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1.  Impact of Pre-Analytical Variables on Cancer Targeted Gene Sequencing Efficiency 
PLoS ONE  2015;10(11):e0143092.
Tumor specimens are often preserved as formalin-fixed paraffin-embedded (FFPE) tissue blocks, the most common clinical source for DNA sequencing. Herein, we evaluated the effect of pre-sequencing parameters to guide proper sample selection for targeted gene sequencing. Data from 113 FFPE lung tumor specimens were collected, and targeted gene sequencing was performed. Libraries were constructed using custom probes and were paired-end sequenced on a next generation sequencing platform. A PCR-based quality control (QC) assay was utilized to determine DNA quality, and a ratio was generated in comparison to control DNA. We observed that FFPE storage time, PCR/QC ratio, and DNA input in the library preparation were significantly correlated to most parameters of sequencing efficiency including depth of coverage, alignment rate, insert size, and read quality. A combined score using the three parameters was generated and proved highly accurate to predict sequencing metrics. We also showed wide read count variability within the genome, with worse coverage in regions of low GC content like in KRAS. Sample quality and GC content had independent effects on sequencing depth, and the worst results were observed in regions of low GC content in samples with poor quality. Our data confirm that FFPE samples are a reliable source for targeted gene sequencing in cancer, provided adequate sample quality controls are exercised. Tissue quality should be routinely assessed for pre-analytical factors, and sequencing depth may be limited in genomic regions of low GC content if suboptimal samples are utilized.
doi:10.1371/journal.pone.0143092
PMCID: PMC4659597  PMID: 26605948
2.  Performance Evaluation of Resource Management in Cloud Computing Environments 
PLoS ONE  2015;10(11):e0141914.
Cloud computing is a computational model in which resource providers can offer on-demand services to clients in a transparent way. However, to be able to guarantee quality of service without limiting the number of accepted requests, providers must be able to dynamically manage the available resources so that they can be optimized. This dynamic resource management is not a trivial task, since it involves meeting several challenges related to workload modeling, virtualization, performance modeling, deployment and monitoring of applications on virtualized resources. This paper carries out a performance evaluation of a module for resource management in a cloud environment that includes handling available resources during execution time and ensuring the quality of service defined in the service level agreement. An analysis was conducted of different resource configurations to define which dimension of resource scaling has a real influence on client requests. The results were used to model and implement a simulated cloud system, in which the allocated resource can be changed on-the-fly, with a corresponding change in price. In this way, the proposed module seeks to satisfy both the client by ensuring quality of service, and the provider by ensuring the best use of resources at a fair price.
doi:10.1371/journal.pone.0141914
PMCID: PMC4640522  PMID: 26555730
3.  Orthodontic approach to treat complex hypodontia using miniscrews in a growing patient 
This article reports orthodontic treatment of a case of hypodontia of five premolars in an 11-year-old female patient with a positive tooth size-arch length discrepancy in both dental arches. The patient had a straight profile with balanced facial growth. Setup manufacture revealed the possibility of achieving ideal occlusion by mesializing permanent molars up to 15 mm, in addition to keeping a primary molar in the dental arch. With the aid of absolute anchorage, the proposed mechanics was performed and the occlusion predicted in the setup was achieved, while profile and facial growth pattern were maintained. The use of miniscrews for extensive orthodontic movements was successful. Furthermore, one primary molar was extensively mesialized. The indication of gingivoplasty to correct gingival smile proved effective. This is considered a useful technique for orthodontists.
doi:10.1590/2176-9451.20.4.082-090.oar
PMCID: PMC4593535  PMID: 26352850
Anodontia; Orthodontic anchorage; Orthodontic space closure
4.  Combined Analysis of SNP Array Data Identifies Novel CNV Candidates and Pathways in Ependymoma and Mesothelioma 
BioMed Research International  2015;2015:902419.
