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BACKGROUND: MGMT (O 6 -methylguanine-DNA methyltransferase) promoter methylation is a commonly assessed prognostic marker in glioblastoma (GBM). Epigenetic silencing of the MGMT gene by promoter methylation is associated with greater overall and progression free survival with alkylating agent regimens. To date, there is marked heterogeneity in how MGMT promoter methylation is tested and which CpG sites are interrogated. METHODS: To further elucidate which MGMT promoter CpG sites are of greatest interest, we performed comprehensive searches in PubMed, Web of Science, and Embase and reviewed 2,925 article abstracts. We followed the GRADE scoring system to assess risk of bias and the quality of the studies we included. RESULTS: We included articles on adult glioblastoma that examined significant sites or regions within MGMT promoter for the outcomes: overall survival, progression free survival, and/or MGMT expression. We excluded systemic reviews and articles on lower grade glioma. fifteen articles met inclusion criteria with variable overlap in laboratory and statistical methods employed, as well as CpG sites interrogated. Pyrosequencing or BeadChip arrays were the most popular methods utilized, and CpG sites between CpGs 70-90 were most frequently investigated. Overall, there was moderate concordance between the CpG sites that the studies reported to be highly predictive of prognosis. Combinations or means of sites between CpGs 73-89 were associated with improved OS and PFS. Six studies identified CpG sites associated with prognosis that were closer to the transcription start site: CpGs 8, 19, 22, 25, 27, 32,38, and CpG sites 21-37, as well as low methylation level of the enhancer regions. CONCLUSION: The following systematic review details a comprehensive investigation of the current literature and highlights several potential key CpG sites that demonstrate significant association with OS, PFS, and MGMT expression. However, the relationship between extent of MGMT promoter methylation and survival may be non-linear and could be influenced by potential CpG hotspots, the extent of methylation at each CpG site, and MGMT enhancer methylation status. There were several limitations within the studies such as smaller sample sizes, variance between methylation testing methods, and differences in the various statistical methods to test for association to outcome. Further studies of high impact CpG sites in MGMT methylation is warranted.

This paper discusses a three-level model that synthesizes and unifies existing learning theories to model the roles of artificial intelligence (AI) in promoting learning processes. The model, drawn from developmental psychology, computational biology, instructional design, cognitive science, complexity and sociocultural theory, includes a causal learning mechanism that explains how learning occurs and works across micro, meso and macro levels. The model also explains how information gained through learning is aggregated, or brought together, as well as dissipated, or released and used within and across the levels. Fourteen roles for AI in education are proposed, aligned with the model's features: four roles at the individual or micro level, four roles at the meso level of teams and knowledge communities and six roles at the macro level of cultural historical activity. Implications for research and practice, evaluation criteria and a discussion of limitations are included. Armed with the proposed model, AI developers can focus their work with learning designers, researchers and practitioners to leverage the proposed roles to improve individual learning, team performance and building knowledge communities.

BACKGROUND: Epigenetic inhibition of the O6-methylguanine-DNA-methyltransferase (MGMT) gene has emerged as a clinically relevant prognostic marker in glioblastoma (GBM). Methylation of the MGMT promoter has been shown to increase chemotherapy efficacy. While traditionally reported as a binary marker, recent methodological advancements have led to quantitative methods of measuring promoter methylation, providing clearer insight into its functional relationship with survival. METHODS: A CLIA assay and bisulfite sequencing was utilized to develop a quantitative, 17-point, MGMT promoter methylation index. GBMs of 240 newly diagnosed patients were sequenced and risk for mortality was assessed. Nonlinearities were captured by fitting splines to Cox proportional hazard models and plotting smoothed residuals. Covariates included age, Karnofsky performance status, IDH1 mutation, and extent of resection. RESULTS: Median follow-up time and progression-free survival were 16 and 9 months, respectively. A total of 176 subjects experienced death. A one-unit increase in promoter CpG methylation resulted in a 4% reduction in hazard (95% CI 0.93-0.99, P

