Submitted by Luis Ricardo Andrade da Silva (lrasilva@uefs.br) on 2016-03-31T01:16:15Z No. of bitstreams: 1 Disserta??o Final.pdf: 2489318 bytes, checksum: 74b79aac96fa73b31d6e0dbb4272efe3 (MD5) / Made available in DSpace on 2016-03-31T01:16:15Z (GMT). No. of bitstreams: 1 Disserta??o Final.pdf: 2489318 bytes, checksum: 74b79aac96fa73b31d6e0dbb4272efe3 (MD5) Previous issue date: 2015-12-15 / HIV infects over 40 million people worldwide and is considered by the World Health Organization a large scale pandemic. Which the associated disease has no cure. New data and analysis can help new treatment and vaccine development. However, the dataset is vast, with over 500,000 sequences available on GenBank. This data still lacks essential information such as subtyping and genome location. To help minimize these problems we developed a system for automated analysis from GenBank data. The tool performs sequence map according to HXB2 and subtyping by comparison with subtype reference sequences. This process uses Needleman-Wusch and Smith-Waterman respectively. All 582,678 sequences were mapped in 5 days and 14 hours and subtyped in 1 day and 7 hours with our algorithm, while the original approach was estimated to finish in 36 and 97 years respectively. Our tool was able to analyse the massive data in a reliable time. No current subtyping tool can analyse this high-throughput data. Our results showed that pol and gag genes were the most prevalent genes on the dataset, and could be explained because treatment and subtyping are based on these genes. Moreover, the structural genes were most prevalent, with 66.41%. This highlighted the low representation of regulatory genes on available data. The subtyping results showed that the subtype B was most frequent, with 45.96%. The recombinants together represent 43.37%. Furthermore, subtype C presented only 4.12% and the other pure subtypes less than 4%. Also, the geographical data was recovered from database and USA presented higher frequency, with 24.50%, showing a significant country bias. Our results present a new HIV subtype distribution with the most complete and recent dataset.Herein, we presented a new user friendly software for massive data analysis of viruses. This software is able to analyse highly mutational virus data, such as HCV and HIV in reliable time. Further, severe country bias raises questions regarding world subtype distribution. The analysis of all sequences from HIV provides new epidemy insights about subtypes and country distribution. / O HIV infecta mais de 40 milh?es de pessoas no mundo e ? considerado pela Organiza??o Mundial de Sa?de como uma pandemia. A doen?a associada n?o possui cura cl?nica. Novas an?lises e informa??es podem ajudar no desenvolvimento de novos tratamentos e vacinas. No entanto, o conjunto de dados sobre o agente etiol?gico dispon?vel ? vasto, contando com mais de 500 mil sequ?ncias no GenBank. Este conjunto de dados ainda carece de informa??es essenciais, como subtipo viral e localiza??o no genoma de refer?ncia. Para auxiliar na minimiza??o destes problemas, desenvolvemos um sistema para an?lise dos dados dispon?veis no GenBank. A ferramenta realiza o mapeamento de acordo com o genoma refer?ncia HXB2 e a subtipagem comparando as sequ?ncias de refer?ncia dos subtipos. Estes processos utilizam os algoritmos de Needleman-Wusch e Smith-Waterman respectivamente. Todas as 582.678 sequ?ncias foram mapeadas em 5 dias e 14 horas, e subtipadas em 1 dia e 7 horas com nosso algoritmo. Enquanto a abordagem original estima terminar em 36 e 97 anos respectivamente. Nenhuma ferramenta de subtipagem dispon?vel atualmente ? capaz de analisar esta quantidade de dados. Nossos resultados mostraram que os genes gag e pol s?o mais prevalentes no conjunto de dados. O que pode ser explicado pelo fato de t?cnicas de avalia??o de resist?ncia aos antirretrovirais e subtipagem serem baseadas nesses genes. Al?m disso, os genes estruturais exibiram uma preval?ncia absoluta de 66.41%. Isto evidencia a pouca representatividade de genes regulat?rios no conjunto de dados. Os resultados da subtipagem mostram que o subtipo B ? o mais frequente com 45,96% de preval?ncia. Os recombinantes, combinados, representam 43.37%. Ademais, o subtipo C apresentou apenas 4,12% de preval?ncia absoluta e outros subtipos puros menos de 4%. Al?m disso, dados geogr?ficos foram recuperados do banco de dados. Os Estados Unidos representam a maior frequ?ncia de sequ?ncias submetidas, com 24,5% de todos os dados dispon?veis. Nossos resultados apresentam uma nova distribui??o genot?pica do HIV, com o conjunto de dados mais recente e completo. Neste trabalho apresentamos um novo software para an?lise das sequ?ncias nucleot?dicas do HIV dispon?veis no GenBank. Este software ? capaz de analisar dados de v?rus com elevado comportamento mutacional como HIV e HCV em um curto espa?o de tempo. A an?lise de todas as sequ?ncias do HIV dispon?veis no GenBank oferece um novo ponto de vista sobre a epidemia, distribui??o de subtipos e geogr?fica.

