Phosphorylation of the androgen receptor is associated with reduced survival in hormonerefractory prostate cancer patients

Cell line studies demonstrate that the PI3K/Akt pathway is upregulated in hormone-refractory prostate cancer (HRPC) and can result in phosphorylation of the androgen receptor (AR). The current study therefore aims to establish if this has relevance to the development of clinical HRPC. Immunohistochemistry was employed to investigate the expression and phosphorylation status of Akt and AR in matched hormone-sensitive and -refractory prostate cancer tumours from 68 patients. In the hormone-refractory tissue, only phosphorylated AR (pAR) was associated with shorter time to death from relapse (<i>P</i>=0.003). However, when an increase in expression in the transition from hormone-sensitive to -refractory prostate cancer was investigated, an increase in expression of PI3K was associated with decreased time to biochemical relapse (<i>P</i>=0.014), and an increase in expression of pAkt<sup>473</sup> and pAR<sup>210</sup> were associated with decreased disease-specific survival (<i>P</i>=0.0019 and 0.0015, respectively). Protein expression of pAkt<sup>473</sup> and pAR<sup>210</sup> also strongly correlated (<i>P</i><0.001, c.c.=0.711) in the hormone-refractory prostate tumours. These results provide evidence using clinical specimens, that upregulation of the PI3K/Akt pathway is associated with phosphorylation of the AR during development of HRPC, suggesting that this pathway could be a potential therapeutic target

Optimization of Naked DNA Delivery for Interferon Subtype Immunotherapy in Cytomegalovirus Infection

Type I interferon (IFN) gene therapy modulates the immune response leading to inflammatory heart disease following cytomegalovirus (CMV) infection in a murine model of post-viral myocarditis. Efficacy of different immunisation protocols for the IFN constructs was influenced by the dose of DNA, subtype choice, combination use, pre-medication, and timing of DNA administration. Optimal efficacy was found with bupivacaine treatment prior to DNA inoculation of 200mg IFN DNA 14 days prior to virus challenge. Maximal antiviral and antimyocarditic effects were achieved with this vaccination schedule. Furthermore, inoculation of synergistic IFN subtypes demonstrated enhanced efficacy when delivered either alone or with CMV gB DNA vaccination in the CMV model. Thus naked DNA delivery of IFN provides an avenue of immunotherapy for regulating herpesvirus-induced diseases

Understanding p300-transcription factor interactions using sequence variation and hybridization

The hypoxic response is central to cell function and plays a significant role in the growth and survival of solid tumours. HIF-1 regulates the hypoxic response by activating over 100 genes responsible for adaptation to hypoxia, making it a potential target for anticancer drug discovery. Although there is significant structural and mechanistic understanding of the interaction between HIF-1α and p300 alongside negative regulators of HIF-1α such as CITED2, there remains a need to further understand the sequence determinants of binding. In this work we use a combination of protein expression, chemical synthesis, fluorescence anisotropy and isothermal titration calorimetry for HIF-1α sequence variants and a HIF-1α-CITED hybrid sequence which we term CITIF. We show the HIF-1α sequence is highly tolerant to sequence variation through reduced enthalpic and less unfavourable entropic contributions, These data imply backbone as opposed to side chain interactions and ligand folding control the binding interaction and that sequence variations are tolerated as a result of adopting a more disordered bound interaction or “fuzzy” complex

Research on Fundamental Breach of Contract:from the perspective of CISG

根本违约是从英国法中产生的一种违约形态，被《联合国国际货物销售合同公约》采纳后成为一个国际性的条款。根本违约制度在《公约》中具有极为重要的地位，扮演了中心的角色。一般认为，根本违约是合同当事人违反了合同中最重要、根本性的条款而构成的违约，另一方当事人不仅有权要求损害赔偿，更重要的是有权宣告合同无效（解除合同）的制度。我国《合同法》第94条也规定了根本违约制度。本文对《公约》的根本违约制度进行了较为全面、深入的分析探讨，指出了我国《合同法》根本违约制度的缺陷并提出了改进的建议。全文除前言和结语外，正文共分为四章：第一章：根本违约制度之国际概览。本章以宏观的角度介绍了根本违约制度在英美法和大陆法两...The mechanism of fundamental breach of contract was derived from British law and adopted by CISG, and had then been developed into an international term. This mechanism plays an extremely important role in CISG. Generally, the mechanism is invoked where one party violates the most important and fundamental terms of the contract and the other party thus has the right to claim damages and to declare...学位：法学硕士院系专业：法学院法律系_国际法学(含国际公法、国际私法、国际经济法)学号：20040810

