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Esophageal adenocarcinoma arises from Barrett's esophagus, a precancerous metaplastic replacement of squamous by columnar epithelium in response to chronic inflammation. Multi-omics profiling, integrating single-cell transcriptomics, extracellular matrix proteomics, tissue-mechanics and spatial proteomics of 64 samples from 12 patients' paths of progression from squamous epithelium through metaplasia, dysplasia to adenocarcinoma, revealed shared and patient-specific progression characteristics. The classic metaplastic replacement of epithelial cells was paralleled by metaplastic changes in stromal cells, ECM and tissue stiffness. Strikingly, this change in tissue state at metaplasia was already accompanied by appearance of fibroblasts with characteristics of carcinoma-associated fibroblasts and of an NK cell-associated immunosuppressive microenvironment. Thus, Barrett's esophagus progresses as a coordinated multi-component system, supporting treatment paradigms that go beyond targeting cancerous cells to incorporating stromal reprogramming.

Abstract Concertive control (CC) theory has primarily been applied to traditional offline, work-based, closed membership teams. New organizational forms such as online communities have opened up additional sites in which CC processes may operate. This article makes several contributions to CC theory and research. First, it increases the applicability of CC theory by extending it from offline to online, work to non-work, and closed to open membership contexts. Second, it increases our understanding of CC processes by elaborating on three mechanisms of CC (group autonomy, group identification, and generative discipline) and how they operate differently in online work/non-work and closed/open contexts. Third, it develops propositions about how these mechanisms interact with three prominent media affordances (visibility, persistence and editability) within those contexts. Extending CC theory to online communities helps to explain individuals’ responses to normative group pressures online, which is highly relevant in our increasingly culturally and politically polarized society.

Can a "nudge" toward engaging, fun, and useful material improve student attitudes toward statistics? We report on the results of a randomized study to assess the effect of a "nudge" delivered via a weekly E-mail digest on the attitudes of students enrolled in a large introductory statistics course taught in both flipped and fully online formats. Students were randomized to receive either a personalized weekly E-mail digest with course information and a "nudge" to read and explore interesting applications of statistics relevant to the weekly course material, or a generic course E-mail digest with the same course information, and no "nudge." Our study found no evidence that "nudging" students to read and explore interesting applications of statistics resulted in better attitudes toward statistics. Supplementary materials for this article are available online.

ObjectivesIn this paper, we discuss leveraging cloud-based platforms to collect, visualize, analyze, and share data in the context of a clinical trial. Our cloud-based infrastructure, Patient Repository of Biomolecular Entities (PRoBE), has given us the opportunity for uniform data structure, more efficient analysis of valuable data, and increased collaboration between researchers.Materials and methodsWe utilize a multi-cloud platform to manage and analyze data generated from the clinical Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2 (I-SPY 2 TRIAL). A collaboration with the Institute for Systems Biology Cancer Gateway in the Cloud has additionally given us access to public genomic databases. Applications to I-SPY 2 data have been built using R Shiny, while leveraging Google's BigQuery tables and SQL commands for data mining.ResultsWe highlight the implementation of PRoBE in several unique case studies including prediction of biomarkers associated with clinical response, access to the Pan-Cancer Atlas, and integrating pathology images within the cloud. Our data integration pipelines, documentation, and all codebase will be placed in a Github repository.Discussion and conclusionWe are hoping to develop risk stratification diagnostics by integrating additional molecular, magnetic resonance imaging, and pathology markers into PRoBE to better predict drug response. A robust cloud infrastructure and tool set can help integrate these large datasets to make valuable predictions of response to multiple agents. For that reason, we are continuously improving PRoBE to advance the way data is stored, accessed, and analyzed in the I-SPY 2 clinical trial.

(Immunity 48, 812–830.e1–e14; April 17, 2018) In the originally published version of this article, the authors neglected to include Younes Mokrab and Aaron M. Newman as co-authors and misspelled the names of authors Charles S. Rabkin and Ilya Shmulevich. The author names have been corrected here and online. In addition, the concluding sentence of the subsection “Immune Signature Compilation” in the Method Details in the original published article was deemed unclear because it did not specify differences among the gene set scoring methods. The concluding sentences now reads “Gene sets from Bindea et al., Senbabaoglu et al., and the MSigDB C7 collection were scored using single-sample gene set enrichment (ssGSEA) analysis (Barbie et al., 2009), as implemented in the GSVA R package (Hänzelmann et al., 2013). All other signatures were scored using methods found in the associated citations.”

Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options. SIGNIFICANCE: Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM.See related commentary by Aggarwal and Albelda, p. 1508.This article is highlighted in the In This Issue feature, p. 1494.

