The dynamics of gene expression changes in a mouse model of oral tumorigenesis may help refine prevention and treatment strategies in patients with oral cancer.

A better understanding of the dynamics of molecular changes occurring during the early stages of oral tumorigenesis may help refine prevention and treatment strategies. We generated genome-wide expression profiles of microdissected normal mucosa, hyperplasia, dysplasia and tumors derived from the 4-NQO mouse model of oral tumorigenesis. Genes differentially expressed between tumor and normal mucosa defined the "tumor gene set" (TGS), including 4 non-overlapping gene subsets that characterize the dynamics of gene expression changes through different stages of disease progression. The majority of gene expression changes occurred early or progressively. The relevance of these mouse gene sets to human disease was tested in multiple datasets including the TCGA and the Genomics of Drug Sensitivity in Cancer project. The TGS was able to discriminate oral squamous cell carcinoma (OSCC) from normal oral mucosa in 3 independent datasets. The OSCC samples enriched in the mouse TGS displayed high frequency of CASP8 mutations, 11q13.3 amplifications and low frequency of PIK3CA mutations. Early changes observed in the 4-NQO model were associated with a trend toward a shorter oral cancer-free survival in patients with oral preneoplasia that was not seen in multivariate analysis. Progressive changes observed in the 4-NQO model were associated with an increased sensitivity to 4 different MEK inhibitors in a panel of 51 squamous cell carcinoma cell lines of the areodigestive tract. In conclusion, the dynamics of molecular changes in the 4-NQO model reveal that MEK inhibition may be relevant to prevention and treatment of a specific molecularly-defined subgroup of OSCC

Peto\u27s Paradox and the Evolution of Cancer Suppression

In order to successfully build and maintain a multicellular body, somatic cells must be constrained from proliferating uncontrollably and destroying the organism. If all mammalian cells were equally susceptible to oncogenic mutations and had identical tumor suppressor mechanisms, one would expect that the risk of cancer would be proportional to the body size and lifespan of a species. This is because a greater number of cells and cell divisions over a lifetime would increase the chance of accumulating mutations that result in malignant transformation. Peto’s paradox is the clash between the theory that cancer incidence should increase with body size and lifespan, and the observation that it does not. In this thesis, I present the first comprehensive survey of empirical evidence across mammals in support of Peto’s paradox in addition to computational models that explore the numerous hypotheses that may help resolve the paradox. I provide a detailed examination of tumor suppression in African elephants (Loxodonta africana) and show that the genome contains redundant copies of the tumor suppressor gene TP53. I give evidence that these redundant copies are actively transcribed and also observe an increased apoptotic response after exposure to ionizing radiation, which may be linked to the expression of these genes. Few genomes of large, long-lived organisms are currently available, which motivated my work to provide the sequence and de novo assembly of the humpback whale (Megaptera novaeangliae) genome. In this genome, I discovered a set of tumor suppressor genes that have evolved at an accelerated rate along the whale lineage, which is suggestive of adaptation. Additionally, I find one gene that has undergone convergent evolution between the African elephant and the humpback whale. The overarching goal of my research is to gain a better understanding of how evolution has suppressed cancer in large, long-lived organisms in the hopes of ultimately developing improved cancer prevention in humans

Evolutionary Action Score of TP53 Identifies High-Risk Mutations Associated with Decreased Survival and Increased Distant Metastases in Head and Neck Cancer

TP53 is the most frequently altered gene in head and neck squamous cell carcinoma, with mutations occurring in over two-thirds of cases, but the prognostic significance of these mutations remains elusive. In the current study, we evaluated a novel computational approach termed evolutionary action (EAp53) to stratify patients with tumors harboring TP53 mutations as high or low risk, and validated this system in both in vivo and in vitro models. Patients with high-risk TP53 mutations had the poorest survival outcomes and the shortest time to the development of distant metastases. Tumor cells expressing high-risk TP53 mutations were more invasive and tumorigenic and they exhibited a higher incidence of lung metastases. We also documented an association between the presence of high-risk mutations and decreased expression of TP53 target genes, highlighting key cellular pathways that are likely to be dysregulated by this subset of p53 mutations that confer particularly aggressive tumor behavior. Overall, our work validated EAp53 as a novel computational tool that may be useful in clinical prognosis of tumors harboring p53 mutations

