To address climate change concerns, and reduce the carbon footprint caused by fossil fuel use, it is likely that blend ratios of renewable biodiesel with commercial mineral diesel fuel will steadily ...increase, resulting in biodiesel use becoming more widespread. Exhaust toxicity of unblended biodiesels changes depending on feedstock type, however the effect of feedstock on blended fuels is less well known. The aim of this study was to assess the impact of biodiesel feedstock on exhaust toxicity of 20% blended biodiesel fuels (B20). Primary human airway epithelial cells were exposed to exhaust diluted 1/15 with air from an engine running on conventional ultra-low sulfur diesel (ULSD) or 20% blends of soy, canola, waste cooking oil (WCO), tallow, palm or cottonseed biodiesel in diesel. Physico-chemical exhaust properties were compared between fuels and the post-exposure effect of exhaust on cellular viability and media release was assessed 24 h later. Exhaust properties changed significantly between all fuels with cottonseed B20 being the most different to both ULSD and its respective unblended biodiesel. Exposure to palm B20 resulted in significantly decreased cellular viability (96.3 ± 1.7%; p < 0.01) whereas exposure to soy B20 generated the greatest number of changes in mediator release (including IL-6, IL-8 and TNF-α, p < 0.05) when compared to air exposed controls, with palm B20 and tallow B20 closely following. In contrast, canola B20 and WCO B20 were the least toxic with only mediators G-CSF and TNF-α being significantly increased. Therefore, exposure to palm B20, soy B20 and tallow B20 were found to be the most toxic and exposure to canola B20 and WCO B20 the least. The top three most toxic and the bottom three least toxic B20 fuels are consistent with their unblended counterparts, suggesting that feedstock type greatly impacts exhaust toxicity, even when biodiesel only comprises 20% of the fuel.
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•Exhaust characteristics changed significantly between different feedstock types.•Cottonseed biodiesel blend exhaust was the most different to commercial diesel.•Biodiesel feedstock type altered exhaust toxicity when making up 20% of the fuel.•Canola biodiesel was the least toxic type tested and Palm and Soy were the most.
Focal cortical dysplasia (FCD), hemimegalencephaly, and megalencephaly constitute a spectrum of malformations of cortical development with shared neuropathologic features. These disorders are ...associated with significant childhood morbidity and mortality.
To identify the underlying molecular cause of FCD, hemimegalencephaly, and diffuse megalencephaly.
Patients with FCD, hemimegalencephaly, or megalencephaly (mean age, 11.7 years; range, 2-32 years) were recruited from Pediatric Hospital A. Meyer, the University of Hong Kong, and Seattle Children's Research Institute from June 2012 to June 2014. Whole-exome sequencing (WES) was performed on 8 children with FCD or hemimegalencephaly using standard-depth (50-60X) sequencing in peripheral samples (blood, saliva, or skin) from the affected child and their parents and deep (150-180X) sequencing in affected brain tissue. Targeted sequencing and WES were used to screen 93 children with molecularly unexplained diffuse or focal brain overgrowth. Histopathologic and functional assays of phosphatidylinositol 3-kinase-AKT (serine/threonine kinase)-mammalian target of rapamycin (mTOR) pathway activity in resected brain tissue and cultured neurons were performed to validate mutations.
Whole-exome sequencing and targeted sequencing identified variants associated with this spectrum of developmental brain disorders.
Low-level mosaic mutations of MTOR were identified in brain tissue in 4 children with FCD type 2a with alternative allele fractions ranging from 0.012 to 0.086. Intermediate-level mosaic mutation of MTOR (p.Thr1977Ile) was also identified in 3 unrelated children with diffuse megalencephaly and pigmentary mosaicism in skin. Finally, a constitutional de novo mutation of MTOR (p.Glu1799Lys) was identified in 3 unrelated children with diffuse megalencephaly and intellectual disability. Molecular and functional analysis in 2 children with FCD2a from whom multiple affected brain tissue samples were available revealed a mutation gradient with an epicenter in the most epileptogenic area. When expressed in cultured neurons, all MTOR mutations identified here drive constitutive activation of mTOR complex 1 and enlarged neuronal size.
