Molecular and clinicopathological markers of prognosis in breast cancer

A vast body of research in breast cancer prognostication has accumulated. Yet despite this, patients within current prognostic categories may have significantly different outcomes. There is a need to more accurately divide those cancer types associated with an excellent prognosis from those requiring more aggressive therapy. Gene expression array studies have revealed the numerous molecular breast cancer subtypes that are associated with differing outcomes. Furthermore, as next generation technologies evolve and further reveal the complexities of breast cancer, it is likely that existing prognostic approaches will become progressively refined. Future prognostication in breast cancer requires a morphomolecular, multifaceted approach involving the assessment of anatomical disease extent and levels of protein, DNA and RNA expression. One of the major challenges in prognostication will be the integration of potential assays into existing clinical systems and identification of appropriate patient subgroups for analysis.

Guidelines and considerations for conducting experiments using tissue microarrays

Tissue microarrays (TMAs) represent a powerful method for undertaking large-scale tissue-based biomarker studies. While TMAs offer several advantages, there are a number of issues specific to their use which need to be considered when employing this method. Given the investment in TMA-based research, guidance on design and execution of experiments will be of benefit and should help researchers new to TMA-based studies to avoid known pitfalls. Furthermore, a consensus on quality standards for TMA-based experiments should improve the robustness and reproducibility of studies, thereby increasing the likelihood of identifying clinically useful biomarkers. In order to address these issues, the National Cancer Research Institute Biomarker and Imaging Clinical Studies Group organized a 1-day TMA workshop held in Nottingham in May 2012. The document herein summarizes the conclusions from the workshop. It includes guidance and considerations on all aspects of TMA-based research, including the pre-analytical stages of experimental design, the analytical stages of data acquisition, and the postanalytical stages of data analysis. A checklist is presented which can be used both for planning a TMA experiment and interpreting the results of such an experiment. For studies of cancer biomarkers, this checklist could be used as a supplement to the REMARK guidelines.

Lymphocytic follicles and aggregates are a determinant of mucosal damage and duration of diarrhea

Nonspecific changes (nonspecific chronic inflammation) in patients with chronic diarrhea represent the commonest diagnosis in colorectal biopsy interpretation, but these changes are of little clinical significance.

Immunohistochemistry in the era of personalised medicine

Immunohistochemistry (IHC) plays a central role in the histopathological classification of diseases, including cancer. More recently, the importance of immunohistochemical staining is increasing. IHC usage in diagnostics is invaluable; however, the genetic and therapeutic significance of biomarker immunostaining has become equally relevant.

RUNX3 downregulation in human lung adenocarcinoma is independent of p53, EGFR or KRAS status

RUNX3 aberrations play a pivotal role in the oncogenesis of breast, gastric, colon, skin and lung tissues. The aim of this study was to characterize further the expression of RUNX3 in lung cancers. To achieve this, a lung cancer tissue microarray (TMA), frozen lung cancer tissues and lung cell lines were examined for RUNX3 expression by immunohistochemistry, while the TMA was also examined for EGFR and p53 expression. RUNX3 promoter methylation status, and EGFR and KRAS mutation status were also investigated. Inactivation of RUNX3 was observed in 70% of the adenocarcinoma samples, and this was associated with promoter hypermethylation but not biased to EGFR/KRAS mutations. Our results suggest a central role of RUNX3 downregulation in pulmonary adenocarcinoma, which may not be dependent of other established cancer-causing pathways and may have important diagnostic and screening implications.

Th1 not Th17 cells drive spontaneous MS-like disease despite a functional regulatory T cell response

Multiple sclerosis is considered a disease of complex autoimmune etiology, yet there remains a lack of consensus as to specific immune effector mechanisms. Recent analyses of experimental autoimmune encephalomyelitis, the common mouse model of multiple sclerosis, have investigated the relative contribution of Th1 and Th17 CD4 T cell subsets to initial autoimmune central nervous system (CNS) damage. However, inherent in these studies are biases influenced by the adjuvant and toxin needed to break self-tolerance. We investigated spontaneous CNS disease in a clinically relevant, humanized, T cell receptor transgenic mouse model. Mice develop spontaneous, ascending paralysis, allowing unbiased characterization of T cell immunity in an HLA-DR15-restricted T cell repertoire. Analysis of naturally progressing disease shows that IFN?(+) cells dominate disease initiation with IL-17(+) cells apparent in affected tissue only once disease is established. Tregs accumulate in the CNS but are ultimately ineffective at halting disease progression. However, ablation of Tregs causes profound acceleration of disease, with uncontrolled infiltration of lymphocytes into the CNS. This synchronous, severe disease allows characterization of the responses that are deregulated in exacerbated disease: the correlation is with increased CNS CD4 and CD8 IFN? responses. Recovery of the ablated Treg population halts ongoing disease progression and Tregs extracted from the central nervous system at peak disease are functionally competent to regulate myelin specific T cell responses. Thus, in a clinically relevant mouse model of MS, initial disease is IFN? driven and the enhanced central nervous system responses unleashed through Treg ablation comprise IFN? cytokine production by CD4 and CD8 cells, but not IL-17 responses.

