Response Detection of Castrate-Resistant Prostate Cancer to Clinically Utilised and Novel Treatments by Monitoring Phospholipid Metabolism

The authors gratefully acknowledge funding from Grampian NHS Endowment. The use of Professor Zanda’s and Jaspar’s NMR equipment and Russell Gray’s assistance are also gratefully acknowledged.Peer reviewedPublisher PD

Triplet Energy Transfer from Ruthenium Complexes to Chiral Eniminium Ions: Enantioselective Synthesis of Cyclobutanecarbaldehydes by [2+2] Photocycloaddition

Chiral eniminium salts, prepared from alpha,beta-unsaturated aldehydes and a chiral proline derived secondary amine, underwent, upon irradiation with visible light, a ruthenium-catalyzed (2.5 mol %) intermolecular [2+2] photocycloaddition to olefins, which after hydrolysis led to chiral cyclobutanecarbaldehydes (17 examples, 49-74 % yield), with high diastereo- and enantioselectivities. Ru(bpz)(3)(PF6)(2) was utilized as the ruthenium catalyst and laser flash photolysis studies show that the catalyst operates exclusively by triplet-energy transfer (sensitization). A catalytic system was devised with a chiral secondary amine co-catalyst. In the catalytic reactions, Ru(bpy)(3)(PF6)(2) was employed, and laser flash photolysis experiments suggest it undergoes both electron and energy transfer. However, experimental evidence supports the hypothesis that energy transfer is the only productive quenching mechanism. Control experiments using Ir(ppy)(3) showed no catalysis for the intermolecular [2+2] photocycloaddition of an eniminium ion

Quantitative magnetic resonance imaging of meniscal pathology ex vivo

OBJECTIVE To determine the ability of conventional spin echo (SE) T2 and ultrashort echo time (UTE) T2* relaxation times to characterize pathology in cadaveric meniscus samples. MATERIALS AND METHODS From 10 human donors, 54 triangular (radially cut) meniscus samples were harvested. Meniscal pathology was classified as normal (n = 17), intrasubstance degenerated (n = 33), or torn (n = 4) using a modified arthroscopic grading system. Using a 3-T MR system, SE T2 and UTE T2* values of the menisci were determined, followed by histopathology. Effect of meniscal pathology on relaxation times and histology scores were determined, along with correlation between relaxation times and histology scores. RESULTS Mean ± standard deviation UTE T2* values for normal, degenerated, and torn menisci were 3.6 ± 1.3 ms, 7.4 ± 2.5 ms, and 9.8 ± 5.7 ms, respectively, being significantly higher in degenerated (p  0.14). In terms of histology, we found significant group-wise differences (each p < 0.05) in fiber organization and inner-tip surface integrity sub-scores, as well as the total score. Finally, we found a significant weak correlation between UTE T2* and histology total score (p = 0.007, R$_{s}$$^{2}$ = 0.19), unlike the correlation between SE T2 and histology (p = 0.09, R$_{s}$$^{2}$ = 0.05). CONCLUSION UTE T2* values were found to distinguish normal from both degenerated and torn menisci and correlated significantly with histopathology

Adaptation-Based Programming in Haskell

We present an embedded DSL to support adaptation-based programming (ABP) in Haskell. ABP is an abstract model for defining adaptive values, called adaptives, which adapt in response to some associated feedback. We show how our design choices in Haskell motivate higher-level combinators and constructs and help us derive more complicated compositional adaptives. We also show an important specialization of ABP is in support of reinforcement learning constructs, which optimize adaptive values based on a programmer-specified objective function. This permits ABP users to easily define adaptive values that express uncertainty anywhere in their programs. Over repeated executions, these adaptive values adjust to more efficient ones and enable the user's programs to self optimize. The design of our DSL depends significantly on the use of type classes. We will illustrate, along with presenting our DSL, how the use of type classes can support the gradual evolution of DSLs.Comment: In Proceedings DSL 2011, arXiv:1109.032

Imaging in population science: cardiovascular magnetic resonance in 100,000 participants of UK Biobank - rationale, challenges and approaches

PMCID: PMC3668194SEP was directly funded by the National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts. SN acknowledges support from the Oxford NIHR Biomedical Research Centre and from the Oxford British Heart Foundation Centre of Research Excellence. SP and PL are funded by a BHF Senior Clinical Research fellowship. RC is supported by a BHF Research Chair and acknowledges the support of the Oxford BHF Centre for Research Excellence and the MRC and Wellcome Trust. PMM gratefully acknowledges training fellowships supporting his laboratory from the Wellcome Trust, GlaxoSmithKline and the Medical Research Council

Reactor physics project final report

"September 30, 1970."Statement of responsibility on title-page reads: Editors, M. J. Driscoll, I. Kaplan, D. D. Lanning, N. C. Rasmussen. Contributors: V. K. Agarwala, F. M. Clikeman, M. J. Driscoll, Y. Hukai, L. L. Izzo, I. Kaplan, M. S. Kazimi, D.D. Lanning, T.C. Leung, E.L. McFarland, N.C. Rasmussen, S.S. Seth, G.E. Sullivan, and A.T. SuppleIncludes bibliographical referencesFinal report; January 1, 1968 to September 30, 1970This is the final report in an experimental and theoretical program to develop and apply single- and few-element methods for the determination of reactor lattice parameters. The period covered by the report is January 1, 1968 through September 30, 1970. In addition to summarizing results for the entire contract period, this report also serves as the final annual report; thus, work completed in the period of October 1, 1969 through September 30, 1970 is dealt with in more detail than the earlier work. Methods were developed to measure the heterogeneous parameters 17, [Gamma] [eta] and [Alpha] for single fuel elements immersed in moderator in an exponential tank using foil activation measurements external to the fuel. These methods were applied to clustered fuel rods in D 20 moderator and single fuel rods in H 20 moderator, and the results were extended to and compared with data on complete multi-element lattices reported by other laboratories. Advanced gamma spectrometric methods using Ge(Li) detectors were applied to the analysis of both prompt and fission product decay gammas for the nondestructive analysis of the fuel used in this work. The latter includes both simulated burned fuel containing plutonium and actual burned fuel irradiated to 20,000 MWD/T in the Dresden BWR.U.S. Atomic Energy Commission contract AT (30-1)-394

