Enhanced IL-12 transgene expression improves oncolytic viroimmunotherapy.

Introduction: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with unacceptably low cure rates occurring often in patients with neurofibromatosis 1 defects. To investigate oncolytic Herpes Simplex Virus (oHSV) as an immunotherapeutic approach, we compared viral replication, functional activity, and immune response between unarmed and interleukin 12 (IL-12)-armed oncolytic viruses in virus-permissive (B109) and -resistant (67C-4) murine MPNSTs. Methods: This study compared two attenuated IL-12-oHSVs with γ134.5 gene deletions (Δγ134.5) and the same transgene expression cassette. The primary difference in the IL-12-oHSVs was in their ability to counter the translational arrest response in infected cells. Unlike M002 (Δγ134.5, mIL-12), C002 (Δγ134.5, mIL-12, IRS1) expresses an HCMV IRS1 gene and evades dsRNA activated translational arrest in infected cells. Results and discussion: Our results show that oHSV replication and gene expression results in vitro were not predictive of oHSV direct oncolytic activity in vivo. Tumors that supported viral replication in cell culture studies resisted viral replication by both oHSVs and restricted M002 transgene expression in vivo. Furthermore, two IL-12-oHSVs with equivalent transcriptional activity differed in IL-12 protein production in vivo, and the differences in IL-12 protein levels were reflected in immune infiltrate activity changes as well as tumor growth suppression differences between the IL-12-oHSVs. C002-treated tumors exhibited sustained IL-12 production with improved dendritic cells, monocyte-macrophage activity (MHCII, CD80/CD86 upregulation) and a polyfunctional Th1-cell response in the tumor infiltrates. Conclusion: These results suggest that transgene protein production differences between oHSVs in vivo, in addition to replication differences, can impact OV-therapeutic activity.

Oncolytic virus-driven immune remodeling revealed in mouse medulloblastomas at single cell resolution.

Oncolytic viruses, modified for tumor-restricted infection, are a promising cancer immunotherapeutic, yet much remains to be understood about factors driving their activity and outcome in the tumor microenvironment. Here, we report that oncolytic herpes simplex virus C134, previously found to exert T cell-dependent efficacy in mouse models of glioblastoma, exerts T cell-independent efficacy in mouse models of medulloblastoma, indicating this oncolytic virus uses different mechanisms in different tumors. We investigated C134's behavior in mouse medulloblastomas, using single cell RNA sequencing to map C134-induced gene expression changes across cell types, timepoints, and medulloblastoma subgroup models at whole-transcriptome resolution. Our work details substantial oncolytic virus-induced transcriptional remodeling of medulloblastoma-infiltrating immune cells, 10 subpopulations of monocytes and macrophages collectively demonstrating M1-like responses to C134, and suggests C134 be investigated as a potential new therapy for medulloblastoma.

Thirty-Two Years of IEEE VIS: Authors, Fields of Study and Citations.

The IEEE VIS Conference (VIS) recently rebranded itself as a unified conference and officially positioned itself within the discipline of Data Science. Driven by this movement, we investigated (1) who contributed to VIS, and (2) where VIS stands in the scientific world. We examined the authors and fields of study of 3,240 VIS publications in the past 32 years based on data collected from OpenAlex and IEEE Xplore, among other sources. We also examined the citation flows from referenced papers (i.e., those referenced in VIS) to VIS, and from VIS to citing papers (i.e., those citing VIS). We found that VIS has been becoming increasingly popular and collaborative. The number of publications, of unique authors, and of participating countries have been steadily growing. Both cross-country collaborations, and collaborations between educational and non-educational affiliations, namely "cross-type collaborations", are increasing. The dominance of the US is decreasing, and authors from China are now an important part of VIS. In terms of author affiliation types, VIS is increasingly dominated by authors from universities. We found that the topics, inspirations, and influences of VIS research is limited such that (1) VIS, and their referenced and citing papers largely fall into the Computer Science domain, and (2) citations flow mostly between the same set of subfields within Computer Science. Our citation analyses showed that award-winning VIS papers had higher citations. Interactive visualizations, replication data, source code and supplementary material are available at https://32vis.hongtaoh.com and https://osf.io/zkvjm.

Seeing What You Believe or Believing What You See? Belief Biases Correlation Estimation.

When an analyst or scientist has a belief about how the world works, their thinking can be biased in favor of that belief. Therefore, one bedrock principle of science is to minimize that bias by testing the predictions of one's belief against objective data. But interpreting visualized data is a complex perceptual and cognitive process. Through two crowdsourced experiments, we demonstrate that supposedly objective assessments of the strength of a correlational relationship can be influenced by how strongly a viewer believes in the existence of that relationship. Participants viewed scatterplots depicting a relationship between meaningful variable pairs (e.g., number of environmental regulations and air quality) and estimated their correlations. They also estimated the correlation of the same scatterplots labeled instead with generic 'X' and 'Y' axes. In a separate section, they also reported how strongly they believed there to be a correlation between the meaningful variable pairs. Participants estimated correlations more accurately when they viewed scatterplots labeled with generic axes compared to scatterplots labeled with meaningful variable pairs. Furthermore, when viewers believed that two variables should have a strong relationship, they overestimated correlations between those variables by an r-value of about 0.1. When they believed that the variables should be unrelated, they underestimated the correlations by an r-value of about 0.1. While data visualizations are typically thought to present objective truths to the viewer, these results suggest that existing personal beliefs can bias even objective statistical values people extract from data.