In this study, mutations of MTOR were associated with a spectrum of brain overgrowth phenotypes extending from FCD type 2a to diffuse megalencephaly, distinguished by different mutations and levels of mosaicism. These mutations may be sufficient to cause cellular hypertrophy in cultured neurons and may provide a demonstration of the pattern of mosaicism in brain and substantiate the link between mosaic mutations of MTOR and pigmentary mosaicism in skin.
The Colorectal MicroRNAome Cummins, Jordan M.; He, Yiping; Leary, Rebecca J. ...
Proceedings of the National Academy of Sciences - PNAS,
03/2006, Letnik:
103, Številka:
10
Journal Article
Recenzirano
Odprti dostop
MicroRNAs (miRNAs) are a class of small noncoding RNAs that have important regulatory roles in multicellular organisms. The public miRNA database contains 321 human miRNA sequences, 234 of which have ...been experimentally verified. To explore the possibility that additional miRNAs are present in the human genome, we have developed an experimental approach called miRNA serial analysis of gene expression (miRAGE) and used it to perform the largest experimental analysis of human miRNAs to date. Sequence analysis of 273,966 small RNA tags from human colorectal cells allowed us to identify 200 known mature miRNAs, 133 novel miRNA candidates, and 112 previously uncharacterized miRNA* forms. To aid in the evaluation of candidate miRNAs, we disrupted the Dicer locus in three human colorectal cancer cell lines and examined known and novel miRNAs in these cells. These studies suggest that the human genome contains many more miRNAs than currently identified and provide an approach for the large-scale experimental cloning of novel human miRNAs in human tissues.
Abstract
Liquid biopsy, particularly the analysis of circulating tumor DNA (ctDNA), has demonstrated considerable promise for numerous clinical intended uses. Successful validation and ...commercialization of novel ctDNA tests have the potential to improve the outcomes of patients with cancer. The goal of the Blood Profiling Atlas Consortium (BloodPAC) is to accelerate the development and validation of liquid biopsy assays that will be introduced into the clinic. To accomplish this goal, the BloodPAC conducts research in the following areas: Data Collection and Analysis within the BloodPAC Data Commons; Preanalytical Variables; Analytical Variables; Patient Context Variables; and Reimbursement. In this document, the BloodPAC’s Analytical Variables Working Group (AV WG) attempts to define a set of generic analytical validation protocols tailored for ctDNA-based Next-Generation Sequencing (NGS) assays. Analytical validation of ctDNA assays poses several unique challenges that primarily arise from the fact that very few tumor-derived DNA molecules may be present in circulation relative to the amount of nontumor-derived cell-free DNA (cfDNA). These challenges include the exquisite level of sensitivity and specificity needed to detect ctDNA, the potential for false negatives in detecting these rare molecules, and the increased reliance on contrived samples to attain sufficient ctDNA for analytical validation. By addressing these unique challenges, the BloodPAC hopes to expedite sponsors’ presubmission discussions with the Food and Drug Administration (FDA) with the protocols presented herein. By sharing best practices with the broader community, this work may also save the time and capacity of FDA reviewers through increased efficiency.
In the context of cancer, clonal hematopoiesis of indeterminate potential (CHIP) is associated with the development of therapy-related myeloid neoplasms and shorter overall survival. Cell-free DNA ...(cfDNA) sequencing is becoming widely adopted for genomic screening of patients with cancer but has not been used extensively to determine CHIP status because of a requirement for matched blood and tumor sequencing. We present an accurate classification approach to determine the CH status from cfDNA sequencing alone, applying our model to 4324 oncology clinical cfDNA samples. Using this method, we determined that 30.3% of patients in this cohort have evidence of CH, and the incidence of CH varies by tumor type. Matched RNA sequencing data show evidence of increased inflammation, especially neutrophil activation, within the tumors and tumor microenvironments of patients with CH. In addition, patients with CH had evidence of neutrophil activation systemically, pointing to a potential mechanism of action for the worse outcomes associated with CH status. Neutrophil activation may be one of many mechanisms, however, because patients with estrogen receptor-positive breast cancer harboring
frameshift mutations had worse outcomes but similar neutrophil frequencies to patients without CH. Together, these data show the feasibility of detecting CH through cfDNA sequencing alone and an application of this method, demonstrating increased inflammation in patients with CH both systemically and in the tumor microenvironment.
