Unraveling the role of low-frequency mutated genes in breast cancer.

Motivation: Breast cancer is the most commonly diagnosed malignancy in women and the second cause of cancer death in developed countries. While advancements in early detection and therapeutic options have led to a significant decrease in mortality, response to treatment is affected by the genetic heterogeneity of the disease. Recent genome-wide DNA mutation analyses revealed the existence of hundreds of low-frequency mutated genes, in addition to known cancer drivers: a finding that is prompting research into the impact of these genes on the pathogenesis of the disease. Results: Herein, we describe a strategy towards the characterization of the role of low-frequency mutated genes in breast cancer. Through the combined analyses of publicly available gene expression and mutational datasets, we identified several Cancer Gene Modules (CMs) that we re-organized in Gene Regulatory Networks (GRN) enriched in low-frequency mutated genes. Importantly, these low-frequency mutated genes were mutually exclusive with known cancer drivers. Finally, we provide evidence that gene expression analysis of these mutated GRNs can predict resistance/sensitivity to chemotherapeutic drugs for breast cancer treatment. Availability and implementation: Datasets are available at https://www.ncbi.nlm.nih.gov/geo/ and at https://www.ebi.ac.uk/ega/datasets/. Molecular signatures and GSEA software are available at http://www.gsea-msigdb.org/gsea/index.jsp. Source codes are available at https://github.com/EleonoraLusito/Reverse_Engineering_BC_GRNs. Supplementary information: Supplementary data are available at Bioinformatics online.

Identification of MicroRNAs Differentially Expressed in Lung Carcinoid Subtypes and Progression.

AIM: To extensively explore microRNA expression profiles in lung carcinoids in correlation with clinical and pathological features. METHODS: A PCR-based array was employed in the screening phase to analyze 752 microRNAs in a discovery set of 12 lung carcinoids, including 6 typical (3 with lymph node metastasis) and 6 atypical (3 with lymph node metastasis). The results were validated by means of real-time PCR in 37 carcinoids, including 22 typical (4 with lymph node metastasis) and 15 atypical (7 with lymph node metastasis), and 19 high-grade neuroendocrine carcinomas. RESULTS: Unsupervised cluster analysis segregated the pilot cases into 3 distinct groups. Twenty-four microRNAs were differentially regulated in atypical versus typical carcinoids, and 29 in metastatic versus nonmetastatic cases. Eleven microRNAs were selected for validation. All but 1 were significantly different among lung neuroendocrine tumor histotypes. Moreover, 5 (miR-129-5p, miR-409-3p, miR-409-5p, miR-185 and miR-497) were significantly upregulated in typical compared to atypical carcinoids. MiR-409-3p, miR-409-5p and miR-431-5p were also significantly downregulated in carcinoids metastatic to the lymph nodes. Predictive in silico analysis of specific target genes showed that these 3 latter microRNAs linked to metastatic potential are implicated in several cellular functions and highlighted several novel genes which may be worth exploring. CONCLUSIONS: Our findings demonstrate that lung carcinoids have distinct microRNA expression profiles as compared to high-grade neuroendocrine carcinomas and that specific microRNAs might have potential implications as diagnostic tools or clinical biomarkers.

Splicy: a web-based tool for the prediction of possible alternative splicing events from Affymetrix probeset data.

