Identification of a tumor-targeting-peptide and development of a tumor-targeted-cytokine vector for systemic treatment of primary and metastatic malignancies

Advances in cancer therapies continue to be improved, yet cancer continues to be one of the deadliest diseases in the world. Harnessing the power of the body’s immune system to attack cancer is a promising strategy that can further improve therapies for neoplastic diseases. As part of this strategy, cytokines such as interleukin (IL) 2 and interferon á are currently accepted cancer treatments, and other cytokines such as IL12 and GM-CSF also show potential as new treatments. Clinical trials with these cytokines have shown less than acceptable therapeutic efficacy and toxicities, but tumor-targeting motifs can improve these effects. Both antibodies and peptides specific for tumor antigens have been used in recombinant protein and gene therapy systems to increase the intratumoral cytokine accumulation and decrease systemic toxicities. Still, these treatments have not been capable of overcoming the obstacles for clinical acceptance. The hypothesis tested in this dissertation is that inserting tumor-targeting peptide coding sequences into IL12 plasmid DNA will create a novel systemic gene therapy approach which will increase the antitumor efficacy and decrease toxicity for cancer treatments. To accomplish this goal, a reporter gene mediated screening strategy was developed to identify a peptide which can target multiple tumor models. While preparing this method, it was discovered that these peptides can have a strong effect on the activity of the conjugated reporter gene. Once this strategy was finalized, the peptide VNTANST was found to increase the intratumoral accumulation of the reporter gene in five tumor models including a human xenogeneic model. The VNTANST coding sequence was then inserted into an IL12 plasmid to examine the antitumor efficacy. In breast adenocarcinoma, squamous cell carcinoma, and colon carcinoma models, VNTANST-IL12 plasmid DNA treatments distal from the tumor site increased tumor inhibition and, in two models, prolonged survival. Also, these treatments reduced the development of metastatic lung tumors in a spontaneous metastatic model. As expected, these tumor-targeted IL12 treatments decreased the level of liver toxicity compared to wild-type treatments. The receptor for VNTANST was identified as vimentin, which is a potentially powerful target for human cancers

Reproducibility and speed of landmarking process in cephalometric analysis using two input devices: mouse-driven cursor versus pen

To define if the new portable appliances, like smartphone, iPad, small laptop and tablet can be used in cephalometric tracing without dropping out the validity of any measurement. METHODS:We investigated and compared the reproducibility and the speed of landmarks identification process on lateral X-rays in two input devices: a mouse-driven cursor and a pen used as input means in mobile devices. One expert located 22 landmarks on 15 lateral X-rays in a repeated measure design two times, at time T1 and T2, after at least one month. The Intraclass Correlation coefficient was used to evaluate the reproducibility for each landmark tracing and the agreement between the value derived from both input devices. Also, the mean errors in measurements, the standard deviation and the Friedman Test significans (P < 0.05) between both input were statistically evaluated. RESULTS:All landmarks had a high agreement and the Friedman Test indicated statistically significant differences (P<0.05) for the identification of Na, Po, Pt, PNS, Ba, Pg, Gn, UIE, UIA, APOcc and PPOcc landmarks. CONCLUSIONS:Even if the mouse input give higher agreement for landmark tracing the differences are really minimal and they can be ignored in private practice. We suggest the adequacy of pen input in clinical setting

Mounting a specific immune response increases energy expenditure of the subterranean rodent Ctenomys talarum (tuco-tuco): Implications for intraspecific and interspecific variation in immunological traits

