Citations

Abstract A genome-wide association study (GWAS) of pancreatic cancer conducted within the NCI Cohort Consortium (PanScan I and II) identified pancreatic cancer susceptibility loci on chromosomes 1q32.1/NR5A2, 5p15.33/CLPTM1L/TERT, 9q34.2/ABO, and 13q22.1. The most significant single-nucleotide polymorphism (SNP) identified on 13q22.1, rs9543325, lies in a ~600 kb gene desert; the nearest genes are KLF5, KLF12, PIBF1, DIS3, and BORA (265–586 kb away). Imputation using the 1000 Genomes and DCEG reference datasets did not improve the GWAS signal, but produced a set of highly correlated SNPs for functional follow-up. We performed eQTL analysis to test for association between the genotypes of these functional candidate variants and expression of nearby genes. Among 64 normal derived pancreatic tissue samples, DIS3 expression showed the strongest association with a 30 bp indel variant in the risk locus (P = 4.8 × 10-4), indicating risk alleles associate with reduced DIS3 expression. Mutations in DIS3 have previously been identified in acute myeloid leukemia and multiple myeloma, and its expression has been correlated with metastatic potential in colorectal cancer, suggesting DIS3 is relevant to cancer biology. Chromosome conformation capture identified a physical interaction between the indel-containing locus and a region near the DIS3 promoter. Luciferase assay for regulatory function of this indel-containing locus revealed allele-specific silencer activity for the insertion allele. Supershift electromobility shift assay (EMSA) demonstrated binding of LEF1 specifically to the insertion allele of the indel, which contains two in silico predicted LEF1 binding elements. Finally, through immunohistochemical analysis, high DIS3 protein levels associated with better survival for pancreatic cancer patients (hazard ratio = 2.87, 95% CI = 1.49–5.53, P = 0.001). Our results suggest that at least one target gene for the pancreatic cancer risk variants on chr13q22.1 may be DIS3, and that the underlying biology may be mediated by the novel indel through a long-range repressive effect on DIS3 expression. Citation Format: Jason W. Hoskins, Abdisamad Ibrahim, Mickey Emmanuel, Sarah Manmiller, Jinping Jia, Hemang Parikh, Irene Collins, Kris Ylaya, Sean F. Altekruse, Stephen M. Hewitt, Gloria M. Petersen, Laufey T. Amundadottir. Functional analysis of the chr13q22.1 pancreatic cancer risk locus suggests allele-specific effects on DIS3 expression with prognostic implications. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-09.

AbstractBackgroundHailey–Hailey disease (HHD) is an autosomal dominant genodermatosis that leads to skin breakdown and blister formation, usually in intertriginous areas. Laser ablation is a known surgical treatment for HHD.ObjectivesWe report outcomes in a series of patients with HHD treated with carbon dioxide (CO2) laser ablation.MethodsA retrospective chart review of data for 13 patients who underwent CO2 laser ablation for HHD was conducted. Questionnaires assessing effectiveness, pain, healing time, recurrence, new disease, complications, additional ablation, improvement in quality of life (QoL), and overall satisfaction were completed by all patients.ResultsAll patients had been recalcitrant to previous treatments prior to CO2 laser ablation. Anatomic sites treated and anesthesia techniques for the procedure varied. The mean ± standard deviation (SD) score for the effectiveness of CO2 laser ablation for HHD was 9.3 ± 0.9 (maximum: 10). All patients reported improved QoL. No patient had recurring disease within the treatment field. Five patients underwent additional CO2 laser treatments at new sites. One patient reported postoperative infection. No other complications were identified. The mean ± SD score for overall satisfaction with CO2 laser ablation was 8.9 ± 1.1.ConclusionsTreatment with CO2 laser ablation is very effective and can lead to prolonged or permanent remission in most HHD patients. Patients are highly satisfied with the results and report a substantial improvement in QoL.

Abstract A genome-wide association study (GWAS) of pancreatic cancer conducted within the NCI Cohort Consortium (PanScan I and II) identified pancreatic cancer susceptibility loci on chromosomes 1q32.1/NR5A2, 5p15.33/CLPTM1L/TERT, 9q34.2/ABO, and 13q22.1. The most significant single-nucleotide polymorphism (SNP) identified on 13q22.1, rs9543325, lies in a 600 kb gene desert; the nearest genes are KLF5, KLF12, PIBF1, DIS3, and BORA (265–586 kb). Imputation using the 1000 Genomes and DCEG reference datasets did not improve the GWAS signal, but produced a set of highly correlated SNPs for functional follow-up. We performed eQTL analysis to test for association between the genotypes of these functional candidate variants and expression of nearby genes. Among 100 normal derived pancreatic tissue samples, DIS3 expression showed the strongest association with a novel 30 bp indel variant in the risk locus (P = 4.0 × 104), indicating risk alleles associate with reduced DIS3 expression. Mutations in DIS3 have previously been identified in acute myeloid leukemia and multiple myeloma, and its expression has been correlated with metastatic potential in colorectal cancer, suggesting DIS3 is relevant to cancer biology. Chromosome conformation capture identified a physical interaction between the indel-containing locus and a region near the DIS3 promoter. Luciferase assay for regulatory function of this indel-containing locus revealed allele-specific silencer activity for the insertion allele. Supershift electromobility shift assay (EMSA) demonstrated binding of LEF1 specifically to the insertion allele of the indel, which contains two in silico predicted LEF1 binding elements. Finally, through immunohistochemical analysis, high DIS3 protein levels associated with better survival for pancreatic cancer patients (hazard ratio = 2.87, 95% CI = 1.49–5.53, P = 0.001). Our results suggest that at least one target gene for the pancreatic cancer risk variants on chr13q22.1 may be DIS3, and that the underlying biology may be mediated by the novel indel through a long-range repressive effect on DIS3 expression. Citation Format: Jason W. Hoskins, Abdisamad Ibrahim, Mickey Emmanuel, Hemang Parikh, Jinping Jia, Irene Collins, Kris Ylaya, Sean F. Altekruse, Stephen M. Hewitt, Gloria M. Petersen, Laufey T. Amundadottir. Functional analysis of the chr13q22.1 pancreatic cancer risk locus suggests allele-specific effects on DIS3 expression with prognostic implications. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B111.

