Heterogeneity for IGF-II production maintained by public goods dynamics in neuroendocrine pancreatic cancer

The extensive intratumor heterogeneity revealed by sequencing cancer genomes is an essential determinant of tumor progression, diagnosis, and treatment. What maintains heterogeneity remains an open question because competition within a tumor leads to a strong selection for the fittest subclone. Cancer cells also cooperate by sharing molecules with paracrine effects, such as growth factors, and heterogeneity can be maintained if subclones depend on each other for survival. Without strict interdependence between subclones, however, nonproducer cells can free-ride on the growth factors produced by neighboring producer cells, a collective action problem known in game theory as the “tragedy of the commons,” which has been observed in microbial cell populations. Here, we report that similar dynamics occur in cancer cell populations. Neuroendocrine pancreatic cancer (insulinoma) cells that do not produce insulin-like growth factor II (IGF-II) grow slowly in pure cultures but have a proliferation advantage in mixed cultures, where they can use the IGF-II provided by producer cells. We show that, as predicted by evolutionary game theory, producer cells do not go extinct because IGF-II acts as a nonlinear public good, creating negative frequency-dependent selection that leads to a stable coexistence of the two cell types. Intratumor cell heterogeneity can therefore be maintained even without strict interdependence between cell subclones. Reducing the amount of growth factors available within a tumor may lead to a reduction in growth followed by a new equilibrium, which may explain relapse in therapies that target growth factors

El respeto al otro y el derecho a la educación

Este trabajo se enmarca dentro de una capacitación pensada para el Instituto de Formación docente de San Luis titulado “El otro en la enseñanza" (Resolución ME SL Nº 146 SPES 2016). El mismo tiene como objetivo desnaturalizar ciertas prácticas docentes que todavía reproducen modelos de enseñanza asentados en el normalismo y se transforman, de ese modo, en una más de las variables de inclusión excluyente planteada por Pablo Gentili (2011). A través del análisis de discursos narrativos y sociales se pretende increpar el habitus de los educadores (Bourdieu, 1999) con el fin de poner en cuestión prácticas pedagógicas “bancarias" y debatir un nuevo sujeto educativo, rescatando “la dialógica…un quehacer problematizante de los hombres – mundo o de los hombres en sus relaciones con el mundo y con los hombres", en este proceso de humanización que intenta poner en escena “la dualidad que se instala en la interioridad" de todo educador (Freire, 1970). Retomando los postulados de Gentili, se espera reconstruir la relación pedagógica desde el derecho a la educación, entendiendo al conocimiento como el elemento central de acceso a determinados espacios de la sociedad, así como un bien público. Además, se intenta reinscribir la escuela como ámbito público y escenario democrático “poniendo en la mesa" la diversidad social, ideológica, religiosa, entre otras. La mirada “manchada" (Skliar, 2009) sobre el otro inscribe a ese sujeto determinados usos del derecho a la educación que acaban reproduciendo las desigualdades sociales, excluyéndolo incluso de sus derechos ciudadanos.Fil: César, Ana Laura . Universidad Nacional de San Luis.Fil: Ferraro, Paula Daniela . Universidad Nacional de San Luis

An Integrated Ecological-Social Simulation Model of Farmer Decisions and Cropping System Performance in the Rolling Pampas (Argentina)

Changes in agricultural systems are a multi-causal process involving climate change, globalization and technological change. These complex interactions regulate the landscape transformation process by imposing land use and cover change (LUCC) dynamics. In order to better understand and forecast the LUCC process we developed a spatially explicit agent-based model in the form of a Cellular Automata: the AgroDEVS model. The model was designed to project viable LUCC dynamics along with their associated economic and environmental changes. AgroDEVS is structured with behavioral rules and functions representing a) crop yields, b) weather conditions, c) economic profits, d) farmer preferences, e) adoption of technology levels and f) natural resource consumption based on embodied energy accounting. Using data from a typical location of the Pampa region (Argentina) for the period 1988-2015, simulation exercises showed that economic goals were achieved, on average, each 6 out of 10 years, but environmental thresholds were only achieved in 1.9 out of 10 years. In a set of 50-years simulations, LUCC patterns converge quickly towards the most profitable crop sequences, with no noticeable trade-off between economic and environmental conditions.Fil: Pessah, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Ferraro, Diego Omar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Blanco, Daniela. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Computación; ArgentinaFil: Castro, Rodrigo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Investigación en Ciencias de la Computación. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Investigación en Ciencias de la Computación; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Computación; Argentin