It was recently hypothesised that specific induced defences, which require substantial time and resources and are mostly beneficial against repeated infections, are more likely to be favoured in 'slow-living-pace' species. Therefore, understanding how different types of immune defences might vary with life history requires knowledge of the costs and benefits of defence components. Studies that have explored the energetic costs of immunity in vertebrates have done so with a focus primarily on birds and less so on mammals, particularly surface-dwelling rodents. In this study, we evaluated whether an experimental induction of the immune system with a non-pathogenic antigen elevates the energetic expenditure of a subterranean rodent: Ctenomys talarum (tuco-tucos). In both seasons studied, a significant increase in oxygen consumption was verified in immunechallenged tuco-tucos injected with sheep red blood cells (SRBC) compared with control animals. The increase in oxygen consumption 10 days after the exposure to SRBC was lower for female tuco-tucos monitored in the breeding season compared with females in the non-breeding season. Interestingly, antibody titres of female tuco-tucos did not decrease during the breeding season. Our results add new insight into the role of other factors such as basal metabolic rate or degree of parasite exposure besides 'pace of life' in modulating the interspecific immunological variation observed in natural populations of mammals.Fil: Cutrera, Ana Paula. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Biología. Laboratorio de Ecofisiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; ArgentinaFil: Zenuto, Roxana Rita. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Biología. Laboratorio de Ecofisiología; ArgentinaFil: Luna, Facundo. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Biología. Laboratorio de Ecofisiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; ArgentinaFil: Antenucci, Carlos Daniel. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Biología. Laboratorio de Ecofisiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentin

Fur changes in the subterranean rodent Ctenomys talarum: possible thermal compensatory mechanism

In this work, the changes in fur density and length in the subterranean rodent Ctenomys talarum were evaluated as a possible compensatory mechanism during seasonal temperature changes in their burrow environment and during pregnancy in females, both situations being thermoregulatory challenging in this species. The ventral fur was shorter and less dense than the dorsal fur in the three groups (males, non pregnant females and pregnant females) and in the two seasons evaluated. Ventral and dorsal furs were significantly shorter during the warm seasons in the three groups. In the warm season, pregnant females had a ventral fur significantly shorter than that of males and non-pregnant females. The possible thermal advantages that the observed fur changes might represent for the species are discussed, with emphasis on the constraints imposed by the subterranean environment on available ways of dissipating body heat.Fil: Cutrera, Ana Paula. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Antinuchi, Carlos. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Biología. Laboratorio de Ecofisiología; Argentin

Rapid Maxillary Expansion Affects the Spheno-occipital Synchondrosis in Youngsters A Study with Low-Dose Computed Tomography

Objective: To test the null hypothesis that the spheno-occipital synchondrosis does not show bony displacement in response to rapid maxillary expansion (RME) therapy in youngsters. Materials and Methods: A total of 16 computed tomography (CT) records were taken from 8 growing patients (2 males and 6 females), before (TO) and after (T1) treatment with RME. All patients had been diagnosed originally with transverse maxillary deficiency. The mean chronological age of the patients was 9.8 +/- 1.8 years (range, 8 to 11.4 years). High-resolution multislice multidetector CT was used to study quantitatively the extent of the opening of the spheno-occipital synchondrosis following RME. A low-dose CT scan protocol was used (80 kV, 10 mA) and the data file of each patient was transferred to a workstation where the anteroposterior width of the spheno-occipital synchondrosis was measured on axial images. Results: Before treatment with RME (TO), the anteroposterior mean width of the spheno-occipital synchondrosis was 1.73 +/- 0.46 mm immediately after the active phase of expansion (T1), and the width of the synchondrosis increased to 2.30 +/- 0.47. This difference was statistically significant according to the Wilcoxon signed rank test (P < .05). Conclusion: Rapid maxillary expansion leads to a small immediate widening of the sphenooccipital synchondrosis in youngsters. (Angle Orthod. 2010;80:106-110.

Acute-Phase Immune Response Involves Fever, Sickness Behavior, and an Elevated Metabolic Rate in the Subterranean Rodent Ctenomys talarum

The acute-phase response (APR) is an induced innate response and may involve pronounced physiological and behavioral changes. One of the most common assays to study the APR involves the use of a lypopolysaccharide (LPS) from the cell wall of gram-negative bacteria. In this study, we determined the energetic costs of the APR in the subterranean rodent Ctenomys talarum, as well as the effects of the exposure to LPS on body temperature, body mass loss, and behavior in this species. Furthermore, we monitored levels of circulating endotoxin after LPS exposure. Our results suggest that in C. talarum, the APR is energetically costly, resulting in a 14% increase in metabolic rate. Animals exposed to LPS experienced a short-term thermal response, weight loss, and changes in their behavior that included more time spent resting and with their eyes totally or partially closed. However, the magnitude of the effects of LPS exposure varied between sexes and among animals. Also, there was a clear peak in circulating endotoxin levels in plasma 3 h postinjection (hpi) and a significant decrease of these levels 24 hpi, but peak endotoxin concentration values recorded were highly variable among animals. In light of these results, ecological determinants of immune function variation in tuco-tucos are discussed considering the roles of pace of life, habitat, and degree of pathogen exposure in these subterranean rodents.Fil: Cutrera, Ana Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Luna, Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Zenuto, Roxana Rita. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; Argentin