This article reports on a trace-based assessment of approaches to learning used by middle school aged children who interacted with NASA Mars Mission science, technology, engineering and mathematics (STEM) games in "Whyville," an online game environment with 8 million registered young learners. The learning objectives of two games included awareness and knowledge of NASA missions, developing knowledge and skills of measurement and scaling, applying measurement for planetary comparisons in the solar system. Trace data from 1361 interactions were analysed with nonparametric multidimensional scaling methods, which permitted visual examination and statistical validation, and provided an example and proof of concept for the multidimensional scaling approach to analysis of time-based behavioural data from a game or simulation. Differences in approach to learning were found illustrating the potential value of the methodology to curriculum and game-based learning designers as well as other creators of online STEM content for pre-college youth. The theoretical framework of the method and analysis makes use of the Epistemic Network Analysis toolkit as a post hoc data exploration platform, and the discussion centres on issues of semantic interpretation of interaction end-states and the application of evidence centred design in post hoc analysis.

BACKGROUNDLong-term prognosis of WHO grade II low-grade gliomas (LGGs) is poor, with a high risk of recurrence and malignant transformation into high-grade gliomas. Given the relatively intact immune system of patients with LGGs and the slow tumor growth rate, vaccines are an attractive treatment strategy.METHODSWe conducted a pilot study to evaluate the safety and immunological effects of vaccination with GBM6-AD, lysate of an allogeneic glioblastoma stem cell line, with poly-ICLC in patients with LGGs. Patients were randomized to receive the vaccines before surgery (arm 1) or not (arm 2) and all patients received adjuvant vaccines. Coprimary outcomes were to evaluate safety and immune response in the tumor.RESULTSA total of 17 eligible patients were enrolled - 9 in arm 1 and 8 in arm 2. This regimen was well tolerated with no regimen-limiting toxicity. Neoadjuvant vaccination induced upregulation of type-1 cytokines and chemokines and increased activated CD8+ T cells in peripheral blood. Single-cell RNA/T cell receptor sequencing detected CD8+ T cell clones that expanded with effector phenotype and migrated into the tumor microenvironment (TME) in response to neoadjuvant vaccination. Mass cytometric analyses detected increased tissue resident-like CD8+ T cells with effector memory phenotype in the TME after the neoadjuvant vaccination.CONCLUSIONThe regimen induced effector CD8+ T cell response in peripheral blood and enabled vaccine-reactive CD8+ T cells to migrate into the TME. Further refinements of the regimen may have to be integrated into future strategies.TRIAL REGISTRATIONClinicalTrials.gov NCT02549833.FUNDINGNIH (1R35NS105068, 1R21CA233856), Dabbiere Foundation, Parker Institute for Cancer Immunotherapy, and Daiichi Sankyo Foundation of Life Science.

Abstract BACKGROUND Epigenetic inhibition of the O6-methylguanine-DNA-methyltransferase (MGMT) gene has emerged as a clinically relevant prognostic marker in glioblastoma (GBM). Methylation of the MGMT promoter has been shown to increase chemotherapy efficacy. While traditionally reported as a binary marker, recent methodological advancements have led to quantitative approaches that measure methylation, providing clearer insights into methylation’s functional relationship with survival. METHODS A CLIA assay and bisulfite sequencing was utilized to develop a quantitative, 17-point MGMT promoter methylation index derived from the number of methylated CpG sites. Retrospective review of 240 newly diagnosed GBM patients was performed in order to discern how risk for mortality transforms as promoter methylation increases. Non-linearities were captured by fitting splines to Cox proportional hazard models, plotting smoothed residuals, and creating survival plots. Covariates included age, KPS, IDH1 mutation, and extent of resection. RESULTS Median follow-up time and progression free survival were 16 and 9 months, respectively. 176 subjects experienced death. A one-unit increase in CpG methylation on a scale of 1-17 resulted in a 4% reduction in hazard (95% CI 0.93–0.99, P< 0.005). Moreover, GBM patients with low-levels of methylation (1-6 CpG sites) fared markedly worse (HR=1.62, 95% CI 1.03-2.54, P< 0.036) than individuals who were unmethylated (reference group). Subjects with medium-levels of methylation (7-12 CpG sites) had the greatest reduction in hazard (HR=0.48, 95% CI 0.29-0.80, P< 0.004), followed by individuals in the highest methylation tertile (HR=0.62, 95% CI 0.40-0.97, P< 0.035). CONCLUSION This novel approach offers greater bisulfite conversion efficiency when compared to alternative methods, reducing the likelihood of false positives. Analysis of the resulting methylation index scores demonstrates a non-linear relationship between MGMT methylation and survival, suggesting conformation of the marker’s protective effect. These findings challenge the current understanding of MGMT’s functional form and underline why implementing an “optimal cutoff point” may be disadvantageous.

