It is not all about the alpha:elevated expression of p53β variants is associated with lower probability of survival in a retrospective melanoma cohort

Background: Melanoma is the deadliest type of skin cancer and despite improvements in treatment outcomes, melanoma claimed 57,043 lives in 2020. In most malignancies, p53 mutation rates are above 50% and provide prognostic indications. However, in melanoma where less than a quarter of cases harbour a p53 mutation, the significance of the tumour suppressor may be questioned. Instead, p53 isoforms, which modulate p53's canonical function, may be of greater clinical importance.Methods: The expression of p53 isoforms was evaluated in 123 melanoma specimens by immunohistochemistry using p53 isoform-specific antibodies (DO-1, KJC8, KJC40, and KJC133). To determine whether TP53 mutations may be driving p53 isoform expression, TP53 was sequenced in 30 FFPE melanoma samples.Results: The C-terminally truncated p53β isoforms (KJC8) were found to be the most highly expressed p53 isoforms compared to all other isoforms. Further, elevated KJC8 staining was found to correlate with reduced probability of melanoma-specific survival, while KJC40 staining (Δ40p53) positively correlated with reduced melanoma thickness. TAp53 isoforms (p53 retaining both transactivation domains, DO-1), were the second highest p53 isoforms expressed across all samples. Elevated DO-1 staining was also associated with worse survival outcomes and more advanced stages of cancer. Given that the isoforms are likely to work in concert, composite isoform profiles were generated. Composite biomarker profiles revealed that elevated TAp53 (DO-1) and p53β (KJC8) expression, accompanied by low Δ40p53 (KJC40) and Δ133p53 (KJC133) expression was associated with the worst survival outcomes. Supporting the lack of predictive biomarker potential of TP53 in melanoma, no clinicopathological or p53 isoform expression associations could be linked to TP53 status.Conclusions: Given the lack of prognostic biomarker potential derived from TP53 status, this study highlights how p53 isoform expression might progress this field and, pending further validation, may provide additional information to treating oncologists that might be factored into treatment decisions.</p

CANNABIS SATIVA: A SYSTEMATIC REVIEW OF PLANT ANALYSIS

Background: Cannabis has been the most widely used illicit drug worldwide throughout many years. Reports from different countries indicate that the potency of cannabis preparation has been increasing, as well as the ratio of tetrahydrocannabinol/cannabidiol has been changing. The high consumption along with the changing chemical profile of the drug has led increasingly to the interest in researching the cannabis plant. Methods: This article reviews available literature on the analytical methods currently used for the detection and quantification of cannabinoids in cannabis plant. The papers were screened by two researchers independently and following a pre-specified protocol. Results and Discussion: The systematic review of the literature allowed to include 42 citations on cannabis plant analysis. Conclusions: The analytical methods for cannabis material published in the included articles of this systematic review showed a lack of relevant information of the development of methods on GC and LC analysis and the limits of detection and quantification of mass detectors

Cytoplasmic p53β Isoforms Are Associated with Worse Disease-Free Survival in Breast Cancer

TP53 mutations are associated with tumour progression, resistance to therapy and poor prognosis. However, in breast cancer, TP53′s overall mutation frequency is lower than expected (~25%), suggesting that other mechanisms may be responsible for the disruption of this critical tumour suppressor. p53 isoforms are known to enhance or disrupt p53 pathway activity in cell- and context-specific manners. Our previous study revealed that p53 isoform mRNA expression correlates with clinicopathological features and survival in breast cancer and may account for the dysregulation of the p53 pathway in the absence of TP53 mutations. Hence, in this study, the protein expression of p53 isoforms, transactivation domain p53 (TAp53), p53β, Δ40p53, Δ133p53 and Δ160p53 was analysed using immunohistochemistry in a cohort of invasive ductal carcinomas (n = 108). p53 isoforms presented distinct cellular localisation, with some isoforms being expressed in tumour cells and others in infiltrating immune cells. Moreover, high levels of p53β, most likely to be N-terminally truncated β variants, were significantly associated with worse disease-free survival, especially in tumours with wild-type TP53. To the best of our knowledge, this is the first study that analysed the endogenous protein levels of p53 isoforms in a breast cancer cohort. Our findings suggest that p53β may be a useful prognostic marker

