Morphoproteomic profiling of the mammalian target of rapamycin (mTOR) signaling pathway in desmoplastic small round cell tumor (EWS/WT1), Ewing's sarcoma (EWS/FLI1) and Wilms' tumor(WT1).

BackgroundDesmoplastic small round cell tumor (DSRCT) is a rare sarcoma in adolescents and young adults. The hallmark of this disease is a EWS-WT1 translocation resulting from apposition of the Ewing's sarcoma (EWS) gene with the Wilms' tumor (WT1) gene. We performed morphoproteomic profiling of DSRCT (EWS-WT1), Ewing's sarcoma (EWS-FLI1) and Wilms' tumor (WT1) to better understand the signaling pathways for selecting future targeted therapies.MethodologyThis pilot study assessed patients with DSRCT, Wilms' tumor and Ewing's sarcoma. Morphoproteomics and immunohistochemical probes were applied to detect: p-mTOR (Ser2448); p-Akt (Ser473); p-ERK1/2 (Thr202/Tyr204); p-STAT3 (Tyr 705); and cell cycle-related analytes along with their negative controls.Principal findingsIn DSRCT the PI3K/Akt/mTOR pathway is constitutively activated by p-Akt (Ser 473) expression in the nuclear compartment of the tumor cells and p-mTOR phosphorylated on Ser 2448, suggesting mTORC2 (rictor+mTOR) as the dominant form. Ewing's sarcoma had upregulated p-Akt and p-mTOR, predominantly mTORC2. In Wilm's tumor, the mTOR pathway is also activated with most tumor cells moderately expressing p-mTOR (Ser 2448) in plasmalemmal and cytoplasmic compartments. This coincides with the constitutive activation of one of the downstream effectors of the mTORC1 signaling pathway, namely p-p70S6K (Thr 389). There was constitutive activation of the Ras/Raf/ERK pathway p-ERK 1/2 (Thr202/Tyr204) expression in the Wilms tumor and metastatic Ewing's sarcoma, but not in the DSRCT.ConclusionMORPHOPROTEOMIC TUMOR ANALYSES REVEALED CONSTITUTIVE ACTIVATION OF THE MTOR PATHWAY AS EVIDENCED BY: (a) expression of phosphorylated (p)-mTOR, p-p70S6K; (b) mTORC 2 in EWS and DSRCT; (c) ERK signaling was seen in the advanced setting indicating these as resistance pathways to IGF1R related therapies. This is the first morphoproteomic study of such pathways in these rare malignancies and may have potential therapeutic implications. Further study using morphoproteomic assessments of these tumors are warranted

Kansas State University Feedlot Boot Camp and Teaching Program: Growing Student Interest and Engagement in the Feedlot Industry

Objective:Our objectives were to summarize the development and structure of the Kansas State University Feedlot Boot Camp and Teaching Program and examine student interest in careers in the feedlot industry after participation. Study Description:Since 2019, 95 Kansas State University College of Agriculture undergraduate students participated in the Feedlot Boot Camp Program. The aim was to develop students’ knowledge, skills, and professional relationships in feedlot management to help meet the critical need for trained professionals in the industry. Components are a four-day Feedlot Boot Camp, student presentations, animal health day, and an optional feedlot internship. Students who completed all components earned a $2,500 scholarship. Results:A total of 163 undergraduate students applied to participate in the program in its first five years. Of those applicants, 95 were selected to participate in the Feedlot Boot Camp Program. In surveys following the completion of the Boot Camp portion of the program, over 96% (91/95) of student participants agreed with the statement, “My interest in pursuing an internship and (or) career in the feedlot industry grew as a result of this Boot Camp.” Approximately 45% of participants proceeded to partic­ipate in feedlot internships or entered full-time jobs working in a feedlot six months after completing the Boot Camp. The Bottom Line:The Feedlot Boot Camp program has made progress in growing student interest and awareness of career opportunities in the feedlot industry and fostering communication between employers and prospective employees

Prospectus, May 9, 1979

CONGRATULATIONS CLASS OF \u2779; All good things must end; Staerkel\u27s farewell; Bookstore heads discussion at recent stu-go meeting; Registration schedule; Tornado season approaching: safety procedures at PC; Health program Tues., May 15; Flynn, graduation speaker; Kelly has new position; Tangora wins election; Energy saving tips can save money and conserve fuel; Do you know when final exams are?; Boyke to perform at PC tomorrow; Parkland College Day at Market Place Mall; McLaughlin captures concert crowd; New program caters to hunger for food service personnel; PC awards banquet tonight at Round Barn; Letter of thanks; Pre-register for classes tomorrow; Congratulations Class Of \u2779; Last Paper Laffs; Classifieds; Campus Paperback Bestsellers; Chuck Mangione at C-U; A day at the races; Cobras stun Danville with 2 shutouts; \u27Still can\u27t win\u27 Cobras take 2nd; Sports editorial: \u27Outlaws\u27 sprint to fans delighthttps://spark.parkland.edu/prospectus_1979/1016/thumbnail.jp

