Identification of an EGFRvIII-JNK2-HGF/c-Met-Signaling Axis Required for Intercellular Crosstalk and Glioblastoma Multiforme Cell Invasion.

Glioblastoma multiforme (GBM) is the most aggressive and common form of adult brain cancer. Current therapeutic strategies include surgical resection, followed by radiotherapy and chemotherapy. Despite such aggressive multimodal therapy, prognosis remains poor, with a median patient survival of 14 months. A proper understanding of the molecular drivers responsible for GBM progression are therefore necessary to instruct the development of novel targeted agents and enable the design of effective treatment strategies. Activation of the c-Jun N-terminal kinase isoform 2 (JNK2) is reported in primary brain cancers, where it associates with the histologic grade and amplification of the epidermal growth factor receptor (EGFR). In this manuscript, we demonstrate an important role for JNK2 in the tumor promoting an invasive capacity of EGFR variant III, a constitutively active mutant form of the receptor commonly found in GBM. Expression of EGFR variant III induces transactivation of JNK2 in GBM cells, which is required for a tumorigenic phenotype in vivo. Furthermore, JNK2 expression and activity is required to promote increased cellular invasion through stimulation of a hepatocyte growth factor-c-Met signaling circuit, whereby secretion of this extracellular ligand activates the receptor tyrosine kinase in both a cell autonomous and nonautonomous manner. Collectively, these findings demonstrate the cooperative and parallel activation of multiple RTKs in GBM and suggest that the development of selective JNK2 inhibitors could be therapeutically beneficial either as single agents or in combination with inhibitors of EGFR and/or c-Met.

Modeling childhood cancer in Drosophila melanogaster.

Childhood cancer is a major cause of death in developed countries, and while treatments and survival rates have improved, long-term side effects remain a challenge. The genetic component of pediatric tumors and their aggressive progression, makes the study of childhood cancer a complex area of research. Here, we introduce the fruit fly Drosophila melanogaster as study model. We emphasize its numerous advantages, including binary gene expression systems that enable precise control over the timing and location of gene expression manipulation, the capacity to combine multiple genes associated with cancer or the testing of human cancer variants within a live, intact animal. As an illustrative example, we focus on the Drosophila cancer paradigm which involves medically relevant genes, the Notch and PI3K/Akt signaling pathways. We describe how this cancer paradigm allows assessing two critical aspects of tumorigenesis during juvenile stages: (1) viability (do animals with particular cancer mutations survive into adulthood?), and (2) tumor burden (what percentage of animals bearing the cancer mutations actually develop cancer and what is the extent of the tumor?). We highlight the potential of Drosophila as a molecular therapeutic tool for drug screening and drug repurposing of medicines already approved to treat other diseases in children, thereby accelerating the potential translation of results into humans. This preclinical animal model sustains huge potential and is cost-effective. It allows screening of thousands of compounds and genes at a relatively low cost and human efforts, opening innovative venues to explore more effective and safer treatments of childhood cancer.

A Blueprint for Cancer-Related Inflammation and Host Innate Immunity.

Both in situ and allograft models of cancer in juvenile and adult Drosophila melanogaster fruit flies offer a powerful means for unravelling cancer gene networks and cancer-host interactions. They can also be used as tools for cost-effective drug discovery and repurposing. Moreover, in situ modeling of emerging tumors makes it possible to address cancer initiating events-a black box in cancer research, tackle the innate antitumor immune responses to incipient preneoplastic cells and recurrent growing tumors, and decipher the initiation and evolution of inflammation. These studies in Drosophila melanogaster can serve as a blueprint for studies in more complex organisms and help in the design of mechanism-based therapies for the individualized treatment of cancer diseases in humans. This review focuses on new discoveries in Drosophila related to the diverse innate immune responses to cancer-related inflammation and the systemic effects that are so detrimental to the host.

Cannabidiol Treatment Results in a Common Gene Expression Response Across Aggressive Cancer Cells from Various Origins.

Background: We previously reported that cannabidiol (CBD), a cannabinoid with a low toxicity profile, downregulated the expression of the prometastatic gene inhibitor of DNA binding 1 (ID1) in cancer cells, leading to inhibition of tumor progression in vivo. While CBD is broadly used, including in the self-medication of cancer patients, and CBD-based therapies are undergoing clinical evaluation for cancer treatment, its mechanisms of action are still poorly understood. Methods: In this study, using microarray analysis and Western blot analysis for validation, we attempted to identify the full spectrum of genes regulated by CBD across various aggressive cancer cell lines, including the breast, brain, head and neck, and prostate. Results: We confirmed that ID1 was a major target downregulated by CBD and also discovered that CBD inhibited FOXM1 (Forkhead box M1), a transcriptional activator involved in cell proliferation, while simultaneously upregulating GDF15 (growth differentiation factor 15), a cytokine associated with tissue differentiation. Conclusion: Our results suggest that, by modulating expression of shared key cancer-driving genes, CBD could represent a promising nontoxic therapeutic for treating tumors of various origins.

