Biopsy confirmation of metastatic sites in breast cancer patients:clinical impact and future perspectives

Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome,and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations,the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio-banks of biopsy material taken from metastatic sites. We believe that such bio-banks will be important for exploring mechanisms of metastasis. In the future,advances in targeted therapy will depend on the availability of metastatic tissue

Evidence for Impaired CARD15 Signalling in Crohn's Disease without Disease Linked Variants

BACKGROUND:Sensing of muramyl dipeptide (MDP) is impaired in Crohn's disease (CD) patients with disease-linked variants of the CARD15 (caspase activation and recruitment domain 15) gene. Animal studies suggest that normal CARD15 signalling prevents inflammatory bowel disease, and may be important for disease development in CD. However, only a small fraction of CD patients carry the disease linked CARD15 variants. The aim of this study was thus to investigate if changes could be found in CARD15 signalling in patients without disease associated CARD15 variants. METHODOLOGY/PRINCIPAL FINDINGS:By mapping the response to MDP in peripheral monocytes obtained from CD patients in remission not receiving immunosuppresives, an impaired response to MDP was found in patients without disease linked CARD15 variants compared to control monocytes. This impairment was accompanied by a decreased activation of IkappaB kinase alpha/beta (IKKalpha/beta), the initial step in the nuclear factor kappaB (NFkappaB) pathway, whereas activation of mitogen-activated protein (MAP)-kinases was unaffected. MDP additionally stimulates the inflammasome which is of importance for processing of cytokines. The inflammasome was constitutively activated in CD, but unresponsive to MDP both in CD and control monocytes. CONCLUSIONS/SIGNIFICANCE:These results suggest that inhibited MDP-dependent pathways in CD patients not carrying the disease-associated CARD15 variants might be of importance for the pathogenesis of CD. The results reveal a dysfunctional immune response in CD patients, not able to sense relevant stimuli on the one hand, and on the other hand possessing constitutively active cytokine processing

TDP-43 Identified from a Genome Wide RNAi Screen for SOD1 Regulators

Amyotrophic Lateral Sclerosis (ALS) is a late-onset, progressive neurodegenerative disease affecting motor neurons in the brain stem and spinal cord leading to loss of voluntary muscular function and ultimately, death due to respiratory failure. A subset of ALS cases are familial and associated with mutations in superoxide dismutase 1 (SOD1) that destabilize the protein and predispose it to aggregation. In spite of the fact that sporadic and familial forms of ALS share many common patho-physiological features, the mechanistic relationship between SOD1-associated and sporadic forms of the disease if any, is not well understood. To better understand any molecular connections, a cell-based protein folding assay was employed to screen a whole genome RNAi library for genes that regulate levels of soluble SOD1. Statistically significant hits that modulate SOD1 levels, when analyzed by pathway analysis revealed a highly ranked network containing TAR DNA binging protein (TDP-43), a major component of aggregates characteristic of sporadic ALS. Biochemical experiments confirmed the action of TDP-43 on SOD1. These results highlight an unexpected relationship between TDP-43 and SOD1 which may have implications in disease pathogenesis

Spelling improvement through letter-sound and whole-word training in two multilingual Greek- and English- speaking children

Case studies of two children with spelling difficulty are reported. LK was multilingual and ED bilingual. A training programme that targeted phonic decoding (or sublexical) spelling processes was conducted with both children. Immediate and delayed post-training assessments showed improvement in spelling nonwords for LK but not for ED. Training that targeted whole word (or lexical) spelling processes was then conducted with ED. Improvement in spelling of irregular words (a marker for lexical spelling processes) was observed. Research into literacy difficulties with multilingual children is sparse, although multilingualism is increasingly widespread. Up to now theoretically based training studies have focused on monolingual children and results were promising. The present findings indicate that theoretically based training programmes for literacy difficulties can also be effective for multilingual children

The influence of torsion on disc herniation when combined with flexion

The role of torsion in the mechanical derangement of intervertebral discs remains largely undefined. The current study sought to investigate if torsion, when applied in combination with flexion, affects the internal failure mechanics of the disc wall when exposed to high nuclear pressure. Thirty ovine lumbar motion segments were each positioned in 2° axial rotation plus 7° flexion. Whilst maintained in this posture, the nucleus of each segment was gradually injected with a viscous radio-opaque gel, via an injection screw placed longitudinally within the inferior vertebra, until failure occurred. Segments were then inspected using micro-CT and optical microscopy in tandem. Five motion segments failed to pressurize correctly. Of the remaining 25 successfully tested motion segments, 17 suffered vertebral endplate rupture and 8 suffered disc failure. Disc failure occurred in mature motion segments significantly more often than immature segments. The most common mode of disc failure was a central posterior radial tear involving a systematic annulus–endplate–annulus failure pattern. The endplate portion of these radial tears often propagated contralateral to the direction of applied axial rotation, and, at the lateral margin, only those fibres inclined in the direction of the applied torque were affected. Apart from the 2° of applied axial rotation, the methods employed in this study replicated those used in a previously published study. Consequently, the different outcome obtained in this study can be directly attributed to the applied axial rotation. These inter-study differences show that when combined with flexion, torsion markedly reduces the nuclear pressure required to form clinically relevant radial tears that involve cartilaginous endplate failure. Conversely, torsion appears to increase the disc wall’s resistance to radial tears that do not involve cartilaginous endplate failure, effectively halving the disc wall’s overall risk of rupture