The matricellular protein CCN3 regulates NOTCH1 signalling in chronic myeloid leukaemia

Deregulated NOTCH1 has been reported in lymphoid leukaemia, although its role in chronic myeloid leukaemia (CML) is not well established. We previously reported BCR-ABL down-regulation of a novel haematopoietic regulator, CCN3, in CML; CCN3 is a non-canonical NOTCH1 ligand. This study characterizes the NOTCH1–CCN3 signalling axis in CML. In K562 cells, BCR-ABL silencing reduced full-length NOTCH1 (NOTCH1-FL) and inhibited the cleavage of NOTCH1 intracellular domain (NOTCH1-ICD), resulting in decreased expression of the NOTCH1 targets c-MYC and HES1. K562 cells stably overexpressing CCN3 (K562/CCN3) or treated with recombinant CCN3 (rCCN3) showed a significant reduction in NOTCH1 signalling (> 50% reduction in NOTCH1-ICD, p < 0.05). Gamma secretase inhibitor (GSI), which blocks NOTCH1 signalling, reduced K562/CCN3 colony formation but increased that of K562/control cells. GSI combined with either rCCN3 or imatinib reduced K562 colony formation with enhanced reduction of NOTCH1 signalling observed with combination treatments. We demonstrate an oncogenic role for NOTCH1 in CML and suggest that BCR-ABL disruption of NOTCH1–CCN3 signalling contributes to the pathogenesis of CML.

Deconstructing Victim and offender Identities in Discourses on Child Sexual Abuse: Hierarchies, Blame and the Good/Evil Dialectic

Contemporary social and political constructions of victimhood and offending behaviour lie at the heart of regulatory policies on child sexual abuse. Legislation is named after specific child victims of high profile cases, and a burgeoning range of pre-emptive measures are enacted to protect an amorphous class of ‘all potential victims’ from the risk sex offenders are seen as posing. Such policies are also heavily premised on the omnipresent predatory stranger. These constructed identities, however, are at odds with the actual identities of victims and offenders of such crimes. Drawing on a range of literatures, the core task of this article is to confront some of the complexities and tensions surrounding constructions of the victim/offender dyad within the specific context of sexual offending against children. In particular, the article argues that discourses on ‘blame’ – and the polarised notions of ‘innocence’ and ‘guilt’ – inform respective hierarchies of victimhood and offending concerning ‘legitimate’ victim and offender status. Based on these insights, the article argues for the need to move beyond such monochromatic understandings of victims and offenders of sexual crime and to reframe the politics of risk accordingly.

How useful are databases in environmental and criminal forensics?

Advances in computational and information technologies have facilitated the acquisition of geospatial information for regional and national soil and geology databases. These have been completed for a range of purposes from geological and soil baseline mapping to economic prospecting and land resource assessment, but have become increasingly used for forensic purposes. On the question of provenance of a questioned sample, the geologist or soil scientist will draw invariably on prior expert knowledge and available digital map and database sources in a ‘pseudo Bayesian’ approach. The context of this paper is the debate on whether existing (digital) geology and soil databases are indeed useful and suitable for forensic inferences. Published and new case studies are used to explore issues of completeness, consistency, compatibility and applicability in relation to the use of digital geology and soil databases in environmental and criminal forensics. One key theme that emerges is that, despite an acknowledgement that databases can be neither exhaustive nor precise enough to portray spatial variability at the scene of crime scale, coupled with expert knowledge, they play an invaluable role in providing background or
reference material in a criminal investigation. Moreover databases can offer an independent control set of samples.

Justice for Victims before the International Criminal Court

Many prosecutors and commentators have praised the victim provisions at the International Criminal Court (ICC) as 'justice for victims', which for the first time include participation, protection and reparations. This book critically examines the role of victims in international criminal justice, drawing from human rights, victimology, and best practices in transitional justice.

Drawing on field research in Northern Uganda, Luke Moffet explores the nature of international crimes and assesses the role of victims in the proceedings of the ICC, paying particular attention to their recognition, participation, reparations and protection. The book argues that because of the criminal nature and structural limitations of the ICC, justice for victims is symbolic, requiring State Parties to complement the work of the Court to address victims' needs.

In advancing an innovative theory of justice for victims, and in offering solutions to current challenges, the book will be of great interest and use to academics, practitioners and students engaged in victimology, the ICC, transitional justice, or reparations.