Copy number variation is a class of structural genomic modifications that includes the gain and loss of a specific genomic region, which may include an entire gene. Many studies have used low-resolution techniques to identify regions that are frequently lost or amplified in cancer. Usually, researchers choose to use proprietary or non-open-source software to detect these regions because the graphical interface tends to be easier to use. In this study, we combined two different open-source packages into an innovative strategy to identify novel copy number variations and pathways associated with cancer. We used a mesothelioma and ependymoma published datasets to assess our tool. We detected previously described and novel copy number variations that are associated with cancer chemotherapy resistance. We also identified altered pathways associated with these diseases, like cell adhesion in patients with mesothelioma and negative regulation of glutamatergic synaptic transmission in ependymoma patients. In conclusion, we present a novel strategy using open-source software to identify copy number variations and altered pathways associated with cancer.
doi:10.1155/2015/902419
PMCID: PMC4491549  PMID: 26185765
5.  AWSCS-A System to Evaluate Different Approaches for the Automatic Composition and Execution of Web Services Flows 
PLoS ONE  2015;10(6):e0127677.
This paper proposes a system named AWSCS (Automatic Web Service Composition System) to evaluate different approaches for automatic composition of Web services, based on QoS parameters that are measured at execution time. The AWSCS is a system to implement different approaches for automatic composition of Web services and also to execute the resulting flows from these approaches. Aiming at demonstrating the results of this paper, a scenario was developed, where empirical flows were built to demonstrate the operation of AWSCS, since algorithms for automatic composition are not readily available to test. The results allow us to study the behaviour of running composite Web services, when flows with the same functionality but different problem-solving strategies were compared. Furthermore, we observed that the influence of the load applied on the running system as the type of load submitted to the system is an important factor to define which approach for the Web service composition can achieve the best performance in production.
doi:10.1371/journal.pone.0127677
PMCID: PMC4466311  PMID: 26068216
6.  First Record of Invasive Lionfish (Pterois volitans) for the Brazilian Coast 
PLoS ONE  2015;10(4):e0123002.
The invasion of the northwestern Atlantic by the Indo-Pacific lionfish has developed extraordinarily fast, and is expected to cause one of the most negative ecological impacts among all marine invasions. In less than 30 years, lionfish have dramatically expanded their distribution range to an area encompassing the eastern coast of the USA, Bermuda, the entire Caribbean region and the Gulf of Mexico. The rapidity of the lionfish spread has raised concerns in other parts of the Atlantic that may be under the reach of the invasion. Despite the anticipation that lionfish would eventually extend their range throughout most of the eastern coast of South America, it had not been recorded in Brazil until now. Here we report the first lionfish appearance for the Brazilian coast and show that the individual collected by us is genetically linked to the invasive Caribbean population. Since small-range endemics are found in several locations in Brazil and are among the species that are most vulnerable to extinction, we recommend urgent control, management and education measures aimed at minimizing the effects of this impending invasion.
doi:10.1371/journal.pone.0123002
PMCID: PMC4406615  PMID: 25901361
7.  Fish Biodiversity of the Vitória-Trindade Seamount Chain, Southwestern Atlantic: An Updated Database 
PLoS ONE  2015;10(3):e0118180.
Despite a strong increase in research on seamounts and oceanic islands ecology and biogeography, many basic aspects of their biodiversity are still unknown. In the southwestern Atlantic, the Vitória-Trindade Seamount Chain (VTC) extends ca. 1,200 km offshore the Brazilian continental shelf, from the Vitória seamount to the oceanic islands of Trindade and Martin Vaz. For a long time, most of the biological information available regarded its islands. Our study presents and analyzes an extensive database on the VTC fish biodiversity, built on data compiled from literature and recent scientific expeditions that assessed both shallow to mesophotic environments. A total of 273 species were recorded, 211 of which occur on seamounts and 173 at the islands. New records for seamounts or islands include 191 reef fish species and 64 depth range extensions. The structure of fish assemblages was similar between islands and seamounts, not differing in species geographic distribution, trophic composition, or spawning strategies. Main differences were related to endemism, higher at the islands, and to the number of endangered species, higher at the seamounts. Since unregulated fishing activities are common in the region, and mining activities are expected to drastically increase in the near future (carbonates on seamount summits and metals on slopes), this unique biodiversity needs urgent attention and management.
doi:10.1371/journal.pone.0118180
PMCID: PMC4349783  PMID: 25738798
8.  Herbivory drives large-scale spatial variation in reef fish trophic interactions 
Ecology and Evolution  2014;4(23):4553-4566.