About breaking barriers, the risk paradox, and other twists

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A systematic review of patient reported factors associated with uptake and completion of cardiovascular lifestyle behaviour change

Background: Healthy lifestyles are an important facet of cardiovascular risk management. Unfortunately many individuals fail to engage with lifestyle change programmes. There are many factors that patients report as influencing their decisions about initiating lifestyle change. This is challenging for health care professionals who may lack the skills and time to address a broad range of barriers to lifestyle behaviour. Guidance on which factors to focus on during lifestyle consultations may assist healthcare professionals to hone their skills and knowledge leading to more productive patient interactions with ultimately better uptake of lifestyle behaviour change support. The aim of our study was to clarify which influences reported by patients predict uptake and completion of formal lifestyle change programmes. Methods: A systematic narrative review of quantitative observational studies reporting factors (influences) associated with uptake and completion of lifestyle behaviour change programmes. Quantitative observational studies involving patients at high risk of cardiovascular events were identified through electronic searching and screened against pre-defined selection criteria. Factors were extracted and organised into an existing qualitative framework. Results: 374 factors were extracted from 32 studies. Factors most consistently associated with uptake of lifestyle change related to support from family and friends, transport and other costs, and beliefs about the causes of illness and lifestyle change. Depression and anxiety also appear to influence uptake as well as completion. Many factors show inconsistent patterns with respect to uptake and completion of lifestyle change programmes. Conclusion: There are a small number of factors that consistently appear to influence uptake and completion of cardiovascular lifestyle behaviour change. These factors could be considered during patient consultations to promote a tailored approach to decision making about the most suitable type and level lifestyle behaviour change support

Políticas lingüísticas y representaciones del español en certificaciones internacionales y en ofertas de enseñanza de español lengua extranjera (ELE)

El papel que actualmente ocupa el español en el ámbito internacional y el visible crecimiento que ha tenido su estudio propician su representación como una lengua codiciada por múltiples razones, un capital lingüístico que vale la pena obtener (Bourdieu, 1985).Este trabajo estudia las políticas y representaciones sobre el español en textos escritos tomados de páginas web vinculadas a exámenes internacionales de certificación de dominio de español lengua extranjera (ELE) y a ofertas de enseñanza de ELE en América Latina. Los textos recabados se trabajan en base a una tipología de representaciones que fue elaborada teniendo en cuenta determinados valores y atributos asignados habitualmente a las lenguas.</p

Experiencia con un módulo del entorno virtual de la asignatura informática básica

Se describe una experiencia desarrollada con el empleo del entorno virtual de enseñanza-aprendizaje, diseñado ad-hoc para la asignatura “Informática Básica” de la carrera Licenciatura en Ciencias de la Información de la Facultad de Humanidades (UNNE).   Se resumen las opciones disponibles en el entorno virtual y los resultados obtenidos al aplicar un módulo en las cohortes 2005 y 2006. Abstract This article describes an experience developed at “Informatica Básica” subject of  Licenciatura en Ciencias de la Información at Facultad de Humanidades (UNNE).  The paper summarizes the options available in the virtual environment and the results obtained by applying a module on the 2005 and 2006 cohorts

Aminoglycoside Susceptibility Profiles of Enterobacter cloacae Isolates Harboring the aac(6')-Ib Gene

The aminoglycoside 6'-N-acetyltransferases of type Ib (aac(6')-Ib) gene confers resistance to amikacin, tobramycin, kanamycin, and netilmicin but not gentamicin. However, some isolates harboring this gene show reduced susceptibility to amikacin. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommends a revision of the phenotypic description for isolates harboring the aac(6')-Ib gene. In this study, we determined the aminoglycoside susceptibility profiles of 58 AAC(6')-Ib-producing Enterobacter cloacae isolates. On the basis of the CLSI and EUCAST breakpoints, a large proportion (84.5% and 55.2%, respectively) of these 58 isolates were found to be susceptible to amikacin. However, among the isolates that were shown to be anikacin-susceptible according to the CLSI and EUCAST breakpoints, only 30.6% and 18.8% isolates, respectively, could be considered to have intermediate resistance on the basis of the EUCAST expert rules. Further studies should be conducted to determine the aminoglycoside susceptibility profiles of aac(6')-Ib-harboring isolates from various geographic regions and to monitor the therapeutic efficacy of amikacin in infections caused by these isolates