Realising Justice for victims before the International Criminal Court

The International Criminal Court (ICC) has been celebrated for its innovative victim provisions, which enable victims to participate in proceedings, avail of protection measures and assistance, and to claim reparations. The impetus for incorporating victim provisions within the ICC, came from victims’ dissatisfaction with the ad hoc tribunals in providing them with more meaningful and tangible justice.1 The International Criminal Tribunals for the former Yugoslavia and Rwanda (ICTY/R) only included victim protection measures, with no provisions for victims to participate in proceedings nor to claim reparations at them. Developments in domestic and international law, in particular human rights such as the 1985 UN Declaration on Justice for Victims and the UN Guidelines on Remedy and Reparations, and transitional justice mechanisms, such as truth commissions and reparations bodies, have helped to expand the notion of justice for international crimes to be more attuned to victims as key stakeholders in dealing with such crimes.

With the first convictions secured at the ICC and the victim participation and reparation regime taking form, it is worth evaluating the extent to which these innovative provisions have translated into justice for victims. The first part of this paper outlines what justice for victims of international crimes entails, drawing from victimology and human rights. The second section surveys the extent to which the ICC has incorporated justice for victims, in procedural and substantive terms, before concluding in looking beyond the Court to how state parties can complement the ICC in achieving justice for victims. This paper argues that while much progress has been made to institutionalise justice for victims within the Court, there is much more progress needed to evolve and develop justice for victims within the ICC to avoid dissatisfaction of past tribunals.

TARGETED BIOMETRIC IMPERSONATION

When applying biometric algorithms to forensic verification, false acceptance and false rejection can mean a failure to identify a criminal, or worse, lead to the prosecution of individuals for crimes they did not commit. It is therefore critical that biometric evaluations be performed as accurately as possible to determine their legitimacy as a forensic tool. This paper argues that, for forensic verification scenarios, traditional performance measures are insufficiently accurate. This inaccuracy occurs because existing verification evaluations implicitly assume that an imposter claiming a false identity would claim a random identity rather than consciously selecting a target to impersonate. In addition to describing this new vulnerability, the paper describes a novel Targeted.. FAR metric that combines the traditional False Acceptance Rate (FAR) measure with a term that indicates how performance degrades with the number of potential targets. The paper includes an evaluation of the effects of targeted impersonation on an existing academic face verification system. This evaluation reveals that even with a relatively small number of targets false acceptance rates can increase significantly, making the analysed biometric systems unreliable.

Partial shoeprint retrieval using multiple point-of-interest detectors and SIFT descriptors

Shoeprint evidence collected from crime scenes can play an important role in forensic investigations. Usually, the analysis of shoeprints is carried out manually and is based on human expertise and knowledge. As well as being error prone, such a manual process can also be time consuming; thus affecting the usability and suitability of shoeprint evidence in a court of law. Thus, an automatic system for classification and retrieval of shoeprints has the potential to be a valuable tool. This paper presents a solution for the automatic retrieval of shoeprints which is considerably more robust than existing solutions in the presence of geometric distortions such as scale, rotation and scale distortions. It addresses the issue of classifying partial shoeprints in the presence of rotation, scale and noise distortions and relies on the use of two local point-of-interest detectors whose matching scores are combined. In this work, multiscale Harris and Hessian detectors are used to select corners and blob-like structures in a scale-space representation for scale invariance, while Scale Invariant Feature Transform (SIFT) descriptor is employed to achieve rotation invariance. The proposed technique is based on combining the matching scores of the two detectors at the score level. Our evaluation has shown that it outperforms both detectors in most of our extended experiments when retrieving partial shoeprints with geometric distortions, and is clearly better than similar work published in the literature. We also demonstrate improved performance in the face of wear and tear. As matter of fact, whilst the proposed work outperforms similar algorithms in the literature, it is shown that achieving good retrieval performance is not constrained by acquiring a full print from a scene of crime as a partial print can still be used to attain comparable retrieval results to those of using the full print. This gives crime investigators more flexibility is choosing the parts of a print to search for in a database of footwear.

LC- HRMS based metabolomics in food safety and doping control – DeTECH21

Issues surrounding the misuse of prohibited and licensed substances in animals destined for food production and performance sport competition continue to be an enormous challenge to regulatory authorities charged with enforcing their control. Efficient analytical strategies are implemented to screen and confirm the presence of a wide range of exogenous substances in various biological matrices. However, such methods rely on the direct measurement of drugs and/or their metabolites in a targeted mode, allowing the detection of restricted number of compounds. As a consequence, emerging practices, in particular the use of natural hormones, designer drugs and low-dose cocktails, remain difficult to handle from a control point of view. A new SME-led FP7 funded project, DeTECH21, aims to overcome current limitations by applying an untargeted metabolomics approach based on liquid chromatography coupled to high resolution mass spectrometry and bioinformatic data analysis to identify bovine and equine animals which have been exposed to exogenous substances and assist in the identification of administered compounds. Markerbased strategies, dealing with the comprehensive analysis of metabolites present in a biological sample (urine/plasma/tissue), offer a reliable solution in the areas of food safety and animal sport doping control by effective, high-throughput and sensitive detection of exogenously administered agents. Therefore, the development of the first commercially available forensic test service based on metabolomics profiling will meet 21st century demands in animal forensics.