Abstract BACKGROUND The prognosis of WHO grade II low-grade gliomas (LGG) is varied with potential for long survival.Given their relatively intact immune system and slow growth rate, vaccines are an attractive treatment strategy for LGG in an attempt to defer more toxic treatments. The goals of this pilot study were to evaluate safety and immunological effects of vaccination with GBM6-AD, an allogeneic glioblastoma stem cell line lysate, with poly-ICLC in LGG. METHODS Eligible patients were ≥ 18 years old, ≥ 70 KPS, with recurrent LGG or imaging consistent with LGG, and amenable to resection. Patients were randomized to vaccine prior to surgery (Arm 1) or not (Arm 2) and all received adjuvant vaccine. Co-primary outcomes were safety and immune response in the tumor, with exploratory outcomes of survival and immunologic effects in peripheral blood. RESULTS A total of 17 eligible patients were evaluable – nine into Arm 1 and eight into Arm 2. Median age was 33 years, with median time from initial diagnosis of 4.7 years (0 – 20). Two patients (11.8%) previously received radiotherapy and seven (41.2%) prior systemic therapy. No dose limiting toxicities or grade 3 AEs were observed. Neoadjuvant vaccination induced up regulation of type-1 cytokines and chemokines in peripheral blood, and CD8+ T cell clones that reacted to the vaccine were also detected in the tumor. Median follow-up time from first post-operative vaccine was 20.8 months with median PFS of 11.0 months and time to change in therapy of 23.7 months. Of the six patients to receive additional treatment, three had second surgery only one confirming malignant progression to anaplastic oligodendroglioma. CONCLUSION Treatment was well-tolerated with no regimen-limiting toxicity. GBM6-AD plus poly-ICLC induced effector CD8+ T cell response in peripheral blood and enables some vaccine-reactive CD8+ T cells to migrate into the TME. Further investigation is warranted.

Abstract BACKGROUND Gliomas are devastating primary tumors of the central nervous system that often present with difficult to manage symptoms in addition to the antineoplastic tumor itself. Due to recent increase in popularity and societal acceptance of cannabis products, their use by glioma patients has increased. METHODS We conducted a single center, prospective study: patients with glioma answered a locally validated survey to inquire about their cannabis use at baseline and every three months. Quality of Life was measured using the EORTC QLQ-C30, its complementary module BN-20 and the EQ-5D-5L instrument. Eligible participants were classified as cannabis users or non-users. We performed linear regression clustered by subjects to see differences by user group and trends overtime. RESULTS To date, 89 patients agreed to participate, enrolled, and answered the baseline questionnaires, and 64 have answered the 3 month follow up survey. The mean age was 49.7(SD 13.74), 55 were male, 55 were cannabis users at baseline (61.8%) and 34 at 3 months (53.13%). Patients who were cannabis users scored 11.73 lower points at baseline when compared to non-users (79.65 [SD 18.93] vs 67.92 [SD 19.22]) in the QLQ-C30 instrument. Similarly, cannabis users recorded 9.624 lower points at 3 months compared to non-users (70.1 [SD 21.33] vs 79.72 [SD13.95]). The difference-in-difference estimator was 2.108 (p< 0.7). CONCLUSION Although we observed cannabis users scoring lower QoL measurements (p< 0.05) at baseline and 3 months, we observed a slight improvement in QoL of cannabis users while observing no change or decline (in some measures) among non-users. Our findings provide insight to the impact that cannabis has in QoL over time. While not conclusive, these preliminary results need to be studied on a longer-term basis with a larger sample size in order to detect trends on quality of life among patients with different tumor types.

