A genomic and transcriptomic approach for a differential diagnosis between primary and secondary ovarian carcinomas in patients with a previous history of breast cancer

<p>Abstract</p> <p>Background</p> <p>The distinction between primary and secondary ovarian tumors may be challenging for pathologists. The purpose of the present work was to develop genomic and transcriptomic tools to further refine the pathological diagnosis of ovarian tumors after a previous history of breast cancer.</p> <p>Methods</p> <p>Sixteen paired breast-ovary tumors from patients with a former diagnosis of breast cancer were collected. The genomic profiles of paired tumors were analyzed using the Affymetrix GeneChip^®Mapping 50 K Xba Array or Genome-Wide Human SNP Array 6.0 (for one pair), and the data were normalized with ITALICS (ITerative and Alternative normaLIzation and Copy number calling for affymetrix Snp arrays) algorithm or Partek Genomic Suite, respectively. The transcriptome of paired samples was analyzed using Affymetrix GeneChip^®Human Genome U133 Plus 2.0 Arrays, and the data were normalized with gc-Robust Multi-array Average (gcRMA) algorithm. A hierarchical clustering of these samples was performed, combined with a dataset of well-identified primary and secondary ovarian tumors.</p> <p>Results</p> <p>In 12 of the 16 paired tumors analyzed, the comparison of genomic profiles confirmed the pathological diagnosis of primary ovarian tumor (n = 5) or metastasis of breast cancer (n = 7). Among four cases with uncertain pathological diagnosis, genomic profiles were clearly distinct between the ovarian and breast tumors in two pairs, thus indicating primary ovarian carcinomas, and showed common patterns in the two others, indicating metastases from breast cancer. In all pairs, the result of the transcriptomic analysis was concordant with that of the genomic analysis.</p> <p>Conclusions</p> <p>In patients with ovarian carcinoma and a previous history of breast cancer, SNP array analysis can be used to distinguish primary and secondary ovarian tumors. Transcriptomic analysis may be used when primary breast tissue specimen is not available.</p

ViralORFeome: an integrated database to generate a versatile collection of viral ORFs

Large collections of protein-encoding open reading frames (ORFs) established in a versatile recombination-based cloning system have been instrumental to study protein functions in high-throughput assays. Such ‘ORFeome’ resources have been developed for several organisms but in virology, plasmid collections covering a significant fraction of the virosphere are still needed. In this perspective, we present ViralORFeome 1.0 (http://www.viralorfeome.com), an open-access database and management system that provides an integrated set of bioinformatic tools to clone viral ORFs in the Gateway® system. ViralORFeome provides a convenient interface to navigate through virus genome sequences, to design ORF-specific cloning primers, to validate the sequence of generated constructs and to browse established collections of virus ORFs. Most importantly, ViralORFeome has been designed to manage all possible variants or mutants of a given ORF so that the cloning procedure can be applied to any emerging virus strain. A subset of plasmid constructs generated with ViralORFeome platform has been tested with success for heterologous protein expression in different expression systems at proteome scale. ViralORFeome should provide our community with a framework to establish a large collection of virus ORF clones, an instrumental resource to determine functions, activities and binding partners of viral proteins

A neural circuit model of decision uncertainty and change-of-mind

Decision-making is often accompanied by a degree of confidence on whether a choice is correct. Decision uncertainty, or lack in confidence, may lead to change-of-mind. Studies have identified the behavioural characteristics associated with decision confidence or change-of-mind, and their neural correlates. Although several theoretical accounts have been proposed, there is no neural model that can compute decision uncertainty and explain its effects on change-of-mind. We propose a neuronal circuit model that computes decision uncertainty while accounting for a variety of behavioural and neural data of decision confidence and change-of-mind, including testable model predictions. Our theoretical analysis suggests that change-of-mind occurs due to the presence of a transient uncertainty-induced choice-neutral stable steady state and noisy fluctuation within the neuronal network. Our distributed network model indicates that the neural basis of change-of-mind is more distinctively identified in motor-based neurons. Overall, our model provides a framework that unifies decision confidence and change-of-mind