Background. Previous studies of the dimensional structure of panic attack symptoms have mostly identified a respiratory and a vestibular/mixed somatic dimension. Evidence for additional dimensions such as a cardiac dimension and the allocation of several of the panic attack symptom criteria is less consistent. Clarifying the dimensional structure of the panic attack symptoms should help to specify the relationship of potential risk factors like anxiety sensitivity and fear of suffocation to the experience of panic attacks and the development of panic disorder. Method. In an outpatient multicentre study 350 panic patients with agoraphobia rated the intensity of each of the ten DSM-IV bodily symptoms during a typical panic attack. The factor structure of these data was investigated with nonlinear confirmatory factor analysis (CFA). The identified bodily symptom dimensions were related to panic cognitions, anxiety sensitivity and fear of suffocation by means of nonlinear structural equation modelling (SEM). Results. CFA indicated a respiratory, a vestibular/mixed somatic and a cardiac dimension of the bodily symptom criteria. These three factors were differentially associated with specific panic cognitions, different anxiety sensitivity facets and suffocation fear. Conclusions. Taking into account the dimensional structure of panic attack symptoms may help to increase the specificity of the associations between the experience of panic attack symptoms and various panic related constructs.

Le rétinoblastome, un cancer pédiatrique de la rétine en développement, est la tumeur intraoculaire la plus fréquente chez l’enfant et représente environ 4 % de tous les cancers infantiles. Bien qu'il s'agisse d'une maladie rare, l'hôpital Curie (centre de référence pour le rétinoblastome en France) accueille environ 50 à 60 nouveaux patients chaque année. Notre groupe a précédemment caractérisé deux sous-types de rétinoblastomes. Les tumeurs de type « cone-like » ou sous-type 1 sont plutôt différenciées et homogènes, présentent une surexpression des gènes liés aux cellules cônes (photorécepteurs) de la rétine, sont diagnostiquées cliniquement plus tôt et regroupent la majorité des formes héréditaires et bilatérales. Les tumeurs « mixed-type » ou sous-type 2, présentent une hétérogénéité intra-tumorale et une surexpression des gènes liés aux cellules des cônes et des cellules ganglionnaires de la rétine, sont enrichies en patients unilatéraux qui sont diagnostiqués cliniquement à des âges plus avancés. Nous avons caractérisé le paysage moléculaire et génomique de 102 rétinoblastomes provenant de trois institutions : l'Institut Curie (France), l'Hôpital Garrahan (Argentine) et l'Hôpital Sant Joan de Déu (Espagne). Le développement d'une signature de méthylation par pyroséquençage pour la classification des échantillons nous a permis d'élargir nos échantillons classés, d'une première série de 72 à notre dernière série de 102 tumeurs. L'analyse du paysage mutationnel de notre série a révélé que les tumeurs du sous-type 2 avaient plus de mutations somatiques par échantillon que les tumeurs du sous-type 1. De plus les gènes BCOR et ARID1A étaient les deux seuls gènes mutés de manière récurrente, et identifiés uniquement dans le sous-type 2. En divisant notre cohorte de tumeurs en sous-type 1 et 2, la distribution des mutations le long de RB1 était significativement différente. Par ailleurs, nous avons identifié une région de la protéine RB1 (dans le Domaine A) enrichie en mutations provenant des tumeurs du sous-type 2, avec très peu de mutations du sous-type 1. En plus, nous avons caractérisé deux événements récurrents de fusion chromosomique perturbant le gène DACH1. Les tumeurs de sous-type 2 sont caractérisées par une surexpression de TFF1, non exprimée dans la rétine normale. L'analyse par immunohistochimie de TFF1 dans des tumeurs localement invasives provenant de l'hôpital Garrahan a révélé la présence de cellules TFF1+ envahissant la région rétrolaminaire du nerf optique. Nous avons exploré un possible rôle oncogène de TFF1 dans le rétinoblastome lié à la survie cellulaire, à la migration cellulaire et à l'invasion cellulaire, qui n'a finalement pas été mis en évidence in vitro. Le sous-type moléculaire 2 regroupe les tumeurs MYCN amplifiées et les tumeurs avec une activation de la voie de signalisation MYC et des gènes cibles de MYC. L'utilisation de JQ1 et OTX015 (inhibiteurs des protéines BET) a fortement réduit la viabilité in vitro de lignées cellulaires de rétinoblastomes représentatives du sous-type 2, avec une régulation négative significative du gène et de la