microRNAs and breast cancer: a genomic study reveals miR-148b as a major coordinator of tumor progression

Breast cancer is a multistep disease controlled by a wide spectrum of genetic and epigenetic changes occurring within a cell as well as environmental influences; and it is the most common malignancy in women worldwide, often fatal because of metastasis dissemination. Aberrant miRNA expression can influence several gene networks and pathways implicated in tumorigenesis and metastasis formation. To unravel the role of miRNAs during breast cancer progression we investigated miRNA expression in 77 ductal breast carcinoma biopsies and 17 mammoplasties by microarray analysis. Sixteen differentially expressed miRNAs were identified comparing patients with or without disease relapse, within 72 months from surgery. This signature correlates with survival and/or distinguishes tumor subtypes in different datasets. Among them, miR-148b, down-regulated in aggressive breast tumors, was found to be a major coordinator of malignancy. In fact, it is able to oppose various steps of tumor progression when overexpressed in cell lines by influencing invasion, survival to anoikis, extravasation, lung metastasis formation, and chemotherapy response. miR-148b controls malignancy by coordinating a novel pathway involving over 130 genes and, in particular, it directly targets players of the integrin signaling, such as ITGA5, ROCK1, PIK3CA/p110α, and NRAS, as well as CSF1, a growth factor for stroma cells. Our findings reveal the importance of the identified 16 miRNAs for disease outcome predictions and suggest a critical role for miR-148b in the control of breast cancer progressio

Photoperiodic modulation of circadian functions in Antarctic krill Euphausia superba Dana, 1850 (Euphausiacea)

An endogenous circadian clock influences metabolic output rhythms in the Antarctic krill (Euphausia superba Dana, 1850), a key species in the Southern Ocean ecosystem. Seasonal changes in photoperiod in Antarctica, ranging from midnight sun (24 h light) during mid-summer to very short days (3\u20134 h light) during mid-winter, represent a challenge for the synchronization of the krill circadian clock. We analyzed clock gene activity and clock output functions in krill exposed to different light conditions during a long-term photoperiodic simulation in the laboratory. In simulated early-autumn (light/dark or LD 16:8) and late-winter (LD 8:16) conditions, the circadian clock of krill was functional and the metabolic output was synchronized to the light/dark cycle, the clock genes Esper and Esclk peaked in antiphase around simulated dusk/dawn and most metabolic-related genes showed upregulation around simulated dusk. In contrast, in simulated mid-summer (light/light or LL) and mid-winter (LD 3:21) conditions, the synchronization of the circadian clock and the metabolic output appeared to be weaker, with clock gene expression becoming arrhythmic and upregulation of metabolic genes occurring at different times during the day. Early-autumn and late-winter photoperiodic cues in the laboratory thus seem to be sufficient to entrain the krill clock and promote metabolic synchronization, whereas midwinter and mid-summer photoperiodic cues seem to be insufficient for krill entrainment. Krill in the field may overcome the seasonal lack of overt photoperiodic cycle occurring during midsummer and mid-winter by using alternative light-related Zeitgebers (i.e., varying light intensity rather than the presence or absence of light) to promote basic homeostatic rhythms over 24 h

Analysis of the circadian transcriptome of the Antarctic krill Euphausia superba

Antarctic krill (Euphausia superba) is a high latitude pelagic organism which plays a central role in the Southern Ocean ecosystem. E. superba shows daily and seasonal rhythms in physiology and behaviour, which are synchronized with the environmental cycles of its habitat. Recently, the main components of the krill circadian machinery have been identified and characterized. However, the exact mechanisms through which the endogenous timing system operates the control and regulation of the overt rhythms remains only partially understood. Here we investigate the involvement of the circadian clock in the temporal orchestration of gene expression by using a newly developed version of a krill microarray platform. The analysis of transcriptome data from krill exposed to both light-dark cycles (LD 18:6) and constant darkness (DD), has led to the identification of 1,564 putative clock-controlled genes. A remarkably large proportion of such genes, including several clock components (clock, period, cry2, vrille, and slimb), show oscillatory expression patterns in DD, with a periodicity shorter than 24\u2009hours. Energy-storage pathways appear to be regulated by the endogenous clock in accordance with their ecological relevance in daily energy managing and overwintering. Our results provide the first representation of the krill circadian transcriptome under laboratory, free-running conditions