Different polyubiquitinated bodies in human dendritic cells: IL-4 causes PaCS during differentiation while LPS or IFNα induces DALIS during maturation

Two types of polyubiquitin-reactive cytoplasmic bodies, particulate cytoplasmic structures (PaCS) and dendritic cell (DC) aggresome-like induced structures (DALIS), were analyzed by electron microscopy, immunocytochemistry, immunoblotting, and flow cytometry in DC obtained from human blood monocytes incubated with GM-CSF plus IL-4 (IL4-DC), GM-CSF plus IFNα (IFN-DC), or GM-CSF alone (GM-DC), with or without LPS maturation. PaCS developed as monomorphic aggregates of proteasome-reactive barrel-like particles only in ribosomes-rich cytoplasmic areas of differentiating IL4-DC. In contrast, DALIS formed as vesicular bodies storing K63-linked ubiquitinated proteins by coalescence of increased endosomal structures, in IFN-DC or after LPS maturation of GM-DC. DALIS-forming cells showed incomplete morphological and functional DC-type differentiation when compared to PaCS-forming IL4-DC. PaCS and DALIS may have different function as well as different origin and cytochemistry. DALIS may be a transient accumulation site of potentially antigenic polyubiquitinated proteins during their processing and presentation. PaCS are found under physiologic or pathologic conditions associated with increased/deranged protein synthesis and increased ubiquitin– proteasome activity. Given its high heat-shock protein content PaCS may work as a quality control structure for newly synthesized, cytosolic proteins. This comparative analysis suggests that PaCS and DALIS have distinctive roles in DC

Role of the Metal Center in the Modulation of the Aggregation Process of Amyloid Model Systems by Square Planar Complexes Bearing 2-(2'-pyridyl)benzimidazole Ligands

The effect of analogue Pd(II)-, Pt(II)-, and Au(III) compounds featuring 2-(2'-pyridyl)benzimidazole on the aggregation propensity of amyloid-like peptides derived from Aβ and from the C-terminal domain of nucleophosmin 1 was investigated. Kinetic profiles of aggregation were evaluated using thioflavin binding assays, whereas the interactions of the compounds with the peptides were studied by UV-Vis absorption spectroscopy and electrospray ionization mass spectrometry. The results indicate that the compounds modulate the aggregation of the investigated peptides using different mechanisms, suggesting that the reactivity of the metal center and the physicochemical properties of the metals (rather than those of the ligands and the geometry of the metal compounds) play a crucial role in determining the anti-aggregation properties

68Ga-PSMA-11 PET/MR Can Be False Positive in Normal Prostatic Tissue

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein expressed in the cytosol of normal prostate tissue and highly overexpressed on the membrane of prostate cancer, therefore increasingly used to image prostate cancer. We report a case of a 65-year-old man with two focal PSMA-positive areas on a Ga-PSMA-11 PET/MR, one corresponding to a prostate carcinoma (Gleason score 4 + 3) and another region without any evidence of malignancy, but with corresponding high PSMA-expression on immunohistochemistry

Functional characterization of WNT7A signaling in PC12 cells: Interaction with a FZD5-LRP6 receptor complex and modulation by dickkopf proteins

