El bullying: una mirada desde los niños y las niñas / Bullying: A scope from boys and girls / Bullying: Um olhar de meninos e meninas

(analítico) Se presentan los resultados sobre cómo se comprende y se asume el bullying, en tanto problema escolar y social, desde la perspectiva infantil. Para ello, se realizó una investigación cualitativa, hermenéutico-comprensiva, con grupos focales mediados por títeres o videos, producción gráfica y narración de historias. Los participantes fueron 626 estudiantes de 5 a 7 años. La comprensión transitó por elementos congruentes con la teoría, como exclusión, acoso verbal, afectación de pertenencias y una nueva tipología: falta de solidaridad. En cuanto a las experiencias, precisan las burlas, el acoso físico y el hurto, asociadas al contexto familiar o a ninguna, estas últimas por la confluencia del espacio escolar y la familia en un mismo lugar en tiempos de educación remota. En cuanto a la solución, está apela a figuras de autoridad, familiares, asumir actitudes reconciliadoras o al juego.

(analytical) The paper presents the results on how bullying, as scholar and social problem, is understood and assumed from the child's perspective. Therefore, a qualitative, hermeneutic-comprehensive research was carried out and focus groups were done by means of moppets and videos, graphic production, and storytelling. The participants were 626 students from 5 to 7 years old. The understanding went through elements consistent with the theory, such as exclusion, verbal harassment, affectation of be-longings and a new typology, lack of solidarity. Regarding the experiences, they specify teasing, physical harassment, theft, associated with the family context or none, the latter due to the confluence of the school space and the family in the same place in times of remote education. As for the solution, it is appealing to authority figures, relatives, assuming reconciliatory attitudes and playing.

(analítico) O artigo apresenta os resultados sobre como o bullying, como um problema social e escolar, é compreendido e assumido na perspectiva da criança. Para isso, realizou-se uma investigação qualitativa, hermenêutica-compreensiva e grupos focais mediados por fantoches ou vídeos, produção gráfica e contação de histórias; os participantes foram 626 alunos de 5 a 7 anos. O entendimento passou por elementos condizentes com a teoria, como exclusão, assédio verbal, afetação de pertences e uma nova tipologia, falta de solidariedade. Quanto às vivências, especificam provocações, assédios físicos, furtos, associados ao contexto familiar ou nenhum, este último devido à confluência do espaço escolar e da família no mesmo local em tempos de educação a distância. Quanto à solução, é apelar a figuras de autoridade, familiares, assumindo atitudes de conciliação e brincadeiras.

Afianzamiento de las habilidades argumentativas de jóvenes universitarios noveles en Envigado

(analítico) Este artículo presenta los resultados de una investigación postdoctoral cuyo objetivo fue afianzar las habilidades argumentativas de jóvenes universitarios del primer semestre de una facultad en Envigado (Colombia), dados los bajos niveles identificados en semestres anteriores. Para ello, se realizó una investigación cualitativa, hermenéutico-comprensiva, apoyada en herramientas de estadística descriptiva. Se hicieron pruebas de entrada y salida a los participantes. Se diseñaron seis talleres a partir de los resultados de la prueba de entrada. Cada taller requería de un entregable. La intervención se realizó bajo el marco de la lingüística textual, el análisis crítico del discurso y la argumentación pragmadialéctica. Aquellos que participaron activamente en los talleres propuestos afianzaron sus habilidades argumentativas considerablemente y, según las participantes entrevistadas, reconocen su utilidad en tareas académicas y en la participación ciudadana.

(analytical) This paper presents the results of a postdoctoral research whose objective was to strengthen young university firstyear students' argumentative skills in a school in Envigado (Colombia), because of the low levels identified in prior semesters. Therefore, qualitative hermeneutics-comprehensive research supported in descriptive statistics was done. Entry and exit tests to participants were carried out. 6 workshops were designed based on the entry test results. Each workshop required a class product. Intervention was proposed from text linguistic, critical discourse analysis and pragma-dialectic argumentation. Those students who participated actively in the workshops significantly strengthened their argumentative skills and, as some interviewees mentioned, they recognized these skills use in academic tasks and citizenship participation.

