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The RUNX1 (AML1) gene is a relatively infrequent mutational target in cases of acute myeloid leukemia (AML). Previous work indicated that RUNX1 mutations can have pathological and prognostic implications. To evaluate prognostic value, we conducted a meta-analysis of 4 previous published works with data for survival according to RUNX1 mutation status. Pooled hazard ratios for overall survival and disease-free survival were 1.55 (95% confidence interval (CI) = 1.11–2.15; p-value = 0.01) and 1.76 (95% CI = 1.24–2.52; p-value = 0.002), respectively, for cases positive for RUNX1 mutations. This evidence supports clinical implications of RUNX1 mutations in the development and progression of AML cases and points to the possibility of a distinct category within the newer WHO classification. Though it must be kept in mind that the present work was based on data extracted from observational studies, the findings suggest that the RUNX1 status can contribute to risk-stratification and decision-making in management of AML., (Creative Commons Attribution License)

Spermatogenesis is a multifactorial process that forms differentiated sperm cells in a complex microenvironment. This process involves the genome, epigenome, transcriptome, and proteome to ensure the stability of the spermatogonia and supporting cells. The identification of signaling pathways linked to infertility has been hampered by the inherent complexity and multifactorial aspects of spermatogenesis. Systems biology is a promising approach to unveil underlying signaling pathways and genes and identify putative biomarkers. In this study, we analyzed thirteen microarray libraries of infertile humans and mice, and different classes of male infertility were compared using differentially expressed genes and functional enrichment analysis. We found regulatory processes, immune response, glutathione transferase and muscle tissue development to be among the most common biological processes in up-regulated genes, and genes involved in spermatogenesis were down-regulated in maturation arrest (MArrest) and oligospermia cases. We also observed the overexpression of genes involved in steroid metabolism in post-meiotic and meiotic arrest. Furthermore, we found that the infertile mouse model most similar to human MArrest was the Dazap1 mutant mouse. The results of this study could help elucidate features of infertility etiology and provide the basis for diagnostic markers.

The shortest path problem is one of the most fundamental networks optimization problems. Nowadays, individuals interact in extraordinarily numerous ways through their offline and online life (e.g., co-authorship, co-workership, or retweet relation in Twitter). These interactions have two key features. First, they have a heterogeneous nature, and second, they have different strengths that are weighted based on their degree of intimacy, trustworthiness, service exchange or influence among individuals. These networks are known as multiplex networks. To our knowledge, none of the previous shortest path definitions on social interactions have properly reflected these features. In this work, we introduce a new distance measure in multiplex networks based on the concept of Pareto efficiency taking both heterogeneity and weighted nature of relations into account. We then model the problem of finding the whole set of paths as a form of multiple objective decision making and propose an exact algorithm for that. The method is evaluated on five real-world datasets to test the impact of considering weights and multiplexity in the resulting shortest paths. As an application to find the most influential nodes, we redefine the concept of betweenness centrality based on the proposed shortest paths and evaluate it on a real-world dataset from two-layer trade relation among countries between years 2000 and 2015.

Online social networks play a major role in modern societies, and they have shaped the way social relationships evolve. Link prediction in social networks has many potential applications such as recommending new items to users, friendship suggestion and discovering spurious connections. Many real social networks evolve the connections in multiple layers (e.g. multiple social networking platforms). In this article, we study the link prediction problem in multiplex networks. As an example, we consider a multiplex network of Twitter (as a microblogging service) and Foursquare (as a location-based social network). We consider social networks of the same users in these two platforms and develop a meta-path-based algorithm for predicting the links. The connectivity information of the two layers is used to predict the links in Foursquare network. Three classical classifiers (naive Bayes, support vector machines (SVM) and K-nearest neighbour) are used for the classification task. Although the networks are not highly correlated in the layers, our experiments show that including the cross-layer information significantly improves the prediction performance. The SVM classifier results in the best performance with an average accuracy of 89%.