Abstract Background Epigenetic inhibition of the O6-methylguanine-DNA-methyltransferase (MGMT) gene has emerged as a clinically relevant prognostic marker in glioblastoma (GBM). Methylation of the MGMT promoter has been shown to increase chemotherapy efficacy. While traditionally reported as a binary marker, recent methodological advancements have led to quantitative methods of measuring methylation, allowing for clearer insights into methylation’s functional relationship with survival. Methods A CLIA assay and bisulfite sequencing was utilized to develop a quantitative, 17-point MGMT promoter methylation index derived from the number of methylated CpG sites. Retrospective review of 242 newly diagnosed GBM patients was performed in order to discern how risk for mortality transforms as promoter methylation increases. Non-linearities were captured by fitting splines to Cox proportional hazard models, plotting smoothed residuals, and creating survival plots. Covariates included age, KPS, IDH1 mutation, and extent of resection. Results Median follow-up time and progression free survival were 15.9 and 9 months, respectively. 176 subjects experienced death. A one-unit increase in CpG methylation resulted in a 4% reduction in hazard (95% CI 0.93–0.99, P

the National Jukebox at the Library of Congress represents one of the largest online collections of early-twentieth-century acoustical sound recordings. Since its initial launch in 2011, the National Jukebox has grown to include more than 16,000 recordings from the Victor, Columbia, and Harmony labels, made up of contributions from organizations such as Sony Music Entertainment, the University of California, Santa Barbara and EMI Music, Inc. as well as recordings donated by individual collectors. In addition to providing access to the recordings themselves, the National Jukebox site includes several resources that allow for further context and interactivity with the content. As the National Jukebox continues to develop, the addition of more features provides teachers, students, and other researchers the opportunity to engage with the recordings in new and exciting ways.

This paper is based on: (1) a literature review focussing on the impact of learning analytics on supporting learning and teaching; (2) a Delphi study involving international expert discussion on current opportunities and challenges of learning analytics; as well as (3) outlining a research agenda for closing identified research gaps. Issues and challenges facing educators linked to learning analytics and current research gaps were organised into four themes, the further development of which by the expert panel, led to six strategy and action areas. The four themes are: (1) development of data literacy in all stakeholders; (2) updating of guiding principles and policies of educational data; (3) standards needed for ethical practices with data quality assurance; and (4) flexible user-centred design for a variety of users of analytics, starting with learners and ensuring that learners and learning is not harmed. The strategies and actions are outcomes of the expert panel discussion and are offered as provocations to organise and focus the researcher, policymaker and practitioner dialogs needed to make progress in the field.

The UCSC Genome Browser (https://genome.ucsc.edu) is a graphical viewer for exploring genome annotations. For almost two decades, the Browser has provided visualization tools for genetics and molecular biology and continues to add new data and features. This year, we added a new tool that lets users interactively arrange existing graphing tracks into new groups. Other software additions include new formats for chromosome interactions, a ChIP-Seq peak display for track hubs and improved support for HGVS. On the annotation side, we have added gnomAD, TCGA expression, RefSeq Functional elements, GTEx eQTLs, CRISPR Guides, SNPpedia and created a 30-way primate alignment on the human genome. Nine assemblies now have RefSeq-mapped gene models.