Trophic interactions play a critical role in the structure and function of ecosystems. Given the widespread loss of biodiversity due to anthropogenic activities, understanding how trophic interactions respond to natural gradients (e.g., abiotic conditions, species richness) through large-scale comparisons can provide a broader understanding of their importance in changing ecosystems and support informed conservation actions. We explored large-scale variation in reef fish trophic interactions, encompassing tropical and subtropical reefs with different abiotic conditions and trophic structure of reef fish community. Reef fish feeding pressure on the benthos was determined combining bite rates on the substrate and the individual biomass per unit of time and area, using video recordings in three sites between latitudes 17°S and 27°S on the Brazilian Coast. Total feeding pressure decreased 10-fold and the composition of functional groups and species shifted from the northern to the southernmost sites. Both patterns were driven by the decline in the feeding pressure of roving herbivores, particularly scrapers, while the feeding pressure of invertebrate feeders and omnivores remained similar. The differential contribution to the feeding pressure across trophic categories, with roving herbivores being more important in the northernmost and southeastern reefs, determined changes in the intensity and composition of fish feeding pressure on the benthos among sites. It also determined the distribution of trophic interactions across different trophic categories, altering the evenness of interactions. Feeding pressure was more evenly distributed at the southernmost than in the southeastern and northernmost sites, where it was dominated by few herbivores. Species and functional groups that performed higher feeding pressure than predicted by their biomass were identified as critical for their potential to remove benthic biomass. Fishing pressure unlikely drove the large-scale pattern; however, it affected the contribution of some groups on a local scale (e.g., large-bodied parrotfish) highlighting the need to incorporate critical functions into conservation strategies.
doi:10.1002/ece3.1310
PMCID: PMC4264904  PMID: 25512851
Brazil; critical functions; feeding pressure; functional groups; geographic variation
9.  Medical Genetics in Paraguay 
doi:10.1002/mgg3.119
PMCID: PMC4303215  PMID: 25614867
10.  Local Ecological Knowledge and Scientific Data Reveal Overexploitation by Multigear Artisanal Fisheries in the Southwestern Atlantic 
PLoS ONE  2014;9(10):e110332.
In the last decades, a number of studies based on historical records revealed the diversity loss in the oceans and human-induced changes to marine ecosystems. These studies have improved our understanding of the human impacts in the oceans. They also drew attention to the shifting baseline syndrome and the importance of assessing appropriate sources of data in order to build the most reliable environmental baseline. Here we amassed information from artisanal fishermen's local ecological knowledge, fisheries landing data and underwater visual census to assess the decline of fish species in Southeastern Brazil. Interviews with 214 fishermen from line, beach seine and spearfishing revealed a sharp decline in abundance of the bluefish Pomatomus saltatrix, the groupers Epinephelus marginatus, Mycteroperca acutirostris, M. bonaci and M. microlepis, and large parrotfishes in the past six decades. Fisheries landing data from a 16-year period support the decline of bluefish as pointed by fishermen's local knowledge, while underwater visual census campaigns show reductions in groupers' abundance and a sharp population decline of the Brazilian endemic parrotfish Scarus trispinosus. Despite the marked decline of these fisheries, younger and less experienced fishermen recognized fewer species as overexploited and fishing sites as depleted than older and more experienced fishermen, indicating the occurrence of the shifting baseline syndrome. Here we show both the decline of multigear fisheries catches – combining anecdotal and scientific data – as well as changes in environmental perceptions over generations of fishermen. Managing ocean resources requires looking into the past, and into traditional knowledge, bringing historical baselines to the present and improving public awareness.
doi:10.1371/journal.pone.0110332
PMCID: PMC4198246  PMID: 25333661
11.  Prevalence of human papillomavirus infection and phylogenetic analysis of HPV-16 E6 variants among infected women from Northern Brazil 
Background
The main cause of cervical cancer in the world is high risks human papillomavirus infection (mainly represented by HPV-16 and HPV-18), that are associated to the development of malign transformation of the epithelium. HPV prevalence exhibits a wide geographical variability and HPV-16 variants have been related to an increased risk of developing cervical intraepithelial lesion. The aim of this study was to describe DNA-HPV prevalence and HPV-16 variants among a women population from Northern Brazil.
Methods
One hundred and forty three women, during routine cervical cancer screening, at Juruti Project, fulfilled an epidemiological inquiry and were screened through a molecular HPV test. HPV-16 variants were determined by sequencing the HPV-16 E6 open reading frame.
Results
Forty two samples were considered HPV positive (29.4%). None of those had abnormal cytology results. HPV prevalence varied between different age groups (Z(U) = 14.62; p = <0.0001) and high-risk HPVs were more frequent among younger ages. The most prevalent type was HPV-16 (14%) and it variants were classified, predominantly, as European (87.5%).