BACKGROUND: The Affymetrix technology is nowadays a well-established method for the analysis of gene expression profiles in cancer research studies. However, changes in gene expression levels are not the only way to link genes and disease. The existence of gene isoforms specifically linked with cancer or apoptosis is increasingly found in literature. Hence it is of great interest to associate the results of a gene expression study with updated evidences on the transcript structure and its possible variants. RESULTS: We present here a web-based software tool, Splicy, whose primary task is to retrieve data on the mapping of Affymetrix probes to single exons of gene transcripts and displaying graphically this information projected on the gene physical structure. Starting from a list of Affymetrix probesets the program produces a series of graphical displays, each relative to a transcript associated with the gene targeted by a given probe. The information on the transcript-by-transcript and exon-by-exon mapping of probe pairs can be retrieved both graphically and in the form of tab-separated files. The mapping of single probes to NCBI RefSeq or EMBL cDNAs is handled by the ISREC mapping tables used in the CleanEx Expression Reference Database Project. We currently maintain these mappings for most popular human and mouse Affymetrix chips, and Splicy can be queried for matches with human and mouse NCBI RefSeq or EMBL cDNAs. CONCLUSION: Splicy generates probeset annotations and images describing the relation between the single probes and intron/exon structure of the target transcript in all its known variants. We think that Splicy will be useful for giving to the researcher a clearer picture of the possible transcript variants linked with a given gene and an additional view on the interpretation of microarray experiment data. Splicy is publicly available and has been realized in the framework of a bioinformatics grant from the Italian Cancer Research Association.

O significado de jogar Xbox Kinect boliche na percepção de idosos residentes de uma Instituição de Longa Permanência para Idosos (ILPI) / The meaning of playing Xbox Kinect bowling in the perception of elderly residents of a Nursing Home / El significado de jugar a los bolos de Xbox Kinect en la percepción de los residentes mayores de un Centro de atención a largo plazo para ancianos (ILPI)

Estudos da literatura sugerem que os jogos com grandes deslocamentos no centro de massa e alterações na base de apoio desafiam o equilíbrio e são suficientes para melhorar o controle postural durante atividades funcionais, assim como promovem a interação social. Este estudo objetivou levantar os benefícios proporcionados pela atividade de jogar o Xbox boliche em idosos institucionalizados, e as motivações que os levaram a participar dela. Foi realizada uma pesquisa qualitativa, utilizando-se como base a Fenomenologia Social de Schütz, e aplicando-se como Instrumento a Escala de Depressão Geriátrica (EDG). Participaram do estudo 14 residentes de uma ILPI (Instituição de Longa Permanência para Idosos). Os resultados mostram-nos que esse tipo de atividade melhorou o humor da maioria dos participantes, além de aumentar a interação social e a satisfação dos residentes.

Studies in the literature suggest that games with large displacements in the center of mass and changes in the support base defy balance and are sufficient to improve postural control during functional activities, as well as promoting social interaction. This study aimed to survey the benefits provided by the activity of playing Xbox bowling in institutionalized elderly, and the motivations that led them to participate in it. A qualitative research was carried out using Schütz Social Phenomenology as the basis and applying the Geriatric Depression Scale (EDG) as an instrument. Methods: 14 residents of an Nursing Home participated in the study. Results and considerations: The result showed us that this type of activity improved the mood of most participants, in addition to increasing social interaction and residents' satisfaction.

Los estudios en la literatura sugieren que los juegos con grandes desplazamientos en el centro de masa y cambios en la base de soporte desafían el equilibrio y son suficientes para mejorar el control postural durante las actividades funcionales, así como para promover la interacción social. Este estudio tuvo como objetivo analizar los beneficios proporcionados por la actividad de jugar bolos de Xbox en ancianos institucionalizados, y las motivaciones que los llevaron a participar en él. Se realizó una investigación cualitativa, utilizando la Fenomenología Social de Schütz como base, y aplicando la Escala de Depresión Geriátrica (EDG) como instrumento. Participaron en el estudio 14 residentes de un LTCF (Centro de atención a largo plazo para ancianos). Los resultados nos muestran que este tipo de actividad mejora el estado de ánimo de la mayoría de los participantes, además de aumentar la interacción social y la satisfacción de los residentes.

Role of hormone receptor expression in patients with advanced-stage lung cancer treated with chemotherapy.