(analítico) Este artigo apresenta os resultados de uma pesquisa de pósdoutorado cujo objetivo foi fortalecer as habilidades argumentativas de jovens universitários do primeiro semestre de uma faculdade de Envigado (Colombia), dados os baixos níveis identificados nos semestres anteriores. Para isso, foi realizada uma pesquisa qualitativa, hermenêutica-abrangente, apoiada em ferramentas estatísticas descritivas. Os participantes foram testados para entrada e saída. 6 workshops foram concebidos com base nos resultados do teste de admissão. Cada workshop exigia uma entrega. A intervenção foi realizada no quadro da linguística textual, da análise crítica do discurso e da argumentação pragmadialética. Aqueles que participaram ativamente das oficinas propostas fortaleceram consideravelmente suas habilidades argumentativas e, segundo os entrevistados, reconhecem sua utilidade nas tarefas acadêmicas e na participação cidadã.

Revisión de las tendencias teóricas e investigativas en el campo de la Psicología de la Actividad Física y del Deporte en Iberoamérica / Review of theoretical and research trends in the field of Psychology of Physical Activity and Sports in Ibero-American

Resumen Introducción: Las tendencias teóricas e investigativas refieren propuestas y contemplaciones de los fenómenos sociales que se desarrollan en el campo de la psicología de la actividad física y del deporte, las cuales permiten tener otras perspectivas y formas de interactuar en el contexto. Objetivo: Revisión de las tendencias teóricas e investigativas en el campo de la Psicología de la Actividad Física y del Deporte en Iberoamérica. Método: La investigación fue cualitativa, hermenéutico-comprensiva. La unidad de análisis se conformó de 20 artículos de revistas iberoamericanas indexadas en Scopus en los años 2016 y 2017. Su selección se hizo a partir de los descriptores Deporte y Actividad Física. La búsqueda se realizó en el título, el resumen y las palabras clave. Para su análisis, se empleó una rúbrica, la cual permitió sistematizar la información bibliométrica del artículo, sus autores y textos citados y las palabras clave. Resultados: Se identificaron los puntos de encuentro y las apuestas teóricas presentes en dichos artículos, agrupadas en trece categorías. Conclusiones: Resulta significativa la presencia de categorías generales de la psicología como motivación, relacionamiento, habilidades para la vida e intereses de intervención dentro de aspectos tan disciplinarios como la Actividad Física y la Psicología del Deporte.

Abstract Introduction: Theoretical and investigative tendencies refer to proposals and contemplations of the social phenomena that are developed in the field of psychology of physical activity and sport, which allow to have other perspectives and ways of interacting in the context. Objective: Review of theoretical and research trends in the field of Psychology of Physical Activity and Sports in Ibero-American. Method: The research was qualitative, hermeneutic-comprehensive. The analysis unit consisted of 20 articles of Ibero-American journals indexed in Scopus in 2016 and 2017. Their selection was made from two descriptors Sport and Physical Activity. The search was carried out in the title, the summary and the keywords. For its analysis, a rubric was used, which allowed systematizing the bibliometric information of the article, its authors and cited texts and the keywords. Results: The agreement points and theoretical bets present in these articles were identified, grouped into thirteen categories. Conclusions: It is significant the presence of general categories of psychology such as motivation, relationship, life skills and intervention interests in such disciplinary aspects as Physical Activity and Sports Psychology.

Estrategias pedagógicas de literacidad: experiencia significativa en una Institución Educativa de Boyacá / Literacy pedagogical strategies: A meaningful experience in a Boyacá´s School (Colombia) / Estratégias pedagógicas de alfabetização: experiência significativa em uma Instituição de Ensino de Boyacá

Resumen (analítico): Este artículo presenta los resultados obtenidos en una investigación acción educativa de tipo cualitativo, realizada en una Institución Educativa Técnica rural en un municipio de Boyacá (Colombia), donde se realizó una intervención a partir de estrategias pedagógicas para fortalecer los niveles de literacidad, teniendo en cuenta el aprendizaje significativo en su diseño dado al bajo nivel de dichos estudiantes. El soporte teórico de la investigación fue la literacidad como desarrollo de competencias en comprensión y producción escritural en contexto. La unidad de análisis fue observación directa a 6 participantes, sus respectivas pruebas de entrada y salida y 5 talleres pedagógicos. Con los resultados logrados en la investigación se evidencian avances en la mayoría de las variables evaluadas; sin embargo, al valorar los resultados finales, algunos alumnos aún presentan dificultades.

