p73 as a Pharmaceutical Target for Cancer Therapy

About half of all human tumors contain an inactivating mutation of p53, while in the remaining tumors, the p53 pathway is frequently abrogated by alterations of other components of its signaling pathway. In humans, the p53 tumor suppressor is part of a small gene family that includes two other members, p73 and p63, structurally and functionally related to p53. Accumulating evidences indicate that all p53-family proteins function as molecular hubs of a highly interconnected signaling network that coordinates cell proliferation, differentiation and death in response to physiological inputs and oncogenic stress. Therefore, not only the p53-pathway but the entire “p53-family pathway” is a primary target for cancer drug development. In particular, the p53-related protein p73 has a crucial role in determining cellular responses to chemotherapy, and can vicariate p53 functions in triggering cell death after DNA damage in multiple experimental models. The biology and regulation of p73 is complex, since the TP73 gene incorporates both tumor-suppressive and proto-oncogenic functions. However, the p73 gene is rarely mutated in tumors, so appropriate pharmacological manipulation of the p73 pathway is a very promising approach for cancer therapy. Here we provide an overview of the principal mechanism of p73 regulation, and describe several examples of pharmacological tools that can induce p73 accumulation and function by acting on upstream p73 modulators or displacing inhibitory p73 interactors. A better understanding of how the p73 pathway works is mandatory to discover additional players intervening in this pathway and has important implications for the improvement of cancer treatment with the development of new molecules or with the reposition of currently available drugs

Shattered Dreams of Anti-Fascist Unity: German Speaking Exiles in Mexico, Argentina and Bolivia, 1937-1945

Between the late 1930s and early 1940s Mexico City and Buenos Aires became the centres of activity for the two most relevant anti-fascist organisations of German-speaking exiles in Latin America: the communist-inspired Free German Movement (Bewegung Freies Deutschland;BFD) and the social-democratic oriented The Other Germany (Das Andere Deutschland;DAD). Both organisations envisaged the creation of an anti-fascist front within Latin America, one which would allow for greater unity of action, and thus carried out extensive congresses at Mexico City and Montevideo in 1943. Due to crucial ideological and tactical differences, this dream of anti-fascist unity led to a power struggle between BFD and DAD, well illustrated in the impact it had on Bolivia. This article seeks a new perspective on how, thanks to the establishment of transnational networks, a continental debate on the meaning and methods of anti-fascism then took place, while also shedding light on the influence the Latin American context had in shaping the exiles' plans for a new Germany

Pin1 and WWP2 regulate GluR2 Q/R site RNA editing by ADAR2 with opposing effects

While the essential role of the adenosine deaminase ADAR2 in RNA editing is well established, how it is regulated remains largely unknown. Here, the prolyl isomerase Pin1 and the E3 ubiquitin ligase WWP2 are shown to play a role in regulating ADAR2 localisation and stability

Genetic signatures of parental contribution in black and white populations in Brazil

Two hundred and three individuals classified as white were tested for 11 single nucleotide polymorphisms plus two insertion/deletions in their Y-chromosomes. A subset of these individuals (n = 172) was also screened for sequences in the first hypervariable segment of their mitochondrial DNA (mtDNA). In addition, complementary studies were done for 11 of the 13 markers indicated above in 54 of 107 black subjects previously investigated in this southern Brazilian population. The prevalence of Y-chromosome haplogroups among whites was similar to that found in the Azores (Portugal) or Spain, but not to that of other European countries. About half of the European or African mtDNA haplogroups of these individuals were related to their places of origin, but not their Amerindian counterparts. Persons classified in these two categories of skin color and related morphological traits showed distinct genomic ancestries through the country. These findings emphasize the need to consider in Brazil, despite some general trends, a notable heterogeneity in the pattern of admixture dynamics within and between populations/groups