BACKGROUND: Evidence that supports a role for hormonal status in lung cancer has been inconsistently reported and is still unclear. We retrospectively assessed the potential correlation between sex-linked hormone receptor expression and the clinical outcome of patients with advanced-stage lung cancer treated with chemotherapy. PATIENTS AND METHODS: Based on tissue availability, 130 consecutive patients diagnosed at San Luigi Hospital from January 2008 to June 2010 were collected, including 24 small-cell lung cancer, 57 adenocarcinomas, 34 squamous cell carcinomas, 5 large-cell carcinomas, and 10 non-small-cell lung cancer-not otherwise specified. The immunohistochemical expression of estrogen receptors (ER-α and ER-ß) and progesterone receptor, aromatase, epidermal growth factor receptor (EGFR), and excision repair cross-complementing 1 (ERCC1) was assessed. RESULTS: ER-ß nuclear expression was higher than ER-α and progesterone receptor, whose expression was null or weak (mainly in women). ER-ß expression was significantly higher in patients with metastatic disease compared with all other disease stages (P = .02). EGFR expression was strongly correlated with non-small-cell lung cancer histology, being higher in squamous types and stage related. In men, aromatase positive cases had a worse outcome (P = .03) as well as in men with non-small-cell lung cancer and high ER-ß expression. In the latter group, the combined aromatase negative and/or low ER-ß expression and low ERCC1 and/or low ER-ß expression showed a better outcome (P = .026; P = .03, respectively). CONCLUSION: In patients with advanced-stage lung cancer treated with chemotherapy, the prognostic and predictive role of sex-linked hormone receptor expression, if any, is of borderline significance and is restricted to selected subgroups of patients.

Transcription factor binding sites are genetic determinants of retroviral integration in the human genome.

Gamma-retroviruses and lentiviruses integrate non-randomly in mammalian genomes, with specific preferences for active chromatin, promoters and regulatory regions. Gene transfer vectors derived from gamma-retroviruses target at high frequency genes involved in the control of growth, development and differentiation of the target cell, and may induce insertional tumors or pre-neoplastic clonal expansions in patients treated by gene therapy. The gene expression program of the target cell is apparently instrumental in directing gamma-retroviral integration, although the molecular basis of this phenomenon is poorly understood. We report a bioinformatic analysis of the distribution of transcription factor binding sites (TFBSs) flanking >4,000 integrated proviruses in human hematopoietic and non-hematopoietic cells. We show that gamma-retroviral, but not lentiviral vectors, integrate in genomic regions enriched in cell-type specific subsets of TFBSs, independently from their relative position with respect to genes and transcription start sites. Analysis of sequences flanking the integration sites of Moloney leukemia virus (MLV)- and human immunodeficiency virus (HIV)-derived vectors carrying mutations in their long terminal repeats (LTRs), and of HIV vectors packaged with an MLV integrase, indicates that the MLV integrase and LTR enhancer are the viral determinants of the selection of TFBS-rich regions in the genome. This study identifies TFBSs as differential genomic determinants of retroviral target site selection in the human genome, and suggests that transcription factors binding the LTR enhancer may synergize with the integrase in tethering retroviral pre-integration complexes to transcriptionally active regulatory regions. Our data indicate that gamma-retroviruses and lentiviruses have evolved dramatically different strategies to interact with the host cell chromatin, and predict a higher risk in using gamma-retroviral vs. lentiviral vectors for human gene therapy applications.

Identification of alternatively spliced dab1 isoforms in zebrafish.

We have investigated the genomic organization, the occurrence of alternative splicing and the differential expression of the zebrafish disabled1 (dab1) gene. Dab1 is a key effector of the Reelin pathway, which regulates neuronal migration during brain development in vertebrates. The coding region of the zebrafish dab1 gene spans over 600 kb of genomic DNA and is composed of 15 exons. Alternative splicing in a region enriched for tyrosine residues generates at least three different isoforms. These isoforms are developmentally regulated and show differential tissue expression. Comparison with mouse and human data shows an overall conservation of the genomic organization with different alternative splicing events generating species-specific isoforms. Because these alternative splicing events give rise to isoforms with different numbers of phosphorylateable tyrosines, we speculate that alternative splicing of the dab1 gene in zebrafish and in other vertebrates regulates the nature of the cellular response to the Reelin signal.