Exploring young people's and youth workers' experiences of spaces for ‘youth development’: creating cultures of participation

The paper focuses on the emergence of ‘positive youth development’ and its impact on older, more established practices of working with young people, such as youth work. Drawing on ethnographic fieldwork in England between 2004 and 2006, in particular young people's and youth workers' accounts of participating in youth work, the analysis engages with the social spaces in which youth work takes place and asks key questions about why young people might participate in youth spaces, what they get out of participating and how such spaces can promote cultures of participation. The analysis shows that such spaces provide young people and their communities with biographical continuity and time becomes a key component for sustaining such spaces. The argument is made for a more nuanced understanding of what young people get out of their participation in youth spaces, and for an epistemological approach to youth praxis that embraces the messiness and inequalities of lived experience

Futureproofing [18F]Fludeoxyglucose manufacture at an Academic Medical Center

Abstract Background We recently upgraded our [18F]fludeoxyglucose (FDG) production capabilities with the goal of futureproofing our FDG clinical supply, expanding the number of batches of FDG we can manufacture each day, and improving patient throughput in our nuclear medicine clinic. In this paper we report upgrade of the synthesis modules to the GE FASTLab 2 platform (Phase 1) and cyclotron updates (Phase 2) from both practical and regulatory perspectives. We summarize our experience manufacturing FDG on the FASTLab 2 module with a high-yielding self-shielded niobium (Nb) fluorine-18 target. Results Following installation of Nb targets for production of fluorine-18, a 55 μA beam for 22 min generated 1330 ± 153 mCi of [18F]fluoride. Using these cyclotron beam parameters in combination with the FASTLab 2, activity yields (AY) of FDG were 957 ± 102 mCi at EOS, corresponding to 72% non-corrected AY (n = 235). Our workflow, inventory management and regulatory compliance have been greatly simplified following the synthesis module and cyclotron upgrades, and patient wait times for FDG PET have been cut in half at our nuclear medicine clinic. Conclusions The combination of FASTlab 2 and self-shielded Nb fluorine-18 targets have improved our yield of FDG, and enabled reliable and repeatable manufacture of the radiotracer for clinical use.https://deepblue.lib.umich.edu/bitstream/2027.42/145727/1/41181_2018_Article_48.pd

Development and implementation of ISAR, a new synthesis platform for radiopharmaceutical production

Abstract Background PET radiopharmaceutical development and the implementation of a production method on a synthesis module is a complex and time-intensive task since new synthesis methods must be adapted to the confines of the synthesis platform in use. Commonly utilized single fluid bus architectures put multiple constraints on synthesis planning and execution, while conventional microfluidic solutions are limited by compatibility at the macro-to-micro interface. In this work we introduce the ISAR synthesis platform and custom-tailored fluid paths leveraging up to 70 individually addressable valves on a chip-based consumable. The ISAR synthesis platform replaces traditional stopcock valve manifolds with a fluidic chip that integrates all fluid paths (tubing) and valves into one consumable and enables channel routing without the single fluid bus constraint. ISAR can scale between the macro- (10 mL), meso- (0.5 mL) and micro- (≤0.05 mL) domain seamlessly, addressing the macro-to-micro interface challenge and enabling custom tailored fluid circuits for a given application. In this paper we demonstrate proof-of-concept by validating a single chip design to address the challenge of synthesizing multiple batches of [13N]NH3 for clinical use throughout the workday. Results ISAR was installed at an academic PET Center and used to manufacture [13N]NH3 in > 96% radiochemical yield. Up to 9 batches were manufactured with a single consumable chip having parallel paths without the need to open the hot-cell. Quality control testing confirmed the ISAR-based [13N]NH3 met existing clinical release specifications, and utility was demonstrated by imaging a rodent with [13N]NH3 produced on ISAR. Conclusions ISAR represents a new paradigm in radiopharmaceutical production. Through a new system architecture, ISAR integrates the principles of microfluidics with the standard volumes and consumables established in PET Centers all over the world. Proof-of-concept has been demonstrated through validation of a chip design for the synthesis of [13N]NH3 suitable for clinical use.https://deepblue.lib.umich.edu/bitstream/2027.42/152186/1/41181_2019_Article_77.pd