Effect of p53 and its N-terminally truncated isoform, Δ40p53, on breast cancer migration and invasion

Breast cancer is the most diagnosed malignancy in women, with over half a million women dying from this disease each year. In our previous studies, ∆40p53, an N‐terminally truncated p53 isoform, was found to be upregulated in breast cancers, and a high ∆40p53 : p53α ratio was linked with worse disease‐free survival. Although p53α inhibits cancer migration and invasion, little is known about the role of ∆40p53 in regulating these metastasis‐related processes and its role in contributing to worse prognosis. The aim of this study was to assess the role of ∆40p53 in breast cancer migration and invasion. A relationship between Δ40p53 and gene expression profiles was identified in oestrogen‐receptor‐positive breast cancer specimens. To further evaluate the role of Δ40p53 in oestrogen‐receptor‐positive breast cancer, MCF‐7 and ZR75‐1 cell lines were transduced to knockdown p53α or Δ40p53 and overexpress Δ40p53. Proliferation, migration and invasion were assessed in the transduced sublines, and gene expression was assessed through RNA‐sequencing and validated by reverse‐transcription quantitative PCR. Knockdown of both p53α and ∆40p53 resulted in increased proliferation, whereas overexpression of ∆40p53 reduced proliferation rates. p53α knockdown was also associated with increased cell mobility. ∆40p53 overexpression reduced both migratory and invasive properties of the transduced cells. Phenotypic findings are supported by gene expression data, including differential expression of LRG1, HYOU1, UBE2QL1, SERPINA5 and PCDH7. Taken together, these results suggest that, at the basal level, ∆40p53 works similarly to p53α in suppressing cellular mobility and proliferation, although the role of Δ40p53 may be cell context‐specific

Alterations in the p53 isoform ratio govern breast cancer cell fate in response to DNA damage

Our previous studies have shown that p53 isoform expression is altered in breast cancer and related to prognosis. In particular, a high ∆40p53:p53α ratio is associated with worse disease-free survival. In this manuscript, the influence of altered Δ40p53 and p53α levels on the response to standard of care DNA-damaging agents used in breast cancer treatment was investigated in vitro. Our results revealed that a high Δ40p53:p53α ratio causes cells to respond differently to doxorubicin and cisplatin treatments. Δ40p53 overexpression significantly impairs the cells’ sensitivity to doxorubicin through reducing apoptosis and DNA damage, whereas Δ40p53 knockdown has the opposite effect. Further, a high Δ40p53:p53α ratio inhibited the differential expression of several genes following doxorubicin and promoted DNA repair, impairing the cells’ canonical response. Overall, our results suggest that the response of breast cancer cells to standard of care DNA-damaging therapies is dependent on the expression of p53 isoforms, which may contribute to outcomes in breast cancer

Do Haiti a São Miguel do Oeste: reflexões sobre o trajeto, chegada e inserção local de haitianos

Migrations are understood as phenomena that accompany the history of humanity. In view of the current scenario of migrations in Brazil, this study aimed to analyze, from life histories, the route, arrival and local insertion of Haitians residing in São Miguel do Oeste (SC). The research was attended by three Haitians living in this city. The methodology chosen was the life history and the data were analyzed from the content analysis. As a result, we identified that Haitians arrived in São Miguel do Oeste by hiring immigrants from local companies in Brazil or by the contact network among Haitians. The local insertion of Haitian immigrants is composed of positive and negative experiences, which are still in the process of being built.As migrações são compreendidas como fenômenos que acompanham a história da humanidade. Diante do cenário atual das migrações no Brasil, este estudo teve como objetivo analisar, a partir de histórias de vida, o trajeto, a chegada e a inserção local de haitianos residentes em São Miguel do Oeste (SC). A pesquisa contou com a participação de três haitianos residentes nesta cidade. A metodologia escolhida foi a história de vida e os dados foram analisados a partir da análise de conteúdo. Como resultados identificamos que os haitianos chegaram a São Miguel do Oeste pela contratação de imigrantes realizadas pelas empresas locais em Brasileira ou pela rede de contato entre os haitianos. A inserção local dos imigrantes haitianos é composta por experiências positivas e negativas, a qual ainda está em processo de construção

