Regulation of the Pro-Tumorigenic Senescence-Associated Secretory Phenotype

Tumorigenesis results from the convergence of cell autonomous mutations and corresponding stromal changes that promote tumor cell growth. Mutations and stromal changes both accumulate with age and together account for the dramatic increase in cancer incidence with age. One change that occurs with age is the accumulation of stromal senescent cells. Senescent stromal cells secrete pro-tumorigenic factors collectively termed the senescence-associated secretory phenotype (SASP). The SASP impacts every stage of tumorigenesis and is a promising therapeutic target. As such, it is important to understand how the SASP is regulated. Many but not all SASP factors are regulated transcriptionally by NF-kB and its upstream activator p38MAPK. However, many pro-tumorigenic SASP factors, including osteopontin (OPN), are not dependent on NF-κB or other canonical SASP regulators such as ATM, leaving the regulation of these factors an open question. Here, I report that the transcription factor c-Myb regulates OPN, IL-6, IL-8 and other SASP factors. The regulation of OPN is direct as c-Myb binds to the OPN promoter in senescent cells, and this binding is required for promoter activation. Further, OPN is also regulated by the known SASP regulator C/EBPβ. In response to senescence, the full-length activating C/EBPβ isoform LAP2 increases binding to the OPN, IL-6, and IL-8 promoters. Using a microarray and RNAi approach, we identified 57 additional putative c-Myb-dependent SASP factors and 125 additional putative C/EBPβ SASP factors. There is a high degree of overlap between c-Myb- and C/EBPβ-dependent factors. The importance of both c-Myb and C/EBPβ is underscored by our finding that the depletion of either factor reduces the ability of senescent fibroblasts to promote the growth of preneoplastic epithelial cells. Furthermore, I describe a post-transcriptional SASP mRNA stability regulator pathway. This pathway is dependent on p38MAPK, but is distinct from p38MAPK’s role in NF-κB transcription of SASP factors. In fully senescent fibroblasts, p38MAPK regulates the removal of mRNA-destabilizing protein AUF1 from the 3’-UTRs of numerous SASP factor mRNAs, resulting in increased mRNA stability. Given p38MAPK’s role in both transcriptional and post-transcriptional regulation of the SASP, we tested the ability of p38MAPK inhibitors to inhibit tumor growth. Treatment of mice with an orallyadministered p38MAPK inhibitor significantly decreased tumor growth in senescent fibroblast-supported xenograft models. Importantly, p38MAPK inhibition acts upon the microenvironment by removing stromal support of tumor growth. Interestingly, p38MAPK inhibition also inhibits the tumor promoting activities of cancer-associated fibroblasts (CAFs). CAFs have a secretory profile similar to senescent fibroblasts. This work indicates that p38MAPK inhibition is a viable therapeutic for targeting both senescent fibroblast and CAF stromal support of tumor cell growth

Evaluation of An Oral Health Education Session for Early Head Start Home Visitors

Objectives Home visiting programs promote the education and health of Early Head Start (EHS) children and pregnant women. However, EHS\u27s oral health component is unevenly implemented. We conducted an educational intervention to improve oral health knowledge and motivational interviewing techniques among Wisconsin EHS home visitors. Methods A questionnaire assessing oral health-related knowledge and confidence was administered to home visitors before and after an educational session. Changes between pre/post-responses were analyzed with McNemar\u27s test and Wilcoxon Signed Rank test. Results After the intervention there were increases in both knowledge and confidence related to oral health communication. Knowledge increases were observed in such topics as fluoridation, dental caries, and caregivers’ role in assisting and supervising children\u27s tooth brushing. Conclusions A brief educational intervention was associated with increased home visitor knowledge and confidence in communicating oral health messages to EHS caregivers and pregnant women

Multi-Retranslation Corpora: Visibility, Variation, Value, and Virtue

Variation among human translations is usually invisible, little understood, and under-valued. Previous statistical research finds that translations vary most where the source items are most semantically significant or express most ‘attitude’ (affect, evaluation, ideology). Understanding how and why translations vary is important for translator training and translation quality assessment, for cultural research, and for machine translation development. Our experimental project began with the intuition that quantitative variation in a corpus of historical retranslations might be used to project quasi-qualitative annotations onto the translated text. We present a web-based system which enables users to create parallel, segment-aligned multi-version corpora, and provides visual interfaces for exploring multiple translations, with their variation projected onto a base text. The system can support any corpus of variant versions. We report experiments using our tools (and stylometric analysis) to investigate a corpus of 40 German versions of a work by Shakespeare. Initial findings lead to more questions than answers

Systems And Method To Deliver Addressable Advertisements

System and method are disclosed for customizable ad delivery to targeted clients with efficient bandwidth usage. The system includes an ad server, asynchronous ad delivery server and an ad client. The ad client in a set top box (STB) device periodically requests for a set of possible ads from the asynchronous ad delivery server. The asynchronous ad delivery server is directly interfaced to the ad server and communicates with the ad server to determine a set of possible ads. The ad delivery server responds to the client request for possible ads by generating the customized ads. The asynchronous ad delivery server delivers customized ads to STB client storage. The STB client shows the customized ads from storage. The ad content cache is limited only by the size of the storage on the STB, which may be used effectively to minimize bandwidth demand by scheduling ad requests during lean usage period

Learning Temporal Sentence Grounding From Narrated EgoVideos

The onset of long-form egocentric datasets such as Ego4D and EPIC-Kitchens presents a new challenge for the task of Temporal Sentence Grounding (TSG). Compared to traditional benchmarks on which this task is evaluated, these datasets offer finer-grained sentences to ground in notably longer videos. In this paper, we develop an approach for learning to ground sentences in these datasets using only narrations and their corresponding rough narration timestamps. We propose to artificially merge clips to train for temporal grounding in a contrastive manner using text-conditioning attention. This Clip Merging (CliMer) approach is shown to be effective when compared with a high performing TSG method -- e.g. mean R@1 improves from 3.9 to 5.7 on Ego4D and from 10.7 to 13.0 on EPIC-Kitchens. Code and data splits available from: https://github.com/keflanagan/CliMerComment: Accepted in BMVC 202

UNG Tuba-Euphonium Quartet

The UNG Tuba-Euphonium Quartet would like to present a performance at the Georgia Undergraduate Research Conference at the University of North Georgia\u27s Gainesville campus, November 2-3, 2018. The Quartet consists of two tubas and two euphoniums. In addition to tubas and euphoniums, we often incorporate percussion into our performances. The UNG Tuba-Euphonium Quartet consists of the top two euphonium players and the top two tuba players from Dr. Adam Freys studio. The quartet plays a wide variety of music, ranging from classical transcriptions, to original compositions for Tuba-Euphonium quartet, and even jazz. Members of the quartet often create their own arrangements/compositions which we perform as well. The quartet has performed at a numerous event around the University, such as \u27OctubaFest\u27, \u27Spring Euphoria\u27, and the Dahlonega campuses instrumental honors recital. In addition to these performances, the UNG Tuba-Euphonium Quartet regularly performs at local churches and last January, the quartet performed at the Georgia Music Educator in Service Conference in Athens, Georgia. The quartet will be competing in the quartet competition of the International Tuba-Euphonium Conference (ITEC) at the University of Iowa this upcoming May