Loss of PPARγ activity characterizes early protumorigenic stromal reprogramming and dictates the therapeutic window of opportunity.

Although robustly expressed in the disease-free (DF) breast stroma, CD36 is consistently absent from the stroma surrounding invasive breast cancers (IBCs). In this study, we primarily observed CD36 expression in adipocytes and intralobular capillaries within the DF breast. Larger vessels concentrated in interlobular regions lacked CD36 and were instead marked by the expression of CD31. When evaluated in perilesional capillaries surrounding ductal carcinoma in situ, a nonobligate IBC precursor, CD36 loss was more commonly observed in lesions associated with subsequent IBC. Peroxisome proliferator-activated receptor γ (PPARγ) governs the expression of CD36 and genes involved in differentiation, metabolism, angiogenesis, and inflammation. Coincident with CD36 loss, we observed a dramatic suppression of PPARγ and its target genes in capillary endothelial cells (ECs) and pericytes, which typically surround and support the stability of the capillary endothelium. Factors present in conditioned media from malignant cells repressed PPARγ and its target genes not only in cultured ECs and pericytes but also in adipocytes, which require PPARγ for proper differentiation. In addition, we identified a role for PPARγ in opposing the transition of pericytes toward a tumor-supportive myofibroblast phenotype. In mouse xenograft models, early intervention with rosiglitazone, a PPARγ agonist, demonstrated significant antitumor effects; however, following the development of a palpable tumor, the antitumor effects of rosiglitazone were negated by the repression of PPARγ in the mouse stroma. In summary, PPARγ activity in healthy tissues places several stromal cell types in an antitumorigenic state, directly inhibiting EC proliferation, maintaining adipocyte differentiation, and suppressing the transition of pericytes into tumor-supportive myofibroblasts.

Ultrasensitive electrochemical immunoassay for melanoma cells using mesoporous polyaniline.

We report the development of an antibody (anti-MC1R antibody)-functionalized polyaniline nanofibers modified screen-printed electrode capable of efficient electrochemical detection of melanoma cells at levels (1 cell per mL) not readily achieved by other methods. This immunosensor is highly selective in its detection of melanoma cells over normal human cells.

Inhalation of concentrated PM2.5 from Mexico City acts as an adjuvant in a guinea pig model of allergic asthma.

Exposure to Particulate Matter (PM) could function as an adjuvant depending on the city of origin in mice allergic asthma models. Therefore, our aim was to determine whether inhalation of fine particles (PM2.5) from Mexico City could act as an adjuvant inducing allergic sensitization and/or worsening the asthmatic response in guinea pig, as a suitable model of human asthma. Experimental groups were Non-Sensitized (NS group), sensitized with Ovalbumin (OVA) plus Aluminum hydroxide (Al(OH)3) as adjuvant (S + Adj group), and sensitized (OVA) without adjuvant (S group). All the animals were exposed to Filtered Air (FA) or concentrated PM2.5 (5 h/daily/3 days), employing an aerosol concentrator system, PM2.5 composition was characterized. Lung function was evaluated by barometric plethysmography (Penh index). Inflammatory cells present in bronchoalveolar lavage were counted as well as OVA-specific IgG1 and IgE were determined by ELISA assay. Our results showed in sensitized animals without Al(OH)3, that the PM2.5 exposure (609 ± 12.73 µg/m3) acted as an adjuvant, triggering OVA-specific IgG1 and IgE concentration. Penh index increased ∼9-fold after OVA challenge in adjuvant-sensitized animals as well as in S + PM2.5 group (∼6-fold), meanwhile NS + FA and S + FA lacked response. S + Adj + PM2.5 group showed an increase significantly of eosinophils and neutrophils in bronchoalveolar lavage. PM2.5 composition was made up of inorganic elements and Polycyclic Aromatic Hydrocarbons, as well as endotoxins and ß-glucan, all these components could act as adjuvant. Our study demonstrated that acute inhalation of PM2.5 acted as an adjuvant, similar to the aluminum hydroxide effect, triggering allergic asthma in a guinea pig model. Furthermore, in sensitized animals with aluminum hydroxide an enhancing influence of PM2.5 exposure was observed as specific-hyperresponsiveness to OVA challenge (quickly response) and eosinophilic and neutrophilic airway inflammation. Fine particles from Mexico City is a complex mix, which play a significant role as adjuvant in allergic asthma.