Independent Evaluation of a Probe-Based Method to Estimate Annual Average Daily Traffic Volume

693JJ319D000007This report documents an independent evaluation of annual average daily traffic (AADT) estimates developed from traffic probes by StreetLight Data, Inc (StL). The Texas A&M Transportation Institute (TTI) researchers performed a systematic process to identify accurate permanent continuous counter sites maintained by public agencies and private entities that could be used as benchmark sites against which to evaluate these AADT estimates. Ultimately, though, TTI could only use 215 bidirectional (552 directional) continuous count sites owned and maintained by state departments of transportation. TTI researchers used several evaluation measures and several statistical hypothesis tests to assess the accuracy and precision of StreetLight Data\u2019s AADT estimates. These multiple evaluation measures and hypothesis tests produced mixed results. Some statistical tests provided contradictory or counterintuitive results while other statistical hypothesis tests indicated that StL\u2019s AADT estimates are statistically the same as the benchmark AADT values. TTI used professional judgment to weight and consider each evaluation result, and concluded that StL\u2019s AADT estimates are valid for traffic monitoring use on roads with bidirectional AADT of 5,000 or greater vehicles per day. Because the evaluation results were mixed and the validity decision was not clear cut, TTI recommends phased implementation that includes two elements: 1) a one-to-three year transition period (DOTs still collecting short duration counts but comparing to StL AADT estimates) should be used to confirm TTI's professional judgment based on these mixed evaluation results; 2) a pilot implementation program initiated by FHWA that includes up to five early adopter state DOTs, to monitor and coordinate findings in early-adopting states

A psycho-educational curriculum for sport career transition practitioners: Development and evaluation

Research question: This paper is an integration of three studies. Study 1 investigates sport career transition organisational intervention programmes for high performance athletes and training and development programmes for sport career transition practitioners in order to find a research gap with regard to sport career transition supporting services. A psycho-educational curriculum was developed for sport career transition practitioner in Study 2 to fill the research gap. In Study 3, the curriculum was examined to see if the curriculum contributed to enhancing practitioners’ confidence in key competences.  Research methods: A range of methods were applied to the studies including One Group Pre- and Post-test design, Case Study, Focus Group, Semi-Structured Interview, two-round Delphi-Method and Questionnaires. The data for Study 1 collected from 19 countries worldwide and total 16 participants based in seven different countries were invited to development and evaluation of the curriculum.  Results and Findings: A novel psycho-educational curriculum for sport career transition practitioner was developed and evaluated concerning four competences as a form of curriculum package. The findings revealed that the curriculum package increased the participants’ confidence in key competences concerning sport career transition.  Implications: The findings deepen the knowledge of sport career transition in the areas of organisational intervention programmes focusing on high performance athletes and sport career transition practitioners. These findings contribute to modifying the Conceptual Model of Adaptation to Career Transition (Lavallee, Park, & Taylor, 2014) by strengthening the organisational intervention perspective and applied work in respect of sporting organisation management strategie

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Targeted Morphoproteomic Profiling of Ewing's Sarcoma Treated with Insulin-Like Growth Factor 1 Receptor (IGF1R) Inhibitors: Response/Resistance Signatures

Insulin-like growth factor 1 receptor (IGF1R) targeted therapies have resulted in responses in a small number of patients with advanced metastatic Ewing's sarcoma. We performed morphoproteomic profiling to better understand response/resistance mechanisms of Ewing's sarcoma to IGF1R inhibitor-based therapy.This pilot study assessed two patients with advanced Ewing's sarcoma treated with IGF1R antibody alone followed by combined IGF1R inhibitor plus mammalian target of rapamycin (mTOR) inhibitor treatment once resistance to single-agent IGF1R inhibitor developed. Immunohistochemical probes were applied to detect p-mTOR (Ser2448), p-Akt (Ser473), p-ERK1/2 (Thr202/Tyr204), nestin, and p-STAT3 (Tyr 705) in the original and recurrent tumor. The initial remarkable radiographic responses to IGF1R-antibody therapy was followed by resistance and then response to combined IGF1R plus mTOR inhibitor therapy in both patients, and then resistance to the combination regimen in one patient. In patient 1, upregulation of p-Akt and p-mTOR in the tumor that relapsed after initial response to IGF1R antibody might explain the resistance that developed, and the subsequent response to combined IGF1R plus mTOR inhibitor therapy. In patient 2, upregulation of mTOR was seen in the primary tumor, perhaps explaining the initial response to the IGF1R and mTOR inhibitor combination, while the resistant tumor that emerged showed activation of the ERK pathway as well.Morphoproteomic analysis revealed that the mTOR pathway was activated in these two patients with advanced Ewing's sarcoma who showed response to combined IGF1R and mTOR inhibition, and the ERK pathway in the patient in whom resistance to this combination emerged. Our pilot results suggests that morphoproteomic assessment of signaling pathway activation in Ewing's sarcoma merits further investigation as a guide to understanding response and resistance signatures