Autophagy is inhibited by ubiquitin ligase activity in the nervous system.

Autophagy is an intracellular catabolic process prominent in starvation, aging and disease. Neuronal autophagy is particularly important, as it affects the development and function of the nervous system, and is heavily implicated in neurodegenerative disease. Nonetheless, how autophagy is regulated in neurons remains poorly understood. Using an unbiased proteomics approach, we demonstrate that the primary initiator of autophagy, the UNC-51/ULK kinase, is negatively regulated by the ubiquitin ligase RPM-1. RPM-1 ubiquitin ligase activity restricts UNC-51 and autophagosome formation within specific axonal compartments, and exerts effects broadly across the nervous system. By restraining UNC-51 activity, RPM-1 inhibits autophagosome formation to affect axon termination, synapse maintenance and behavioral habituation. These results demonstrate how UNC-51 and autophagy are regulated subcellularly in axons, and unveils a mechanism for restricting initiation of autophagy across the nervous system. Our findings have important implications beyond nervous system development, given growing links between altered autophagy regulation and neurodegenerative diseases.

In Silico HTS and Structure Based Optimization of Indazole-Derived ULK1 Inhibitors.

We present the outcome of an in silico high throughput screen (HTS) and optimization of a small molecule Unc-51-Like Kinase 1 (ULK1) inhibitor hit, SR-17398, with an indazole core. Docking studies guided design efforts that led to inhibitors with increased activity vs ULK1 (IC50 < 50 nM). The most advanced molecules in this inhibitor series (3a and 3g) hold promise for further development into selective ULK1 molecular probes to interrogate the biology of ULK1 and to assess whether selectively targeting autophagy is an effective anticancer strategy.

DGCR8-mediated disruption of miRNA biogenesis induces cellular senescence in primary fibroblasts.

The regulation of gene expression by microRNAs (miRNAs) is critical for normal development and physiology. Conversely, miRNA function is frequently impaired in cancer, and other pathologies, either by aberrant expression of individual miRNAs or dysregulation of miRNA synthesis. Here, we have investigated the impact of global disruption of miRNA biogenesis in primary fibroblasts of human or murine origin, through the knockdown of DGCR8, an essential mediator of the synthesis of canonical miRNAs. We find that the inactivation of DGCR8 in these cells results in a dramatic antiproliferative response, with the acquisition of a senescent phenotype. Senescence triggered by DGCR8 loss is accompanied by the upregulation of the cell-cycle inhibitor p21CIP1. We further show that a subset of senescence-associated miRNAs with the potential to target p21CIP1 is downregulated during DGCR8-mediated senescence. Interestingly, the antiproliferative response to miRNA biogenesis disruption is retained in human tumor cells, irrespective of p53 status. In summary, our results show that defective synthesis of canonical microRNAs results in cell-cycle arrest and cellular senescence in primary fibroblasts mediated by specific miRNAs, and thus identify global miRNA disruption as a novel senescence trigger.

Id-1 is a key transcriptional regulator of glioblastoma aggressiveness and a novel therapeutic target.

Glioblastoma is the most common form of primary adult brain tumors. A majority of glioblastomas grow invasively into distant brain tissue, leading to tumor recurrence, which is ultimately incurable. It is, therefore, essential to discover master regulators that control glioblastoma invasiveness and target them therapeutically. We show here that the transcriptional regulator Id-1 plays a critical role in modulating the invasiveness of glioblastoma cell lines and primary glioblastoma cells. Id-1 expression levels positively correlate with glioma cell invasiveness in culture and with histopathologic grades in patient biopsies. Id-1 knockdown dramatically reduces glioblastoma cell invasion that is accompanied by profound morphologic changes and robust reduction in expression levels of "mesenchymal" markers, as well as inhibition of self-renewal potential and downregulation of glioma stem cell markers. Importantly, genetic knockdown of Id-1 leads to a significant increase in survival in an orthotopic model of human glioblastoma. Furthermore, we show that a nontoxic compound, cannabidiol, significantly downregulates Id-1 gene expression and associated glioma cell invasiveness and self-renewal. In addition, cannabidiol significantly inhibits the invasion of glioblastoma cells through an organotypic brain slice and glioma progression in vivo. Our results suggest that Id-1 regulates multiple tumor-promoting pathways in glioblastoma and that drugs targeting Id-1 represent a novel and promising strategy for improving the therapy and outcome of patients with glioblastoma.