Genome of Herbaspirillum seropedicae Strain SmR1, a Specialized Diazotrophic Endophyte of Tropical Grasses

The molecular mechanisms of plant recognition, colonization, and nutrient exchange between diazotrophic endophytes and plants are scarcely known. Herbaspirillum seropedicae is an endophytic bacterium capable of colonizing intercellular spaces of grasses such as rice and sugar cane. The genome of H. seropedicae strain SmR1 was sequenced and annotated by The Paraná State Genome Programme—GENOPAR. The genome is composed of a circular chromosome of 5,513,887 bp and contains a total of 4,804 genes. The genome sequence revealed that H. seropedicae is a highly versatile microorganism with capacity to metabolize a wide range of carbon and nitrogen sources and with possession of four distinct terminal oxidases. The genome contains a multitude of protein secretion systems, including type I, type II, type III, type V, and type VI secretion systems, and type IV pili, suggesting a high potential to interact with host plants. H. seropedicae is able to synthesize indole acetic acid as reflected by the four IAA biosynthetic pathways present. A gene coding for ACC deaminase, which may be involved in modulating the associated plant ethylene-signaling pathway, is also present. Genes for hemagglutinins/hemolysins/adhesins were found and may play a role in plant cell surface adhesion. These features may endow H. seropedicae with the ability to establish an endophytic life-style in a large number of plant species

Good Cop, Bad Cop: Defining the Roles of Δ40p53 in Cancer and Aging

The tumour suppressor p53 is essential for maintaining DNA integrity, and plays a major role in cellular senescence and aging. Understanding the mechanisms that contribute to p53 dysfunction can uncover novel possibilities for improving cancer therapies and diagnosis, as well as cognitive decline associated with aging. In recent years, the complexity of p53 signalling has become increasingly apparent owing to the discovery of the p53 isoforms. These isoforms play important roles in regulating cell growth and turnover in response to different stressors, depending on the cellular context. In this review, we focus on &Delta;40p53, an N-terminally truncated p53 isoform. &Delta;40p53 can alter p53 target gene expression in both a positive and negative manner, modulating the biological outcome of p53 activation; it also functions independently of p53. Therefore, proper control of the &Delta;40p53: p53 ratio is essential for normal cell growth, aging, and responses to cancer therapy. Defining the contexts and the mechanisms by which &Delta;40p53 behaves as a &ldquo;good cop or bad cop&rdquo; is critical if we are to target this isoform therapeutically