Abstract (analytical): This paper shows the results obtained in a qualitative, educative action research carried out in a rural Technical Educational Institution in Boyacá Department (Colombia), where an intervention was made from pedagogical strategies to strengthen literacy levels, taking into account students´ meaningful learning in their design due to its students´ low level. The theoretical support of the research was literacy as the development of competences in comprehension and written production in context. The analysis unit was a direct observation to 6 participants, their entry and exit tests and 5 pedagogical workshops. With the results obtained in the research, progress is evidenced in most of the evaluated variables; however, some students still presenting difficulties when the final results are assessed.

Resumo (analítico): Este artigo apresenta os resultados obtidos em uma pesquisa de ação educativa do tipo qualitativa realizada em uma Instituição de Ensino Técnico rural em um município de Boyáca (Colômbia), onde foi feita uma intervenção a partir de estratégias pedagógicas para fortalecer os níveis de alfabetização, levando em consideração o aprendizado significativo em sua desenho dado o baixo nível de tais alunos. O suporte teórico da pesquisa foi a alfabetização como o desenvolvimento de competências em compreensão e produção de escrituras em contexto. A unidade de análise foi observação direta para 6 participantes, seus respectivos testes de entrada e saída e 5 workshops pedagógicas. Com os resultados obtidos na pesquisa, evidencia-se progresso na maioria das variáveis avaliadas; no entanto, ao avaliar os resultados finais, alguns alunos ainda têm dificuldades.

An agent-based model of the fission yeast cell cycle.

The objective of this paper is to develop a computational model of the fission yeast (Schizosaccharomyces pombe) cell cycle using agent-based modeling (ABM), to study the sequence of states of the proteins and time of the cell cycle phases, under the action of proteins that regulate its cell cycle. The model relies only on the conceptual model of the yeast cell cycle regulatory network, where each protein has been represented as an agent with a property called activity that represents its biological function and a stochastic Brownian movement. The results indicate that the simulated phase time did have similar results in comparison with other models using mathematical approaches. Similarly, the correct sequence of states was achieved, and the model was run under different initial states to understand its emergent behaviors. The cell reached the G1 stationary state 94% of the times when running the model under biological initial conditions and 87% of the times when running the model through all the different combinations of initial states. Such results imply that the cell was capable to fix toward the biological expected phenomena. These results show that ABM is a suitable technique to study protein-protein interactions without using, often unavailable, kinetic parameters, or differential equations. This model sets as a base for further studies that involve the cell cycle of the fission yeast, with a special attention to studies and development of drug treatments for specific types of cancer.

Niveles de literacidad en jóvenes universitarios: entrevistas cualitativas y análisis sociolingüístico / Literacy levels in University Students: Qualitative Interviews and Sociolinguistic Analysis / Níveis de literacidade em jovens universitários: entrevistas qualitativas e análise sociolinguística

Resumen (descriptivo): Se presentan algunos hallazgos emanados de la investigación denominada "Análisis sociolingüístico de los niveles de literacidad en jóvenes de la Institución Universitaria de Envigado", realizada por uno de los autores, para optar al título de "Doctor en Ciencias Sociales, Niñez y Juventud" de la Universidad de Manizales-Cinde. Pretende ser una contribución en una doble dirección. Por una parte, denunciar que es común que los jóvenes comiencen sus estudios universitarios con unos niveles de literacidad extremadamente bajos, lo que exige unos esfuerzos especializados en el proceso de enseñanza/aprendizaje de esta población. Por otra, aportar a los aspectos metodológicos, al examinar las posibilidades que ofrece el análisis sociolingüístico de las entrevistas en la investigación empírica. El diseño de la investigación incluyó una intervención académica realizada a una muestra experimental compuesta por 21 estudiantes que ingresaban a la universidad a los cuales se les pidió que diligenciaran una encuesta elemental de perfil sociocultural. Esto se complementó con 5 entrevistas cualitativas. Se concluye que el contexto biográfico desde la infancia y las instituciones involucradas como la familia y la escuela son preponderantes en la adquisición de las competencias en comprensión lectora, producción escritural y apropiación discursiva.