protéine MYC/MYCN. Nos résultats préliminaires suggèrent une nouvelle piste thérapeutique par l'inhibition des protéines BET dans le rétinoblastome. Les modèles précliniques largement utilisés dans la recherche sur le rétinoblastome n'ont pas été caractérisés ou classés au niveau moléculaire. Nous avons utilisé la même approche que pour la classification des tumeurs primaires et avons constaté que la plupart des modèles cellulaires et PDX étudiés étaient classés dans le sous-type moléculaire 2 et partageaient des caractéristiques moléculaires, génomiques et protéiques trouvés dans les tumeurs primaires de ce sous-type moléculaire. En conclusion, nous avons pu caractériser de façon plus approfondie le sous-type 2 des rétinoblastomes, qui semble présenter un phénotype plus agressif et qui est le sous-type représenté dans les modèles précliniques analysés. / Retinoblastoma (RB) is a rare pediatric cancer of the developing retina that represents the most common intraocular tumor in children, and accounts for about 4% of all childhood cancers. Although being a rare disease, the Curie Hospital (the referral center for retinoblastoma in France) treats about 50-60 new patients each year. Our group has previously characterized two retinoblastoma subtypes. The cone-like or subtype 1 tumors rather differentiated and homogenous, presenting an overexpression of genes related to cone photoreceptor retinal cells, clinically diagnosed earlier and grouping the majority of hereditary and bilateral forms. The mixed-type or subtype 2 tumors, displaying an intra-tumoral heterogeneity and showing overexpression of genes related to cone and retinal ganglion cells, are enriched in unilateral patients clinically diagnosed at older ages. The general goal of my thesis was to extend the molecular characterization of these subtype 2 retinoblastomas. We characterized the molecular and genomic landscape of retinoblastoma in a series of 102 primary tumors, integrating samples from three institutions: the Curie Institute (France), the Garrahan Hospital (Argentina) and Sant Joan de Déu Hospital (Spain). The development of a pyrosequencing-based tool for sample classification allowed us to enlarge our classed samples, from an initial series of 72, to our final series of 102 tumors. Analysis of the mutational landscape in our series revealed that tumors from the subtype 2 had significantly more somatic mutations per sample than tumors from the subtype 1. Besides RB1 gene, BCOR and ARID1A where the only two recurrently mutated genes, and identified only in the subtype 2. Distribution of mutations alongside the RB1 gene has so far been analyzed in terms of a single group of retinoblastomas. When splitting our cohort in subtype 1 and subtype 2 tumors, the distribution of mutations was significantly different. Besides, we identified a region of the RB1 protein (in Domain A) enriched in mutations from tumors of the subtype 2, and devoid of mutations of the subtype 1. Besides somatic mutations, we characterized two recurrent chromosomal fusion events disrupting DACH1. Subtype 2 tumors are characterized by an overexpression of TFF1, not expressed in the normal retina. Immunohistochemical analysis of TFF1 in locally invasive tumors coming from the Garrahan Hospital revealed the presence of TFF1+ cells invading the retrolaminar region of the optic nerve. We then explored a possible oncogenic role of TFF1 in retinoblastoma related to cell survival, cell migration and cell invasion, which was not fully uncovered. Molecular subtype 2 regroups the MYCN amplified tumors and tumors with MYC signaling pathway activation and upregulation of hallmark MYC target genes. The use of JQ1 and OTX015 (BET bromodomains inhibitors) strongly reduced the viability in vitro of retinoblastoma cell lines representatives of the subtype 2, together with a significant MYC/MYCN gene and protein downregulation. We provided preliminary results to explore a new therapeutic avenue of BET protein inhibition in retinoblastoma. Preclinical models widely used in retinoblastoma research has not been characterized or classified at the molecular level. We have used the same approach as for primary human tumor’s classification, and found that most cellular and PDX models studied classed in the molecular subtype 2 and shared many of the molecular, genomic and protein characteristics found in primary tumors of this molecular subtype. Taken together, we have performed a deeper characterization of subtype 2 retinoblastomas, which seems to represent a more aggressive phenotype, and is the represented subtype in the preclinical models analyzed.