WNT factors represent key mediators of many processes in animal development and homeostasis and act through a receptor complex comprised of members of the Frizzled and low density lipoprotein-related receptors (LRP). In mammals, 19 genes encoding Wingless and Int-related factor (WNTs), 10 encoding Frizzled, and 2 encoding LRP proteins have been identified, but little is known of the identities of individual Frizzled-LRP combinations mediating the effects of specific WNT factors. Additionally, several secreted modulators of WNT signaling have been identified, including at least three members of the Dickkopf family. WNT7A is a WNT family member expressed in the vertebrate central nervous system capable of modulating aspects of neuronal plasticity. Gene knock-out models in the mouse have revealed that WNT7A plays a role in cerebellar maturation, although its function in the development of distal limb structures and of the reproductive tract have been more intensely studied. To identify a receptor complex for this WNT family member, we have analyzed the response of the rat pheochromocytoma cell line PC12 to WNT7A. We find that PC12 cells are capable of responding to WNT7A as measured by increased beta-catenin stability and activation of a T-cell factor-based luciferase reporter construct and that these cells express three members of the Frizzled family (Frizzled-2, -5, and -7) and LRP6. Our functional analysis indicates that WNT7A can specifically act via a Frizzled-5.LRP6 receptor complex in PC12 cells and that this activity can be antagonized by Dickkopf-1 and Dickkopf-3

Breast cancer chemotherapeutic options: a general overview on the preclinical validation of a multi-target ruthenium(III) complex lodged in nucleolipid nanosystems

In this review we have showcased the preclinical development of original amphiphilic nanomaterials designed for ruthenium‐based anticancer treatments, to be placed within the current metallodrugs approach leading over the past decade to advanced multitarget agents endowed with limited toxicity and resistance. This strategy could allow for new options for breast cancer (BC) interventions, including the triple‐negative subtype (TNBC) with poor therapeutic alternatives. BC is currently the second most widespread cancer and the primary cause of cancer death in women. Hence, the availability of novel chemotherapeutic weapons is a basic requirement to fight BC subtypes. Anticancer drugs based on ruthenium are among the most explored and advanced nextgeneration metallotherapeutics, with NAMI‐A and KP1019 as two iconic ruthenium complexes having undergone clinical trials. In addition, many nanomaterial Ru complexes have been recently conceived and developed into anticancer drugs demonstrating attractive properties. In this field, we focused on the evaluation of a Ru(III) complex—named AziRu—incorporated into a suite of both zwitterionic and cationic nucleolipid nanosystems, which proved to be very effective for the in vivo targeting of breast cancer cells (BBC). Mechanisms of action have been widely explored in the context of preclinical evaluations in vitro, highlighting a multitarget action on cell death pathways which are typically deregulated in neoplasms onset and progression. Moreover, being AziRu inspired by the well‐known NAMI‐A complex, information on non‐nanostructured Ru‐based anticancer agents have been included in a precise manner

Dependence of the Ce(III)/Ce(IV) ratio on intracellular localization in ceria nanoparticles internalized by human cells

CeO2 nanoparticles (CNPs) have been investigated as promising antioxidant agents with significant activity in the therapy of diseases involving free radicals or oxidative stress. However, the exact mechanism responsible for CNP activity has not been completely elucidated. In particular, in situ evidence of modification of the oxidative state of CNPs in human cells and their evolution during cell internalization and subsequent intracellular distribution has never been presented. In this study we investigated modification of the Ce(iii)/Ce(iv) ratio following internalization in human cells by X-ray absorption near edge spectroscopy (XANES). From this analysis on cell pellets, we observed that CNPs incubated for 24 h showed a significant increase in Ce(iii). By coupling on individual cells synchrotron micro-X-ray fluorescence (μXRF) with micro-XANES (μXANES) we demonstrated that the Ce(iii)/Ce(iv) ratio is also dependent on CNP intracellular localization. The regions with the highest CNP concentrations, suggested to be endolysosomes by transmission electron microscopy, were characterized by Ce atoms in the Ce(iv) oxidation state, while a higher Ce(iii) content was observed in regions surrounding these areas. These observations suggest that the interaction of CNPs with cells involves a complex mechanism in which different cellular areas play different roles