Conclusions
HPV prevalence in our population was higher than described by others and the most prevalent HPV types were high-risk HPVs. The European HPV-16 variant was the most prevalent among HPV-16 positive samples. Our study reinforces the fact that women with normal cytology and a positive molecular test for high-risk HPVs should be submitted to continuous follow up, in order to verify persistence of infection, promoting an early diagnosis of cervical cancer and/or its precursors.
doi:10.1186/1750-9378-9-25
PMCID: PMC4138943  PMID: 25143783
Prevalence; HPV; HPV-16; Variants
12.  Randomized clinical trial on percutaneous minimally invasive osteosynthesis of fractures of the distal extremity of the radius☆☆☆ 
Revista Brasileira de Ortopedia  2014;49(3):218-226.
Objectives
the purpose of this study was to compare the postoperative radiological and clinical outcomes with minimally invasive percutaneous osteosynthesis using three implants: volar locking plate, intramedullary nail system and nonbridging external fixator for distal radius fractures.
Methods
forty-eight patients (A group, 16; B group 16; C group 16) underwent minimally invasive percutaneous osteosynthesis of reductible and unstable displaced (Type IIB by Rayhack Classification) distal radius fractures. In B group intramedullary nail system was used, in A group the patients were treated with volar locking plate and in C group the patients were treated by nonbridging external fixator from January 2011 to December 2012. The mean follow-up period was 12 months. Radiologic parameters, range of motion, grip strength, and disability of the arm, shoulder, and hand score were evaluated at each examination (3rd and 6th week, and 12th months). The visual analog scale of wrist pain and complications were assessed at the final follow-up.
Results
the groups did not differ significantly in radiological outcomes after 12 months, but the clinical results, VAS scale and dash score in group A (volar locking plate) and B (nail intramedullary) were statistically significantly better than that of C group (nonbridging external fixator). One patient underwent an osteosynthesis with nail intramedullary and another with external fixator (C group) developed persistent pain near the site of the superficial radial nerve because of the distal's screw and pins, respectively.
Conclusion
in clinical parameters, significant differences in outcomes were found between groups A and B after six weeks versus C group.
doi:10.1016/j.rboe.2014.04.003
PMCID: PMC4511660
Fractures of the radius; Internal fracture fixation; Bone plate; Fraturas do rádio; Fixação interna de fraturas; Placas ósseas
13.  KRAS mutations: variable incidences in a Brazilian cohort of 8,234 metastatic colorectal cancer patients 
BMC Gastroenterology  2014;14:73.
Background
KRAS mutations are frequently found in colorectal cancer (CRC) indicating the importance of its genotyping in the study of the molecular mechanisms behind this disease. Although major advances have occurred over the past decade, there are still important gaps in our understanding of CRC carcinogenesis, particularly whether sex-linked factors play any role.
Methods
The profile of KRAS mutations in the Brazilian population was analyzed by conducting direct sequencing of KRAS codons 12 and 13 belonging to 8,234 metastatic CRC patient samples. DNA was extracted from paraffin-embedded tissue, exon 1 was amplified by PCR and submitted to direct sequencing. The data obtained was analysed comparing different geographical regions, gender and age.
Results
The median age was 59 years and the overall percentage of wild-type and mutated KRAS was 62.8% and 31.9%, respectively. Interestingly, different percentages of mutated KRAS patients were observed between male and female patients (32.5% versus 34.8%, respectively; p = 0.03). KRAS Gly12Asp mutation was the most prevalent for both genders and for most regions, with the exception of the North where Gly12Val was the most frequent mutation found.
Conclusions
To the best of our knowledge this is one of the largest cohorts of KRAS genotyping in CRC patients and the largest to indicate a higher incidence of KRAS mutation in females compared to males in Brazil. Nevertheless, further research is required to better address the impact of gender differences in colorectal cancer.
doi:10.1186/1471-230X-14-73
PMCID: PMC3997472  PMID: 24720724
KRAS; Mutation; Gender; Cohort; Colorectal cancer
14.  Complete internal audit of a mammography service in a reference institution for breast imaging*  
Radiologia Brasileira  2014;47(2):74-78.