Relación de los mecanismos inmunológicos del asma y la contaminación ambiental / Correlation of immunologic mechanisms of asthma and air pollution

Resumen Introducción. Se calcula que más de 300 millones de personas alrededor del mundo padecen asma y se estima que para el año 2025 esta cifra se incremente a 400 millones debido a los contaminantes criterio. Sin embargo, dadas sus limitaciones, los estudios epidemiológicos son controversiales sobre la contaminación y el desarrollo de asma. Objetivos. Describir las diferencias y similitudes de la respuesta inmunológica de pacientes asmáticos y los modelos animales de asma alérgica después de la exposición a contaminantes criterio y elementos biológicos, para así identificar los factores inmunológicos relacionados con el desarrollo de asma. Materiales y método. Se realizó una búsqueda sistemática en las bases de datos sobre asma y los diferentes contaminantes criterio. Resultados. La respuesta Th2 es activada por la inhalación de ozono, dióxido de nitrógeno, azufre y la exposición aguda a material particulado, mientras que el contacto con ciertos tipos de pólenes y glucanos y la exposición crónica de partículas incrementa la respuesta Th1, la cual inhibe a la respuesta Th2 produciendo un "efecto protector". Conclusiones. La respuesta Th1 podría causar baja o nula asociación entre la exposición a contaminación y el desarrollo de asma en las diferentes ciudades, adicionando de esta manera otra limitación a los estudios epidemiológicos.

Abstract Introduction: More than 300 million people around the world suffer from asthma, and estimations indicate that this figure will increase to 400 million by 2025 due to criteria pollutants. However, given their limitations, epidemiological studies on pollution and its role in the development of asthma are controversial. Objectives: To describe the differences and similarities of the immunological response of asthmatic patients and animal models to allergic asthma after exposure to criteria pollutants and biological elements, in order to identify the immunological factors related to the development of asthma. Materials and methods: A systematic search was conducted in asthma databases and criteria pollutants. Results: The Th2 response is activated by the inhalation of ozone, nitrogen dioxide, sulfur and acute exposure to particulate matter. On the other hand, contact with certain types of pollens and glucans and the chronic exposure of particles increases the Th1 response, which inhibits Th2 response producing a "protective effect". Conclusions: Th1 response could cause low or no association between exposure to pollution and the development of asthma in different cities, which constitutes another limitation in epidemiological studies.

Particulate matter inside of the alveolar macrophage / Material particulado dentro del macrófago alveolar

The inhalation of toxic environmental particles is a worldwide public health issue. To avoid the pulmonary damage, the lungs contain the alveolar macrophages, which are the primary defense of the innate immune system, since it engulfs the toxic or allergic particles. Morphologically, particulate matter inside of macrophage is observed as numerous round dark granules of vari­ous size. In guinea pig, the inhalation of fine particles in real time showed single round dark granules inside of the macrophages. After particles exposure, the alveolar macrophage can activate some cytokines such as TNF-α, IL-1β, IL-6, IL-8, and GM-CSF, which increases the inflammatory response or to activate the Th2 response. The alveolar macrophage interacts with bronchial and bronchiolar epithelium, heart, and blood vessels producing a variety of problems, such as nonfatal heart attacks, irregular heartbeat, decreased lung function, and increases respiratory symptoms such as irritation of the airways, coughing or difficulty breathing, ag­gravated asthma, and produce premature death in people with heart or lung disease.