Seasonal and Form-Specific Gene Expression Signatures Uncover Different Generational Strategies of the Pelagic Tunicate Salpa thompsoni During the Southern Ocean Winter

The pelagic tunicate Salpa thompsoni is recognized as a major metazoan grazer in the Southern Ocean. Long term observations show an increase in this species’ biomass and a southward shift in its distribution both of which are positively correlated with ocean warming and winter sea ice decline around the Antarctic Peninsula. However, our understanding on how salps adapt their life cycle to the extreme seasonality of the Southern Ocean and the putative differences between its two reproductive forms (aggregates, solitaries) is rudimentary. In particular, our current knowledge of whether and how S. thompsoni overwinter is limited, largely due to winter sampling constraints. In this study, we investigated the form-specific gene expression profiles of Salpa thompsoni during the austral autumn and winter. Between the seasons, genes related to translation showed the biggest difference in gene expression. We found more genes were upregulated in solitaries compared to aggregates, indicating a potentially form-specific overwintering strategy. Our data provide first insights into the seasonal and form-specific physiology of salps by considering their complex life cycle, thereby contributing to a more comprehensive understanding of the response of salps to seasonal changes in their environment and to anthropogenic induced global climate change

Factor structure of the Positive and Negative Syndrome Scale (PANSS) in Brazil: convergent validation of the Brazilian version

Objectives: The Positive and Negative Syndrome Scale (PANSS) was developed to assess the symptoms of schizophrenia dimensionally. Although it is widely used in clinical trials in Brazil, it is not fully validated. The aim of this study is to assess the factor structure of the Brazilian PANSS and generate validation data for its current version. Methods: A total of 292 patients diagnosed with schizophrenia were enrolled. Results: Principal component analysis suggested a forced five-factor final model that accounted for 58.44% of the total variance, composed of negative, disorganization/cognition, excitement, positive, and depression/anxiety. Conclusion: The Brazilian PANSS has a similar factor structure and internal consistency compared to its other country versions.Universidade Federal de São Paulo (UNIFESP) Department of Psychiatry Interdisciplinary Laboratory in Clinical Neuroscience (LiNC)UNIFESP Schizophrenia Program (PROESQ)Faculdade de Ciências Médicas da Santa Casa de São Paulo Center for Integrated Mental HealthUniversidade Federal de São Paulo (UNIFESP) Department of PsychiatryUNIFESP Genetics Division, Department of Morphology and GeneticsUNIFESP, Department of Psychiatry Interdisciplinary Laboratory in Clinical Neuroscience (LiNC)UNIFESP, Schizophrenia Program (PROESQ)UNIFESP, Department of PsychiatryUNIFESP, Genetics Division, Department of Morphology and GeneticsSciEL

Identifying pathways modulating sleep duration: from genomics to transcriptomics

Recognizing that insights into the modulation of sleep duration can emerge by exploring the functional relationships among genes, we used this strategy to explore the genome-wide association results for this trait. We detected two major signalling pathways (ion channels and the ERBB signalling family of tyrosine kinases) that could be replicated across independent GWA studies meta-analyses. To investigate the significance of these pathways for sleep modulation, we performed transcriptome analyses of short sleeping flies' heads (knockdown for the ABCC9 gene homolog;dSur). We found significant alterations in gene-expression in the short sleeping knockdowns versus controls flies, which correspond to pathways associated with sleep duration in our human studies. Most notably, the expression of Rho and EGFR (members of the ERBB signalling pathway) genes was down-and up-regulated, respectively, consistently with the established role of these genes for sleep consolidation in Drosophila. Using a disease multifactorial interaction network, we showed that many of the genes of the pathways indicated to be relevant for sleep duration had functional evidence of their involvement with sleep regulation, circadian rhythms, insulin secretion, gluconeogenesis and lipogenesis

microRNAs and breast cancer: a genomic study reveals miR-148b as a major coordinator of tumor progression