In 2010, Nolan and Temple Lang proposed "integration of computing concepts into statistics curricula at all levels." The unprecedented growth in data and emphasis on data science has provided an impetus to finally realizing full implementations of this in new statistics and data science programs and courses. We discuss a proposal for the stealth development of computational skills in students' exposure to introductory data science through careful, scaffolded exposure to computation and its power. Our intent is to support students, regardless of interest and self-efficacy in coding, in becoming data-driven learners, who are capable of asking complex questions about the world around them, and then answering those questions through the use of data-driven inquiry. Reference is made to the computer science and statistics consensus curriculum frameworks the International Data Science in Schools Project (IDSSP) recently published for secondary school data science or introductory tertiary programs, designed to optimize data-science accessibility.

Background: Although receiving the HPV vaccine can help to prevent the development of cancer and HPV-related diseases, many individuals are not vaccinated in adolescence. Purpose: To examine knowledge about changes to the FDA's approval of the HPV vaccine for adults ages 26-45 years and to utilize the Integrated Behavioral Model (IBM) constructs to understand the relationship between beliefs and HPV vaccine intention. Methods: An online survey was used to examine HPV vaccine-related beliefs, knowledge, and uptake among a sample of 421 U.S. adults 18-45 years old in April 2019. Results: Perceived norms, perceived control, sex, and provider recommendation were significantly related to vaccine intention. Perceived norms, age, and healthcare provider recommendation were significantly related to receiving the full dose of the vaccine. Fewer than half of the participants indicated having at least one dose of the HPV vaccine or having had a provider recommend the vaccine. Less than 4% knew the vaccine had been approved by the FDA for up to 45 years old. Discussion: Results highlight the importance of social norms and patient education on HPV vaccine uptake and intention. Translation to Health Education Practice: Findings can inform future interventions and instrument development

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that is challenging to diagnose and treat. Current methods to measure disease burden, monitor treatment response, and predict disease progression have significant limitations. This study explores the utility of circulating neoplastic-immune hybrid cells (CHCs) as a novel blood-based biomarker. We find that pre-operative CHC levels can predict the presence of metastatic disease that may only be detected during surgical exploration, as well as identify patients who are likely to experience rapid metastatic progression after surgery. Further, CHC levels and protein expression patterns are reflective of disease response to chemotherapy. Collectively, these results suggest that CHCs could serve as crucial indicators of disease status and treatment efficacy, offering great potential to enhance survival outcomes for patients with PDAC. Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) presents significant diagnostic and prognostic challenges, as current biomarkers frequently fail to accurately stage disease, predict rapid metastatic recurrence (rPDAC), or assess response to neoadjuvant therapy (NAT). We investigated the potential for circulating neoplastic-immune hybrid cells (CHCs) as a non-invasive, multifunctional biomarker for PDAC. Methods: Peripheral blood specimens were obtained from patients diagnosed with PDAC. CHCs were detected by co-expression of pan-cytokeratin and CD45, normalized to 50,000 peripheral blood mononuclear cells. rPDAC was defined as metastatic recurrence within six months of margin-negative pancreatectomy. Cyclic immunofluorescence (CyCIF) analyses compared hybrid phenotypes in blood and tumors. Results: Blood samples were collected from 42 patients with PDAC prior to resection. Those with radiographically occult metastatic disease and rPDAC had higher preoperative CHC numbers compared to patients who did not (65.0 and 74.4, vs. 11.52 CHCs; p < 0.001). Patients with complete or near-complete pathologic responses to NAT had lower preoperative CHC numbers than partial and/or non-responders (1.7 vs. 13.1 CHCs; p = 0.008). When assessed longitudinally, those with partial pathologic response saw CHC levels become undetectable while on treatment but increase in the interval between NAT completion and resection. In contrast, patients with poor responses or development of metastatic disease experienced persistent CHC detection during therapy or rising levels prior to radiographic evidence of metastases. Further, in metastatic PDAC patients, treatment-induced phenotypic changes in hybrid cells mirrored those in paired metastatic tumor samples. Conclusions: CHC enumeration and phenotyping display promise as a real-time indicator of disease burden, recurrence risk, and treatment response in PDAC. CHCs have great potential as tumor-derived biomarkers to optimize therapeutic strategies and improve survival in patients with PDAC. [ABSTRACT FROM AUTHOR]

We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.

The Cancer Genome Atlas (TCGA) has catalyzed systematic characterization of diverse genomic alterations underlying human cancers. At this historic junction marking the completion of genomic characterization of over 11,000 tumors from 33 cancer types, we present our current understanding of the molecular processes governing oncogenesis. We illustrate our insights into cancer through synthesis of the findings of the TCGA PanCancer Atlas project on three facets of oncogenesis: (1) somatic driver mutations, germline pathogenic variants, and their interactions in the tumor; (2) the influence of the tumor genome and epigenome on transcriptome and proteome; and (3) the relationship between tumor and the microenvironment, including implications for drugs targeting driver events and immunotherapies. These results will anchor future characterization of rare and common tumor types, primary and relapsed tumors, and cancers across ancestry groups and will guide the deployment of clinical genomic sequencing.