The UCSC Genome Browser (https://genome.ucsc.edu) provides a web interface for exploring annotated genome assemblies. The assemblies and annotation tracks are updated on an ongoing basis-12 assemblies and more than 28 tracks were added in the past year. Two recent additions are a display of CRISPR/Cas9 guide sequences and an interactive navigator for gene interactions. Other upgrades from the past year include a command-line version of the Variant Annotation Integrator, support for Human Genome Variation Society variant nomenclature input and output, and a revised highlighting tool that now supports multiple simultaneous regions and colors.

Since its 2001 debut, the University of California, Santa Cruz (UCSC) Genome Browser (http://genome.ucsc.edu/) team has provided continuous support to the international genomics and biomedical communities through a web-based, open source platform designed for the fast, scalable display of sequence alignments and annotations landscaped against a vast collection of quality reference genome assemblies. The browser's publicly accessible databases are the backbone of a rich, integrated bioinformatics tool suite that includes a graphical interface for data queries and downloads, alignment programs, command-line utilities and more. This year's highlights include newly designed home and gateway pages; a new 'multi-region' track display configuration for exon-only, gene-only and custom regions visualization; new genome browsers for three species (brown kiwi, crab-eating macaque and Malayan flying lemur); eight updated genome assemblies; extended support for new data types such as CRAM, RNA-seq expression data and long-range chromatin interaction pairs; and the unveiling of a new supported mirror site in Japan.

This study extends the understanding of the process of teachers' technology adoption by investigating the dynamic nature of the adoption process. We propose a nonhomogeneous hidden Markov model that reveals the dynamics of teachers' adoption over time and examines the impact of internal and external factors, including experiences, interventions, and heterogeneity of teachers' intention and usage. The model builds its estimates on longitudinal action data from an e-textbook platform with extracted covariates based on direct observations and in-depth interviews. Three latent states representing the adoption dynamics in the data are identified. Results show that teachers encounter difficulty moving to and continuously staying in an active state of technology adoption without exogenous impacts, such as learning from peers and practice in the classroom. In addition to impacts from one's own experiences, inactive teachers benefit from external interventions, whereas teachers in active states benefit from peer demonstrations and experience sharing. The proposed dynamic model allows researchers to distinguish short- and long-term effects that may improve the assessment of interventions. The new approach and findings have implications in dynamically facilitating and sustaining teachers' technology-adoption processes.

With the increasing relevance of information and communication technologies (ICT) and the global transition towards the knowledge society, school systems and higher education now face increasing challenges involved in preparing students for successful participation in the knowledge society. In many countries, this is leading to manifold efforts and changes in national policies concerning ICT integration into education systems. This paper outlines four challenges concerning the design, implementation, and evaluation of national policy: (1) creating future ready policy, (2) achieving systemic perspectives in stakeholders, (3) promoting commitment to learning from policy, and (4) developing and implementing supportive processes. The paper shares an international perspective on these four major challenges and proposes strategy perspectives and solutions, as well as tactics that could be applied to advance a nation's educational system empowered by technology.

Higher education institutions are developing the capacity for learning analytics. However, the technical development of learning analytics has far exceeded the consideration of ethical issues around learning analytics. We examined higher education academics' knowledge, attitudes, and concerns about the use of learning analytics though four focus groups (N = 35). Thematic analysis of the focus group transcripts identified five key themes. The first theme, 'Facilitating learning', represents academics' perceptions that, while currently unrealized, there could be several benefits to learning analytics that would help their students. Three themes; 'Where are the ethics?', 'What about the students!', and 'What about me!' represented academics' perceptions of how learning analytics could pose some considerable difficulties within a higher education context. A final theme 'Let's move forward together' reflected that despite some challenges and concerns about learning analytics, academics perceived scope for learning analytics to be beneficial if there is collaboration between academics, students, and the university. The findings highlight the need to include academics in the development of learning analytics policies and procedures to promote the suitability and widespread adoption of learning analytics in the higher education sector.