Recent findings suggest, that perception of acoustic stimuli in the mouse auditory cortex relies on categorization of object-based representations. Local neuronal populations in L2/3 of the mouse auditory cortex reportedly exhibit a limited number (1-3) of stable modes of response, each possibly evoked by multiple complex sounds of variable acoustic features. Stimulation using linear intensity mixing of sounds evoking different response modes revealed an attractor-like dynamic of the underlying representation. These modes of response were hypothesized to represent the neural correlate of perceptual categorization. We have developed an experimental protocol enabling chronic two-photon imaging of the previously described population coding under awake conditions. Using this protocol we acquired data suggesting that the pattern of population activity underlying a mode of response, is stable during a week-long timeframe. We have also recorded the neural activity of a local subpopulation of somatostatin-positive inhibitory interneurons (SST+ INs) during abrupt changes in cortical representation. Our preliminary results suggest that local SST+ INs exhibit maximal firing when the neural correlate of a mode of response is exhibited by the surrounding population of principal cells. In addition, we observed a...

Die Behandlung menopausaler und postmenopausaler Beschwerden ist mit einem erhöhten Risiko verbunden, an Mamma- und Endometriumskarzinomen zu erkranken. Darüber hinaus zeigen epidemiologische Studien, dass in ostasiatischen Ländern postmenopausale Beschwerden, osteoporotische Frakturen und Herz-Kreislauferkrankungen seltener auftreten als in westlichen Ländern. Vor diesem Hintergrund war es Ziel der Untersuchungen dieser Arbeit, in dem Tiermodell der ovarektomierten Ratte die mögliche Bedeutung von estrogenrezeptorsubtypspezifischen Einflüssen für hormonell bedingte Erkrankungen und Beschwerden zu untersuchen. Hierbei sollten gewebespezifische Wirkungen estrogenrezeptorsubtypspezifischer Liganden untersucht und explizit die Bedeutung der Estrogenrezeptorsubtypen ERα und ERβ bei der Gewebehomöostase in Knochen und Darm analysiert werden. Darüber hinaus sollten vor dem Hintergrund estrogenrezeptorsubtypspezifischer Wirkungsweisen gewebespezifische Einflüsse des Phytoestrogens Genistein (Gen) näher charakterisiert werden. Es konnte gezeigt werden, dass nach einer subkutanen Applikation der knochenprotektive Einfluss von Gen mit dem von Estradiol (E2) vergleichbar ist, durch die Kombination mit Bewegung verstärkt wird und über den ERα vermittelt zu sein scheint. Es zeigte sich außerdem, dass der stimulierende Einfluss von E2 auf den motorischen Antrieb ERα-vermittelt ist und ERβ-spezifische Liganden ebenso wie Gen diesen Effekt antagonisieren. Des Weiteren wurde deutlich, dass E2, nicht aber Gen über den ERα Einfluss auf die Körperfettverteilung nimmt. Mit einer phytoestrogenreichen Diät konnten in adulten Ratten physiologisch relevante Gen/Dai-Plasmaspiegel erreicht werden, allerdings blieben hierbei die nach einer subkutanen Applikation beobachteten knochenprotektiven Effekte dieser Phytoestrogene aus. Bei der näheren Betrachtung der Gewebehomöostase im Dünndarm zeigte sich, dass über den im Darm verstärkt exprimierten ERβ antiproliferative und proapoptotische Effekte vermittelt werden und Gen in diesem Gewebe wie ein ERβ-spezifischer Agonist wirkt. Bezogen auf eine hormonell bedingte Osteoporose, wie sie bei einem Großteil postmenopausaler Frauen auftritt, scheint das Phytoestrogen Genistein eine mögliche Alternative zur Hormonersatztherapie darzustellen. Außerdem zeigt sich, dass Genistein gewebe- und estrogenrezeptorsubtypspezifische antagonistische und agonistische Einflüsse hat und somit die Charakterisierung als „Phyto-SERMs“ (pflanzlicher selektiver Estrogenrezeptormodulator) zutreffend ist. Sollten sich in weiterführenden Studien die beobachteten Effekte im Dünndarm auch für die Gewebehomöostase im Kolon beschreiben lassen, können vor diesem Hintergrund Genistein und ERβ-spezifische Liganden für die Darmkrebsprävention diskutiert werden…

