PRAJA is overexpressed in glioblastoma and contributes to neural precursor development

PRAJA, a RING-H2 E3 ligase, is abundantly expressed in brain tissues such as the cerebellum and frontal cortex, amongst others, and more specifically in neural progenitor cells as well as in multiple cancers that include glioblastomas. However, the specific role that Praja plays in neural development and gliomas remains unclear. In this investigation, we performed bioinformatic analyses to examine Praja1 and Praja2 expression across 29 cancer types, and observed raised levels of Praja1 and Praja2 in gliomas with an inverse relationship between Praja1 and apoptotic genes and Praja substrates such as Smad3. We analyzed the role of Praja in the developing brain through loss of function studies, using morpholinos targeting Praja1 in embryonic zebrafish, and observed that Praja1 is expressed prominently in regions enriched with neural precursor cell subtypes. Antisense Praja morpholinos resulted in multiple embryonic defects including delayed neural development likely through increased apoptosis. Further studies revealed high levels of Cdk1 with loss of Praja1 in TGF-β or insulin treated cells, supporting the link between Praja1 and cell cycle regulation. In summary, these studies underscore Praja\u27s role in mammalian brain development and Praja1 deregulation may lead to gliomas possibly through the regulation of cell cycle and/or apoptosis

Alcohol, Stem Cells and Cancer.

Dosage, gender, and genetic susceptibility to the effects of alcohol remained only partially elucidated. In this review, we summarize the current knowledge of the mechanisms underlying the role of alcohol in liver and gastrointestinal cancers. In addition, two recent pathways- DNA repair and TGF-β signaling which provide new insights into alcohol in the regulation of cancers and stem cells are also discussed here

Salt consumption awareness in Portugal: comparison between the ECOS surveys of 2014 and 2018

O consumo excessivo de sal aumenta o risco de doenças crónicas, pelo que a sensibilização da população é uma medida recomendada pela Organização Mundial de Saúde (OMS) e pela Direção-Geral da Saúde (DGS) para a diminuição do seu consumo. O objetivo deste estudo foi estimar a prevalência relativa à preocupação com o consumo de sal, em 2014 e 2018 em Portugal, avaliar a sua evolução e caracterizar o perfil sociodemográfico dos participantes que manifestaram preocupação com o consumo de sal nos dois anos em análise. Os dados foram recolhidos no âmbito do inquérito telefónico ECOS (Em Casa Observamos Saúde) para esses anos. Em 2014, 77% dos inquiridos referiram ter preocupação quanto ao consumo de sal face a 75% em 2018. Em ambos os anos, as mulheres revelaram uma maior preocupação quanto ao consumo de sal, comparativamente ao sexo masculino, embora essa diferença fosse mais evidente em 2014. Adicionalmente, verificou-se que a preocupação com o consumo de sal aumenta com a idade, sendo o grupo etário com mais de 65 anos o que registou uma maior preocupação relativamente ao consumo do sal, nos dois anos em análise. Não se observaram diferenças estatisticamente significativas entre os níveis de escolaridade ou as regiões.Excessive salt consumption increases the risk of chronic diseases. Thus raising awareness is a measure to reduce its consumption, recommended by the World Health Organization (WHO) and the Portuguese Directorate General of Health. The aim of this study was to estimate the prevalence of individuals who reported awareness regarding their salt consumption in 2014 and 2018, and to investigate its distribution among several sociodemographic characteristics. Data was collected by means of a national representative panel telephonic survey, ECOS. In 2014, 77% of respondents reported watching or reducing salt consumption, compared to 75% in 2018, but this difference between years was not significant. In both years, women were more aware of salt intake than men, although this difference was more significant in 2014. Additionally, awareness regarding salt consumption increased with age, with the age group over 65 years old being the most aware, in the two years under analysis. No statistically significant differences were found among the different educational level groups, or regions.info:eu-repo/semantics/publishedVersio

Precision Medicine for CRC Patients in the Veteran Population: State-of-the-Art, Challenges and Research Directions.