Abstract (descriptive): Findings from a research study on sociolinguistic analysis of the literacy levels of students from the University of Envigado are presented in this article, which is based on one of the author's thesis for a Doctorate in Social Science, Childhood and Youth at University of Manizales-Cinde. This paper aims to make two distinct contributions to this field. On one hand, it highlights that it is common that young students start their university studies with extremely low literacy levels, which requires specialized efforts in the learning/teaching process of this population. On the other hand, the study provides some interesting methodological aspects, examining the possibilities offered by a sociolinguistic analysis of interviews in empirical research. The research design included an academic intervention, which was carried out with an experimental sample consisting of by 21 students who were in their first semester of an undergraduate degree. These students filled out a basic sociocultural profile survey, which was complemented with 5 qualitative interviews. In conclusion, the study identifies that a student's biographical context since infancy and the institutions involved in their lives, such as family and school, are prevailing factors in the acquisition of reading comprehension and writing production competencies and discursive appropriation.

Resumo (descritivo): São apresentados alguns achados que fazem parte da pesquisa chamada de "Análise sociolinguística dos níveis de literacidade em jovens da Institución Universitaria de Envigado", realizada por um dos autores, para a obtenção do título de "Doutorado em ciências sociais, infância e juventude" da Universidade de Manizales-Cinde. O trabalho visa ser uma contribuição em dupla direção. No primeiro lugar, visa expor o fato de ser comum para os jovens o começo do ensino universitário com níveis de literacidade extremamente baixos, o que exige esforços especiais no processo de ensino/aprendizado para essa população. Alem disso, a pesquisa aporta aspectos metodológicos, ao examinar as possibilidades oferecidas pela análise sociolinguística nas entrevistas da pesquisa empírica. O projeto de investigação incluiu uma intervenção acadêmica feita com uma amostra experimental de 21 estudantes que entraram na universidade para a qual foram convidados, que deve processar uma pesquisa elementar de perfil sociocultural. Esta foi complementada por cinco entrevistas qualitativas. Concluiu-se que o contexto biográfico desde a infância e instituições envolvidas neste contexto como a família e a escola são preponderantes na aquisição de competências em compreensão de leitura, produção literária e apropriação discursiva.

Stages of Change for Mammography Among Mexican Women and a Decisional Balance Comparison Across Countries.

An analysis of the adoption of secondary preventive behaviors is significant in regions with disparities in mammography use and breast cancer survival. Therefore, we determined the cognitive factors and the degree to which they differentiate stages of change in mammography among Mexican women. We also compared the decisional balance performance at Mexico, Switzerland, South Korea, and the USA. A cross-sectional study was designed for women in the stages of precontemplation (n = 240), contemplation (n = 243), action (n = 205), maintenance (n = 311), and relapse (n = 348). We only considered those ≥40 years with no cancer history. We measured the pros, cons, and self-efficacy, among other components. The decisional balance was estimated, and the result was transformed into T-scores. Odds ratios (OR) and 95% confidence intervals (CI) were estimated with multinomial logistic regression using precontemplation as the reference group. The decisional balance distinguished stages partially: in contemplation, the OR was 1.26 (95%CI 1.08, 1.47) and in maintenance, 1.34 (95%CI 1.13, 1.59); in action and relapse, the statistical significance was marginal (p < 0.10). The decisional balance T-score performance registered variations among countries. Additionally, the effect of self-efficacy progressively ascended from contemplation to action and maintenance (OR = 1.29 [95%CI 1.05, 1.58], 1.53 [95%CI 1.20, 1.96], and 2.48 [95%CI 1.82, 3.39], respectively). Furthermore, risk perception and severity did not have an effect on stages of change among Mexican women. Recognition of what provokes action in a population is a key factor in the efficacy of screening programs. Variations among countries highlight the necessity for importance of investigating cognitive determinants for mammography in specific areas.

