Isolation and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas

The question of whether dedicated progenitor cells exist in adult vertebrate pancreas remains controversial. Centroacinar cells and terminal duct (CA/TD) cells lie at the junction between peripheral acinar cells and the adjacent ductal epithelium, and are frequently included among cell types proposed as candidate pancreatic progenitors. However these cells have not previously been isolated in a manner that allows formal assessment of their progenitor capacities. We have found that a subset of adult CA/TD cells are characterized by high levels of ALDH1 enzymatic activity, related to high-level expression of both Aldh1a1 and Aldh1a7. This allows their isolation by FACS using a fluorogenic ALDH1 substrate. FACS-isolated CA/TD cells are relatively depleted of transcripts associated with differentiated pancreatic cell types. In contrast, they are markedly enriched for transcripts encoding Sca1, Sdf1, c-Met, Nestin, and Sox9, markers previously associated with progenitor populations in embryonic pancreas and other tissues. FACS-sorted CA/TD cells are uniquely able to form self-renewing 'pancreatospheres' in suspension culture, even when plated at clonal density. These spheres display a capacity for spontaneous endocrine and exocrine differentiation, as well as glucose-responsive insulin secretion. In addition, when injected into cultured embryonic dorsal pancreatic buds, these adult cells display a unique capacity to contribute to both the embryonic endocrine and exocrine lineages. Finally, these cells demonstrate dramatic expansion in the setting of chronic epithelial injury. These findings suggest that CA/TD cells are indeed capable of progenitor function and may contribute to the maintenance of tissue homeostasis in adult mouse pancreas

Data Quality Automation: a Generic Approach for Large Linked Research Datasets

Introduction When datasets are collected mainly for administrative rather than research purposes, data quality checks are necessary to ensure robust findings and to avoid biased results due to incomplete or inaccurate data. When done manually, data quality checks are time-consuming. We introduced automation to speed up the process and save effort. Objectives and Approach We have devised a set of automated generic quality checks and reporting, which can be run on any dataset in a relational database without any dataset-specific knowledge or configuration. The code is written in Python. Checks include: linkage quality, agreement with a population data source, comparison with previous data version, duplication checks, null count, value distribution and range, etc. Where dataset metadata is available, checks for validity against lookup tables are included, and the output report includes documentation on data contents. An HTML report with dynamic datatables and interactive graphs, allowing easy exploration of the results, is produced using RMarkdown. Results The automation of the generic data quality check provides an easy and quick tool to report on data issues with minimal effort. It allows comparison with reference tables, lookups and previous versions of the same table to highlight differences. Moreover, this tool can be provided for researchers as a means to get more detailed understanding about their data. While other research data quality tools exist, this tool is distinguished by its features specific to linked data research, as well as implementation in a relational database environment. It has been successfully tested on datasets of over two billion rows. The tool was designed for use within the SAIL Databank, but could easily be adapted and used in other settings. Conclusion/Implications The effort spent on automating generic testing and reporting on data quality of research datasets is more than compensated by its outputs. Benefits include quick detection and scrutiny of many sources of invalid and incomplete data. This process can easily be expanded to accommodate more standard tests

Archival learning in a global context

The Archival / Preservation Education SIG panel explores ongoing developments and innovative classroom pedagogy in teaching preservation and archival studies. Panel includes four presentations of 15 minutes each plus moderated Q&A. Presentations address the role and outcomes of original research assignments, teaching preservation online, a networked curriculum survey, and developing digital hands-on learning experiences; presenters bring perspectives from four states. “Stepping into Original Research in Archival Practice” by Sarah Buchanan discusses application of the SAA GPAS framework to the design of an Archival Studies specialization in concert with programmatic student learning outcomes. The presentation assesses the role, origins, and outcomes of two years of students' original research papers on local/global issues and considers gaps in archival curricular studies and research on the archival profession. “The Challenges of Teaching Preservation Online: Best Practices and Lessons Learned” by Reem Alkhaledi and Suliman Hawamdeh considers the preservation of three types of materials: physical printed formats, electronic material such as films, videos, and microforms, and digital material stored in databases and digital repositories. Presenters discuss the challenges involved in teaching preservation online and the ability to provide rich content. “A Networked Survey of Archival Studies Curriculum: A Case Study from Queens College, CUNY” by Johnathan Thayer asks how do we best facilitate and navigate connections between students with global information contexts and work environments? The presenter reviews the results of a two-part GSLIS survey and invites participants’ perspectives, ultimately seeking to extend our networks as archival educators beyond the walls of our classrooms (physical or virtual) and into an increasingly competitive and global job market. “Online Archival Education and the Challenge of Meeting Experiential Learning Expectations” by Ayoung Yoon and Andrea Copeland discusses the process and strategies of developing an online archives management specialization as a part of a 100% online master's program. Our institution has employed strategies used in the online master’s program and developed several new strategies while still conveying core archival concepts and theories. The moderator facilitates Q&A within and across the four presentations