A Comparison of Machine Learning Methods for Cross-Domain Few-Shot Learning

We present an empirical evaluation of machine learning algorithms in cross-domain few-shot learning based on a fixed pre-trained feature extractor. Experiments were performed in five target domains (CropDisease, EuroSAT, Food101, ISIC and ChestX) and using two feature extractors: a ResNet10 model trained on a subset of ImageNet known as miniImageNet and a ResNet152 model trained on the ILSVRC 2012 subset of ImageNet. Commonly used machine learning algorithms including logistic regression, support vector machines, random forests, nearest neighbour classification, naïve Bayes, and linear and quadratic discriminant analysis were evaluated on the extracted feature vectors. We also evaluated classification accuracy when subjecting the feature vectors to normalisation using p-norms. Algorithms originally developed for the classification of gene expression data—the nearest shrunken centroid algorithm and LDA ensembles obtained with random projections—were also included in the experiments, in addition to a cosine similarity classifier that has recently proved popular in few-shot learning. The results enable us to identify algorithms, normalisation methods and pre-trained feature extractors that perform well in cross-domain few-shot learning. We show that the cosine similarity classifier and ℓ² -regularised 1-vs-rest logistic regression are generally the best-performing algorithms. We also show that algorithms such as LDA yield consistently higher accuracy when applied to ℓ² -normalised feature vectors. In addition, all classifiers generally perform better when extracting feature vectors using the ResNet152 model instead of the ResNet10 model

Improving the repeatability of heterochromatic flicker photometry for measurement of macular pigment optical density

Background: Heterochromatic flicker photometry (HFP) is a psychophysical technique used to measure macular pigment optical density (MPOD). We used the MPS 9000 (MPS) HFP device. Our aim was to determine if the repeatability of the MPS could be improved to make it more suitable for monitoring MPOD over time. Methods: Intra-session repeatability was assessed in 25 participants (aged 20-50 years). The resulting data was explored in detail, e.g., by examining the effect of removal and adjustment of data with less than optimal quality parameters. A protocol was developed for improved overall reliability, which was then tested in terms of inter-session repeatability in a separate group of 27 participants (aged 19-52 years). Results: Removal and adjustment of data reduced the intra-session coefficient of repeatability (CR) by 0.04, on average, and the mean individual standard deviation by 0.004. Raw data observation offered further insight into ways of improving repeatability. The proposed protocol resulted in an inter-session CR of 0.08. Conclusions: Removal and adjustment of less than optimal data improved repeatability, and is therefore recommended. To further improve repeatability, in brief we propose that each patient perform each part of the test twice, and a third time where necessary (described in detail by the protocol). Doing so will make the MPS more useful in research and clinical settings. © 2012 Springer-Verlag

Patterns and correlates of hepatitis C virus phylogenetic clustering among people living with HIV in Australia in the direct-acting antiviral era: A molecular epidemiology study among participants in the CEASE cohort

Background and Aims: In moving towards the elimination of hepatitis C virus (HCV) infection among people living with HIV, understanding HCV transmission patterns may provide insights to guide and evaluate interventions. In this study, we evaluated patterns of, and factors associated with HCV phylogenetic clustering among people living with HIV/HCV co-infection in Australia in the direct-acting antiviral era. Methods: HCV RNA was extracted from dried blood spot (DBS) samples collected between 2014 and 2018 in the CEASE cohort study. The HCV Core-E2 region was amplified by a polymerase chain reaction and Sanger sequenced. Maximum likelihood phylogenetic trees (1000 bootstrap replicates) were used to identify patterns of clustering (3% genetic distance threshold). Mixed-effects logistic regression was used to determine correlates of phylogenetic clustering. Factors assessed were sexual risk behavior, education, injecting drug use, housing, employment, HIV viral load, age, sex, and sexuality. Results: Phylogenetic trees were reconstructed for HCV subtype 1a (n = 139) and 3a (n = 63) sequences, with 29% (58/202) in a pair or cluster. Overall (n = 202), phylogenetic clustering was positively associated with younger age (under 40; adjusted odds ratio [aOR] 2.52, 95% confidence interval [CI] 1.20–5.29), and among gay and bisexual men (n = 168), was positively associated with younger age (aOR 2.61, 95% CI 1.10–6.19), higher education (aOR 2.58, 95% CI 1.09–6.13), and reporting high-risk sexual behavior (aOR 3.94, 95% CI 1.31–11.84). During follow-up, five reinfections were observed, but none were in phylogenetic clusters. Conclusion: This study found a high proportion of phylogenetic relatedness, predominantly among younger people and gay and bisexual men reporting high-risk sexual behavior. Despite this, few reinfections were observed, and reinfections demonstrated little relationship with known clusters. These findings highlight the importance of rapid HCV treatment initiation, together with monitoring of the phylogeny

Fetal leg posture in uncomplicated breech and cephalic pregnancies

Background The objective of our study was to determine differences in prenatal leg posture development between breech and cephalic-born babies. Materials and methods Ten healthy fetuses in breech and ten healthy fetuses in cephalic presentation were observed by means of weekly ultrasounds from 33 weeks gestational age until birth to assess leg posture. Results The breech fetuses showed a clear preference for an extended leg position; they spent significantly more time with their knees in extension than the cephalic fetuses (p<0.001). The cephalic fetuses showed significantly more leg-crossing than the breech fetuses (p<0.01). For both findings, no significant change over time could be observed in either group. Conclusion These findings show that the intra-uterine position does influence the fetal postural and motor development. However, it seems unlikely that intra-uterine movement restriction can solely be held accountable for the observed differences in leg position between breech and cephalic fetuses. © 2008 The Author(s)

Border Terriers under primary veterinary care in England: demography and disorders

The Border Terrier is a working terrier type that is generally considered to be a relatively healthy and hardy breed. This study aimed to characterise the demography and common disorders of Border Terriers receiving veterinary care in England using de-identified electronic patient record data within the VetCompass™ Programme