Specific staining of human chromosomes in Chinese hamster x man hybrid cell lines demonstrates interphase chromosome territories

In spite of Carl Rabl's (1885) and Theodor Boveri's (1909) early hypothesis that chromosomes occupy discrete territories or domains within the interphase nucleus, evidence in favor pf this hypothesis has been limited and indirect so far in higher plants and animals. The alternative possibility that the chromatin fiber of single chromosomes might be extended throughout the major part of even the whole interphase nucleus has been considered for many years. In the latter case, chromosomes would only exist as discrete chromatin bodies during mitosis but not during interphase. Both possibilities are compatible with Boveri's well established paradigm of chromosome individuality. Here we show that an active human X chromosome contained as the only human chromosome in a Chinese hamster x man hybrid cell line can be visualized both in metaphse plates and in interphase nuclei after in situ hybridization with either 3H- or biotin-labeled human genomic DNA. We demonstrate that this chromosome is organized as a distinct chromatin body throughout interphase. In addition, evidence for the territorial organization of human chromosomes is also presented for another hybrid cell line containing several autosomes and the human X chromosome. These findings are discussed in the context of our present knowledge of the organization and topography of interphase chromosomes. General applications of a strategy aimed at specific staining of individual chromosomes in experimental and clinical cytogenetics are briefly considered

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

Low Self-Esteem and Impairments in Emotion Recognition Predict Behavioural Problems in Children

Research indicates that low self-esteem and impaired emotion recognition are risk factors for antisocial behaviour (ASB). Self-esteem and emotion recognition are essential for successful social interaction and previous research suggests that self-esteem and emotional intelligence are positively related. However, to our knowledge the relationship between these two risk factors for ASB has not been explored in children with behavioural problems. Thus, this study investigated self-esteem and emotion recognition, their relationship with one another and with behavioural problem severity. Participants were 8–11 year olds with behavioural problems (BP; n = 78) who were taking part in an early intervention program, and typically developing controls (TD; n = 54). Participants completed a self-esteem questionnaire and a computerised emotion recognition task. Teachers and parents rated children’s emotional and behavioural problems. BP participants had significantly lower self-esteem and exhibited an impairment in emotion recognition. Self-esteem and emotion recognition were positively related and inversely associated with behavioural problem severity and they predicted behaviour problems independently of one another. This is the first study to show that self-esteem and emotion recognition are related processes in children with behavioural problems and that both predict behavioural problems. This has important implications for the development of intervention strategies

Proximity of Transmembrane Segments 5 and 8 of the Glutamate Transporter GLT-1 Inferred from Paired Cysteine Mutagenesis

BACKGROUND: GLT-1 is a glial glutamate transporter which maintains low synaptic concentrations of the excitatory neurotransmitter enabling efficient synaptic transmission. Based on the crystal structure of the bacterial homologue Glt(Ph), it has been proposed that the reentrant loop HP2, which connects transmembrane domains (TM) 7 and 8, moves to open and close access to the binding pocket from the extracellular medium. However the conformation change between TM5 and TM8 during the transport cycle is not clear yet. We used paired cysteine mutagenesis in conjunction with treatments with Copper(II)(1,10-Phenanthroline)(3) (CuPh), to verify the predicted proximity of residues located at these structural elements of GLT-1. METHODOLOGY/PRINCIPAL FINDINGS: To assess the proximity of transmembrane domain (TM) 5 relative to TM8 during transport by the glial glutamate transporter GLT-1/EAAT2, cysteine pairs were introduced at the extracellular ends of these structural elements. A complete inhibition of transport by Copper(II)(1,10-Phenanthroline)(3) is observed in the double mutants I295C/I463C and G297C/I463C, but not in the corresponding single mutants. Glutamate and potassium, both expected to increase the proportion of inward-facing transporters, significantly protected against the inhibition of transport activity of I295C/I463C and G297C/I463C by CuPh. Transport by the double mutants I295C/I463C and G297C/I463C also was inhibited by Cd(2+). CONCLUSIONS/SIGNIFICANCE: Our results suggest that TM5 (Ile-295, Gly-297) is in close proximity to TM8 (Ile-463) in the mammalian transporter, and that the spatial relationship between these domains is altered during the transport cycle

Pineoblastoma segregates into molecular sub-groups with distinct clinico-pathologic features: a Rare Brain Tumor Consortium registry study.

Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (DICER1, DROSHA, and DGCR8) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic MYC-miR-17/92-RB1 pathway were observed in the RB and MYC sub-group, respectively, characterized by RB1 loss with gain of miR-17/92, and recurrent gain or amplification of MYC. PB sub-groups exhibited distinct clinical features: group 1-3 arose in older children (median ages 5.2-14.0 years) and had intermediate to excellent survival (5-year OS of 68.0-100%), while Group RB and MYC PB patients were much younger (median age 1.3-1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors

A randomized controlled trial of an online, compassion-based intervention for maternal psychological well-being in the first year postpartum

Objectives New self-help interventions have been called for to promote psychological well-being amongst mothers in the first year postpartum, with compassion-based interventions having potential in this regard. The present study developed and evaluated a low-intensity, online, compassion-based intervention for this population called Kindness for Mums Online (KFMO). Methods UK mothers of infants under one year (N = 206) participated in a pragmatic randomized controlled trial, comparing KFMO with a waitlist control. Results The effect of the intervention on well-being (the primary outcome) was small and was sensitive to the way missing data were treated. However, KFMO robustly increased self-compassion relative to control, from baseline (week 0) to post-intervention (week 6), and from baseline to follow-up (week 12). No effects were observed on other secondary outcomes. Conclusions The findings suggest that self-compassion can be increased in postpartum mothers via an accessible, low-intensity, web-based, self-help program. However, this did not translate into robust improvements in well-being. Study limitations include relatively high attrition rates and limited generalizability to more diverse samples

Constructing a biodiversity terminological inventory.

The increasing growth of literature in biodiversity presents challenges to users who need to discover pertinent information in an efficient and timely manner. In response, text mining techniques offer solutions by facilitating the automated discovery of knowledge from large textual data. An important step in text mining is the recognition of concepts via their linguistic realisation, i.e., terms. However, a given concept may be referred to in text using various synonyms or term variants, making search systems likely to overlook documents mentioning less known variants, which are albeit relevant to a query term. Domain-specific terminological resources, which include term variants, synonyms and related terms, are thus important in supporting semantic search over large textual archives. This article describes the use of text mining methods for the automatic construction of a large-scale biodiversity term inventory. The inventory consists of names of species, amongst which naming variations are prevalent. We apply a number of distributional semantic techniques on all of the titles in the Biodiversity Heritage Library, to compute semantic similarity between species names and support the automated construction of the resource. With the construction of our biodiversity term inventory, we demonstrate that distributional semantic models are able to identify semantically similar names that are not yet recorded in existing taxonomies. Such methods can thus be used to update existing taxonomies semi-automatically by deriving semantically related taxonomic names from a text corpus and allowing expert curators to validate them. We also evaluate our inventory as a means to improve search by facilitating automatic query expansion. Specifically, we developed a visual search interface that suggests semantically related species names, which are available in our inventory but not always in other repositories, to incorporate into the search query. An assessment of the interface by domain experts reveals that our query expansion based on related names is useful for increasing the number of relevant documents retrieved. Its exploitation can benefit both users and developers of search engines and text mining applications

Challenges for Australia's Bio/Nanopharma Policies: trade deals, public goods and reference pricing in sustainable industrial renewal

Industrial renewal in the bio/nanopharma sector is important for the long term strength of the Australian economy and for the health of its citizens. A variety of factors, however, may have caused inadequate attention to focus on systematically promoting domestic generic and small biotechnology manufacturers in Australian health policy

An integrated analysis of molecular aberrations in NCI-60 cell lines

<p>Abstract</p> <p>Background</p> <p>Cancer is a complex disease where various types of molecular aberrations drive the development and progression of malignancies. Large-scale screenings of multiple types of molecular aberrations (e.g., mutations, copy number variations, DNA methylations, gene expressions) become increasingly important in the prognosis and study of cancer. Consequently, a computational model integrating multiple types of information is essential for the analysis of the comprehensive data.</p> <p>Results</p> <p>We propose an integrated modeling framework to identify the statistical and putative causal relations of various molecular aberrations and gene expressions in cancer. To reduce spurious associations among the massive number of probed features, we sequentially applied three layers of logistic regression models with increasing complexity and uncertainty regarding the possible mechanisms connecting molecular aberrations and gene expressions. Layer 1 models associate gene expressions with the molecular aberrations on the same loci. Layer 2 models associate expressions with the aberrations on different loci but have known mechanistic links. Layer 3 models associate expressions with nonlocal aberrations which have unknown mechanistic links. We applied the layered models to the integrated datasets of NCI-60 cancer cell lines and validated the results with large-scale statistical analysis. Furthermore, we discovered/reaffirmed the following prominent links: (1)Protein expressions are generally consistent with mRNA expressions. (2)Several gene expressions are modulated by composite local aberrations. For instance, CDKN2A expressions are repressed by either frame-shift mutations or DNA methylations. (3)Amplification of chromosome 6q in leukemia elevates the expression of MYB, and the downstream targets of MYB on other chromosomes are up-regulated accordingly. (4)Amplification of chromosome 3p and hypo-methylation of PAX3 together elevate MITF expression in melanoma, which up-regulates the downstream targets of MITF. (5)Mutations of TP53 are negatively associated with its direct target genes.</p> <p>Conclusions</p> <p>The analysis results on NCI-60 data justify the utility of the layered models for the incoming flow of cancer genomic data. Experimental validations on selected prominent links and application of the layered modeling framework to other integrated datasets will be carried out subsequently.</p