Multimodal perioperative pain protocol for Gynecologic Oncology laparotomy reduces length of hospital stay

Our primary objective was to evaluate the impact of a multimodal perioperative pain regimen on length of hospital stay for patients undergoing laparotomy with a gynecologic oncologist

Ensuring phenotyping algorithms using national electronic health records are FAIR:Meeting the needs of the cardiometabolic research community

Phenotyping algorithms enable the extraction of clinically-relevant information (such as diagnoses, prescription information, or a blood pressure measurement) from electronic health records for use in research. They have enormous potential and wide-ranging utility in research to improve disease understanding, health, and healthcare provision. While great progress has been achieved over the past years in standardising how genomic data are represented and curated (e.g. VCF files for variants), phenotypic data are significantly more fragmented and lack a common representation approach. This lack of standards creates challenges, including a lack of comparability, transparency and reproducibility, and limiting the subsequent use of phenotyping algorithms in other research studies. The FAIR guiding principles for scientific data management and stewardship state that digital assets should be findable, accessible, interoperable and reusable, yet the current lack of phenotyping algorithm standards means that phenotyping algorithms are not FAIR. We have therefore engaged with the community to address these challenges, including defining standards for the reporting and sharing of phenotyping algorithms. Here we present the results of our engagement with the community to identify and explore their requirements and outline our recommendations to ensure FAIR phenotyping algorithms are available to meet the needs of the cardiometabolic research community

Global Genomic Analysis of Intraductal Papillary Mucinous Neoplasms of the Pancreas Reveals Significant Molecular Differences Compared to Ductal Adenocarcinoma

Objective: To determine whether intraductal papillary mucinous neoplasms of the pancreas (IPMNs) have a different genetic background compared with ductal adenocarcinoma (PDAC). Summary Background Data: The biologic and clinical behavior of IPMNs and IPMN-associated adenocarcinomas is different from PDAC in having a less aggressive tumor growth and significantly improved survival. Up to date, the molecular mechanisms underlying the clinical behavior of IPMNs are incompletely understood. Methods: 128 cystic pancreatic lesions were prospectively identified during the course of 2 years. From the corresponding surgical specimens, 57 IPMNs were separated and subdivided by histologic criteria into those with low-grade dysplasia, moderate dysplasia, high-grade dysplasia, and invasive cancer. Twenty specimens were suitable for DNA isolation and subsequent performance of array CGH. Results: While none of the IPMNs with low-grade dysplasia displayed detectable chromosomal aberrations, IPMNs with moderate and high-grade dysplasia showed frequent copy number alterations. Commonly lost regions were located on chromosome 5q, 6q, 10q, 11q, 13q, 18q, and 22q. The incidence of loss of chromosome 5q, 6q, and 11q was significantly higher in IPMNs with high-grade dysplasia or invasion compared with PDAC. Ten of 13 IPMNs with moderate dysplasia or malignancy had loss of part or all of chromosome 6q, with a minimal deleted region between linear positions 78.0 and 130.0. Conclusions: This study is the first to use array CGH to characterize IPMNs. Recurrent cytogenetic alterations were identified and were different than those described in PDAC. Array CGH may help distinguish between these 2 entities and give insight into the differences in their biology and prognosis

Pancreatic Duct Glands Are Distinct Ductal Compartments That React to Chronic Injury and Mediate Shh-Induced Metaplasia