Objective
Undertaking of a complete audit of the service of mammography, as recommended by BI-RADS®, in a private reference institution for breast cancer diagnosis in the city of São Paulo, SP, Brazil, and comparison of results with those recommended by the literature.
Materials and Methods
Retrospective, analytical and cross-sectional study including 8,000 patients submitted to mammography in the period between April 2010 and March 2011, whose results were subjected to an internal audit. The patients were followed-up until December 2012.
Results
The radiological classification of 7,249 screening mammograms, according to BI-RADS, was the following: category 0 (1.43%), 1 (7.82%), 2 (80.76%), 3 (8.35%), 4 (1.46%), 5 (0.15%) and 6 (0.03%). The breast cancer detection ratio was 4.8 cases per 1,000 mammograms. Ductal carcinoma in situ was found in 22.8% of cases. Positive predictive values for categories 3, 4 and 5 were 1.3%, 41.3% and 100%, respectively. In the present study, the sensitivity of the method was 97.1% and specificity, 97.4%.
Conclusion
The complete internal audit of a service of mammography is essential to evaluate the quality of such service, which reflects on an early breast cancer detection and reduction of mortality rates.
doi:10.1590/S0100-39842014000200007
PMCID: PMC4337155  PMID: 25741052
Breast cancer; Mammographic screening; BI-RADS; Audit of mammography service; Percutaneous biopsy; Positive predictive value
15.  Anterior/Posterior Competitive Deactivation/Activation Dichotomy in the Human Hippocampus as Revealed by a 3D Navigation Task 
PLoS ONE  2014;9(1):e86213.
Anterior/posterior long axis specialization is thought to underlie the organization of the hippocampus. However it remains unclear whether antagonistic mechanisms differentially modulate processing of spatial information within the hippocampus. We used fMRI and a virtual reality 3D paradigm to study encoding and retrieval of spatial memory during active visuospatial navigation, requiring positional encoding and retrieval of object landmarks during the path. Both encoding and retrieval elicited BOLD activation of the posterior most portion of hippocampus, while concurrent deactivations (recently shown to reflect decreases in neural responses) were found in the most anterior regions. Encoding elicited stronger activity in the posterior right than the left hippocampus. The former structure also showed significantly stronger activity for allocentric vs. egocentric processing during retrieval. The anterior vs. posterior pattern mimics, from a functional point, although at much distinct temporal scales, the previous anatomical findings in London taxi drivers, whereby posterior enlargement was found at the cost of an anterior decrease, and the mirror symmetric findings observed in blind people, in whom the right anterior hippocampus was found to be larger, at the cost of a smaller posterior hippocampus, as compared with sighted people. In sum, we found a functional dichotomy whereby the anterior/posterior hippocampus shows antagonistic processing patterns for spatial encoding and retrieval of 3D spatial information. To our knowledge, this is the first study reporting such a dynamical pattern in a functional study, which suggests that differential modulation of neural responses within the human hippocampus reflects distinct roles in spatial memory processing.
doi:10.1371/journal.pone.0086213
PMCID: PMC3903506  PMID: 24475088
16.  A Framework for Integration of Heterogeneous Medical Imaging Networks 
Medical imaging is increasing its importance in matters of medical diagnosis and in treatment support. Much is due to computers that have revolutionized medical imaging not only in acquisition process but also in the way it is visualized, stored, exchanged and managed. Picture Archiving and Communication Systems (PACS) is an example of how medical imaging takes advantage of computers. To solve problems of interoperability of PACS and medical imaging equipment, the Digital Imaging and Communications in Medicine (DICOM) standard was defined and widely implemented in current solutions. More recently, the need to exchange medical data between distinct institutions resulted in Integrating the Healthcare Enterprise (IHE) initiative that contains a content profile especially conceived for medical imaging exchange: Cross Enterprise Document Sharing for imaging (XDS-i). Moreover, due to application requirements, many solutions developed private networks to support their services. For instance, some applications support enhanced query and retrieve over DICOM objects metadata.
This paper proposes anintegration framework to medical imaging networks that provides protocols interoperability and data federation services. It is an extensible plugin system that supports standard approaches (DICOM and XDS-I), but is also capable of supporting private protocols. The framework is being used in the Dicoogle Open Source PACS.
doi:10.2174/1874431101408010020
PMCID: PMC4181172  PMID: 25279021
Cloud computing; data integration; DICOM; medical imaging; PACS and XDS-I.