Cross-National Differences in Victimization : Disentangling the Impact of Composition and Context

Varying rates of criminal victimization across countries are assumed to be the outcome of countrylevel structural constraints that determine the supply ofmotivated o¡enders, as well as the differential composition within countries of suitable targets and capable guardianship. However, previous empirical tests of these ‘compositional’ and ‘contextual’ explanations of cross-national di¡erences have been performed upon macro-level crime data due to the unavailability of comparable individual-level data across countries. This limitation has had two important consequences for cross-national crime research. First, micro-/meso-level mechanisms underlying cross-national differences cannot be truly inferred from macro-level data. Secondly, the e¡ects of contextual measures (e.g. income inequality) on crime are uncontrolled for compositional heterogeneity. In this paper, these limitations are overcome by analysing individual-level victimization data across 18 countries from the International CrimeVictims Survey. Results from multi-level analyses on theft and violent victimization indicate that the national level of income inequality is positively related to risk, independent of compositional (i.e. micro- and meso-level) di¡erences. Furthermore, crossnational variation in victimization rates is not only shaped by di¡erences in national context, but also by varying composition. More speci¢cally, countries had higher crime rates the more they consisted of urban residents and regions with lowaverage social cohesion.

Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide

Sal-like 4 (SALL4) is a nuclear factor central to the maintenance of stem cell pluripotency and is a key component in hepatocellular carcinoma, a malignancy with no effective treatment. In cancer cells, SALL4 associates with nucleosome remodeling deacetylase (NuRD) to silence tumor-suppressor genes, such as PTEN. Here, we determined the crystal structure of an amino-terminal peptide of SALL4(1-12) complexed to RBBp4, the chaperone subunit of NuRD, at 2.7 Å, and subsequent design of a potent therapeutic SALL4 peptide (FFW) capable of antagonizing the SALL4-NURD interaction using systematic truncation and amino acid substitution studies. FFW peptide disruption of the SALL4-NuRD complex resulted in unidirectional up-regulation of transcripts, turning SALL4 from a dual transcription repressor-activator mode to singular transcription activator mode. We demonstrate that FFW has a target affinity of 23 nM, and displays significant antitumor effects, inhibiting tumor growth by 85% in xenograft mouse models. Using transcriptome and survival analysis, we discovered that the peptide inhibits the transcription-repressor function of SALL4 and causes massive up-regulation of transcripts that are beneficial to patient survival. This study supports the SALL4-NuRD complex as a drug target and FFW as a viable drug candidate, showcasing an effective strategy to accurately target oncogenes previously considered undruggable

Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling

Objective The generation of acinar and ductal cells from human pluripotent stem cells (PSCs) is a poorly studied process, although various diseases arise from this compartment. Design We designed a straightforward approach to direct human PSCs towards pancreatic organoids resembling acinar and ductal progeny. Results Extensive phenotyping of the organoids not only shows the appropriate marker profile but also ultrastructural, global gene expression and functional hallmarks of the human pancreas in the dish. Upon orthotopic transplantation into immunodeficient mice, these organoids form normal pancreatic ducts and acinar tissue resembling fetal human pancreas without evidence of tumour formation or transformation. Finally, we implemented this unique phenotyping tool as a model to study the pancreatic facets of cystic fibrosis (CF). For the first time, we provide evidence that in vitro, but also in our xenograft transplantation assay, pancreatic commitment occurs generally unhindered in CF. Importantly, cystic fibrosis transmembrane conductance regulator (CFTR) activation in mutated pancreatic organoids not only mirrors the CF phenotype in functional assays but also at a global expression level. We also conducted a scalable proof-of-concept screen in CF pancreatic organoids using a set of CFTR correctors and activators, and established an mRNA-mediated gene therapy approach in CF organoids. Conclusions Taken together, our platform provides novel opportunities to model pancreatic disease and development, screen for disease-rescuing agents and to test therapeutic procedures.This study was funded by the Deutsche Forschungsgemeinschaft (DFG, K.L. 2544/1-1 and 1-2), the Forschungskern SyStaR to AK, BIU (Böhringer Ingelheim Ulm to AK), the Fritz-Thyssen Foundation (Az. 10.15.2.040), the German Cancer Aid (111879) and the Else-Kröner-Fresenius-Stiftung (2011_A200). AK is indebted to the Baden-Württemberg Stiftung for the financial support of this research project by the Eliteprogramme for Postdocs. AK is also an Else-Kröner-Fresenius Memorial Fellow. LP is supported by a research fellowship of the Else-Kröner-Fresenius-Stiftung. MH was supported by the International Graduate School in Molecular Medicine and the Bausteinprogramme (L.SBN. 110), Ulm University. MM is supported by a grant of Ulm University (Baustein for Senior Clinician Scientists). IGC is funded by the Interdisciplinary Center for Clinical Research (IZKF Aachen) and Start Program, RWTH Aachen University Medical School, Aachen, German