La inhalación de partículas tóxicas ambientales es un problema de salud pública en todo el mundo. Para prevenir el daño, los pulmones contienen a los macrófagos alveolares, los cuales son la defensa primaria del sistema inmune, ya que fagocitan los tóxicos o partículas alérgicas. Morfológicamente, el material particulado dentro de los macrófagos alveolares se observa como numerosos gránulos redondos de varios tamaños. En cobayos, la inhalación de partículas finas en tiempo real mostró gránulos re­dondos oscuros dentro de los macrófagos. Después de la exposición a las partículas, el macrófago alveolar puede activar algunas citocinas como TNF-α, IL-1β, IL-6, IL-8, and GM-CSF, las cuales incrementan la respuesta inflamatoria o activan la respuesta Th2. El macrófago alveolar interactúa con el epitelio bronquial y bronquiolar, corazón y vasos sanguíneos, produciendo una variedad de problemas, tales como afecciones cardíacas, arritmias, disminución de la función pulmonar, e incrementa los síntomas res­piratorios como irritación de las vías respiratorias, tos, dificultad para respirar, agrava el asma y produce muertes prematuras en personas con enfermedades cardiacas y pulmonares.

Suicide in University students in Bogotá, Colombia, 2004-2014. / Suicidio en estudiantes universitarios en Bogotá, Colombia, 2004­2014.

We report the results of a retrospective, descriptive, qualitative study of suicide among university students in Bogotá, Colombia. The objective of this study was to document the magnitude, principal characteristics, and impact of this phenomenon in the selected population. A semi-structured survey was employed to collect information from 66 individuals linked to the universities. A total of 45 cases of suicide were documented in the study period (2004 - 2014). Of these, 69% occurred in males and 31% in females. The age range was 17 - 27 years, with 62% of the cases in the 19 - 22 year-old group. The most common mechanisms employed were suffocation and poisoning, followed by intentional falls, use of a firearm, and drug overdose. The selected location was the place of residence in 52% of cases and the university campus in 16% of cases. The distribution of students by area of knowledge showed a predominance of social and human science (44%) followed by engineering (22%). A history of difficulties in family and affective relationships was common among victims, as was a history of exposure to intolerance of differences in sexual orientation. The individuals surveyed expressed a wide range of interpretations of the significance of suicide, both positive (courage, self-affirmation, autonomy) and negative (defeat, despair, and an inability to adapt).

Suicidio en estudiantes universitarios en Bogotá, Colombia, 2004-2014 / Suicide in University students in Bogotá, Colombia, 2004-2014

Resumen Estudio cualitativo, exploratorio, descriptivo y retrospectivo en cinco universidades de Bogotá, Colombia, para conocer la magnitud, las principales características y significados y el impacto del suicidio de estudiantes universitarios. Se realizaron 66 entrevistas semiestructuradas a personal institucional. Se identificaron 45 casos de suicidio consumado en el período 2004 - 2014. El 69% de los casos fueron hombres y el 31% mujeres. El rango de edad estuvo entre 17 y 27 años; 62% entre 19 y 22 años. Las formas más frecuentes de cometer el suicidio fueron el ahorcamiento y el envenenamiento, seguidos del lanzamiento al vacío, el uso de armas de fuego y el consumo de sustancias psicoactivas. El 52% de los casos eligió el lugar de residencia para cometer el hecho; el 16% eligió el campus universitario. Áreas de conocimiento: el 44% pertenecía a ciencias sociales y humanas y el 22% a ingenierías. Motivos y procesos desencadenantes del suicidio identificados, el principal grupo se relaciona con lo familiar, en especial desintegración familiar, ruptura de relaciones de pareja e intolerancia a opciones sexuales diferentes. Los entrevistados expresaron diversos significados del suicidio, tanto positivos: acto de valor y ejercicio de la autonomía, como negativos: impotencia, desadaptación y derrota.

Abstract We report the results of a retrospective, descriptive, qualitative study of suicide among university students in Bogotá, Colombia. The objective of this study was to document the magnitude, principal characteristics, and impact of this phenomenon in the selected population. A semi-structured survey was employed to collect information from 66 individuals linked to the universities. A total of 45 cases of suicide were documented in the study period (2004 – 2014). Of these, 69% occurred in males and 31% in females. The age range was 17 – 27 years, with 62% of the cases in the 19 – 22 year-old group. The most common mechanisms employed were suffocation and poisoning, followed by intentional falls, use of a firearm, and drug overdose. The selected location was the place of residence in 52% of cases and the university campus in 16% of cases. The distribution of students by area of knowledge showed a predominance of social and human science (44%) followed by engineering (22%). A history of difficulties in family and affective relationships was common among victims, as was a history of exposure to intolerance of differences in sexual orientation. The individuals surveyed expressed a wide range of interpretations of the significance of suicide, both positive (courage, self-affirmation, autonomy) and negative (defeat, despair, and an inability to adapt).