BACKGROUND & AIMS: Pancreatic intraepithelial neoplasia (PanIN) are pancreatic cancer precursor lesions of unclear origin and significance. PanIN aberrantly express sonic hedgehog (Shh), an initiator of pancreatic cancer, and gastrointestinal mucins. A majority of PanIN are thought to arise from ducts. We identified a novel ductal compartment that is gathered in gland-like outpouches (pancreatic duct glands [PDG]) of major ducts and characterized its role in injury and metaplasia. METHODS: The ductal system was analyzed in normal pancreata and chronic pancreatitis in humans and mice. Anatomy was assessed by serial hematoxylin and eosin sections and scanning electron microscopy of corrosion casts. Expression of mucins and developmental genes and proliferation were assessed by immunohistochemistry or real-time quantitative polymerase chain reaction. Effects of Shh on ductal cells were investigated by exposure to Shh in vitro and transgenic misexpression in vivo. RESULTS: Three-dimensional analysis revealed blind-ending outpouches of ducts in murine and human pancreata. These PDG are morphologically and molecularly distinct from normal ducts; even in normal pancreata they display PanIN and metaplastic features, such as expression of Shh and gastric mucins. They express other developmental genes, such as Pdx-1 and Hes-1. In injury, Shh is up-regulated along with gastric mucins. Expansion of the PDG compartment results in a mucinous metaplasia. Shh promotes this transformation in vitro and in vivo. CONCLUSIONS: PDG are distinct gland-like mucinous compartments with a distinct molecular signature. In response to injury, PDG undergo an Shh-mediated mucinous gastrointestinal metaplasia with PanIN-like features. PDG may provide a link between Shh, mucinous metaplasia, and neoplasia

Ensuring phenotyping algorithms using national electronic health records are FAIR:Meeting the needs of the cardiometabolic research community

Phenotyping algorithms enable the extraction of clinically-relevant information (such as diagnoses, prescription information, or a blood pressure measurement) from electronic health records for use in research. They have enormous potential and wide-ranging utility in research to improve disease understanding, health, and healthcare provision. While great progress has been achieved over the past years in standardising how genomic data are represented and curated (e.g. VCF files for variants), phenotypic data are significantly more fragmented and lack a common representation approach. This lack of standards creates challenges, including a lack of comparability, transparency and reproducibility, and limiting the subsequent use of phenotyping algorithms in other research studies. The FAIR guiding principles for scientific data management and stewardship state that digital assets should be findable, accessible, interoperable and reusable, yet the current lack of phenotyping algorithm standards means that phenotyping algorithms are not FAIR. We have therefore engaged with the community to address these challenges, including defining standards for the reporting and sharing of phenotyping algorithms. Here we present the results of our engagement with the community to identify and explore their requirements and outline our recommendations to ensure FAIR phenotyping algorithms are available to meet the needs of the cardiometabolic research community

Effect of parasympathetic stimulation on brain activity during appraisal of fearful expressions

Autonomic nervous system activity is an important component of human emotion. Mental processes influence bodily physiology, which in turn feeds back to influence thoughts and feelings. Afferent cardiovascular signals from arterial baroreceptors in the carotid sinuses are processed within the brain and contribute to this two-way communication with the body. These carotid baroreceptors can be stimulated non-invasively by externally applying focal negative pressure bilaterally to the neck. In an experiment combining functional neuroimaging (fMRI) with carotid stimulation in healthy participants, we tested the hypothesis that manipulating afferent cardiovascular signals alters the central processing of emotional information (fearful and neutral facial expressions). Carotid stimulation, compared with sham stimulation, broadly attenuated activity across cortical and brainstem regions. Modulation of emotional processing was apparent as a significant expression-by-stimulation interaction within left amygdala, where responses during appraisal of fearful faces were selectively reduced by carotid stimulation. Moreover, activity reductions within insula, amygdala, and hippocampus correlated with the degree of stimulation-evoked change in the explicit emotional ratings of fearful faces. Across participants, individual differences in autonomic state (heart rate variability, a proxy measure of autonomic balance toward parasympathetic activity) predicted the extent to which carotid stimulation influenced neural (amygdala) responses during appraisal and subjective rating of fearful faces. Together our results provide mechanistic insight into the visceral component of emotion by identifying the neural substrates mediating cardiovascular influences on the processing of fear signals, potentially implicating central baroreflex mechanisms for anxiolytic treatment targets