Breast cancer is a multistep disease controlled by a wide spectrum of genetic and epigenetic changes occurring within a cell as well as environmental influences; and it is the most common malignancy in women worldwide, often fatal because of metastasis dissemination. Aberrant miRNA expression can influence several gene networks and pathways implicated in tumorigenesis and metastasis formation. To unravel the role of miRNAs during breast cancer progression we investigated miRNA expression in 77 ductal breast carcinoma biopsies and 17 mammoplasties by microarray analysis. Sixteen differentially expressed miRNAs were identified comparing patients with or without disease relapse, within 72 months from surgery. This signature correlates with survival and/or distinguishes tumor subtypes in different datasets. Among them, miR-148b, down-regulated in aggressive breast tumors, was found to be a major coordinator of malignancy. In fact, it is able to oppose various steps of tumor progression when overexpressed in cell lines by influencing invasion, survival to anoikis, extravasation, lung metastasis formation, and chemotherapy response. miR-148b controls malignancy by coordinating a novel pathway involving over 130 genes and, in particular, it directly targets players of the integrin signaling, such as ITGA5, ROCK1, PIK3CA/p110α, and NRAS, as well as CSF1, a growth factor for stroma cells. Our findings reveal the importance of the identified 16 miRNAs for disease outcome predictions and suggest a critical role for miR-148b in the control of breast cancer progressionIl tumore al seno è una malattia multifattoriale controllata sia da un ampio spettro di variazioni genetiche ed epigenetiche che si verificano all'interno di una cellula, sia da fattori ambientali. E’ sicuramente la neoplasia più diffusa tra le donne di tutto il mondo ed è spesso fatale a causa della diffusione metastatica. Recentemente è emerso che l’espressione aberrante dei miRNA può influenzare il comportamento di diverse reti genetiche e pathway biologici implicati nel processo tumorigenico e nella formazione di metastasi. Per meglio comprendere il ruolo dei miRNA, durante la progressione tumorale, abbiamo definito il loro profilo trascrizionale, utilizzando una piattaforma microarray, in settantasette pazienti affetti da carcinoma mammario duttale e diciassette mammoplastie (controlli sani). Abbiamo identificato sedici miRNA differenzialmente espressi in grado di discriminare i pazienti che presentano, o meno, recidiva dopo 72 mesi dall’intervento chirurgico. E’ interessante notare come l’espressione di questo gruppo di miRNA correla con la sopravvivenza dei pazienti e sia in grado di distinguere sottotipi tumorali in altri dataset di espressione. All’interno di questo gruppo è stato identificato il miR-148b, sottoespresso nei pazienti con prognosi più infausta, che si è dimostrato essere uno dei principali coordinatori del processo metastatico. In particolare questo miRNA, una volta sovraespresso nelle linee cellulari, è in grado di bloccare la formazione di metastasi influenzando l’invasività, la sopravvivenza delle cellule tumorali nel torrente circolatorio (anoikis), la fuoriuscita dai vasi sanguigni, la formazione di metastasi polmonari e la risposta alla chemioterapia. Abbiamo dimostrato che il miR-148b coordina l’azione di 130 geni e, in particolare, regola direttamente l’espressione di vari membri della via di segnalazione mediata dalle integrine tra cui ITGA5, ROCK1, PIK3CA/p110α e NRAS, così come CSF1, che è un fattore di crescita delle cellule stromali. I nostri dati dimostrano il valore prognostico dei 16 miRNA identificati e suggeriscono un ruolo critico del miR-148b nel controllo del processo metastatico in pazienti affetti da carcinoma mammari

The DNA damage response to ionizing radiation is modulated by miR-27a

Perturbations during the DNA Damage Response (DDR) can originate from alteration in the functionality of the microRNA-mediated gene regulation, being microRNAs (miRNAs) small noncoding RNA that act as post-transcriptional regulators of gene expression. By integrating the transcriptome and microRNome, we provided evidence that modeled microgravity can affects the DNA-damage response to IR in human peripheral blood lymphocytes (PBL) (Girardi et al., 2012). By functional assays using luciferase reporter constructs we have shown that miR-27a targets ATM, the gene coding for the main kinase of DDR pathway. Since miR-27a is classified as an oncomir, being overexpressed in several tumors, we investigated the miR-27a-ATM interaction by validating miR-27a as a direct regulator of ATM through site-direct mutagenesis of the reporter vector containing the 3\u2019UTR of ATM gene. We also analyzed the in vitro effects of ionizing radiation in cells overexpressing miR-27a, by assessing cell survival, DNA repair and cell cycle progression. Our results show that overexpression of miR-27a diminishes cellular radiosensitivity, suggesting a role of this miRNA during DDR