VisHikers' Guide to Evaluation: Competing Considerations in Study Design.

In this Viewpoint article, we describe the persistent tensions between various camps on the "right" way to conduct evaluations in visualization. Visualization as a field is the amalgamation of cognitive and perceptual sciences and computer graphics, among others. As a result, the relatively disjointed lineages in visualization understandably approach the topic of evaluation very differently. It is both a blessing and a curse to our field. It is a blessing, because the collaboration of diverse perspectives is the breeding ground of innovation. Yet it is a curse, because as a community, we have yet to resolve an appreciation for differing perspectives on the topic of evaluation. We explicate these differing expectations and conventions to appreciate the spectrum of evaluation design decisions. We describe some guiding questions that researchers may consider when designing evaluations to navigate differing readers' evaluation expectations.

How Home Child Care Providers Purchase, Prepare, and Serve Healthy Foods: In-Depth Interviews with Child and Adult Care Food Program Participants.

Background: Child care settings can enhance children's access and exposure to healthy foods through participation in The Child and Adult Care Food Program (CACFP), which reimburses child care providers for purchasing healthy foods. To identify challenges and facilitators to CACFP participation, we carried out in-depth interviews with CACFP-participating home child care providers to discuss purchasing, preparing, and serving food under CACFP guidelines. Methods: We carried out 20 in-depth telephone interviews with CACFP-participating home child care providers. Transcribed interviews were coded to develop themes using a deductive approach. Results: Interviews indicated that food costs still burden CACFP-participating child care providers despite reimbursements. CACFP-participating providers who described prioritizing healthy foods and nutrition showed a greater inclination toward purchasing, preparing, and serving healthy foods to children. Conclusions: We offer recommendations for how to effectively support CACFP-participating providers in offering healthy food to their children within a food choice framework, a multilevel categorization of factors that influence food choice. Recommendations include increased reimbursement rates for food purchases under CACFP and support for peer-to-peer mentoring and health promotion programs targeting child care provider health.

Communicating Visualizations without Visuals: Investigation of Visualization Alternative Text for People with Visual Impairments.

Alternative text is critical in communicating graphics to people who are blind or have low vision. Especially for graphics that contain rich information, such as visualizations, poorly written or an absence of alternative texts can worsen the information access inequality for people with visual impairments. In this work, we consolidate existing guidelines and survey current practices to inspect to what extent current practices and recommendations are aligned. Then, to gain more insight into what people want in visualization alternative texts, we interviewed 22 people with visual impairments regarding their experience with visualizations and their information needs in alternative texts. The study findings suggest that participants actively try to construct an image of visualizations in their head while listening to alternative texts and wish to carry out visualization tasks (e.g., retrieve specific values) as sighted viewers would. The study also provides ample support for the need to reference the underlying data instead of visual elements to reduce users' cognitive burden. Informed by the study, we provide a set of recommendations to compose an informative alternative text.

Eliciting an immune-mediated antitumor response through oncolytic herpes simplex virus-based shared antigen expression in tumors resistant to viroimmunotherapy.

BACKGROUND: Oncolytic virotherapy (OV) is an immunotherapy that incorporates viral cancer cell lysis with engagement of the recruited immune response against cancer cells. Pediatric solid tumors are challenging targets because they contain both an inert immune environment and a quiet antigenic landscape, making them more resistant to conventional OV approaches. Further complicating this, herpes simplex virus suppresses host gene expression during virotherapy infection. METHODS: We therefore developed a multimodal oncolytic herpes simplex virus (oHSV) that expresses ephrin A2 (EphA2), a shared tumor-associated antigen (TAA) expressed by many tumors to improve immune-mediated antitumor activity. We verified the virus genotypically and phenotypically and then tested it in an oHSV-resistant orthotopic model (including immunophenotypic analysis), in flank and in T cell-deficient mouse models. We then assessed the antigen-expressing virus in an unrelated peripheral tumor model that also expresses the shared tumor antigen and evaluated functional T-cell response from the treated mice. RESULTS: Virus-based EphA2 expression induces a robust acquired antitumor immune responses in both an oHSV-resistant murine brain and peripheral tumor model. Our new multimodal oncolytic virus (1) improves survival in viroimmunotherapy resistant tumors, (2) alters both the infiltrating and peripheral T-cell populations capable of suppressing tumor growth on rechallenge, and (3) produces EphA2-specific CD8 effector-like populations. CONCLUSIONS: Our results suggest that this flexible viral-based platform enables immune recognition of the shared TAA and improves the immune-therapeutic response, thus making it well suited for low-mutational load tumors.