Relación maestro - alcance del logro: Una mirada a los procesos de enseñanza en la escuela

El presente artículo tiene como objetivo contribuir a la reflexión sobre las prácticas pedagógicas y didácticas orientadas al alcance del logro académico que los docentes desarrollan en el escenario educativo de la escuela. Del mismo modo, observar si los ambientes de aprendizaje se encuentran direccionados a potenciar los saberes previos, la construcción de planteamientos y posiciones que permiten comprender desde una posición crítica las condiciones del contexto de desenvolvimiento de las y los educandos. Y por último, reconocer los cambios que deben asimilar los docentes en una sociedad que paulatinamente exige nuevos conocimientos y competencias. Por tanto, es una invitación a repensar las acciones pedagógicas, los procesos de enseñanza aprendizaje, las didácticas en las que se apoyan los docentes para orientar el alcance del logro académico de las y los educandos.

This article aims to contribute to the reflection on pedagogical and didactic practices oriented to the scope of academic achievement and teachers developed in the educational setting for the school. In the same way see if learning environments are directed to enhance the knowledge previous to the construction of approaches and positions that allow to understand from a position criticized conditions in the context of unfolding of the learners. And finally to recognize the changes that must be gradually assimilate the teachers in a society that requires new knowledge and skills. Therefore, it is an invitation to rethink the pedagogical actions, teaching-learning processes, and the didactics that support teachers to guide to achieve the academic achievement of the students.

Este artigo pretende contribuir para a reflexão sobre as práticas pedagógicas e didáticas destinadas a alcançar o desempenho acadêmico que os professores desenvolvem cenário educacional na escola. Da mesma forma, observar se os ambientes de aprendizagem são direcionados para aumentar o conhecimento prévio, a construção de abordagens e posições que permitam a compreensão de um condições de contexto posição crítica e desenvolvimento dos alunos. E, finalmente, reconhecer as mudanças que os professores deveriam assimilar em uma sociedade que exige gradualmente novos conhecimentos e habilidades. Portanto, é um convite a repensar os processos de ações, de ensino e aprendizagem pedagógicas, ensinando nas quais os professores são suportados para orientar o alcance e desempenho acadêmico dos estudantes.

Análisis sociolingüístico de literacidad en jóvenes de la Institución Universitaria de Envigado

Introducción. Este artículo se desprende de la tesis doctoral Análisis sociolingüístico de los niveles de literacidad en jóvenes de la Institución Universitaria de Envigado (IUE). Por ello, tiene en cuenta variables como estrato social, edad, sexo y nivel educativo de los padres, factores que influyen sobre los niveles de literacidad de los estudiantes. Objetivo. Describir tales niveles y su correlación con los factores sociolingüísticos previamente señalados. Materiales y métodos. Para ello, se realizaron dos pruebas (una inicial y otra final) a dos grupos de primer semestre (Psicología 2010-II y Derecho 2011-II). Además, los participantes diligenciaron una encuesta sociocultural. Resultados. Los resultados en la prueba final indican que ambos grupos mejoraron, pero de manera desigual. El grupo de Psicología obtuvo resultados más significativos que el de Derecho. Conclusiones. Hay variables sociales que afectan el desarrollo de competencias en comprensión lectora y producción escritural; no obstante, estas probablemente puedan ser subsanadas a través de un curso dirigido desde la lingüística textual, el análisis crítico del discurso y la argumentación pragmadialéctica.

Introduction. This article is derived from the PhD thesis Análisis sociolingüístico de los niveles de literacidad en jóvenes de la Institución Universitaria de Envigado (IUE). Therefore, it takes into account variables such as social stratum, age, sex and educative level of the parents, given the fact that these factors affect the literacy levels of students. Objective. Describe such levels and their correlation with the sociolinguistic factors previously mentioned. Materials and methods. Two tests were performed, one at the beginning and another at the end, in two first semester groups (Psychology 2010-II and Law 2011-II). The participants also answered a sociocultural survey. Results. The results of the test performed at the end indicate that both groups improved, but in an uneven way. The group from psychology had more significant results that from Law. Conclusions. There are social variables that affect the development of reading comprehension and written production competencies. Nevertheless, they can be remedied by means of a special course proposed from textual linguistics, the critical analysis of speech and the pragma-dialectical argumentation.

Introdução. Este artículo se desprende da tese doutoral Análise sociolinguístico dos níveis de literacidade em jovens da Instituição Universitária de Envigado (IUE). Por isso, tenha em conta variáveis como estrato social, idade, sexo e nível educativo dos pais, fatores que influem sobre os níveis de literacidade dos estudantes. Objetivo. Descrever tais níveis e sua correlação com os fatores sociolinguísticos previamente mostrados. Materiais e métodos. Para isso, se realizaram duas provas (uma inicial e outra final) a dos grupos de primeiro semestre (Psicologia 2010-II e Direito 2011-II). Ademais, os participantes preencheram uma enquete sociocultural. Resultados. Os resultados na prova final indicam que ambos grupos melhoraram, mas de maneira desigual. O grupo de Psicologia obteve resultados mais significativos do que o de Direito. Conclusões. Há variáveis sociais que afetam o desenvolvimento de competências em compreensão leitora e produção escritural; embora, estas provavelmente possam ser corrigidas através de um curso dirigido desde a linguística textual, a análise crítica do discurso e a argumentação pragma-dialéctica.

Patient-derived xenografts for individualized care in advanced sarcoma.

BACKGROUND: Patients with advanced, metastatic sarcoma have a poor prognosis, and the overall benefit from the few standard-of-care therapeutics available is small. The rarity of this tumor, combined with the wide range of subtypes, leads to difficulties in conducting clinical trials. The authors previously reported the outcome of patients with a variety of common solid tumors who received treatment with drug regimens that were first tested in patient-derived xenografts using a proprietary method ("TumorGrafts"). METHODS: Tumors resected from 29 patients with sarcoma were implanted into immunodeficient mice to identify drug targets and drugs for clinical use. The results of drug sensitivity testing in the TumorGrafts were used to personalize cancer treatment. RESULTS: Of 29 implanted tumors, 22 (76%) successfully engrafted, permitting the identification of treatment regimens for these patients. Although 6 patients died before the completion of TumorGraft testing, a correlation between TumorGraft results and clinical outcome was observed in 13 of 16 (81%) of the remaining individuals. No patients progressed during the TumorGraft-predicted therapy. CONCLUSIONS: The current data support the use of the personalized TumorGraft model as an investigational platform for therapeutic decision-making that can guide treatment for rare tumors such as sarcomas. A randomized phase 3 trial versus physician's choice is warranted.

Integrated next-generation sequencing and avatar mouse models for personalized cancer treatment.

BACKGROUND: Current technology permits an unbiased massive analysis of somatic genetic alterations from tumor DNA as well as the generation of individualized mouse xenografts (Avatar models). This work aimed to evaluate our experience integrating these two strategies to personalize the treatment of patients with cancer. METHODS: We performed whole-exome sequencing analysis of 25 patients with advanced solid tumors to identify putatively actionable tumor-specific genomic alterations. Avatar models were used as an in vivo platform to test proposed treatment strategies. RESULTS: Successful exome sequencing analyses have been obtained for 23 patients. Tumor-specific mutations and copy-number variations were identified. All samples profiled contained relevant genomic alterations. Tumor was implanted to create an Avatar model from 14 patients and 10 succeeded. Occasionally, actionable alterations such as mutations in NF1, PI3KA, and DDR2 failed to provide any benefit when a targeted drug was tested in the Avatar and, accordingly, treatment of the patients with these drugs was not effective. To date, 13 patients have received a personalized treatment and 6 achieved durable partial remissions. Prior testing of candidate treatments in Avatar models correlated with clinical response and helped to select empirical treatments in some patients with no actionable mutations. CONCLUSION: The use of full genomic analysis for cancer care is encouraging but presents important challenges that will need to be solved for broad clinical application. Avatar models are a promising investigational platform for therapeutic decision making. While limitations still exist, this strategy should be further tested.

Synthesis and antitumor evaluation of 6-aryl-substituted benzo[j]phenanthridine- and benzo[g]pyrimido[4,5-c]isoquinolinequinones.