Prostate cancer is the most common cancer in Sweden. Patients with the condition have a good prognosis in general and most cases can be treated. Localized prostate cancer is primarily treated via surgery or radiation therapy and is diagnosed with the help of different imaging modalities, such as magnetic resonance imaging, MRI, and positron emission tomography, PET. The diagnosis is confirmed and the aggressiveness of the cancer is determined through biopsies. Samples from a small part of the prostate are extracted and then examined. This could mean that parts of higher aggressiveness may be missed, which in turn could lead to under-treatment of the cancer. The aggressiveness of a lesion can be described by Gleason Score, GS, which is determined by an visual assessment of the shape, size and arrangement of the cells. The aim of this study was to correlate GS with in-vivo images using MRI and PET. This was accomplished by investigating image data from PSMA PET, Acetate PET, Ktrans MRI and T2-weighted MRI from a cohort of 26 prostate cancer patients containing 74 lesions. Regions of interests, ROI:s, were created and applied on all images. Statistics such as median and max value were extracted from each ROI. The statistics were combined to get a wide range of descriptive variables for each respective imaging modality. These were normalised against a certain zone of the prostate or only the absolute value. The results indicated that PSMA PET, Acetate PET and Ktrans MRI were correlated to GS, while T2-weighted MRI was not. Data also indicated that PSMA PET, Acetate PET and Ktrans MRI give complementary information to each other, which could indicate that a combination of the modalities would better predict GS. The implications of these findings could affect both the diagnostics and the treatment of prostate cancer.

Le cancer du sein est une maladie hétérogène définie actuellement par plusieurs sous-types classés en fonction de leurs profils d'expression génique et reliés à différentes altérations moléculaires et options thérapeutiques. Les tumeurs luminales, exprimant le récepteur des oestrogènes alpha (ERa), sont traitées par des thérapies endocriniennes. Les tumeurs HER2+ bénéficient également de traitement par des médicaments ciblant ce récepteur. Cependant, les tumeurs de types basal-like, molecular apocrine et claudin-low, sont principalement traitées par chimiothérapie à défaut de cibles thérapeutiques. Les différents sous-types moléculaires du cancer du sein sont supposés provenir d'un blocage de la différenciation épithéliales mammaires à différents stades. Les tumeurs luminales, HER2+ et basal-like sont caractérisées par un phénotype épithélial, alors que les tumeurs claudin-low se distinguent par un phénotype mésenchymateux moins différencié. Jusqu'à présent, les facteurs de transcription qui dictent l'identité épithéliale des tumeurs mammaires et les mécanismes sous-jacents de la spécification des sous-types de cancer du sein restent imparfaitement compris. Dans cette étude, nous montrons que le facteur de transcription (FT) Grainyhead-like 2 (GRHL2) agit en tant que gardien et régulateur principale de phénotype épithélial des lignées cellulaires du cancer du sein. La surexpression de GRHL2 dans des cellules cancéreuses du sein claudin-low induit une transition mésenchymateuse à épithéliale en induisant directement l'expression de plusieurs FT épithéliaux, cofacteurs et microARNs et par interférence avec d'autres voies de signalisation. La surexpression de GRHL2 dans les cellules MDA-MB-231 a entraîné l'ouverture de la chromatine et l'activation transcriptionnelle des gènes cibles tels que les inhibiteurs de l’EMT OVOL1 et OVOL2, réprimés dans les cellules mésenchymateuses. De plus, nous avons identifié le marqueur de type basal-like VGLL1, un cofacteur des TEADs, en tant que nouveau cofacteur de GRHL2, qui médie une partie des effets de GRHL2 dans les cellules MDA-MB-468. L'axe GRHL2/VGLL1 oppose les effecteurs de la voie de signalisation Hippo YAP / TEADs, qui sont dérégulés dans de nombreux cancers, et inhibe l'activation de certains de leurs gènes cibles impliqués dans la progression tumorale et les métastases. Dans la deuxième partie de notre étude, nous avons identifié, par une analyse de corrélation génique dans plusieurs jeux de données transcriptomiques de tumeurs du sein, un cluster de gènes hautement corrélés et spécifiquement exprimés dans les tumeurs basal-like, incluant FOXC1, VGLL1, BCL11A, GABRP, SOX6/8/10 et ELF5. Nous avons montré que la surexpression de FOXC1 dans des cellules épithéliales et mésenchymateuses active des voies de signalisation et induit