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Biologically Important Areas II for cetaceans within U.S. and adjacent waters – Hawaiʻi Region

In this assessment we incorporated published and unpublished information to delineate and score Biologically Important Areas (BIAs) for cetaceans in the Hawaiʻi region following standardized criteria. Twenty-six cetacean species have been documented in Hawaiʻi. Eleven odontocete species have distinct small populations resident to one or more island areas: rough-toothed dolphins, pantropical spotted dolphins, common bottlenose dolphins, spinner dolphins, short-finned pilot whales, false killer whales, pygmy killer whales, melon-headed whales, Blainville’s beaked whales, Cuvier’s beaked whales, and dwarf sperm whales. Eight species of mysticetes have been documented, although their occurrence and behavior are poorly understood, with the exception of breeding humpback whales and, more recently, common minke whales. Thirty-five BIAs were delineated or revised from the initial 2015 effort: 33 for small and resident odontocete populations and two for humpback whale reproductive areas. Hierarchical BIAs reflecting core areas of use or population-specific ranges were delineated for nine species. Reproductive watch list areas were designated for common minke whales in the main Hawaiian Islands (MHI) and humpback whales in the Northwestern Hawaiian Islands (NWHI); these areas did not meet the criteria for a BIA due to limited supporting information. All but three BIAs were in the MHI, reflecting the disparities in research effort between this region and the NWHI. Spatial extents of BIA boundaries ranged from 457 km2 to 138,001 km2 (median = 8,299 km2). Scores (range: 1-3) for Data Support and Boundary Certainty were moderate to high (mean = 2.40 and 2.43, respectively), while Intensity and Importance scores were slightly lower (mean = 1.94 and 1.89, respectively). Many of the Hawaiʻi species have been extensively studied over several decades; accordingly, this region ranks among the highest in terms of Data Support relative to other regions. BIAs presented here describe known ranges of small resident populations, intensities of use, and uncertainties in important areas for cetaceans in Hawaiʻi based on the best available data, and have also revealed knowledge gaps to guide future research efforts

Cytochrome P450 CYP1B1 activity in renal cell carcinoma

Renal cell carcinoma (RCC) is the most common malignancy of the kidney and has a poor prognosis due to its late presentation and resistance to current anticancer drugs. One mechanism of drug resistance, which is potentially amenable to therapeutic intervention, is based on studies in our laboratory. CYP1B1 is a cytochrome P450 enzyme overexpressed in a variety of malignant tumours. Our studies are now elucidating a functional role for CYP1B1 in drug resistance. Cytochrome P450 reductase (P450R) is required for optimal metabolic activity of CYP1B1. Both CYP1B1 and P450R can catalyse the biotransformation of anticancer drugs at the site of the tumour. In this investigation, we determined the expression of CYP1B1 and P450R in samples of normal kidney and RCC (11 paired normal and tumour and a further 15 tumour samples). The O-deethylation of ethoxyresorufin to resorufin was used to measure CYP1B1 activity in RCC. Cytochrome P450 reductase activity was determined by following the reduction of cytochrome c at 550 nm. The key finding of this study was the presence of active CYP1B1 in 70% of RCC. Coincubation with the CYP1B1 inhibitor alpha-naphthoflavone (10nM) inhibited this activity. No corresponding CYP1B1 activity was detected in any of the normal tissue examined (n = 11). Measurable levels of active P450R were determined in all normal (n = 11) and tumour samples (n = 26). The presence of detectable CYP1B1, which is capable of metabolising anticancer drugs in tumour cells, highlights a novel target for therapeutic intervention

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts