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

Interaction of immune complexes with glomerular heparan sulfate–proteoglycans

Interaction of immune complexes with glomerular heparan sulfate–proteoglycans. The binding characteristics of cationic and more neutral immune complexes with heparan sulfate–proteoglycan enriched anionic sites of glomerular basement membrane and mesangial matrix were studied. Rat kidneys were treated either with buffers alone or buffers containing heparitinase or chondroitinase-ABC followed by perfusion with cationic or native immune complexes. Tissues were processed for immunofluorescence and transmission electron microscopy after fixation with glutaraldehyde or tannic acid glutaraldehyde. Kidneys perfused with radioiodinated immune complexes were processed for light and electron microscopic autoradiography. In addition, glomeruli from kidneys perfused with radioiodinated immune complexes were isolated and counted for radioactivity. By immunofluorescence the cationic immune complexes deposited linearly along the glomerular basement membrane. By electron microscopy, the cationic complexes localized mainly in the inner and outer layers of the glomerular basement membrane and to a certain extent in the mesangial matrix in a distribution that corresponded to previously documented anionic sites. Whereas heparitinase treatment abrogated the binding of cationic immune complexes in both glomerular basement membrane and mesangial matrix, chondroitinase-ABC treatment did not cause any decrease in binding. In contrast, more neutral immune complexes appeared to be nonspecifically trapped in the mesangium, and their distribution was unaffected by both enzymatic treatments. Light and electron microscopic autoradiography and counts of isolated glomeruli confirmed these findings. The results overall indicate that cationic immune complexes bind electrostatically to the heparan sulfate–proteoglycan enriched anionic sites of the glomerular basement membrane and mesangial matrix, while more neutral immune complexes are nonspecifically trapped in the mesangium of the renal glomerulus

About breaking barriers, the risk paradox, and other twists

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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

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

Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans

Importance: Evolutionary medicine may provide insights into human physiology and pathophysiology, including tumor biology. Objective: To identify mechanisms for cancer resistance in elephants and compare cellular response to DNA damage among elephants, healthy human controls, and cancer-prone patients with Li-Fraumeni syndrome (LFS). Design, Setting, and Participants: A comprehensive survey of necropsy data was performed across 36 mammalian species to validate cancer resistance in large and long-lived organisms, including elephants (n = 644). The African and Asian elephant genomes were analyzed for potential mechanisms of cancer resistance. Peripheral blood lymphocytes from elephants, healthy human controls, and patients with LFS were tested in vitro in the laboratory for DNA damage response. The study included African and Asian elephants (n = 8), patients with LFS (n = 10), and age-matched human controls (n = 11). Human samples were collected at the University of Utah between June 2014 and July 2015. Exposures: Ionizing radiation and doxorubicin. Main Outcomes and Measures: Cancer mortality across species was calculated and compared by body size and life span. The elephant genome was investigated for alterations in cancer-related genes. DNA repair and apoptosis were compared in elephant vs human peripheral blood lymphocytes. Results: Across mammals, cancer mortality did not increase with body size and/or maximum life span (eg, for rock hyrax, 1% [95% CI, 0%-5%]; African wild dog, 8% [95% CI, 0%-16%]; lion, 2% [95% CI, 0%-7%]). Despite their large body size and long life span, elephants remain cancer resistant, with an estimated cancer mortality of 4.81% (95% CI, 3.14%-6.49%), compared with humans, who have 11% to 25% cancer mortality. While humans have 1 copy (2 alleles) of TP53, African elephants have at least 20 copies (40 alleles), including 19 retrogenes (38 alleles) with evidence of transcriptional activity measured by reverse transcription polymerase chain reaction. In response to DNA damage, elephant lymphocytes underwent p53-mediated apoptosis at higher rates than human lymphocytes proportional to TP53 status (ionizing radiation exposure: patients with LFS, 2.71% [95% CI, 1.93%-3.48%] vs human controls, 7.17% [95% CI, 5.91%-8.44%] vs elephants, 14.64% [95% CI, 10.91%-18.37%]; P \u3c .001; doxorubicin exposure: human controls, 8.10% [95% CI, 6.55%-9.66%] vs elephants, 24.77% [95% CI, 23.0%-26.53%]; P \u3c .001). Conclusions and Relevance: Compared with other mammalian species, elephants appeared to have a lower-than-expected rate of cancer, potentially related to multiple copies of TP53. Compared with human cells, elephant cells demonstrated increased apoptotic response following DNA damage. These findings, if replicated, could represent an evolutionary-based approach for understanding mechanisms related to cancer suppression