17.  Heterogeneous Persister Cells Formation in Acinetobacter baumannii 
PLoS ONE  2013;8(12):e84361.
Bacterial persistence is a feature that allows susceptible bacteria to survive extreme concentrations of antibiotics and it has been verified in a number of species, such as Escherichia coli, Pseudomonas aeruginosa, Staphylococcus spp., Mycobacterium spp. However, even though Acinetobacter baumannii is an important nosocomial pathogen, data regarding its persistence phenotype are still lacking. Therefore, the aim of this study was to evaluate the persistence phenotype in A. baumannii strains, as well as its variation among strains after treatment with polymyxin B and tobramycin. Stationary cultures of 37 polymyxin B-susceptible clinical strains of A. baumannii were analyzed for surviving cells after exposure to 15 µg/mL of polymyxin B for 6 h, by serial dilutions and colony counting. Among these, the 30 tobramycin-susceptible isolates also underwent tobramycin treatment at a concentration of 160 µg/mL and persister cells occurrence was evaluated equally. A high heterogeneity of persister cells formation patterns among isolates was observed. Polymyxin B-treated cultures presented persister cells corresponding from 0.0007% to 10.1% of the initial population and two isolates failed to produce detectable persister cells under this condition. A high variability could also be observed when cells were treated with tobramycin: the persister fraction corresponded to 0.0003%–11.84% of the pre-treatment population. Moreover, no correlation was found between persister subpopulations comparing both antibiotics among isolates, indicating that different mechanisms underlie the internal control of this phenotype. This is the first report of persister cells occurrence in A. baumannii. Our data suggest that distinct factors regulate the tolerance for unrelated antibiotics in this species, contrasting the multi-drug tolerance observed in other species (eg. dormancy-mediated tolerance). Supporting this observation, polymyxin B – an antibiotic that is believed to act on non-dividing cells as well – failed to eradicate persister cells in the majority of the isolates, possibly reflecting a disconnection between persistence and dormancy.
doi:10.1371/journal.pone.0084361
PMCID: PMC3877289  PMID: 24391945
18.  A specific polymerase chain reaction method to identify Stenotrophomonas maltophilia  
Memórias do Instituto Oswaldo Cruz  2013;108(3):390-391.
Stenotrophomonas maltophilia is a multidrug-resistant nosocomial pathogen that is difficult to identify unequivocally using current methods. Accordingly, because the presence of this microorganism in a patient may directly determine the antimicrobial treatment, conventional polymerase chain reaction (PCR) and real-time PCR assays targeting 23S rRNA were developed for the specific identification of S. maltophilia. The PCR protocol showed high specificity when tested against other species of Stenotrophomonas, non-fermentative Gram-negative bacilli and 100 clinical isolates of S. maltophilia previously identified using the Vitek system.
doi:10.1590/S0074-02762013000300020
PMCID: PMC4005581  PMID: 23778655
Stenotrophomonas maltophilia; identification; PCR
19.  Discriminating Different Classes of Biological Networks by Analyzing the Graphs Spectra Distribution 
PLoS ONE  2012;7(12):e49949.
The brain's structural and functional systems, protein-protein interaction, and gene networks are examples of biological systems that share some features of complex networks, such as highly connected nodes, modularity, and small-world topology. Recent studies indicate that some pathologies present topological network alterations relative to norms seen in the general population. Therefore, methods to discriminate the processes that generate the different classes of networks (e.g., normal and disease) might be crucial for the diagnosis, prognosis, and treatment of the disease. It is known that several topological properties of a network (graph) can be described by the distribution of the spectrum of its adjacency matrix. Moreover, large networks generated by the same random process have the same spectrum distribution, allowing us to use it as a “fingerprint”. Based on this relationship, we introduce and propose the entropy of a graph spectrum to measure the “uncertainty” of a random graph and the Kullback-Leibler and Jensen-Shannon divergences between graph spectra to compare networks. We also introduce general methods for model selection and network model parameter estimation, as well as a statistical procedure to test the nullity of divergence between two classes of complex networks. Finally, we demonstrate the usefulness of the proposed methods by applying them to (1) protein-protein interaction networks of different species and (2) on networks derived from children diagnosed with Attention Deficit Hyperactivity Disorder (ADHD) and typically developing children. We conclude that scale-free networks best describe all the protein-protein interactions. Also, we show that our proposed measures succeeded in the identification of topological changes in the network while other commonly used measures (number of edges, clustering coefficient, average path length) failed.
doi:10.1371/journal.pone.0049949
PMCID: PMC3526608  PMID: 23284629
20.  Bioinformatics of Cancer ncRNA in High Throughput Sequencing: Present State and Challenges 
Frontiers in Genetics  2012;3:287.