Fisiología ecológica de mamíferos en argentina: Un campo en desarrollo y prometedor

La fisiología ecológica es una disciplina que surge de la conjunción entre la fisiología comparada, la ecología y la evolución, centrándose en los patrones y procesos que explican el surgimiento y mantenimiento de la diversidad fisiológica en la naturaleza. En el presente trabajo, nuestro objetivo es realizar una revisión de los artículos del campo de la fisiología ecológica que emplean mamíferos de Argentina como organismos de estudio, incluyendo estudios realizados tanto en el campo como en el laboratorio en los últimos 25 anos. La variación en las respuestas fisiológicas es considerada en relación a cambios en las condiciones ecológicas, centrándonos en la energética, la endocrinología ecológica y la ecoinmunología. De estos tres temas, los estudios relacionados con la adquisición y el gasto de energía son los más numerosos, con menor cantidad de trabajos en el área de la endocrinología ecológica y, en especial, en la ecoinmunología, dado el desarrollo más reciente de estas disciplinas en Argentina. El número de especies estudiadas es limitado y la mayoría de ellos son roedores, lo cual probablemente sea el reflejo de las dificultades que representa monitorear parámetros fisiológicos en la naturaleza, así como implementar estudios controlados en cautiverio. Comprender los roles de la historia de vida, el hábitat y la filogenia en dar forma a las respuestas fisiológicas de los animales a las condiciones ambientales requiere estudios adicionales que consideren más especies de diferentes clados de mamíferos y que incluyan datos recolectados en escalas geográficas y temporales más extensas. Al lograr estos objetivos, esperamos un impacto importante en la expansión de nuestro conocimiento científico, la conservación de nuestra fauna local y una gestión ambiental más eficiente.Ecological physiology is a discipline that occurs at the intersection of comparative physiology, ecology and evolution, with emphasis on patterns and processes by which physiological diversity arises and persists in nature. Here, our objective is to review articles on ecological physiology that use mammals from Argentina as study organisms, including studies conducted in both field and laboratory settings over the last 25 years. Variation in physiological responses is considered in relation to changes in ecological conditions, focusing on energetics, ecological endocrinology and ecoimmunology. Of these topics, studies related to energy acquisition and expenditure are the most numerous, with a less substantive body of research available for ecological endocrinology and ecoimmunology due to their their more recent development in Argentina. The number of species studied is limited and most are rodents, likely reflecting the difficulties of monitoring physiological parameters in nature as well as implementing controlled studies in captivity. Understanding the roles of life history, habitat, and phylogeny in shaping the physiological responses of animals to environmental conditions requires additional studies that consider more species from different clades of mammals and that include data collected over larger geographical and temporal scales. We anticipate that such studies of physiology will substantially expand our knowledge of mammalian biology while also resulting in improved conservation of these animals and a more effective management of South American environments.A fisiologia ecológica é uma disciplina que ocorre na interseção da fisiologia comparada, ecologia e evolução, com ênfase em padrões e processos pelos quais a diversidade fisiológica surge e persiste na natureza. Aqui, nosso objetivo é revisar artigos sobre fisiologia ecológica que utilizem mamíferos da Argentina como organismos de estudo, incluindo estudos realizados tanto em campo quanto em laboratório nos últimos 25 anos. A variação nas respostas fisiológicas é considerada em relação às mudanças nas condições ecológicas, com foco em energética, endocrinologia ecológica e ecoimunologia. Desses tópicos, os estudos relacionados à aquisição e gasto de energia são os mais numerosos, com um corpo de pesquisa menos substantivo disponível para endocrinologia ecológica e ecoimunologia, devido ao seu desenvolvimento mais recente na Argentina. O número de espécies estudadas é limitado e a maioria é de roedores, provavelmente refletindo as dificuldades de monitorar os parâmetros fisiológicos da natureza, além de implementar estudos controlados em cativeiro. A compreensão dos papéis da história de vida, habitat e filogenia na formação das respostas fisiológicas dos animais às condições ambientais exige estudos adicionais que considerem mais espécies de diferentes espécies de mamíferos e que incluam dados coletados em escalas geográficas e temporais maiores. Prevemos que esses estudos de fisiologia expandirão substancialmente nosso conhecimento da biologia de mamíferos e, ao mesmo tempo, resultarão em melhor conservação desses animais e em um gerenciamento mais eficaz dos ambientes sul-americanosFil: Luna, Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Cutrera, Ana Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Zenuto, Roxana Rita. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; Argentin

EL LENGUAJE ORAL COMO PUENTE ENTRE EL INGRESANTE Y LA DISCIPLINA PROYECTUAL: UNA EXPERIENCIA EN LOS TALLERES DE DISEÑO1

Podemos aseverar que pertenecer a un grupo, sea este cultural, disciplinar o etario, está definido, entre otras&nbsp;cosas, por compartir un lenguaje común. Este lenguaje oral es un instrumento de comunicación y, a la vez,&nbsp;es la herramienta que nos permite construir nuestros pensamientos y hace posible la generación de conocimiento. Las representaciones de dibujos y maquetas, en sus versiones digitales o analógicas, así como las&nbsp;fotografías, entre otras técnicas, son lenguajes específicos de las disciplinas proyectuales; a través de ellos&nbsp;pensamos y comunicamos nuestras ideas y pensamientos. Pero también&nbsp;en el proceso de enseñanza del diseño es primordial la palabra para iniciar al estudiante en la&nbsp;comprensión, uso y gestión de esos lenguajes específicos que lo acercarán y habilitarán para el&nbsp;pensamiento proyectual. La enseñanza de un lenguaje específico y los códigos propios de la disciplina tienen una presencia permanente en los talleres proyectuales. Se produce igual fenómeno&nbsp;que con la disciplina misma, se aprende a partir de la práctica y de la reflexión sobre esa práctica.&nbsp;Si afirmamos que “a proyectar se aprende proyectando” podemos decir que “se aprende el lenguaje disciplinar argumentando sobre el proyecto y para argumentar se necesita la palabra (Cutrera,&nbsp;2016b, p. 1),&nbsp;esa palabra que connota significados propios de la disciplina. En este sentido indagaremos en la importancia&nbsp;del lenguaje oral como mediador entre lenguajes específicos de la disciplina proyectual y en el valor del silencio como espacio de reflexión. Cuanto más aprenda el estudiante el lenguaje específico de nuestra disciplina,&nbsp;mejor será su producción en el campo proyectual y mayor será su comprensión de la arquitectura.&nbsp;Palabras claveDidáctica-lenguaje-taller proyectual-diálogo-palabra- silencio-mediación.AbstractIt is possible to affirm that belonging to a group, either cultural, disciplinary, or age group, is defined among&nbsp;other things by sharing a common language. This oral language is an instrument for communication as well&nbsp;as a tool that allows the construction of thoughts that enhance the generation of knowledge. The representations of drawings and models in their digital or analogue version, as well as photographs and other techniques, are specific languages of the project disciplines through which we think and communicate ideas&nbsp;and thoughts. Also, in the process of teaching design, the word is essential to initiate the student in the&nbsp;comprehension, use, and management of those specific languages that will approach and enable students&nbsp;for project thinking. The teaching of a specific language and the codes of the discipline have a permanent&nbsp;presence in project workshops. The same phenomenon occurs with the discipline itself which is learned&nbsp;from practice and reflection on practice. If we affirm that how "to project is learned by projecting" we can&nbsp;say that " we learn the disciplinary language by arguing about the project, and in order to argue, the word&nbsp;is needed” (Cutrera, 2016b, p.1), as the word connotes meanings typical to the discipline. In this sense wewill investigate the importance of oral language as a mediator between specific languages of design and the&nbsp;value of silence as a space for reflection. The more the student learns the specific language of our discipline,&nbsp;the better their production and understanding is in the field of design and architecture.KeywordsDidactic-language-workshopproject-dialogue-word-silence-mediation