A POSSIBILIDADE DE CONVERSÃO DA PRISÃO EM REGIME FECHADO EM PRISÃO DOMICILIAR DIANTE DA PANDEMIA DO CORONAVÍRUS

This article discusses the possibility for those who are serving a sentence in a closed regime to pass house arrest due to the coronavirus, from the perspective of the principle of human dignity. Given the current situation, in which the health crisis is forcing all Brazilian citizens to take restrictive measures to combat the proliferation of the covid-19 virus, the concern here is with those incarcerated, who are unable to afford the restrictions established by CNJ Resolution 62. The main objective refers to the need for knowledge by the population and greater debate in society, since there are positions (contrary and favorable) to the granting of such benefit, respecting the aforementioned principle. To develop the present work, it was carried out by means of bibliographic research, as for the methodological aspect, the research can be understood as qualitative. With historical-cultural explanation, as well as an analysis of the current prison reality, it is concluded through guaranteeing principles, that house arrest in due case has been shown to be effective for the purposes for which it is proposed and, thus, the rights are respected. fundamental rights of the human person. In addition, it is concluded that in addition to preventing covid-19 from entering the prison where prisoners are detained, the measure also prevents the disease from flowing backwards. Keywords: Human Rights. Coronavirus. Prison system.Este artículo analiza la posibilidad de que quienes cumplen una condena en un régimen cerrado pasen el arresto domiciliario debido al coronavirus, desde la perspectiva del principio de dignidad humana. Dada la situación actual, en la que la crisis de salud está obligando a todos los ciudadanos brasileños a tomar medidas restrictivas para combatir la proliferación del virus covid-19, la preocupación aquí es con los encarcelados, que no pueden permitirse el lujo de restricciones establecidas por la resolución 62 del CNJ. El objetivo principal se refiere a la necesidad de conocimiento por parte de la población y a un mayor debate en la sociedad, ya que existen posturas (contrarias y favorables) a la concesión de dicho beneficio, respetando el principio antes mencionado. Para desarrollar el presente trabajo, se realizó mediante investigación bibliográfica, en cuanto al aspecto metodológico, la investigación puede entenderse como cualitativa. Con una explicación histórico-cultural, así como un análisis sobre la realidad carcelaria actual, se concluye a través de principios de garantía, que el arresto domiciliario en su debido momento ha demostrado ser efectivo para los fines para los que se propone y, por lo tanto, se respetan los derechos. derechos fundamentales de la persona humana. Además, se concluye que, además de evitar que covid-19 ingrese a la prisión donde están detenidos, la medida también evita que la enfermedad fluya hacia atrás. Palabras clave: Derechos humanos. Coronavirus. Sistema penitenciario.Este artigo discorre sobre a possibilidade àqueles que se encontram cumprindo pena em regime fechado passar a prisão domiciliar devido ao coronavírus, sob a perspectiva do princípio da dignidade da pessoa humana. Dada a situação atual, em que a crise na saúde está forçando todos os cidadãos brasileiros a tomar medidas restritivas para combater a proliferação do vírus covid-19, a preocupação aqui, dá-se aqueles encarcerados, o qual não possuem possibilidade de arcar com as restrições estabelecidas pela Resolução nº 62 do CNJ. O objetivo principal refere-se à necessidade de conhecimento pela população e maior debate em sociedade, eis que há posicionamentos (contrários e favoráveis) à concessão de tal benefício, respeitando o princípio supracitado. Para desenvolver o presente trabalho, foi realizado por meio de pesquisa bibliográfica, quanto ao aspecto metodológico, a pesquisa pode ser entendida como qualitativa. Com explanação histórico-cultural, bem como análise acerca da realidade carcerária atual, conclui-se através de princípios garantidores, que a prisão domiciliar no devido caso tem se mostrado eficaz para os fins a que se propõe e, desse modo, resta respeitado os direitos fundamentais da pessoa humana. Ademais, conclui-se que além de se evitar que o covid-19 ingresse no estabelecimento prisional onde os encarcerados se encontram recolhidos, a medida também evita o fluxo contrário da doença. Palavras-chave: Direitos Humanos. Coronavírus. Sistema prisional

p53 Dysregulation in Breast Cancer: Insights on Mutations in the <i>TP53</i> Network and p53 Isoform Expression

In breast cancer, p53 expression levels are better predictors of outcome and chemotherapy response than TP53 mutation. Several molecular mechanisms that modulate p53 levels and functions, including p53 isoform expression, have been described, and may contribute to deregulated p53 activities and worse cancer outcomes. In this study, TP53 and regulators of the p53 pathway were sequenced by targeted next-generation sequencing in a cohort of 137 invasive ductal carcinomas and associations between the identified sequence variants, and p53 and p53 isoform expression were explored. The results demonstrate significant variability in levels of p53 isoform expression and TP53 variant types among tumours. We have shown that TP53 truncating and missense mutations modulate p53 levels. Further, intronic mutations, particularly polymorphisms in intron 4, which can affect the translation from the internal TP53 promoter, were associated with increased Δ133p53 levels. Differential expression of p53 and p53 isoforms was associated with the enrichment of sequence variants in p53 interactors BRCA1, PALB2, and CHEK2. Taken together, these results underpin the complexity of p53 and p53 isoform regulation. Furthermore, given the growing evidence associating dysregulated levels of p53 isoforms with cancer progression, certain TP53 sequence variants that show strong links to p53 isoform expression may advance the field of prognostic biomarker study in breast cancer