The UNESCO Institute for Statistics (UIS) has been measuring ICT in education since 2009, but with such rapid change in technology and its use in education, it is important now to revise the collection mechanisms to focus on how technology is being used to enhance learning and teaching. Sustainable development goal (SDG) 4, for example, moves beyond measures of access and increasingly focuses on the sustainability of education including issues of educational quality and student outcomes. A reassessment of how ICT in education is measured to support the attainment of the SDGs by 2030 is thus a timely endeavour. The paper discusses four aspects: (1) evolving mission, methods and core principles of ICT in learning and teaching; (2) nature of ICT in education in accelerating the emergence of new learner-centred pedagogies; (3) types of learning activities associated with the use of ICT including those for leaders, teachers and students; and (4) usage and deployment patterns. This paper proposes extensions and adaptions to the existing UIS data collection instrument to enrich its capacity for understanding how ICT is being used in learning and teaching.

Learning design has traditionally been thought of as an activity occurring prior to the presentation of a learning experience or a description of that activity. With the advent of near real-time data and new opportunities of representing the decisions and actions of learners in digital learning environments, learning designers can now apply dynamic learning analytics information on the fly in order to evaluate learner characteristics, examine learning designs, analyse the effectiveness of learning materials and tasks, adjust difficulty levels, and measure the impact of interventions and feedback. In a case study with 3550 users, the navigation sequence and network graph analysis demonstrate a potential application of learning analytics design. Implications based on the case study show that integration of analytics data into the design of learning environments is a promising approach.

This article describes how the Global Challenge allows high school students to do something for the environment while winning an award that will help them financially through college. The Global Challenge is an online competition for high school students across the world. Students from other nations can pair up with students in the U.S. and together they can become an International Team. Through e-mail exchanges and Skype (a free voice and file sharing application for synchronous meetings) conversations, participating students get to work on socially significant issues, such as global warming. The Global Challenge is funded in part by the National Science Foundation ITEST (Information Technology Experiences for Students and Teachers) Program. This article provides several tips on how teachers can utilize the learning opportunities offered by the Global Challenge.

RationaleIncreasing epithelial repair and regeneration may hasten resolution of lung injury in patients with the acute respiratory distress syndrome (ARDS). In animal models of ARDS, keratinocyte growth factor (KGF) reduces injury and increases epithelial proliferation and repair. The effect of KGF in the human alveolus is unknown.ObjectivesTo test whether KGF can attenuate alveolar injury in a human model of ARDS.MethodsVolunteers were randomized to intravenous KGF (60 μg/kg) or placebo for 3 days, before inhaling 50 μg LPS. Six hours later, subjects underwent bronchoalveolar lavage (BAL) to quantify markers of alveolar inflammation and cell-specific injury.Measurements and main resultsKGF did not alter leukocyte infiltration or markers of permeability in response to LPS. KGF increased BAL concentrations of surfactant protein D, matrix metalloproteinase (MMP)-9, IL-1Ra, granulocyte-macrophage colony-stimulating factor (GM-CSF), and C-reactive protein. In vitro, BAL fluid from KGF-treated subjects inhibited pulmonary fibroblast proliferation, but increased alveolar epithelial proliferation. Active MMP-9 increased alveolar epithelial wound repair. Finally, BAL from the KGF-pretreated group enhanced macrophage phagocytic uptake of apoptotic epithelial cells and bacteria compared with BAL from the placebo-treated group. This effect was blocked by inhibiting activation of the GM-CSF receptor.ConclusionsKGF treatment increases BAL surfactant protein D, a marker of type II alveolar epithelial cell proliferation in a human model of acute lung injury. Additionally, KGF increases alveolar concentrations of the antiinflammatory cytokine IL-1Ra, and mediators that drive epithelial repair (MMP-9) and enhance macrophage clearance of dead cells and bacteria (GM-CSF). Clinical trial registered with ISRCTN 98813895.