IRGM Is a Common Target of RNA Viruses that Subvert the Autophagy Network

Autophagy is a conserved degradative pathway used as a host defense mechanism against intracellular pathogens. However, several viruses can evade or subvert autophagy to insure their own replication. Nevertheless, the molecular details of viral interaction with autophagy remain largely unknown. We have determined the ability of 83 proteins of several families of RNA viruses (Paramyxoviridae, Flaviviridae, Orthomyxoviridae, Retroviridae and Togaviridae), to interact with 44 human autophagy-associated proteins using yeast two-hybrid and bioinformatic analysis. We found that the autophagy network is highly targeted by RNA viruses. Although central to autophagy, targeted proteins have also a high number of connections with proteins of other cellular functions. Interestingly, immunity-associated GTPase family M (IRGM), the most targeted protein, was found to interact with the autophagy-associated proteins ATG5, ATG10, MAP1CL3C and SH3GLB1. Strikingly, reduction of IRGM expression using small interfering RNA impairs both Measles virus (MeV), Hepatitis C virus (HCV) and human immunodeficiency virus-1 (HIV-1)-induced autophagy and viral particle production. Moreover we found that the expression of IRGM-interacting MeV-C, HCV-NS3 or HIV-NEF proteins per se is sufficient to induce autophagy, through an IRGM dependent pathway. Our work reveals an unexpected role of IRGM in virus-induced autophagy and suggests that several different families of RNA viruses may use common strategies to manipulate autophagy to improve viral infectivity

Individual differences in first- and second-order temporal judgment

The ability of subjects to identify and reproduce brief temporal intervals is influenced by many factors whether they be stimulus-based, task-based or subject-based. The current study examines the role individual differences play in subsecond and suprasecond timing judgments, using the schizoptypy personality scale as a test- case approach for quantifying a broad range of individual differences. In two experiments, 129 (Experiment 1) and 141 (Experiment 2) subjects completed the O-LIFE personality questionnaire prior to performing a modified temporal-bisect ion task. In the bisection task, subjects responded to two identical instantiations of a luminance grating presented in a 4deg window, 4deg above fixation for 1.5 s Experiment 1) or 3 s (Experiment 2). Subjects initiated presentation with a button- press, and released the button when they considered the stimulus to be half-way through (750/1500 ms). Subjects were then asked to indicate their ‘most accurate estimate’ of the two intervals. In this way we measure both performance on the task (a first-order measure) and the subjects’ knowledge of their performance (a second-order measure). In Experiment 1 the effect of grating-drift and feedback on performance was also examined. Experiment 2 focused on the static/no-feedback condition. For the group data, Experiment 1 showed a significant effect of presentation order in the baseline condition (no feedback), which disappeared when feedback was provided. Moving the stimulus had no effect on perceived duration. Experiment 2 showed no effect of stimulus presentation order. This elimination of the subsecond order-effect was at the expense of accuracy, as the mid-point of the suprasecond interval was generally underestimated. Response precision increased as a proportion of total duration, reducing the variance below that predicted by Weber’s law. This result is consistent with a breakdown of the scalar properties of time perception in the early suprasecond range. All subjects showed good insight into their own performance, though that insight did not necessarily correlate with the veridical bisection point. In terms of personality, we found evidence of significant differences in performance along the Unusual Experiences subscale, of most theoretical interest here, in the subsecond condition only. There was also significant correlation with Impulsive Nonconformity and Cognitive Disorganisation in the sub- and suprasecond conditions, respectively. Overall, these data support a partial dissocation of timing mechanisms at very short and slightly longer intervals. Further, these results suggest that perception is not the only critical mitigator of confidence in temporal experience, since individuals can effectively compensate for differences in perception at the level of metacognition in early suprasecond time. Though there are individual differences in performance, these are perhaps less than expected from previous reports and indicate an effective timing mechanism dealing with brief durations independent of the influence of significant personality trait differences

Connected cutsets of a graph and triangle bases of the cycle space

AbstractWe investigate some properties of graohs whose cycle space has a basis constituted of triangles (‘null-homotopic’ graphs). We obtain characterizations in the case of planar graphs, and more generally, of graphs not contractible onto K5. These characterizations involve separating subsets and decompositions into triangulations of discs

Saccade impairments in patients with fronto-temporal dementia

Objective: To study saccade tasks in a group of 23 patients with FTD and compare the results with aged matched healthy controls. Methods: Triggering and inhibition of reflexive prosaccades were evaluated in a prosaccade and an antisaccade task, respectively, while the ability to withhold an antisaccade during a delay was explored in a delayed antisaccade task. Patients with progressive supranuclear palsy (PSP), in whom the pattern of eye movement deficit is well documented, were studied with the same protocol. To characterise the frontal lobe dysfunction in FTD more precisely, a battery of neuropsychological tests was carried out in these patients. Results: Patients with FTD showed impaired reflexive saccade inhibition, similar to that observed in patients with PSP, and a decreased ability to withhold an antisaccade. Conclusions: Inhibition of reflexive and voluntary saccades appears to be independently processed. A delayed antisaccade task could be useful for the early diagnosis of FTD