Colorectal cancer (CRC) accounts for ~9% of all cancers in the Veteran population, a fact which has focused a great deal of the attention of the VA\u27s research and development efforts. A field-based meeting of CRC experts was convened to discuss both challenges and opportunities in precision medicine for CRC. This group, designated as the VA Colorectal Cancer Cell-genomics Consortium (VA4C), discussed advances in CRC biology, biomarkers, and imaging for early detection and prevention. There was also a discussion of precision treatment involving fluorescence-guided surgery, targeted chemotherapies and immunotherapies, and personalized cancer treatment approaches. The overarching goal was to identify modalities that might ultimately lead to personalized cancer diagnosis and treatment. This review summarizes the findings of this VA field-based meeting, in which much of the current knowledge on CRC prescreening and treatment was discussed. It was concluded that there is a need and an opportunity to identify new targets for both the prevention of CRC and the development of effective therapies for advanced disease. Also, developing methods integrating genomic testing with tumoroid-based clinical drug response might lead to more accurate diagnosis and prognostication and more effective personalized treatment of CRC

A Pan-cancer analysis reveals high-frequency genetic alterations in mediators of signaling by the tgf-β superfamily

We present an integromic analysis of gene alterations that modulate transforming growth factor β (TGF-β)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA). Focusing on genes that encode mediators and regulators of TGF-β signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers. We identified mutation hotspots in genes that encode TGF-β ligands (BMP5), receptors (TGFBR2, AVCR2A, and BMPR2), and Smads (SMAD2 and SMAD4). Alterations in the TGF-β superfamily correlated positively with expression of metastasis-associated genes and with decreased survival. Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-β signaling in each cancer type. This study provides a broad molecular perspective relevant for future functional and therapeutic studies of the diverse cancer pathways mediated by the TGF-β superfamily

Vav3 Potentiation of Androgen Receptor Activity in Prostate Cancer

Most patients undergoing androgen deprivation therapy relapse eventually and progress to androgen-independent (AI) prostate cancer. Although the mechanisms underlying progression to AI prostate cancer are not well understood, studies suggest that androgen receptor (AR) is still required for AI prostate cancer. Our lab found that Vav3, a Rho GTPase guanine nucleotide exchange factor (GEF), is up-regulated during the progression of androgen-dependent human prostate cancer cells to androgen-independence in vivo and in cell-based experiments. Since Vav3 significantly increases ligand-dependent AR transcriptional activity and this action requires the Vav3 pleckstrin homology (PH) domain but not Vav3 GEF activity, we explored the role of the Vav3 PH domain in ligand-dependent AR coactivation by Vav3. We found that targeting the Vav3 PH mutant into nuclei but not the plasma membrane restored Vav3 PH mutant in AR coactivation. Targeting Vav3 to the plasma membrane eliminated the capacity of Vav3 to coactivate AR. In agreement with nuclear targeting of Vav3 via its PH domain, chromatin immunoprecipitation assays showed that Vav3 enhancement of AR transcriptional activity was accompanied by Vav3 recruitment to AR transcriptional complexes at an AR target gene enhancer. Further, Vav3 increased AR occupancy at the target gene enhancer upon androgen treatment and this may underlie the capacity of Vav3 to enhance AR transcriptional activity. Because Vav3 can also be activated by growth factors (GFs) and GFs activate AR in the absence of androgen (ligand-independent), we investigated the crosstalk between Vav3 and GF activation of AR and found Vav3 strongly enhanced AR transcriptional activity induced by GFs. GEF function and the downstream Rho GTPase, Rac1 were required for constitutively active (Ca) Vav3 activation of AR, which differs from Vav3 activation of AR in the presence of androgen. We also investigated the possible signal pathways contributing to AR activation by Ca Rac1. Ca Rac1 caused ligand-independent activation of AR in part through MAPK/ERK signaling and conferred prostate cancer growth in the absence of androgen in cell culture, soft agar and mouse tumor xenografts. Thus, our findings indicate that Vav3 activates AR in the presence or absence of ligand through two distinct mechanisms, which supports a versatile regulatory effect of Vav3 in AR signaling and prostate cancer progression