Association between Eosinophilic Esophagitis and Food Protein-Induced Enterocolitis Syndrome in Children

Background: The prevalence of food allergy in the pediatric population is increasing. Classic IgE-mediated allergies have been well studied. However, less is known about non-IgE-mediated allergies. Eosinophilic Esophagitis (EoE), a mixed IgE and non-IgE-mediated allergy, and Food Protein-Induced Enterocolitis Syndrome (FPIES), a non-IgE-mediated allergy, have similar symptoms but different ages of presentation (any age vs.age; respectively). The purpose of this study is to determine the odds of developing EoE in children previously diagnosed with FPIES or who exhibited symptoms characteristic of FPIES. Methods: Analysis of retrospectively reviewed medical record data included demographic, clinical, and nutrition characteristics as well as history of gastrointestinal symptoms, diagnosis of EoE, and diagnosis or symptoms of FPIES (history of vomiting) in a large cohort of children receiving care at an urban pediatric gastroenterology clinic. Nutrition characteristics included infant feeding regimen (breast fed vs. formula fed) and age of complementary food introduction. The population sample was provided by the GI Care for Kids Clinical Dietitian. Medical records were reviewed for all patients diagnosed with FPIES between March 1, 2016 and May 30, 2018 and an equivalent number of patients diagnosed with EoE in the same time frame. Results: The majority of the population (N=148) was male (57.4%) and Caucasian (97.7%). The odds of developing EoE (mean age 9.3 + 5.4 years) by prior diagnosis of FPIES (median age 0.83 [Interquartile range; 0.6, 1.2]) or symptoms of FPIES was 0 and 0.25 (95% Confidence Interval; 0.109, -0.575), respectively. Logistic regression analysis revealed that gender, previous history of food allergy and intolerance, and history of vomiting explain 23% to 31% of the variation in EoE diagnosis. Conclusions: A history of symptoms characteristic of FPIES reported in the first year of life were observed to be protective for the development of EoE during childhood. The treatment for FPIES or its symptoms includes the elimination of common food allergens. Additional studies are needed to evaluate the effect of early infant diet on the future development of EoE

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Perceptions About Work/Life Balance Among DU Community Members with Young Children

Background: In the past fifty years, families in the USA have changed in configuration, size and dynamics. The percentage of families that do not conform to the traditional family unit (married mother and father with children) has increased as there are more single-parent families, LGBTQ families and interracial families. The proportion of unmarried or divorced families has also increased, as it has the number of married and unmarried couples that opt to not have children and, additionally, more couples are opting for adoption and foster parenting (Pew Research Center 2010). Furthermore, the percentage of households where all the adults work has increased, which impacts the amount and quality of time available for family activities and household chores (Bianchi, Robinson and Milkie 2006). These and other trends have led to the identification of “work-family balance” as an important challenge of our times, one that families have been facing for decades and that institutions are only starting to pay attention to (Hochschild 2013). Although there are many aspects of family life that are challenging to balance with workplace demands, childcare has been specifically identified as one that needs attention (Desilver 2014). Methods: Study goal: To describe the perceptions that some DU community members with children have about work-family balance with attention to challenges, difficulties and institutional responses. Study design: Descriptive, cross-sectional, qualitative study. Population and sample: We recruited 63 University of Denver students (13), staff (14) and faculty (36) who are responsible of parenting at least one child under 10 years of age. We used purposive sampling. which consists in actively finding individuals who meet the criteria. Data collection: Semi structured interviews (January 23-February 8, 2017), in person, audio recorded and transcribed within one week. Participants’ autonomy, confidentiality and anonymity were protected throughout the process. Data analysis: Thematic analysis, which consists in the systematic identification of themes in the interview transcripts, followed by their conceptual organization and hierarchization. Research team: sixty-six undergraduate students taking Cultural Anthropology (ANTH 2010) in winter 2017, four graduate teaching assistants and one course instructor. Findings: Student participants portrayed work/life balance as set of interconnected situations and relations that go from the deeply personal to the interpersonal, communal and institutional. Aiming at capturing such complexity, we organized our findings in four themes: work/life balance, family dynamics, personal challenges and support. Participants told us about their struggles when negotiating work and life responsibilities which often lead to feelings of guilt, which are mediated by their colleagues’ reactions, schedule flexibility, their job situation and the presence or absence of maternity leave. Family dynamics reflected a tension between a narrative of independence and one of dependence in raising children, highlighting the importance of social networks, both of which are also affected by immigration status and intra-household negotiations particularly, Perceptions about work/life balance among DU community members with young children Cultural Anthropology (ANTH 2010) winter 2017 4 with their partners. Personal challenges relate primarily with time management and establishing clear boundaries between work and family, which related to managing emails, organization and scheduling of activities, maintaining a financial balance, and solving transportation needs, all of which were mediated the ability parents have of controlling a flexible work schedule, an ability greatly diminished among students. Support parents need related to child care goes from the one that happens in interpersonal interactions with neighbors, friends, relatives and colleagues, to the institutionalized forms of support, where participants expressed their frustration for the insufficiency of accessible options in Denver, the lack of options at DU, and the inaccessibility of DU’s Fisher Early Learning Center. Conclusions and recommendations: Participant’s ability to control their schedules together with their financial and social capital seem to shape important differences in the ability that parents have for balancing work and life. Students, single parents and recent immigrants seem to have a combination of elements that add to the challenges. At the interpersonal level, simple acts of kindness, sympathy and empathy in the everyday interactions seem to make an important difference to parents. The perception that many of the student participants expressed about the academy not being comfortable with children, families or parents could be addressed by making it normal to talk about all these aspects of life. At the institutional level, efforts could be made at reaching out to parents, especially students and single parents, to offer them guidance and support that is already in place at DU, such as counselling and wellbeing resources, as well as orientation related to institutional policies. Policies related to maternity and paternity leave should be refined to ensure that they do not negatively affect those they are supposed to support. Convenient, affordable and sustainable on-campus child care options should be seriously considered given that they would enhance the possibilities for parents to participate in activities at DU. Events should be organized where members of the DU community have the opportunity to share not as students, staff or faculty, but as members of families

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

Protein ubiquitination is a dynamic and reversibleprocess of adding single ubiquitin molecules orvarious ubiquitin chains to target proteins. Here,using multidimensional omic data of 9,125 tumorsamples across 33 cancer types from The CancerGenome Atlas, we perform comprehensive molecu-lar characterization of 929 ubiquitin-related genesand 95 deubiquitinase genes. Among them, we sys-tematically identify top somatic driver candidates,including mutatedFBXW7with cancer-type-specificpatterns and amplifiedMDM2showing a mutuallyexclusive pattern withBRAFmutations. Ubiquitinpathway genes tend to be upregulated in cancermediated by diverse mechanisms. By integratingpan-cancer multiomic data, we identify a group oftumor samples that exhibit worse prognosis. Thesesamples are consistently associated with the upre-gulation of cell-cycle and DNA repair pathways, char-acterized by mutatedTP53,MYC/TERTamplifica-tion, andAPC/PTENdeletion. Our analysishighlights the importance of the ubiquitin pathwayin cancer development and lays a foundation fordeveloping relevant therapeutic strategies

Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation.

Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation

Molecular characterization and clinical relevance of metabolic expression subtypes in human cancers.

Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1—master regulators of carbohydrate metabolic subtypes-modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility