The Illusions of Post-Feminism, Ghosts of Gender and the Discourses of Law

This article seeks to consider evidence of post-feminist and "post-equality" gender narratives contained in the discourses of law in the UK and European contexts. Analysis of perennial ghosts of gender in the areas of gender-neutrality in policy, legislative regulation of sexual crimes, and the adjudication of gendered issues by judges will be undertaken in order to renew and reinstate the focus of the legal feminist project and advocate for continued scrutiny in these three practical areas.

The United Kingdom, the United Nations Human Rights Council and the first cycle of the Universal Periodic Review

The introduction of the Universal Periodic Review (UPR) mechanism as an innovative component of the new Human Rights Council in 2006 has suffered little academic scrutiny. This is partly because it holds as its objective an improvement in human rights situations on the ground, a goal that is difficult to test amongst so many possible causal factors attributable to law reform and policy change, and partly due to the fact that the mechanism has only completed one full cycle of review. This article seeks to remedy this absence of analysis by examining the experience of the United Kingdom during its first review. In doing so, the article first considers the conception of the UPR, before progressing to examine the procedure and recommendations made to the UK by its peers. Finally, the article considers the five year review of the UPR which occurred as a subset of the Human Rights Council Review in 2011 and the resulting changes to the process modalities.

Framing Wrongs, Performing Rights in Northern Ireland: Toward a Butlerian Approach to Life in Abortion Strategising

Feminist strategising on abortion has been dominated by a “pro-choice” frame. Increasingly, however, pro-choice discourse is being viewed as inadequate to meet contemporary and complex feminist aims and analyses, in particular due to the individualising ontological framework upon which it appears to be based. The work of Judith Butler is one location where such concerns have been explored and an alternative approach based upon a renewed analysis of the concept of “life” has been asserted. Foregrounding the fundamental precariousness of intersubjective life and opening the socio-political conditions sustaining precarious life to democratic public engagement carries significant implications for feminist strategising for Butler, and envisages a reconceptualisation of debate on abortion. In this article Butler’s work on life will be combined with her theoretical tool of the frame to explore space which may exist within pro-choice strategising to potentially work towards such a renewed approach to life in social debate on abortion. This space may be used to rethink feminist strategising on abortion beyond pro-choice discourse, and presents an accessible starting point from which to do so. In carrying out this analysis insights will be drawn from feminist advocacy and activism in the contingent location of Northern Ireland where recent employment of a health frame and a rights frame demonstrate instances of pro-choice strategising which may be reiterated to shift feminist activism towards more radical engagement with life as a precarious social process demanding critical attention.

Gendered Violence and International Human Rights: Thinking Non-Discrimination Beyond the Sex Binary

The concept of non-discrimination has been central in the feminist challenge to gendered violence within international human rights law. This article critically explores non-discrimination and the challenge it seeks to pose to gendered violence through the work of Judith Butler. Drawing upon Butler’s critique of heteronormative sex/gender, the article utilises an understanding of gendered violence as effected by the restrictive scripts of sex/gender within heteronormativity to illustrate how the development of non-discrimination within international human rights law renders it ineffective to challenge gendered violence due to its own commitments to binarised and asymmetrical sex/gender. However, the article also seeks to encourage a reworking of non-discrimination beyond the heteronormative sex binary through employing Butler’s concept of cultural translation. Analysis via the lens of cultural translation reveals the fluidity of non-discrimination as a universal concept and offers new possibilities for feminist engagement with universal human rights.

From the Right to Life to the Right to Livability: Radically Re-approaching ‘Life’ in Human Rights Politics

This article critically reflects on current mainstream debate on abortion in international human rights discourse and the conception of life underpinning it. The public health focus on access to safe abortion which has dominated this discourse can be detected as committed to a fundamentally liberal idea of bounded and individual subjecthood which mirrors the commitments of the liberal right to life more generally. However, feminist challenges to this frame seeking to advance wider access to reproductive freedoms appear equally underpinned by a liberal conception of life. It is asserted that feminists may offer a more radical challenge to the current impasse in international debate on abortion by engaging with the concept of livability which foregrounds life as an interdependent and conditioned process. The trope of the ‘right to livability’ developed in this article presents a means to reposition the relation between rights and life and facilitate such radical engagement which better attends to the socio-political conditions shaping our interdependent living and being.

Trace elements as predictors of preeclampsia in type 1 diabetic pregnancy

Preeclampsia (PE) affects approximately 5% of all pregnancies, but is increased several-fold in women with pre-gestational type 1 diabetes mellitus (T1DM). Increased oxidative stress and altered maternal plasma trace elements that modulate the antioxidant system have been implicated in PE. In non-diabetic women, increased plasma copper and iron and decreased manganese, selenium, and zinc have been associated with PE in cross-sectional studies. In a longitudinal study, we hypothesized that plasma levels of trace elements differ between T1DM women with vs. without subsequent PE. Samples were collected during the first (gestation 12.2 ± 1.9 weeks, [mean ± SD]), second (21.6 ± 1.5 weeks), and third (31.5 ± 1.7 weeks) trimesters of pregnancy, all before the onset of PE. We compared 23 T1DM women who subsequently developed PE with 24 T1DM women who remained normotensive; and we included 19 non-diabetic (non-DM) normotensive pregnant women as reference controls. Trace elements were measured using inductively coupled plasma mass spectroscopy. In T1DM women with subsequent PE vs normotensive, only plasma zinc was significantly higher at the first trimester, while copper:zinc and copper:high-density lipoprotein cholesterol ratios were higher throughout gestation (all P < .05). These findings persisted after adjustment for covariates. Higher copper:zinc ratios may contribute to oxidative stress in T1DM women who develop PE. Ratios of pro- to anti-oxidant factors may predict risk for PE in diabetic pregnancies more effectively than individual trace element levels.

UAP1 is overexpressed in prostate cancer and is protective against inhibitors of N-linked glycosylation

Prostate cancer is the second most common cause of cancer-associated deaths in men, and signaling via a transcription factor called androgen receptor (AR) is an important driver of the disease. Consequently, AR target genes are prominent candidates to be specific for prostate cancer and also important for the survival of the cancer cells. Here we assess the levels of all hexosamine biosynthetic pathway (HBP) enzymes in 15 separate clinical gene expression data sets and identify the last enzyme in the pathway, UDP-N-acetylglucosamine pyrophosphorylase 1 (UAP1), to be highly overexpressed in prostate cancer. We analyzed 3261 prostate cancers on a tissue microarray and found that UAP1 staining correlates negatively with Gleason score (P=0.0039) and positively with high AR expression (P<0.0001). Cells with high UAP1 expression have 10-fold increased levels of the HBP end-product, UDP-N-acetylglucosamine (UDP-GlcNAc). UDP-GlcNAc is essential for N-linked glycosylation occurring in the endoplasmic reticulum (ER) and high UAP1 expression associates with resistance against inhibitors of N-linked glycosylation (tunicamycin and 2-deoxyglucose) but not with a general ER stress-inducing agent, the calcium ionophore A23187. Knockdown of UAP1 expression re-sensitized cells towards inhibitors of N-linked glycosylation, as measured by proliferation and activation of ER stress markers. Taken together, we have identified an enzyme, UAP1, which is highly overexpressed in prostate cancer and protects cancer cells from ER stress conferring a growth advantage.

O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells

Metabolic disruptions that occur widely in cancers offer an attractive focus for generalized treatment strategies. The hexosamine biosynthetic pathway (HBP) senses metabolic status and produces an essential substrate for O-linked β-N-acetylglucosamine transferase (OGT), which glycosylates and thereby modulates the function of its target proteins. Here, we report that the HBP is activated in prostate cancer cells and that OGT is a central regulator of c-Myc stability in this setting. HBP genes were overexpressed in human prostate cancers and androgen regulated in cultured human cancer cell lines. Immunohistochemical analysis of human specimens (n = 1987) established that OGT is upregulated at the protein level and that its expression correlates with high Gleason score, pT and pN stages, and biochemical recurrence. RNA interference-mediated siliencing or pharmacologic inhibition of OGT was sufficient to decrease prostate cancer cell growth. Microarray profiling showed that the principal effects of OGT inhibition in prostate cancer cells were related to cell-cycle progression and DNA replication. In particular, c-MYC was identified as a candidate upstream regulator of OGT target genes and OGT inhibition elicited a dose-dependent decrease in the levels of c-MYC protein but not c-MYC mRNA in cell lines. Supporting this relationship, expression of c-MYC and OGT was tightly correlated in human prostate cancer samples (n = 1306). Our findings identify HBP as a modulator of prostate cancer growth and c-MYC as a key target of OGT function in prostate cancer cells.

LYRIC/AEG-1 is targeted to different subcellular compartments by ubiquitinylation and intrinsic nuclear localization signals

PURPOSE: LYRIC/AEG-1 has been reported to influence breast cancer survival and metastases, and its altered expression has been found in a number of cancers. The cellular function of LYRIC/AEG-1 has previously been related to its subcellular distribution in cell lines. LYRIC/AEG-1 contains three uncharacterized nuclear localization signals (NLS), which may regulate its distribution and, ultimately, function in cells.

EXPERIMENTAL DESIGN: Immunohistochemistry of a human prostate tissue microarray composed of 179 prostate cancer and 24 benign samples was used to assess LYRIC/AEG-1 distribution. Green fluorescent protein-NLS fusion proteins and deletion constructs were used to show the ability of LYRIC/AEG-1 NLS to target green fluorescent protein from the cytoplasm to the nucleus. Immunoprecipitation and Western blotting were used to show posttranslational modification of LYRIC/AEG-1 NLS regions.

RESULTS: Using a prostate tissue microarray, significant changes in the distribution of LYRIC/AEG-1 were observed in prostate cancer as an increased cytoplasmic distribution in tumors compared with benign tissue. These differences were most marked in high grade and aggressive prostate cancers and were associated with decreased survival. The COOH-terminal extended NLS-3 (amino acids 546-582) is the predominant regulator of nuclear localization, whereas extended NLS-1 (amino acids 78-130) regulates its nucleolar localization. Within the extended NLS-2 region (amino acids 415-486), LYRIC/AEG-1 can be modified by ubiquitin almost exclusively within the cytoplasm.

CONCLUSIONS: Changes in LYRIC/AEG-1 subcellular distribution can predict Gleason grade and survival. Two lysine-rich regions (NLS-1 and NLS-3) can target LYRIC/AEG-1 to subcellular compartments whereas NLS-2 is modified by ubiquitin in the cytoplasm.

Heterogeneity and clinical significance of ETV1 translocations in human prostate cancer

A fluorescence in situ hybridisation (FISH) assay has been used to screen for ETV1 gene rearrangements in a cohort of 429 prostate cancers from patients who had been diagnosed by trans-urethral resection of the prostate. The presence of ETV1 gene alterations (found in 23 cases, 5.4%) was correlated with higher Gleason Score (P=0.001), PSA level at diagnosis (P=<0.0001) and clinical stage (P=0.017) but was not linked to poorer survival. We found that the six previously characterised translocation partners of ETV1 only accounted for 34% of ETV1 re-arrangements (eight out of 23) in this series, with fusion to the androgen-repressed gene C15orf21 representing the commonest event (four out of 23). In 5'-RACE experiments on RNA extracted from formalin-fixed tissue we identified the androgen-upregulated gene ACSL3 as a new 5'-translocation partner of ETV1. These studies report a novel fusion partner for ETV1 and highlight the considerable heterogeneity of ETV1 gene rearrangements in human prostate cancer.

Alterations in beta-catenin expression and localization in prostate cancer

BACKGROUND: Wnt signaling is thought to be important in prostate cancer, in part because proteins such as beta-catenin can also affect androgen receptor signaling. beta-Catenin forms a cell adhesion complex with E-cadherin raising the possibility that loss of expression or a change in beta-catenin distribution in the cell could also alter downstream signaling, decreased inter-cellular adhesion and the promotion of metastasis. A number of studies have reported the altered expression and/or localization of beta-catenin as a biomarker in prostate cancer.

METHODS: Tissue microarrays comprised of BPH and low, moderate and high-grade prostate cancer (n=77) were assessed for beta-catenin expression and distribution using immunohistochemistry. Staining was also performed on a tissue microarray containing tissue from patients before and after hormone manipulation. The effects of fixation and different antibodies was assessed on fixed LNCaP cell pellets and small prostate tissue microarrays.

RESULTS: We have observed increased beta-catenin expression in only high Gleason score (>7) prostate cancer. A nuclear re-distribution of beta-catenin has previously been reported. We noted nuclear beta-catenin in benign prostatic hyperplasia and a gradual loss in nuclear distribution with increasing Gleason grade. We found no evidence for an alteration in beta-catenin expression or re-distribution with hormone ablation. Altered fixation, antibodies and antibody concentration did affect the intensity and specificity of staining.

CONCLUSIONS: A loss of nuclear beta-catenin is the most consistent feature in prostate cancer rather than absolute levels of expression. We also suggest that variation in immunohistochemical protocols may explain variations in the reported literature.

Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene

AIMS/HYPOTHESIS: Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic risk factors for sight-threatening diabetic retinopathy using a genome-wide association study.

METHODS: Retinopathy was assessed in white Australians with type 2 diabetes mellitus. Genome-wide association analysis was conducted for comparison of cases of sight-threatening diabetic retinopathy (n = 336) with diabetic controls with no retinopathy (n = 508). Top ranking single nucleotide polymorphisms were typed in a type 2 diabetes replication cohort, a type 1 diabetes cohort and an Indian type 2 cohort. A mouse model of proliferative retinopathy was used to assess differential expression of the nearby candidate gene GRB2 by immunohistochemistry and quantitative western blot.

RESULTS: The top ranked variant was rs3805931 with p = 2.66 × 10(-7), but no association was found in the replication cohort. Only rs9896052 (p = 6.55 × 10(-5)) was associated with sight-threatening diabetic retinopathy in both the type 2 (p = 0.035) and the type 1 (p = 0.041) replication cohorts, as well as in the Indian cohort (p = 0.016). The study-wide meta-analysis reached genome-wide significance (p = 4.15 × 10(-8)). The GRB2 gene is located downstream of this variant and a mouse model of retinopathy showed increased GRB2 expression in the retina.

CONCLUSIONS/INTERPRETATION: Genetic variation near GRB2 on chromosome 17q25.1 is associated with sight-threatening diabetic retinopathy. Several genes in this region are promising candidates and in particular GRB2 is upregulated during retinal stress and neovascularisation.

Reclaiming the Radical in Universal Human Rights: Universality as Universalisation

The universality of human rights has been a fiercely contested issue throughout their history. This article contributes to scholarly engagements with the universality of human rights by proposing a re-engagement with this concept in a way that is compatible with the aims of radical politics. Instead of a static attribute or characteristic of rights this article proposes that universality can be thought of as, drawing from Judith Butler, an ongoing process of universalisation. Universality accordingly emerges as a site of powerful contest between competing ideas of what human rights should mean, do or say, and universal concepts are continually reworked through political activity. This leads to a differing conception of rights politics than traditional liberal approaches but, moreover, challenges such approaches. This understanding of universality allows human rights to come into view as potentially of use in interrupting liberal regimes and, crucially, opens possibilities to reclaim the radical in rights.

Physical rehabilitation interventions for adult intensive care patients across the continuum of recovery (i.e. within the intensive care unit (ICU) and following ICU and hospital discharge): an overview of systematic reviews

Background
Patients admitted to the intensive care unit with critical illness often experience significant physical impairments, which typically persist for many years following resolution of the original illness. Physical rehabilitation interventions that enhance restoration of physical function have been evaluated across the continuum of recovery following critical illness including within the intensive care unit, following discharge to the ward and beyond hospital discharge. Multiple systematic reviews have been published appraising the expanding evidence investigating these physical rehabilitation interventions, although there appears to be variability in review methodology and quality. We aim to conduct an overview of existing systematic reviews of physical rehabilitation interventions for adult intensive care patients across the continuum of recovery.

Methods/design
This protocol has been developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) guidelines. We will search the Cochrane Systematic Review Database, Database of Abstracts of Reviews of Effectiveness, Cochrane Central Register of Controlled Trials, MEDLINE, Excerpta Medica Database and Cumulative Index to Nursing and Allied Health Literature databases. We will include systematic reviews of randomised controlled trials of adult patients, admitted to the intensive care unit and who have received physical rehabilitation interventions at any time point during their recovery. Data extraction will include systematic review aims and rationale, study types, populations, interventions, comparators, outcomes and quality appraisal method. Primary outcomes of interest will focus on findings reflecting recovery of physical function. Quality of reporting and methodological quality will be appraised using the PRISMA checklist and the Assessment of Multiple Systematic Reviews tool.

Discussion
We anticipate the findings from this novel overview of systematic reviews will contribute to the synthesis and interpretation of existing evidence regarding physical rehabilitation interventions and physical recovery in post-critical illness patients across the continuum of recovery.