Neoplastic disorders are a leading cause of mortality and morbidity worldwide. Studying the relationships between different cancers using high throughput-generated data may elucidate undisclosed aspects of cancer etiology, diagnosis, and treatment. Several studies have described relationships between different diseases based on genes, proteins, pathways, gene ontology, comorbidity, symptoms, and other features. In this study, we first constructed an integrated human disease network based on nine different biological aspects, including molecular, functional, and clinical features. Next, we extracted the cancerome as a cancer-related subnetwork. Further investigation of cancerome could reveal hidden mechanisms of cancer and could be useful in developing new diagnostic tests and effective new drugs., (Copyright © 2016. Published by Elsevier Ltd.)

The human brain can be modelled as a complex networked structure with brain regions as individual nodes and their anatomical/functional links as edges. Functional brain networks are constructed by first extracting weighted connectivity matrices, and then binarizing them to minimize the noise level. Different methods have been used to estimate the dependency values between the nodes and to obtain a binary network from a weighted connectivity matrix. In this work we study topological properties of EEG-based functional networks in Alzheimer's Disease (AD). To estimate the connectivity strength between two time series, we use Pearson correlation, coherence, phase order parameter and synchronization likelihood. In order to binarize the weighted connectivity matrices, we use Minimum Spanning Tree (MST), Minimum Connected Component (MCC), uniform threshold and density-preserving methods. We find that the detected AD-related abnormalities highly depend on the methods used for dependency estimation and binarization. Topological properties of networks constructed using coherence method and MCC binarization show more significant differences between AD and healthy subjects than the other methods. These results might explain contradictory results reported in the literature for network properties specific to AD symptoms. The analysis method should be seriously taken into account in the interpretation of network-based analysis of brain signals.

In this paper, distributed electroencephalographic (EEG) sources in the brain have been mapped with the objective of early diagnosis of Alzheimer's disease (AD). To this end, records from a montage of a high-density EEG from 17 early AD patients and 17 matched healthy control subjects were considered. Subjects were in eyes-closed, resting-state condition. Cortical EEG sources were modeled by the standardized low-resolution brain electromagnetic tomography (sLORETA) method. Relative logarithmic power spectral density values were obtained in the four conventional frequency bands (alpha, beta, delta, and theta) and 12 cortical regions. Results show that in the left brain hemisphere, the theta band of AD subjects shows an increase in the power, whereas the alpha band shows a decreased activity (P-value <0.05). In the right brain hemisphere of AD subjects, a decreased activity is observed in all frequency bands. It was also noticed that the right temporal region shows a significant difference between the two groups in all frequency bands. Using a support vector machine, control and patient groups are discriminated with an accuracy of 84.4%, sensitivity 75.0%, and specificity of 93.7%.

Schizophrenia is often considered as a dysconnection syndrome in which, abnormal interactions between large-scale functional brain networks result in cognitive and perceptual deficits. In this article we apply the graph theoretic measures to brain functional networks based on the resting EEGs of fourteen schizophrenic patients in comparison with those of fourteen matched control subjects. The networks were extracted from common-average-referenced EEG time-series through partial and unpartial cross-correlation methods. Unpartial correlation detects functional connectivity based on direct and/or indirect links, while partial correlation allows one to ignore indirect links. We quantified the network properties with the graph metrics, including mall-worldness, vulnerability, modularity, assortativity, and synchronizability. The schizophrenic patients showed method-specific and frequency-specific changes especially pronounced for modularity, assortativity, and synchronizability measures. However, the differences between schizophrenia patients and normal controls in terms of graph theory metrics were stronger for the unpartial correlation method., (2011 Elsevier Ltd. All rights reserved.)