l’expression de gènes enrichis dans les tumeurs basal-like, y compris le marqueur de type basal-like C1orf106, quoique ces effets soient largement spécifiques du contexte cellulaire. D’un autre côté, nous avons montré que les FT luminaux ERa, FOXA1 et GATA3 répriment directement l'expression des marqueurs de type basal-like VGLL1 et GABRP dans les cellules luminales MCF7. Ces études permettent de mieux comprendre le rôle et les mécanismes de la régulation transcriptionnelle par GRHL2 et ont identifié de nouveaux gènes cibles de VGLL1 et de FOXC1 dans les cellules cancéreuses du sein. Étant donné que les sous-types de cancer du sein sont liés à des aberrations génétiques affectant de manière distincte les patrons d'expression des gènes, l’identification des réseaux de régulation transcriptionnels spécifiques à chaque sous-type et une meilleure compréhension de l'impact de leur dérégulation sur les phénotypes tumoraux peuvent conduire à la découverte de nouvelles cibles thérapeutiques spécifiques à chaque sous-type. / Breast cancer is a heterogenous disease currently defined by several subtypes that have been identified based on gene expression profiling and are related to different molecular alterations and clinical outcomes. Luminal tumors, expressing estrogen receptor alpha (ERa), are treated with endocrine therapies. HER2-enriched tumors also benefit from treatment with drugs targeting this receptor. However, basal-like, molecular apocrine and claudin-low tumors, lacking the expression of specific molecular targets, are mainly treated by chemotherapy. Breast cancer molecular subtypes are thought to be originated from a block of mammary epithelial cell differentiation at different stages. Luminal, HER2-enriched and basal-like tumors are characterized by an epithelial phenotype, however claudin-low tumors are distinguished by a less differentiated mesenchymal phenotype. Until now, transcription factors that dictate the epithelial identity of breast tumors and that underlie breast cancer subtype specification have not been well characterized. Here, we show that the transcription factor (TF) Grainyhead-like 2 (GRHL2) is a gatekeeper and a master regulator of the epithelial phenotype of breast cancer cell lines. GRHL2 overexpression in claudin-low breast cancer cells induces mesenchymal to epithelial transition by directly upregulating the expression of several epithelial TFs, cofactors and microRNAs and by crosstalk with other signaling pathways. GRHL2 overexpression in MDA-MB-231 cells resulted in chromatin opening and transcriptional activation of direct target genes such as the EMT inhibitors OVOL1 and OVOL2, repressed in mesenchymal cells. In addition, we uncovered the basal-like marker VGLL1, a TEAD cofactor, as a novel cofactor of GRHL2, which mediates part of GRHL2 effects in MDA-MB-468 cells. The GRHL2/VGLL1 axis counteracts the downstream effectors of the Hippo signaling pathway YAP/TEADs, which are deregulated in many cancers, and inhibits the activation of some of their target genes implicated in tumor progression and metastasis. In the second part of our study, we identified by performing gene correlation analysis in large transcriptome datasets of breast tumors a cluster of highly correlated genes specifically expressed in basal-like tumors, comprising FOXC1, VGLL1, BCL11A, GABRP, SOX6/8/10 and ELF5. We showed that FOXC1 overexpression in both mesenchymal and epithelial cells upregulates basallike signaling pathways and markers such as the basal-like marker C1orf106, although with little overlap indicating context-dependent gene regulation. Conversely, we showed that luminal TFs ERa, FOXA1 and GATA3 directly repress the expression of basal-like markers VGLL1 and GABRP in MCF7 luminal cells. These studies help to better understand the role and the mechanisms of transcriptional regulation by the epithelial transcription factor GRHL2 and identified previously unknown targets of basallike transcription factor FOXC1 and cofactor VGLL1 in breast cancer cells. As breast cancer subtypes are linked to genetic defects differentially affecting gene expression patterns, the characterization of relevant subtype-specific transcriptional regulatory networks and better understanding of the impact of their deregulation on the tumor phenotype may lead to the discovery of new therapeutic strategies specific to each subtype.