A variety of novel 6-arylsubstituted benzo[j]phenanthridine- and benzo[g]-pyrimido[4,5-c]isoquinolinequinones were synthesized from 1,4-naphthoquinone, aryl-aldehydes and enaminones via a two-step synthetic approach. The cytotoxic activity of the aminoquinone derivatives was evaluated in vitro against one normal cell line (MRC-5 lung fibroblasts) and three human cancer cell lines (AGS human gastric adenocarcinoma; SK-MES-1 human lung cancer cells, and J82 human bladder carcinoma) in 72-h drug exposure assays using the MTT colorimetric method. Structure-activity relationships within the series of angular quinones reveal that the insertion of pyrrol-2-yl and furan-2-yl groups at the 6-position is more significant for the increase of the potency and selectivity index of the pharmacophores.

Inhibition of human topoisomerase I and activation of caspase-3 by aza-angucyclinones and arylaminopyrimido[4,5-c]isoquinoline-7,10-quinones.

Cancer is the second cause of death in the world after cardiovascular diseases. Cancer cells acquire capacities not present in normal cells, such as self-sufficiency, resistance to antiproliferative stimuli, evasion of apoptosis, unlimited replication, invasiveness and metastasis. Consequently, it is of major interest to explore and develop molecules with anticancer activity directed to specific targets. In this study, we aimed to evaluate two series of polycyclic quinones: aza-angucyclinone and arylaminopyrimido[4,5-c]isoquinoline-7,10-quinones, in their capacity to inhibit human topoisomerase I (TOP1) and to trigger apoptosis through activation of caspase-3. We evaluated the capacity of the two series of polycyclic quinones to inhibit TOP1, using a DNA supercoiled relaxation assay and their capacity to induce apoptosis through the activation of caspase-3 in HL60 cells. Both series of quinones inhibited TOP1 activity over 50%. When we evaluated the pro-apoptotic capacity of both series of quinones, at therapeutically relevant concentrations, the arylaminoquinones ADPA-1CC (methyl 7-(4-methoxyphenyl)amino-1,3-dimethyl-5,8-dioxo-5,8-dihydroisoquinoline-4-carboxylate), P4 (9-phenylamino-3,4-dihydrophenanthridine-1,7,10(2H)-trione) and the aza-angucyclinone OH-6H (8-hydroxy-2,4-dimethyl-2H,4H-benzo[g]pyrimido[4,5-c]isoquinoline-1,3,7,12-tetraone) increased the caspase-3 activity by approximately 2-fold over the control. The series of the arylaminoquinones and aza-angucyclinones showed differential antiproliferative capacity. We further identified a group of them that showed antiproliferative capacity possibly through inhibition of TOP1 and by activation of caspase-3. This group of molecules may represent a potential pharmacological tool in the treatment against cancer.

Aminopyrimidoisoquinolinequinone (APIQ) redox cycling is potentiated by ascorbate and induces oxidative stress leading to necrotic-like cancer cell death.

Several phenylaminopyrimidoisoquinolinequinones (APIQs) were tested for their cytotoxicity against different cancer cell lines (K562, T24, HepG2) in the presence or absence of ascorbate. Ascorbate enhanced the toxic effects of quinones with first half-wave potential E(I) (1/2) values in the range of -480 to -660 mV. Phenylaminoquinones that were unsubstituted at position 6 exhibited greater cytotoxic activity than did their 6-methyl-substituted analogues. Two groups of compounds were further selected, namely 8-10 and 20-22, to study the cellular mechanisms involved in quinone cytotoxicity. Indeed, these compounds have the same range of redox potentials but differed considerably in their capacity to induce cell death. In the presence of ascorbate, the cell demise induced by compounds 8-10 was not caspase-3 dependent, as shown by the lack of activation of caspase-3 and the absence of cleaved PARP fragments. In addition, an index of ER stress (eIF2α phosphorylation) was activated by these compounds. Quinones 8-10 decreased the cellular capacity to reduce MTT dye and caused marked ATP depletion. Taken together, our results show that ascorbate enhances quinone redox-cycling and leads to ROS formation that inhibits cell proliferation and provokes caspase-independent cell death. Interestingly, we also observed that quinone 8 had a rather selective effect given that freshly isolated peripheral blood leukocytes from human healthy donors were more resistant than human leukemia K562 cells.

Studies on quinones. Part 46. Synthesis and in vitro antitumor evaluation of aminopyrimidoisoquinolinequinones.