Purpose: The long-term follow-up results of patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid and chemotherapy show high cure rates. Several studies have shown high efficacy of single-agent arsenic trioxide in newly diagnosed APL. However, long-term follow-up results are needed., Patients and Methods: One hundred ninety-seven patients with newly diagnosed APL were treated with arsenic trioxide 0.15 mg/kg daily intravenous infusion until complete remission (CR). After achieving CR, the patients received one to four more courses of therapy with arsenic trioxide as consolidation and were observed with reverse-transcriptase polymerase chain reaction studies from peripheral blood (to detect of minimal residual disease) every 3 months or until relapse or death., Results: The morphologic CR rate was 85.8%. The most common cause of remission failure was early death owing to APL differentiation syndrome (13.2%). The most important prognostic factor for early mortality was a high WBC count at presentation. The 5-year disease-free survival (DFS) rate was 66.7% ± 4% (SE). Relapse after 5 years in CR was rare. The 5-year overall survival (OS) rate by intention-to-treat analysis was 64.4% ± 4%. In patients who achieved CR, OS and DFS were identical., Conclusion: The long-term follow-up of newly diagnosed patients with APL treated with single-agent arsenic trioxide shows high rates of DFS and OS.

Objective: Psychogenic non-epileptic seizures (PNES) are paroxysmal events that, in contrast to epileptic seizures, are related to psychological causes without the presence of epileptiform EEG changes. Recent models suggest a multifactorial basis for PNES. A potentially paramount, but currently poorly understood factor is the interplay between psychiatric features and a specific vulnerability of the brain leading to a clinical picture that resembles epilepsy. Hypothesising that functional cerebral network abnormalities may predispose to the clinical phenotype, the authors undertook a characterisation of the functional connectivity in PNES patients., Methods: The authors analysed the whole-head surface topography of multivariate phase synchronisation (MPS) in interictal high-density EEG of 13 PNES patients as compared with 13 age- and sex-matched controls. MPS mapping reduces the wealth of dynamic data obtained from high-density EEG to easily readable synchronisation maps, which provide an unbiased overview of any changes in functional connectivity associated with distributed cortical abnormalities. The authors computed MPS maps for both Laplacian and common-average-reference EEGs., Results: In a between-group comparison, only patchy, non-uniform changes in MPS survived conservative statistical testing. However, against the background of these unimpressive group results, the authors found widespread inverse correlations between individual PNES frequency and MPS within the prefrontal and parietal cortices., Interpretation: PNES appears to be associated with decreased prefrontal and parietal synchronisation, possibly reflecting dysfunction of networks within these regions.

Background and Objective: Hematopoietic cell transplantation (HCT) is the only therapeutic modality capable of correcting the hematologic manifestations of Fanconi anemia (FA). The development of well-tolerated immunosuppressive conditioning regimens for FA patients undergoing HCT has proven to be a challenging task for hematologists., Design and Settings: Retrospective, patients referred to the hematology, oncology and stem cell transplantation research center., Patients and Methods: We analyzed the outcome of 53 FA patients who had undergone HCT between 1992 and 2010. The median age at transplantation was 9 years. Patients received transplants from an HLA-identical sibling (n=39) or matched relative (n=9) and one-antigen locus mismatched other relative/sibling (n=5). All of the patients underwent transplantation with fludarabine and non-fludarabine-based conditioning regimens. No radiation therapy was given., Results: The median follow-up period for survivors was 13.5 months (range, 3 months-13.5 years). The 3-year overall survival (OS) was 60.6%. The 3-year OS for patients who did or did not receive fludarabine-based preparative regimens for the allograft was 36.4%, and 70%, respectively. However, there were no statistically significant differences in OS rates between these two groups (P=.112). Graft failure occurred in 4 patients (7.5%). All of these 4 patients had received fludarabine-based conditioning regimens. The incidence of acute GVHD after fludarabine-based regimens was 45% versus 79% in non-fludarabine-based regimens (P=.03)., Conclusion: Despite the high incidence of acute GVHD (78.6%) in the non-fludarabine group, which resulted in the death of some patients, the OS rate was significantly better than in fludarabine recipients. Therefore, in spite of the fact that recent studies advocate the fludarabine-based conditioning regimens, we propose to conduct a multicenter, prospective study to evaluate the outcomes of regimens employed in FA patients.

