The 8p11-P12 Amplicon Oncogenes ASH2L and NSD3 Regulate Cell Cycle Progression via Epigenetic Alterations and Result in Overexpression and Estrogen-Independent Activation of ERα in Breast Cancer

Breast cancer is a highly heterogeneous disease classified clinically by expression of estrogen receptor alpha ERα, progesterone receptor, and human epidermal growth factor receptor. Molecular expression profiling identified a luminal breast cancer sub-type that can be sub-divided into luminal A and B. Compared to luminal A, luminal B tumors have increased proliferation, poor prognosis, endocrine therapy resistance, and complex genomes, including amplification of the 8p11-p12 genomic region. This amplicon occurs in 15% of primary breast tumors, correlates with poor prognosis and tamoxifen resistance, and harbors several oncogenes. Two of these oncogenes, ASH2L and NSD3 (WHSC1L1), promote transcription via epigenetic modification of histone proteins. NSD3 has a long isoform that is associated with di-methylation of lysine 36 on histone 3 (H3K36me2) and a short isoform that lacks a catalytic SET domain but retains the ability to interact with chromatin. ASH2L also lacks a catalytic SET domain yet is tightly and specifically linked to tri-methylation of lysine 4 on histone 3 (H3K4me3) in gene promoters. In this study, we tested the hypothesis that ASH2L and NSD3 cooperate to regulate expression of a suite of genes important in breast cancer, including ESR1, which encodes ERα. We discovered that NSD3-short is the major oncogenic isoform of NSD3 and its amplification and overexpression leads to overexpression and estrogen-independent activation of ERα. We also demonstrated that knockdown of ASH2L reduces H3K4me3 specifically in promoters of genes important to cell cycle progression. ASH2L also regulates promoter H3K4me3 at NSD3 and expression of both NSD3 and ERα. Knockdown of ASH2L reduced sensitivity to the cell cycle inhibitor palbociclib in the 8p11-p12 amplicon-bearing SUM-44 cell line. Together, the data presented here identify a role for ASH2L and NSD3 in cooperative regulation of genes important to cell cycle regulation, including ESR1, and demonstrate that ERα is active in an estrogen-independent manner in the context of overexpression of these oncogenes. We have discovered a novel mechanism of endocrine resistance in luminal B breast cancers and provided evidence for the 8p11-p12 amplicon as a biomarker of patients who will respond to cell cycle inhibitors and epigenetic therapies against histone methyltransferase enzymes

The Evolution of Distributive Benefits: The Rise of Letter-Marking in the United States Congress

THE RECENT MORATORIUM ON EARMARKS HAS GIVEN RISE TO A NEW AND LARGELY HIDDEN PRACTICE FOR SECURING DISTRIBUTIVE BENEFITS: LETTER-MARKING. LETTER-MARKING OCCURS WHEN MEMBERS OF CONGRESS ASK (IN WRITING) THE HEAD OF AN AGENCY TO RETAIN OR ALLOCATE DISTRIBUTIVE BENEFITS IN THEIR DISTRICTS. WHILE LETTER-MARKING IS COMMON IN WASHINGTON, THE SCHOLARLY LITERATURE HAS IGNORED THIS PRACTICE. WE USE A UNIQUE DATASET OF 101 CONGRESSIONAL LETTERS RELATING TO FAA FUNDING AND EMPIRICALLY ASSESS THE DEGREE TO WHICH THE LETTER-WRITER’S CHARACTERISTICS AND THE LETTER’S CONTENT IMPACT THE LIKELIHOOD OF ACHIEVING THE OBJECTIVES. IN DOING SO, WE OFFER A NUANCED UNDERSTANDING OF LETTER-MARKING

An exploration of materials for music integration in elementary science education

Strong educators always look for different ways to excite and enthrall their students in the curriculum. The field of science education often loses student interest due to the complexities and vocabulary found in the scientific realm. Incorporating music into the classroom has shown positive results as a way to integrate student learning and a different way of facilitating students in the learning process (Brewer, 1992; Davies, 200). Resources for implementing the integration of music and science exist throughout the Internet in a variety of mediums. This study looks at the availability of said resources and the concepts they cover, for what students they are intended for, how are they intended to be used and the level of accuracy they maintain. Those resources upholding the accuracy desired for use in the classroom were then compiled onto one webpage for use by elementary science educators. The webpage is open and free to the public and may be shared

Beyond the Checklist Approach: A Librarian-Faculty Collaboration to Teach the BEAM Method of Source Evaluation

Evaluating information is an essential skill, valued across disciplines. While librarians and instructors share the responsibility to teach this skill, they need a common framework in order to collaborate to design assignments that give students multiple opportunities to learn. Librarians and First Year Seminar faculty at Belmont University collaborated to design a unit of instruction on source evaluation using the BEAM method. BEAM requires students to apply a use-based approach to evaluation, to read and engage with sources more closely, and to think about how they might use a source for a specific purpose. Structured annotated bibliographies that included BEAM were assessed, along with student, instructor, and librarian feedback. The BEAM method may be an effective method for teaching information evaluation when paired with other sequenced assignments that guide students through the research and writing process