Emissions of Tetrafluoromethane (CF4) and Hexafluoroethane (C2F6) From East Asia: 2008 to 2019.

The perfluorocarbons (PFCs), tetrafluoromethane (CF4) and hexafluoroethane (C2F6), are potent greenhouse gases with very long atmospheric lifetimes. They are emitted almost entirely from industrial sources, including the aluminum and rare earth metal smelting industries that emit them as by-products, and the semiconductor and flat panel display manufacturing industries that use them and vent unutilized amounts to the atmosphere. Despite extensive industrial efforts to quantify and curb these emissions, "top-down" PFC emission estimates derived from atmospheric measurements continue to rise and are significantly greater than reported process- and inventory-based "bottom-up" emissions. In this study, we estimate emissions of CF4 and C2F6 from East Asia, where PFC emitting industries are heavily concentrated, using a top-down approach (a Bayesian inversion) with high-frequency atmospheric measurements at Gosan (Jeju Island, South Korea) for 2008-2019. We also compile and analyze the available bottom-up CF4 and C2F6 emissions in East Asia from industrial and government reports. Our results suggest that the observed increases in global PFC emissions since 2015 are driven primarily by China's aluminum industry, with significant contributions from Japan's and Korea's semiconductor industry. Our analysis suggests that Chinese emissions occur predominantly from the aluminum industry, although their emissions per production ratio may be improving. Our results for Japan and Korea find significant discrepancies between top-down and bottom-up emissions estimates, suggesting that the effectiveness of emission reduction systems (abatement) used in their semiconductor industries may be overestimated. Overall, our top-down results for East Asia contribute significantly to reducing the gap in the global PFC emission budgets.

Bayesian-Assisted Inference from Visualized Data.

A Bayesian view of data interpretation suggests that a visualization user should update their existing beliefs about a parameter's value in accordance with the amount of information about the parameter value captured by the new observations. Extending recent work applying Bayesian models to understand and evaluate belief updating from visualizations, we show how the predictions of Bayesian inference can be used to guide more rational belief updating. We design a Bayesian inference-assisted uncertainty analogy that numerically relates uncertainty in observed data to the user's subjective uncertainty, and a posterior visualization that prescribes how a user should update their beliefs given their prior beliefs and the observed data. In a pre-registered experiment on 4,800 people, we find that when a newly observed data sample is relatively small (N=158), both techniques reliably improve people's Bayesian updating on average compared to the current best practice of visualizing uncertainty in the observed data. For large data samples (N=5208), where people's updated beliefs tend to deviate more strongly from the prescriptions of a Bayesian model, we find evidence that the effectiveness of the two forms of Bayesian assistance may depend on people's proclivity toward trusting the source of the data. We discuss how our results provide insight into individual processes of belief updating and subjective uncertainty, and how understanding these aspects of interpretation paves the way for more sophisticated interactive visualizations for analysis and communication.

Imagining Replications: Graphical Prediction & Discrete Visualizations Improve Recall & Estimation of Effect Uncertainty.

People often have erroneous intuitions about the results of uncertain processes, such as scientific experiments. Many uncertainty visualizations assume considerable statistical knowledge, but have been shown to prompt erroneous conclusions even when users possess this knowledge. Active learning approaches been shown to improve statistical reasoning, but are rarely applied in visualizing uncertainty in scientific reports. We present a controlled study to evaluate the impact of an interactive, graphical uncertainty prediction technique for communicating uncertainty in experiment results. Using our technique, users sketch their prediction of the uncertainty in experimental effects prior to viewing the true sampling distribution from an experiment. We find that having a user graphically predict the possible effects from experiment replications is an effective way to improve one's ability to make predictions about replications of new experiments. Additionally, visualizing uncertainty as a set of discrete outcomes, as opposed to a continuous probability distribution, can improve recall of a sampling distribution from a single experiment. Our work has implications for various applications where it is important to elicit peoples' estimates of probability distributions and to communicate uncertainty effectively.

Data Through Others' Eyes: The Impact of Visualizing Others' Expectations on Visualization Interpretation.

In addition to visualizing input data, interactive visualizations have the potential to be social artifacts that reveal other people's perspectives on the data. However, how such social information embedded in a visualization impacts a viewer's interpretation of the data remains unknown. Inspired by recent interactive visualizations that display people's expectations of data against the data, we conducted a controlled experiment to evaluate the effect of showing social information in the form of other people's expectations on people's ability to recall the data, the degree to which they adjust their expectations to align with the data, and their trust in the accuracy of the data. We found that social information that exhibits a high degree of consensus lead participants to recall the data more accurately relative to participants who were exposed to the data alone. Additionally, participants trusted the accuracy of the data less and were more likely to maintain their initial expectations when other people's expectations aligned with their own initial expectations but not with the data. We conclude by characterizing the design space for visualizing others' expectations alongside data.