Pancreatoblastoma (PB) is a rare malignant neoplasm of the pancreas, which occurs mostly during childhood. Presently, the optimal treatment strategy is neither clear nor uniform for patients in advanced stages, in particular those with metastasis, inoperable, or recurrent tumors. To our knowledge, until now, only one patient with PB has been treated with hematopoietic stem cell transplantation (HSCT) following aggressive chemotherapy and surgical resection. Here we report the second case of PB who was treated with aggressive chemotherapy combined with autologous peripheral blood stem cell transplantation., (2010 Wiley-Liss, Inc.)

Alzheimer's disease (AD) is likely to disrupt the synchronization of the bioelectrical processes in the distributed cortical networks underlying cognition. We analyze the surface topography of the multivariate phase synchronization (MPS) of multichannel EEG in 17 patients (Clinical Dementia Rating (CDR) Scale: 0.5-1; Functional Assessment Staging (FAST): 3-4) compared to 17 controls by applying a combination of global and regional MPS measures to the resting EEG. In early AD, whole-head mapping reveals a specific landscape of synchronization characterized by a decrease in MPS over the fronto-temporal region and an increase over the temporo-parieto-occipital region predominantly of the left hemisphere. These features manifest themselves through the EEG delta-beta bands and discriminate patients from controls with an accuracy of up to 94%. Moreover, the abnormal MPS in both anterior and posterior clusters correlates with the Mini Mental State Examination score, binding regional EEG synchronization to cognitive decline in AD patients. The MPS technique reveals that the EEG phenotype of early AD is relevant to the clinical picture and may ultimately become its sensitive and specific biomarker., (Copyright 2008 Elsevier Inc. All rights reserved.)

By considering the eigenratio of the Laplacian of the connection graph as a synchronizability measure, we propose a procedure for weighting dynamical networks to enhance their synchronizability. The method is based on node and edge betweenness centrality measures and is tested on artificially constructed scale-free, Watts-Strogatz, and random networks as well as on some real-world graphs. It is also numerically shown that the same procedure could be used to enhance the phase synchronizability of networks of nonidentical oscillators.

Background: The dysconnection hypothesis has been proposed to account for pathophysiological mechanisms underlying schizophrenia. Widespread structural changes suggesting abnormal connectivity in schizophrenia have been imaged. A functional counterpart of the structural maps would be the EEG synchronization maps. However, due to the limits of currently used bivariate methods, functional correlates of dysconnection are limited to the isolated measurements of synchronization between preselected pairs of EEG signals., Methods/results: To reveal a whole-head synchronization topography in schizophrenia, we applied a new method of multivariate synchronization analysis called S-estimator to the resting dense-array (128 channels) EEG obtained from 14 patients and 14 controls. This method determines synchronization from the embedding dimension in a state-space domain based on the theoretical consequence of the cooperative behavior of simultaneous time series-the shrinking of the state-space embedding dimension. The S-estimator imaging revealed a specific synchronization landscape in schizophrenia patients. Its main features included bilaterally increased synchronization over temporal brain regions and decreased synchronization over the postcentral/parietal region neighboring the midline. The synchronization topography was stable over the course of several months and correlated with the severity of schizophrenia symptoms. In particular, direct correlations linked positive, negative, and general psychopathological symptoms to the hyper-synchronized temporal clusters over both hemispheres. Along with these correlations, general psychopathological symptoms inversely correlated within the hypo-synchronized postcentral midline region. While being similar to the structural maps of cortical changes in schizophrenia, the S-maps go beyond the topography limits, demonstrating a novel aspect of the abnormalities of functional cooperation: namely, regionally reduced or enhanced connectivity., Conclusion/significance: The new method of multivariate synchronization significantly boosts the potential of EEG as an imaging technique compatible with other imaging modalities. Its application to schizophrenia research shows that schizophrenia can be explained within the concept of neural dysconnection across and within large-scale brain networks.