Tenofovir-Diphosphate as a Marker of HIV Pre-exposure Prophylaxis Use Among East African Men and Women

Background: Controlled pharmacokinetic (PK) studies in United States populations have defined categories of tenofovir-diphosphate (TFV-DP) in dried blood spots (DBS) for various pre-exposure prophylaxis (PrEP) adherence targets. It is unknown how these categories perform in other populations. Therefore, we evaluated the sensitivity and specificity of these PK-derived categories compared to daily medication electronic adherence monitoring (MEMS) data among East African men and women using daily PrEP.Methods: Participants were enrolled as members of HIV serodiscordant couples as part of an open-label PrEP study in Kenya and Uganda. Blood samples were taken at quarterly visits and stored as DBS, which were analyzed for TFV-DP concentrations.Results: Among 150 samples from 103 participants, MEMs data indicated that 87 (58%) took ≥4 doses and 62 (41%) took ≥6 per week consistently over the 4 weeks prior to sample collection. Sensitivities of DBS TFV-DP levels were 62% for the ≥4 doses/week category (≥700 fmol/punch TFV-DP) and 44% for the ≥6 doses/week category (≥1050 fmol/punch TFV-DP); specificities were 86 and 94%, respectively. There were no statistically significant differences in these sensitivities and specificities by gender.Conclusion: In this sample of East African PrEP users, categories of TFV-DP concentrations developed from directly observed PrEP use among United States populations had high specificity but lower than expected sensitivity. Sensitivity was lowest when MEMS data indicated high adherence (i.e., ≥6 doses/week). PrEP studies and implementation programs should carefully consider the sensitivity and specificity of the TFV-DP levels used for adherence feedback

The Relationship between Phytoplankton Distribution and Water Column Characteristics in North West European Shelf Sea Waters

Phytoplankton underpin the marine food web in shelf seas, with some species having properties that are harmful to human health and coastal aquaculture. Pressures such as climate change and anthropogenic nutrient input are hypothesized to influence phytoplankton community composition and distribution. Yet the primary environmental drivers in shelf seas are poorly understood. To begin to address this in North Western European waters, the phytoplankton community composition was assessed in light of measured physical and chemical drivers during the “Ellett Line” cruise of autumn 2001 across the Scottish Continental shelf and into adjacent open Atlantic waters. Spatial variability existed in both phytoplankton and environmental conditions, with clear differences not only between on and off shelf stations but also between different on shelf locations. Temperature/salinity plots demonstrated different water masses existed in the region. In turn, principal component analysis (PCA), of the measured environmental conditions (temperature, salinity, water density and inorganic nutrient concentrations) clearly discriminated between shelf and oceanic stations on the basis of DIN∶DSi ratio that was correlated with both salinity and temperature. Discrimination between shelf stations was also related to this ratio, but also the concentration of DIN and DSi. The phytoplankton community was diatom dominated, with multidimensional scaling (MDS) demonstrating spatial variability in its composition. Redundancy analysis (RDA) was used to investigate the link between environment and the phytoplankton community. This demonstrated a significant relationship between community composition and water mass as indexed by salinity (whole community), and both salinity and DIN∶DSi (diatoms alone). Diatoms of the Pseudo-nitzschia seriata group occurred at densities potentially harmful to shellfish aquaculture, with the potential for toxicity being elevated by the likelihood of DSi limitation of growth at most stations and depths

Foraging for foundations in decision neuroscience: insights from ethology

Modern decision neuroscience offers a powerful and broad account of human behaviour using computational techniques that link psychological and neuroscientific approaches to the ways that individuals can generate near-optimal choices in complex controlled environments. However, until recently, relatively little attention has been paid to the extent to which the structure of experimental environments relates to natural scenarios, and the survival problems that individuals have evolved to solve. This situation not only risks leaving decision-theoretic accounts ungrounded but also makes various aspects of the solutions, such as hard-wired or Pavlovian policies, difficult to interpret in the natural world. Here, we suggest importing concepts, paradigms and approaches from the fields of ethology and behavioural ecology, which concentrate on the contextual and functional correlates of decisions made about foraging and escape and address these lacunae