Development of a mammalian neurosensory full‐thickness skin equivalent and its application to screen sensitizing stimuli

Human skin equivalents (HSEs) are an increasingly popular research tool due to limitations associated with animal testing for dermatological research. They recapitulate many aspects of skin structure and function, however, many only contain two basic cell types to model dermal and epidermal compartments, which limits their application. We describe advances in the field skin tissue modeling to produce a construct containing sensory-like neurons that is responsive to known noxious stimuli. Through incorporation of mammalian sensory-like neurons, we were able to recapitulate aspects of the neuroinflammatory response including secretion of substance P and a range of pro-inflammatory cytokines in response to a well-characterized neurosensitizing agent: capsaicin. We observed that neuronal cell bodies reside in the upper dermal compartment with neurites extending toward the keratinocytes of the stratum basale where they exist in close proximity to one another. These data suggest that we are able to model aspects of the neuroinflammatory response that occurs during exposure to dermatological stimuli including therapeutics and cosmetics. We propose that this skin construct can be considered a platform technology with a wide range of applications including screening of actives, therapeutics, modeling of inflammatory skin diseases, and fundamental approaches to probe underlying cell and molecular mechanisms

Examining IS Curriculum Profiles and the IS 2010 Model Curriculum Guidelines in AACSB-Accredited Schools

The IS 2010 Model Curriculum Guidelines were developed to provide recommendations for standardized information systems curricula while simultaneously allowing for customization within individual programs. While some studies have examined program adherence to the IS 2010 Model Curriculum Guidelines, a more detailed analysis of IS curriculum profiles has not yet been conducted. The purpose of this study is to identify and describe IS curriculum profiles that exist among 127 AACSB IS programs using the IS 2010 guidelines as a framework for analysis. A cluster analysis reveals four distinct profiles of IS program structure: Independent, Focused, Adoptive, and Flexible. Prototypes of each profile are described along with significant differences between each profile as revealed by a discriminant analysis. Identifying and describing these curriculum profiles offers a snapshot of the state of the IS curriculum as a whole and provides a resource for programs seeking to examine and modify their respective curriculum models

Validation of a Forensic Method to be used in Food Fraud Investigation

Food fraud is the act in which food is purposefully mislabeled, adulterated, or contaminated, often to make up a percentage of a missing substance when the product is being made. It is often done purposefully to mislead consumers into thinking some ingredient is or is not present in the food, which can be hazardous to the consumer. This project aimed to validate a forensic domestic animal species reference ladder and multiplex PCR kit that can be used in animal investigations, with a focus on food fraud. A multiplex PCR protocol targeting mitochondrial DNA (mtDNA) markers and a species reference ladder can quickly identify DNA from chicken, cow, sheep, turkey, goat, horse, dog, and cat. To validate the kit, it was tested on five different brands of dog food, specifically four brands of kibble alongside a canned wet stew dog food. DNA extraction was performed using the QIAamp MinElute Column kit or the Qiagen EZ1 investigator kit, then DNA quantification, multiplex PCR, gel electrophoresis, and capillary electrophoresis to build species mtDNA profiles for each food’s contents. Results from one dog food kibble yielded some speculation as DNA for sheep and goat contents not listed in the ingredients were detected using both the gel and capillary electrophoresis

'Thrown Out Into the World': Transition to Post Schooling for Autistic Young People

Autistic Young People in Australia experience poorer employment outcomes upon transition out of school than their non-disabled peers. This can lead to significant disadvantages in terms of financial, social, physical and mental well being as they may not be able to experience the benefits of work. the transition from school to post-school has been identified as a period where Autistic young people do not receive adequate support and, regrettably, understanding how to improve support remains a gap in the research literature. The introduction of the National Disability Insurance Scheme (NDIS) changed the funding landscape for Autistic young people in terms of the supports they may be eligible to receive, leaving potential gaps in support at a critical time in an Autistic Young Person's life. This research was co-produced and adopted a qualitative methodology and aimed to understand the perspectives and experiences of key stakeholders (Autistic Young People, Parent/Carers, Educators and Disability Employment Service Providers) around the transition of Autistic young people from school to post-school education and employment options. Reflective Thematic Analysis was adopted to analyse transcribed interview data from 39 participants across the four stakeholder groups. Key Findings indicated the uniqueness of young autistic peoples' experiences and their desire to prove themselves as well as the importance of harnessing autistic strengths and interests and the need for early, collaborative transition planning. It calls attention to gaps in transition, including delayed planning, limited and inconsistent supports, siloed approaches to transition planning, strain on families and the impact of ongoing stigma and discrimination toward neurodivergent people. Recommendations are posed to optimise post school transition. This study contributes new knowledge to the evidence base surrounding the transition of Autistic Young People out of school. It highlights recommendations for research, policy, education, and practice to improve outcomes for Autistic Young People