</b> Mutations in recurrently mutated genes are color-coded and ordered by significance. <b>(C)</b> Boxplots represent the distributions of allelic fractions observed per sample where the thick line represents 25-75<sup>th</sup> percentile, and thin line 5-95<sup>th</sup>. <b>(D)</b> The percentage of tumor cells (CCF) harboring a given mutation in the primary tumor in comparison to a metastatic liver sample from the same patient (UM45). <b>(E)</b> As in (D), but comparing a pre-treatment metastatic tumor sample to a post-treatment metastasis (Trio 2).</p
Decreased EIF1AX expression impairs translation of protein synthesis machinery in wildtype, but not mutated setting.
<p><b>(A)</b> Principal component analysis depicts 4 color-coded clusters of 141 genes. <b>(B)</b> The trend in translational efficiency is depicted for each cluster in cells expressing control shRNAs (CN) or <i>EIF1AX</i> shRNAs (KD). Each line represents a different gene. Ribosomal protein genes are highlighted in red. Translational efficiency was calculated as polysome CPM / total CPM. <b>(C)</b> Boxplots demonstrate the distribution of the translational efficiencies of 78 ribosomal proteins in cells as in (B).</p
A Landscape of Driver Mutations in Melanoma
Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic UV light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19, and ARID2), three of which—RAC1, PPP6C, and STK19—harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis.National Human Genome Research Institute (U.S.) (Large Scale Sequencing Program Grant U54 HG003067)Melanoma Research AllianceNational Cancer Institute (U.S.) (Support Grant CA-16672