To think about peace”. About the Negotiations between some Governors of Tucumán and several Caciques of Chaco in the 1770s

El objetivo del trabajo es reflexionar sobre la paz convenida entre algunos gobernadores del Tucumán y varios caciques autónomos del interior chaqueño ?tobas, mocovíes y vilelas- a fines del siglo XVIII. Se atiende al recorrido histórico de las negociaciones establecidas entre ellos; al contexto político, económico y relacional que condujo a concebir la idea de la paz en ambas partes; y a las razones que tuvo cada una de ellas para acordarla. También se analiza críticamente el tratado firmado entre Gerónimo de Matorras y el cacique Paikín, y se contrasta lo establecido allí con los acontecimientos que lo sucedieron. Por último, se explica por qué las tratativas iniciadas en Salta concluyeron diez años después, con la construcción de dos reducciones en el corazón del Chaco, pero en jurisdicción de Buenos Aires.The objective of the work is to reflect on the peace agreed between some governors of Tucumán and several autonomous caciques of the interior of the Chaco - tobas, Mocovi and Vilelas - at the end of the 18th century. The historical evolution of the negotiations established between them is attended to; also the political, economic and relational context that led to conceive the idea of peace on both sides; and the reasons that each of them had to agree on it. In addition, the treaty signed between Gerónimo de Matorras and the cacique Paikín is critically analyzed, and what is established there with the events that followed it is contrasted. Finally, it is explained why the negotiations started in Salta concluded ten years later, with the construction of two reductions in the heart of the Chaco, but in the jurisdiction of Buenos Aires.Fil: Cutrera, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto de Historia Argentina y Americana "Dr. Emilio Ravignani". Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto de Historia Argentina y Americana "Dr. Emilio Ravignani"; Argentin

There is no dacalapata (meat), there is no reduction: The Indian escape from San Ignacio de los Tobas at the beginning of the 19th century

El trabajo toma como punto de partida un artículo de Martha Bechis en que se utiliza la Teoría matemática del Drama o Teoría de la Confrontación. Se recurre a ella en tanto herramienta metodológica que permite entender un episodio histórico cuyos sentidos profundos se encuentran en un proceso más amplio, dentro del que se cargan de significados y relaciones. Analizamos la fuga de los tobas de la reducción de San Ignacio (jurisdicción de Jujuy) a comienzos del siglo XIX. Para ello, ubicamos el episodio dentro del ?drama? de la crónica inestabilidad fronteriza y la escasez de recursos destinados al mantenimiento de fuertes y reducciones, y lo cruzamos con episodios del mismo drama y de otro (la suspensión de las raciones al pueblo, la explotación indígena en las haciendas y las malas conductas del fray Ortiz). Proponemos que la fuga era una estrategia a la que los indígenas recurrían para hacer valer sus intereses y necesidades frente a los hispanocriollos.This paper is based on an article by Martha Bechis which utilized the mathematical theory of drama or confrontation theory. This methodological instrument allows us to understand a historical episode whose deeper meanings are rooted in a broader process which gives them significance and relationships. We will analyze the escape of the Tobas from the San Ignacio reduction -Jujuy jurisdiction- at the beginning of the 19th century. To this purpose, we will contextualize the episode within the drama of the chronic frontier instability and the scarcity of resources assigned to the maintenance of forts and reductions, and we will connect it with other episodes of the same drama and another -the suspension of the rations to the reduction, the indigenous exploitation on the haciendas and the misconduct of friar Ortiz. We propose that the escape was a strategy to which the indigenous people resorted to assert their interests and needs against the Spanish Creoles.Fil: Cutrera, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto de Historia Argentina y Americana "Dr. Emilio Ravignani". Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto de Historia Argentina y Americana "Dr. Emilio Ravignani"; Argentin