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

New microRNAs regulating the p53 pathway

2008/2009A vast body of evidence from clinical and basic research studies has demonstrated that the p53 pathway acts as an essential barrier in preventing cancer onset and development. ------------------------ A vast body of evidence from clinical and basic research studies has demonstrated that the p53 pathway acts as an essential barrier in preventing cancer onset and development. p53 receives and integrates a wide variety of cytotoxic and genotoxic stress signals from upstream sensors translating them into different cellular outcomes, ranging from apoptosis, cell cycle arrest, se-nescence, DNA repair or other tumor-suppressive responses. p53 exerts its role mainly at the transcriptional level and its timely activation/inactivation in response to stress depends on a complex repertoire of post-translational modifications and interactions with proteins. The crucial role of the p53 pathway in tumor suppression is highlighted by the fact that almost all tumors select for its functional inactivation, either by directly mutating the p53 gene or by altering the expression and functions of key p53 regulators and effectors. Therefore, identification of cellular factors that modulate this pathway and that could be altered in cancer cells, thus allowing to eva-de p53 control, is crucial for understanding cancer development and for designing novel effecti-ve therapeutic approaches. In this context, the aberrant expression or function of microRNAs (miRNAs) might be highly relevant. microRNAs are small non coding RNAs that finely regulate gene expression by binding the 3’UTR of their target mRNAs, thus altering their translation, stability and localization. It has been shown that several miRNAs modulate critical cellular processes deregulated in cancer, ac-ting either as oncogenes or tumor suppressors. On this basis, the aim of this thesis has been the identification and characterization of novel miRNAs able to modulate p53 functions by altering either upstream regulators (i.e. stress-activated kinases) or cofactors of p53. With this purpose we initially selected a panel of twenty-one candidate oncogenic miRNAs from the literature. First, we tested these miRNAs in a functional screening for their ability to modula-te p53-dependent functions in response to cisplatin (apoptosis) and nutlin-3 (cell cycle arrest). Second, miRNAs were also screened for their ability to impair p53 transcriptional activity through a reporter-based assay. We identified five candidate miRNAs from the first approach, and three from the second. miR-26a was identified through both approaches, suggesting that it might repersent a critical modulator of p53 functions. We demonstrated that miR-26a overe-xpression is able to dampen p53 transcriptional activity towards several p53 target promoters (Bax, Pig3 and p21). Moreover, we have shown that miR-26a strongly reduces p53-dependent apoptosis upon DNA damage in different cell lines, to a similar extent as obtained by RNAi-mediated p53 knock-down. At the molecular level, we observed that miR-26a impairs p53 activation by targeting multiple stress-activated kinases that phosphorylate p53, such as ATM, HIPK2 and PKCδ. Accordingly, miR-26a reduces p53 phosphorylation on Ser15 and Ser46 upon DNA damage. As a consequen-ce, miR-26a overexpression allows cells to proliferate in the presence of oncogenic stress, bypassing the induction of senescence (OIS) driven by RASV12 oncogene similar to what obtai-ned by knockdown of either p53 or its activationg kinase ATM. Considering our data and the reports describing miR-26a overexpression in several tumors (e.g. glioblastomas), we speculate that aberrant expression of miR-26a might represent an oncogenic process by preventing activation of the p53 pathway and thus relieving a primary barrier against transformation. For all these reasons, the perspective to block miR-26a expression/functions could represent a new important way to tackle tumors.XXI Ciclo198

Student Perceptions of the Role of Portfolios in Evaluating the Outcomes of Pharmacy Education

Class of 2011 AbstractOBJECTIVES: The Accreditation Council for Pharmacy Education recommends incorporation of portfolios as part of the pharmacy curriculum. A study was conducted to evaluate students’ perceived benefits of the portfolio process and to gather suggestions for improving the process. METHODS: A questionnaire was designed, administered, and answered by 250 pharmacy first, second, and third year pharmacy students at the University of Arizona College of Pharmacy. The dependent variable was the students’ perceived benefit of the portfolio process. RESULTS: Students perceived increased benefit if the portfolio helped them: gain an understanding of the expected outcomes, understand the impact of extracurricular activities on attaining competencies, identify what should be learned, identify their strengths and weaknesses, and modify their approach to learning. First year students wanted more examples of portfolios while second and third years suggested more time with their advisor. CONCLUSION: Overall, students perceived the portfolio process as having moderate benefit.This item is part of the Pharmacy Student Research Projects collection, made available by the College of Pharmacy and the University Libraries at the University of Arizona. For more information about items in this collection, please contact Jennifer Martin, Librarian and Clinical Instructor, Pharmacy Practice and Science, [email protected]