Molecular mechanisms of lower-grade (II–III) diffuse gliomas (LGG) are still poorly understood, mainly because of their heterogeneity. They split into astrocytoma- (IDH-A) and oligodendroglioma-like (IDH-O) tumors both carrying mutations(s) at the isocitrate dehydrogenase (IDH) gene and into IDH wild type (IDH-wt) gliomas of glioblastoma resemblance. We generated detailed maps of the transcriptomes and DNA methylomes, revealing that cell functions divided into three major archetypic hallmarks: (i) increased proliferation in IDH-wt and, to a lesser degree, IDH-O; (ii) increased inflammation in IDH-A and IDH-wt; and (iii) the loss of synaptic transmission in all subtypes. Immunogenic properties of IDH-A are diverse, partly resembling signatures observed in grade IV mesenchymal glioblastomas or in grade I pilocytic astrocytomas. We analyzed details of coregulation between gene expression and DNA methylation and of the immunogenic micro-environment presumably driving tumor development and treatment resistance. Our transcriptome and methylome maps support personalized, case-by-case views to decipher the heterogeneity of glioma states in terms of data portraits. Thereby, molecular cartography provides a graphical coordinate system that links gene-level information with glioma subtypes, their phenotypes, and clinical context.

Background: The blood transcriptome is expected to provide a detailed picture of an organism’s physiological state with potential outcomes for applications in medical diagnostics and molecular and epidemiological research.We here present the analysis of blood specimens of 3,388 adult individuals, together with phenotype characteristics such as disease history, medication status, lifestyle factors, and body mass index (BMI). The size and heterogeneity of this data challenges analytics in terms of dimension reduction, knowledge mining, feature extraction, and data integration. Methods: Self-organizing maps (SOM)-machine learning was applied to study transcriptional states on a population-wide scale. This method permits a detailed description and visualization of the molecular heterogeneity of transcriptomes and of their association with different phenotypic features. Results: The diversity of transcriptomes is described by personalized SOM-portraits, which specify the samples in terms of modules of co-expressed genes of different functional context. We identified two major blood transcriptome types where type 1 was found more in men, the elderly, and overweight people and it upregulated genes associated with inflammation and increased heme metabolism, while type 2 was predominantly found in women, younger, and normal weight participants and it was associated with activated immune responses, transcriptional, ribosomal, mitochondrial, and telomere-maintenance cell-functions. We find a striking overlap of signatures shared by multiple diseases, aging, and obesity driven by an underlying common pattern, which was associated with the immune response and the increase of inflammatory processes. Conclusions: Machine learning applications for large and heterogeneous omics data provide a holistic view on the diversity of the human blood transcriptome. It provides a tool for comparative analyses of transcriptional signatures and of associated phenotypes in population studies and medical applications.

Yes / It is unclear whether people with dementia (PwD) have more negative attitudes toward own aging (ATOA) than people without dementia and what factors influence ATOA among PwD. We investigated whether PwD have more negative ATOA than individuals without dementia and whether cognition and dementia subtype are associated with ATOA in PwD. Data from the IDEAL and PROTECT studies were used to compare ATOA between 1502 PwD (mean (SD) age = 76.3 (8.5)) and 6377 individuals without dementia (mean (SD) age = 66.1 (7.1)). Linear regressions and ANOVA were used. PwD reported slightly more negative ATOA than people without dementia; this relationship disappeared after controlling for depression and self-rated health. In PwD more positive ATOA showed negligible associations with better general cognition, memory performance, verbal fluency, and visuospatial ability. However, after adjusting for covariates only better visuospatial ability predicted more positive ATOA. Additional analyses showed that before and after controlling for covariates, individuals with poorer self-reported visual acuity have more negative ATOA. Amongst dementia subtypes, people with Parkinson's disease dementia and dementia with Lewy bodies reported most negative ATOA. ATOA between PwD and people without dementia do not differ. ATOA in PwD appear to be affected not by cognitive impairment but by other characteristics that vary across dementia subtypes. Among PwD, those with Parkinson's disease dementia and dementia with Lewy bodies may have higher risk of experiencing negative ATOA due to the motor and visual impairments that they experience. / Improving the experience of Dementia and Enhancing Active Life: living well with dementia. The IDEAL study’ was funded jointly by the Economic and Social Research Council (ESRC) and the National Institute for Health and Care Research (NIHR) through grant ES/L001853/2. The IDEAL-2 study’ is funded by Alzheimer’s Society, grant number 348, AS-PR2-16-001