The numerous genome sequencing projects produced unprecedented amount of data providing significant information to the discovery of novel non-coding RNA (ncRNA). Several ncRNAs have been described to control gene expression and display important role during cell differentiation and homeostasis. In the last decade, high throughput methods in conjunction with approaches in bioinformatics have been used to identify, classify, and evaluate the expression of hundreds of ncRNA in normal and pathological states, such as cancer. Patient outcomes have been already associated with differential expression of ncRNAs in normal and tumoral tissues, providing new insights in the development of innovative therapeutic strategies in oncology. In this review, we present and discuss bioinformatics advances in the development of computational approaches to analyze and discover ncRNA data in oncology using high throughput sequencing technologies.
doi:10.3389/fgene.2012.00287
PMCID: PMC3523245  PMID: 23251139
bioinformatics; high throughput sequencing; cancer; non-coding RNA; gene expression
21.  Dicoogle - an Open Source Peer-to-Peer PACS 
Journal of Digital Imaging  2010;24(5):848-856.
Picture Archiving and Communication Systems (PACS) have been widely deployed in healthcare institutions, and they now constitute a normal commodity for practitioners. However, its installation, maintenance, and utilization are still a burden due to their heavy structures, typically supported by centralized computational solutions. In this paper, we present Dicoogle, a PACS archive supported by a document-based indexing system and by peer-to-peer (P2P) protocols. Replacing the traditional database storage (RDBMS) by a documental organization permits gathering and indexing data from file-based repositories, which allows searching the archive through free text queries. As a direct result of this strategy, more information can be extracted from medical imaging repositories, which clearly increases flexibility when compared with current query and retrieval DICOM services. The inclusion of P2P features allows PACS internetworking without the need for a central management framework. Moreover, Dicoogle is easy to install, manage, and use, and it maintains full interoperability with standard DICOM services.
doi:10.1007/s10278-010-9347-9
PMCID: PMC3180530  PMID: 20981467
PACS; Digital Imaging and Communications in Medicine (DICOM); Medical imaging; Peer-to-peer; Computer communication networks; Open source; PACS implementation; Information storage and retrieval
22.  Compensatory T-Cell Regulation in Unaffected Relatives of SLE Patients, and Opposite IL-2/CD25-Mediated Effects Suggested by Coreferentiality Modeling 
PLoS ONE  2012;7(3):e33992.
In human systemic lupus erythematosus (SLE), diverse autoantibodies accumulate over years before disease manifestation. Unaffected relatives of SLE patients frequently share a sustained production of autoantibodies with indiscriminable specificity, usually without ever acquiring the disease. We studied relations of IgG autoantibody profiles and peripheral blood activated regulatory T-cells (aTregs), represented by CD4+CD25bright T-cells that were regularly 70–90% Foxp3+. We found consistent positive correlations of broad-range as well as specific SLE-associated IgG with aTreg frequencies within unaffected relatives, but not patients or unrelated controls. Our interpretation: unaffected relatives with shared genetic factors compensated pathogenic effects by aTregs engaged in parallel with the individual autoantibody production. To study this further, we applied a novel analytic approach named coreferentiality that tests the indirect relatedness of parameters in respect to multivariate phenotype data. Results show that independently of their direct correlation, aTreg frequencies and specific SLE-associated IgG were likely functionally related in unaffected relatives: they significantly parallelled each other in their relations to broad-range immunoblot autoantibody profiles. In unaffected relatives, we also found coreferential effects of genetic variation in the loci encoding IL-2 and CD25. A model of CD25 functional genetic effects constructed by coreferentiality maximization suggests that IL-2-CD25 interaction, likely stimulating aTregs in unaffected relatives, had an opposed effect in SLE patients, presumably triggering primarily T-effector cells in this group. Coreferentiality modeling as we do it here could also be useful in other contexts, particularly to explore combined functional genetic effects.
doi:10.1371/journal.pone.0033992
PMCID: PMC3315511  PMID: 22479496
23.  Efficient Blockade of Akt signaling is a determinant factor to overcome resistance to Matuzumab 
Molecular Cancer  2011;10:151.