Increasing Student Use of a Learner Dashboard Sansom, Rebecca L.; Bodily, Robert; Bates, Caroline O. ...
Journal of science education and technology,
06/2020, Letnik:
29, Številka:
3
Journal Article
Recenzirano
Use of online learning systems, such as learner dashboards, is increasing in university chemistry courses. Learning analytics can support student learning by providing feedback on concept mastery. ...This paper investigated how student use of a chemistry learner dashboard might be increased through class structure, instructor practice, and dashboard design changes across three iterations in a general chemistry course. Once acceptable levels of student dashboard use were achieved, further investigation of how students interacted with the dashboard, including accessing the variety of available resources, was conducted. Survey data and clickstream data from the dashboard were collected and analyzed in a convergent mixed methods design. This study found that changes in course structure, teacher practice, and dashboard design increased use of the dashboard and utilization of the variety of materials offered in it. Recommendations for instructors to effectively utilize a learner dashboard and increase student trust in the system are provided.
The conect4children (c4c) initiative was established to facilitate the development of new drugs and other therapies for paediatric patients. It is widely recognised that there are not enough ...medicines tested for all relevant ages of the paediatric population. To overcome this, it is imperative that clinical data from different sources are interoperable and can be pooled for larger post hoc studies. c4c has collaborated with the Clinical Data Interchange Standards Consortium (CDISC) to develop cross-cutting data resources that build on existing CDISC standards in an effort to standardise paediatric data. The natural next step was an extension to disease-specific data items. c4c brought together several existing initiatives and resources relevant to disease-specific data and analysed their use for standardising disease-specific data in clinical trials. Several case studies that combined disease-specific data from multiple trials have demonstrated the need for disease-specific data standardisation. We identified three relevant initiatives. These include European Reference Networks, European Joint Programme on Rare Diseases, and Pistoia Alliance. Other resources reviewed were National Cancer Institute Enterprise Vocabulary Services, CDISC standards, pharmaceutical company-specific data dictionaries, Human Phenotype Ontology, Phenopackets, Unified Registry for Inherited Metabolic Disorders, Orphacodes, Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP), and Observational Medical Outcomes Partnership. The collaborative partners associated with these resources were also reviewed briefly. A plan of action focussed on collaboration was generated for standardising disease-specific paediatric clinical trial data. A paediatric data standards multistakeholder and multi-project user group was established to guide the remaining actions—FAIRification of metadata, a Phenopackets pilot with RDCA-DAP, applying Orphacodes to case report forms of clinical trials, introducing CDISC standards into European Reference Networks, testing of the CDISC Pediatric User Guide using data from the mentioned resources and organisation of further workshops and educational materials.
In its decades-long effort to assure the safety, efficacy, and security of medicines and other products, the Food and Drug Administration has struggled with issues of funding, proper associations ...with industry, and the balance between consumer choice and consumer protection. Today, these challenges are compounded by the pressures of globalization, the introduction of novel technologies, and fast-evolving threats to public health. With essays by leading scholars and government and private-industry experts,FDA in the Twenty-First Centuryaddresses perennial and new problems and the improvements the agency can make to better serve the public good.
The collection features essays on effective regulation in an era of globalization, consumer empowerment, and comparative effectiveness, as well as questions of data transparency, conflicts of interest, industry responsibility, and innovation policy, all with an emphasis on pharmaceuticals. The book also intervenes in the debate over off-label drug marketing and the proper role of the FDA before and after a drug goes on the market. Dealing honestly and thoroughly with the FDA's successes and failures, these essays rethink the structure, function, and future of the agency and the effect policy innovations may have on regulatory institutions abroad.
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