ABSTRACT Our understanding of adenovirus (Ad) biology is largely extrapolated from human species C Ad5. Most humans are immune to Ad5, so lower-seroprevalence viruses like human Ad6 and Ad26 are being tested as therapeutic vectors. Ad6 and Ad26 differ at the DNA level by 34%. To better understand how this might impact their biology, we examined the life cycle of the two viruses in human lung cells in vitro . Both viruses infected A549 cells with similar efficiencies, executed DNA replication with identical kinetics within 12 h, and began killing cells within 72 h. While Ad6-infected cells remained adherent until death, Ad26-infected cells detached within 12 h of infection but remained viable. Next-generation sequencing (NGS) of mRNA from infected cells demonstrated that viral transcripts constituted 1% of cellular mRNAs within 6 h and 8 to 16% within 12 h. Quantitative PCR and NGS revealed the activation of key early genes at 6 h and transition to late gene activation by 12 h by both viruses. There were marked differences in the balance of E1A and E1B activation by the two viruses and in the expression of E3 immune evasion mRNAs. Ad6 was markedly more effective at suppressing major histocompatibility complex class I (MHC I) display on the cell surface and in evading TRAIL-mediated apoptosis than was Ad26. These data demonstrate shared as well as divergent life cycles in these genetically distant human adenoviruses. An understanding of these differences expands the knowledge of alternative Ad species and may inform the selection of related Ads for therapeutic development. IMPORTANCE A burgeoning number of adenoviruses (Ads) are being harnessed as therapeutics, yet the biology of these viruses is generally extrapolated from Ad2 and Ad5. Here, we are the first to compare the transcriptional programs of two genetically distant Ads by mRNA next-generation sequencing (NGS). Species C Ad6 and Ad26 are being pursued as lower-seroprevalence Ad vectors but differ at the DNA level by 34%. Head-to-head comparison in human lung cells by NGS revealed that the two viruses generally conform to our general understanding of the Ad transcriptional program. However, fine mapping revealed subtle and strong differences in how these two viruses execute these programs, including differences in the balance of E1A and E1B mRNAs and in E3 immune evasion genes. This suggests that not all adenoviruses behave like Ad2 and Ad5 and that they may have unique strategies to infect cells and evade the immune system.

Context Health care trainees demonstrate implicit (automatic, unconscious) and explicit (conscious) bias against people from stigmatised and marginalised social groups, which can negatively influence communication and decision making. Medical schools are well positioned to intervene and reduce bias in new physicians. Objectives This study was designed to assess medical school factors that influence change in implicit and explicit bias against individuals from one stigmatised group: people with obesity. Methods This was a prospective cohort study of medical students enrolled at 49 US medical schools randomly selected from all US medical schools within the strata of public and private schools and region. Participants were 1795 medical students surveyed at the beginning of their first year and end of their fourth year. Web‐based surveys included measures of weight bias, and medical school experiences and climate. Bias change was compared with changes in bias in the general public over the same period. Linear mixed models were used to assess the impact of curriculum, contact with people with obesity, and faculty role modelling on weight bias change. Results Increased implicit and explicit biases were associated with less positive contact with patients with obesity and more exposure to faculty role modelling of discriminatory behaviour or negative comments about patients with obesity. Increased implicit bias was associated with training in how to deal with difficult patients. On average, implicit weight bias decreased and explicit bias increased during medical school, over a period of time in which implicit weight bias in the general public increased and explicit bias remained stable. Conclusions Medical schools may reduce students’ weight biases by increasing positive contact between students and patients with obesity, eliminating unprofessional role modelling by faculty members and residents, and altering curricula focused on treating difficult patients.

In the anatomy laboratory, skill remains a critical component to unlocking the true value of learning from cadaveric dissection. However, there is little if any room for provision of instruction in proper dissection technique. We describe how near‐peer instructors designed a supplemental learning activity to enhance the dissection experience for first‐year medical students. This study aimed to evaluate the efficacy of this curriculum in improving participants' understanding of dissection technique and its impact on perceived challenges associated with the anatomy course. Curriculum was designed under faculty guidance and included didactic sessions, low‐fidelity models, dissection, student presentations, and clinical correlations. Participants' (n = 13) knowledge of basic dissection techniques and concepts were assessed before the selective, and both participants' and nonparticipants' (n = 39) knowledge was assessed at the end of week one and week seven of the anatomy course. Scores were compared using repeated measures ANOVA followed by post hoc t‐tests. Thirteen deidentified reflective essays were reviewed by four independent reviewers for themes that aligned with learning objectives. Participants in the selective course scored higher on assessment of dissection techniques and concepts one week after the selective compared to both nonparticipants and their own baseline scores before the selective. Analysis of student reflections resulted in four themes: confidence with dissection skill, sharing resources and transfer of knowledge, learning environment, and psychological impact of perceived challenges of the anatomy course. Near‐peer driven supplemental exercises are effective in facilitating dissection skills. This dissection primer increases student confidence and alleviates apprehension associated with anatomy courses. Clin. Anat. 28:985–993, 2015. © 2015 Wiley Periodicals, Inc.