Background
Clinical studies have shown antineoplastic effectiveness of monoclonal antibodies (MAbs) against EGFR for different indications. Several MAbs directed to EGFR were developed recently, such as matuzumab, but there is still lack of information on preclinical data on its combination with chemo-radiation. Thus, the present study intended to examine the molecular pathways triggered by matuzumab alone or associated to chemo-radiotherapy in gynecological cell lines and its impact on cell growth and signaling.
Results
Combination of matuzumab with radiation and cisplatin did not enhance its cytostatic effects on A431, Caski and C33A cells (high, intermediate and low EGFR expression, respectively) in clonogenic assays, when compared to controls. The lack of effect was mediated by persistent signaling through EGFR due to its impaired degradation. In spite of the fact that matuzumab inhibited phosphorylation of EGFR, it had no effect upon cell viability. To analyze which downstream molecules would be involved in the EGFR signaling in the presence of matuzumab, we have tested it in combination with either PD98059 (MAPK inhibitor), or LY294002 (PI3K inhibitor). Matuzumab exhibited a synergic effect with LY294002, leading to a reduction of Akt phosphorylation that was followed by a decrease in A431 and Caski cells survival. The combination of PD98059 and matuzumab did not show the same effect suggesting that PI3K is an important effector of EGFR signaling in matuzumab-treated cells. Nonetheless, matuzumab induced ADCC in Caski cells, but not in the C33A cell line, suggesting that its potential therapeutic effects in vitro are indeed dependent on EGFR expression.
Conclusions
Matuzumab combined with chemoradiation did not induce cytotoxic effects on gynecological cancer cell lines in vitro, most likely due to impaired EGFR degradation. However, a combination of matuzumab and PI3K inhibitor synergistically inhibited pAkt and cell survival, suggesting that the use of PI3K/Akt inhibitors could overcome intrinsic resistance to matuzumab in vitro. Altogether, data presented here can pave the way to a rational design of clinical strategies in patients with resistant profile to anti-EGFR inhibitors based on combination therapy.
doi:10.1186/1476-4598-10-151
PMCID: PMC3295690  PMID: 22185378
Matuzumab; PI3K/Akt pathway; EGFR; gynecological cancer; cervical cancer; Cetuximab
24.  Assessment of quality in screening colonoscopy for colorectal cancer 
Introduction
The effectiveness of screening colonoscopy in decreasing the incidence of colorectal cancer (CRC) is largely dependent on the detection of polyps and the quality of the procedure. Several key quality measures have been proposed to improve the effectiveness of screening colonoscopies.
Aim
To evaluate quality indicators of screening colonoscopy in a tertiary hospital.
Methods
All CRC screening colonoscopies performed between 2005 and 2009 in a single tertiary center were reviewed for internationally accepted quality measures.
Results
Of the 1545 individuals who underwent first-time screening colonoscopy 38% were male and 62% were female. The mean age of the patients was 60.4 years and the mean difference in ages was ± 10.3 years. Cecal intubation rate was 91% (1336), however ileocecal valve photo documentation was performed in only 81% (1248) colonoscopies. The quality of bowel preparation was classified as: good 76% (1171), reasonable 11% (174), and poor 13% (200). Polyp detection rate (PDR) was 33% (503). The prevalence of polyps ≥1 cm in size was 5% (82). PDR was significantly higher in men than in women (44% [260] vs 25% [243], P = 0.0001). Other factors significantly influencing PDR were quality of bowel preparation (odds ratio [OR]: 1.28, 95% confidence interval [CI]: 0.9–1.6) and age over 50 (OR: 1.9, 95% CI: 1.3–2.9). Left colonic polyps were associated with a risk ratio of 2.3 (95% CI: 1.8–2.9) of lesions in the other colonic segments compared to no polyps in the left colon. None of the colonoscopists reported withdrawal time.
Conclusion
Cecal intubation rate and quality of bowel preparation were suboptimal. The polyp detection rate compares favorably to accepted standards and its main determinants are male sex, age >50 years, quality of bowel preparation, and the presence of left colonic polyps.
doi:10.2147/CEG.S25596
PMCID: PMC3254205  PMID: 22235171
colorectal cancer; screening colonoscopy; quality indicators

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