In the search of structure-activity relationship studies and to explore the antitumor effect associated with the pyrimidoisoquinolinequinone scaffold, several diversily substituted 8-aminopyrimido[4,5-c]isoquinolinequinones were regioselectively synthesized. Variation in the structure of the nitrogen substituent bonded to the 8-position of the pyrimidoisoquinolinequinone system led to a set of alkylamino-, phenylamino- and alkyphenylamino derivatives. The cytotoxic activity of the aminoquinone derivatives was evaluated in vitro using the MTT colorimetric method against one normal cell line (MRC-5 lung fibroblasts) and four human cancer cell lines (AGS human gastric adenocarcinoma; SK-MES-1 human lung cancer cells, and J82 human bladder carcinoma; HL-60 human leukemia) in 72-h drug exposure assays. Among the series, five compounds exhibited interesting antitumor activity against AGS human gastric adenocarcinoma and human lung cancer cells. The SAR studies revealed that both the nature of the nitrogen substituent into the quinone ring and the methyl group at the 6-position play key roles in the antitumor activity.

Weight Loss via exercise with controlled dietary intake may affect phospholipid profile for cancer prevention in murine skin tissues.

Exercise has been linked to a reduced cancer risk in animal models. However, the underlying mechanisms are unclear. This study assessed the effect of exercise with dietary consideration on the phospholipid profile in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin tissues. CD-1 mice were randomly assigned to one of the three groups: ad libitum-fed sedentary control; ad libitum-fed treadmill exercise at 13.4 m/min for 60 min/d, 5 d/wk (Ex+AL); and treadmill-exercised but pair-fed with the same amount as the control (Ex+PF). After 14 weeks, Ex+PF but not Ex+AL mice showed approximately 25% decrease in both body weight and body fat when compared with the controls. Of the total 338 phospholipids determined by electrospray ionization-tandem mass spectrometry, 57 were significantly changed, and 25 species could distinguish effects of exercise and diet treatments in a stepwise discriminant analysis. A 36% to 75% decrease of phosphatidylinositol (PI) levels in Ex+PF mice occurred along with a significant reduction of PI 3-kinase in TPA-induced skin epidermis, as measured by both Western blotting and immunohistochemistry. In addition, approximately 2-fold increase of the long-chain polyunsaturated fatty acids, docosahexaenoic and docosapentaenoic acids, in phosphatidylcholines, phosphatidylethanolamines, and lysophosphatidylethanolamines was observed in the Ex+PF group. Microarray analysis indicated that the expression of fatty acid elongase-1 increased. Taken together, these data indicate that exercise with controlled dietary intake, but not exercise alone, significantly reduced body weight and body fat as well as modified the phospholipid profile, which may contribute to cancer prevention by reducing TPA-induced PI 3-kinase and by enhancing omega-3 fatty acid elongation.

Synthesis and antitumor evaluation of 8-phenylaminopyrimido[4,5-c]isoquinolinequinones.

A series of 8-phenylaminopyrimido[4,5-c]isoquinoline-7,10-quinone derivatives were prepared by regioselective amination reaction of pyrimido[4,5-c]isoquinoline-7,10-quinones with arylamines in the presence of a Lewis acid catalyst. Preliminary evaluation of the members of the series against cancer cell lines and assays of activation of their cytotoxic activity on K562 cells with ascorbic acid are reported.

Studies on quinones. Part 44: Novel angucyclinone N-heterocyclic analogues endowed with antitumoral activity.

In the search for new potentially anticancer drugs, series of angucyclinone aza-analogues containing pyridine and pyridopyridazine rings have been designed and synthesized by a highly efficient sequence involving a one-pot step for the synthesis of tricyclic quinone intermediate and highly regiocontrolled cycloaddition reactions with polarized 1,3-dienes. The new N-heterocyclic angular quinones were evaluated in vitro on normal human fibroblasts and on a panel of four distinct human cancer cell lines. All tested compounds showed high to moderate antitumor activity. Among the compounds, those with one and two pyridine moieties fused to the quinone system have shown the best effect. Structure-activity relationships established the main structural requirement for the activity of the new potential anticancer drugs.