O método de Rorschach como instrumento no estudo da terceira idade / The Rorschach method as an instrument for the study of the third age

Trata-se de um estudo do perfil psicológico da terceira idade hoje. O instrumento utilizado foi o Método de Rorschach e a amostra constou de 200 indivíduos, 100 residentes em seus lares e 100 radicados em abrigos e casas de repouso. Além de posiçäo vivencial, a criatividade e os mecanismos de adaptaçäo, no processo de envelhecimento psicológico, relatam-se as diferenças encontradas entre o grupo institucionalizado e aquele que permanece em seu lar

Perfil da terceira idade masculina pela técnica de Rorschach / Profile of the male third age, using Rorschach technique

A autora fez um estudo mediante a Técnica de Rorchach de 100 indivíduos do sexo masculino na fase da vida considerada como "terceira idade". Säo analisados o tipo de vivência ou posicionamento diante da vida, as possibilidades criativas, defesas, sinais de deterioraçäo e possíveis alteraçöes de identidade

Estudo de indivíduos com handicap físico, psicológico e cultural / Study of person with physical, psychological and cultural handicap

Foi analisada a influência da cultura no desenvolvimento da personalidade através do Método de Rorschach. Revisäo crítica de algumas pesquisas a esse respeito mostram que tal fator näo é o mais importante para o equilíbrio da personalidade. Culturas diferentes säo muito mais atuantes que um nível mais ou menos elevado de cultrura. Levanta-se a hipótese de que o handicap psicológico e as carências afetivas podem ser os fatores mais destrutivos dentre todos os tipos de carência

Questöes teóricas e metodológicas da técnica de Rorschach: problemas concernentes a aplicabilidade transcultural de dados normativos / Theoretical and methodological questions about Rorschach's technique: problemas related to the transcultural applicability of standard data

A autora defende o mesmo ponta de vista por ela levantado em estudos e pesquisas anteriores, relativo a necessidade de os psicólogos realizarem pesquisas com indivíduos de seus respectivos países para ter dados normativos a seu respeito. Nega a universidade desses dados, embora aceite que existem aspectos ontológicos, transcendentais e essenciais que säo comuns a generalidae dos homens. Ilustra sua opiniäo com dados referentes a suas pesquisas com criança, adolescentes, adultos e idosos

Perfil da terceira idade masculina pela Tecnica de Rorschach

A autora fez um estudo mediante a Tecnica de Rorschach de 100 individuos do sexo masculino na fase da vida considerada como 'terceira idade'. Sao analisados o tipo de vivencia ou posicionamento diante da vida, as possibilidades criativas, defesas, sinais de deterioracao, e possiveis alteracoes de identidade.

Estudo com individuos com handicap fisico, psicologico e cultural

Foi analisada a influencia da cultura no desenvolvimento da personalidade atraves do metodo de Rorschach. Revisa critica de algumas pesquisas a esse respeito monstram que tal fator nao e o mais importante para o equilibrio da personalidade. Culturas diferentes sao muito mais atuantes que um nivel mais ou menos elevado de cultura. Levanta-se a hipotese de que o handicap psicologico e as carencias afetivas podem ser os fatores mais destrutivos dentre todos os tipos de carencia.

O Metodo de Rorschach como instrumento no estudo da terceira idade

Trata-se de um estudo do perfil psicologico da terceira idade hoje. O instrumento utilizado foi o Metodo de Rosrchach e a amostra constou de 200 idividuos, 100 residentes em seus lares e 100 radicados em abrigos e casas de repouso. Alem de posicao vivencial, a criatividade e os mecanismos de adaptacao, no processo de envelhecimento psicologico, relatam-se as diferencas encontradas entre o grupo institucionalizado e aquele que permanece em seu lar.

Questoes teoricas e metodologicas da tecnicas de Rorschach-problemas concernentes a aplicabilidade transcultural de dados normativos

A autora defende o mesmo ponto de vista por ela levantando em estudos e pesquisas anteriores, relativo a necessidade de os psicologos realizarem pesquisas com individuos de seus respectivos paises para ter dados normativos a seu respeito. Nega a universalidade desses dados, embora aceite que existem aspectos ontologicos, transcendentais e essenciais que sao comuns a generalidade dos homens. Ilustra sua opiniao com dados referentes a suas pesqusas com criancas, adolescentes, adultos e idosos.

Rorschach: revision critica de los contenidos predictivos de homosexualidad / Rorschach: revision critica de los contenidos predictivos de homosexualidad

La autora leva al V Congreso de Rorschach y otras tecnicas projectivas sus inquietaciones cuanto a la validad de los contenidos relativos al diagnostico de homosexualidad. Ultimamente, personas sin cualquier alteracion de la libido y de su inversion en relacion con el objeto del instinto tambien proyectan ese tipo de contenidos. La actual permisividad social seria responsable por ese fenomeno? La autora se propone a realizar una pesquisa para mejor observar el tema en pauta y verificar la necessidad o no de revisar los conceptos relativos a esos contenidos.

La tecnica de Rorschach en la tercera edad / La tecnica de Rorschach en la tercera edad

La autora pretende verificar si la afirmacion levantada por Hermann Rorschach, en relacion a los cambios de resonancia intima en el transcurso de la vida, todavia es valida en lo que respecta a la tercera edad. Otros aspectos de esa fase de la vida tambien son estudiados: defensas en los procesos de envejecimiento psicologico; efectos del envejecimiento sobre la creatividad y, finalmente, posibles alteraciones de la identidad.