Cyclic AMP (cAMP) signaling in melanocytes and melanoma.

G-protein coupled receptors (GPCRs), which include melanocortin-1 receptor (MC1R), play a crucial role in melanocytes development, proliferation and differentiation. Activation of the MC1R by the α-melanocyte stimulating hormone (α-MSH) leads to the activation of the cAMP signaling pathway that is mainly associated with differentiation and pigment production. Some MC1R polymorphisms produce cAMP signaling impairment and pigmentary phenotypes such as the red head color and fair skin phenotype (RHC) that is usually associated with higher risk for melanoma development. Despite its importance in melanocyte biology, the role of cAMP signaling cutaneous melanoma is not well understood. Melanoma is primarily driven by mutations in the components of mitogen-activated protein kinases (MAPK) pathway. Increasing evidence, however, now suggests that cAMP signaling also plays an important role in melanoma even though genetic alterations in components of this pathway are note commonly found in melanoma. Here we review these new roles for cAMP in melanoma including its contribution to the notorious treatment resistance of melanoma.

[General aspects of pulmonary innervation]. / Aspectos generales de la inervación pulmonar.

Practically all organs of the respiratory system are under the control of the autonomic nervous system. Double vegetative innervation, sympathetic and parasympathetic, contributes to the regulation of airway smooth muscle tone, and modulates secretion from the submucosal glands. Nevertheless, more than 20 years ago, the classical view of excitatory cholinergic and inhibitory adrenergic innervation changed considerably when the existence was proved of the non-adrenergic non-cholinergic system (NANC), which is able to produce both effects. Several purines and peptides have been postulated as neurotransmitters of this system, and some of them coexist with the acetylcholine or norepinephrine; for example, vasoactive intestinal peptide (VIP) on cholinergic nerves and neuropeptide Y in the adrenergic nerves. The aim of this paper is to describe the anatomo-physiological aspects of the airways' autonomic innervation and the possible implication of a neural mechanism that contributes in the development of the symptomatology in respiratory diseases.

[Signaling pathways involved in megakaryopoiesis]. / Vías de señalización implicadas en la megacariopoyesis.

Hematotoxicology has been studied with less interest than other fields associated with atmospheric pollution. There is limited knowledge about on the effects that certain atmospheric pollutants may provoke in the blood and bone marrow. Suspended particle pollution has become an area of scientific inquiry due to the contaminants adhering to its surface. We have identified the association of inhaled vanadium and variations in megakaryopoyesis and thrombopoyesis. Platelets are the smallest elements in the blood, but they play a strategic role in hemostasis. They are derived from the largest cell of the bone marrow, the megakaryocite. This cell size is about 150 microm, with apolyploid nucleus and unknown origin until few years ago. When TPO was cloned in 1994 the knowledge about megakaryocyte began to growth exponentially, elucidating the mechanisms of proliferation, differentiation and release of platelets. More information is still needed in order to translate knowledge into clinical application for diseases such as thrombocytopenia or thrombocytosis. A review of the current concepts of megakaryopoiesis and its regulation, with emphasis on signaling pathways are presented in this paper; a classification in TPO-dependent and TPO-independent is also detailed. In addition, we review some diseases associated with changes in the signaling pathway of megakaryopoyesis, as well as possible perspectives in this field, including toxicology.

Vías de señalización implicadas en la megacariopoyesis / Signaling pathways involved in megakaryopoiesis

La hematotoxicología es un área poco estudiada en nuestro país y es limitado el conocimiento sobre el efecto que ciertos contaminantes atmosféricos inducen en la sangre y en la médula ósea. La contaminación por partículas suspendidas ha cobrado más interés, por los contaminantes que se adhieren a su superficie. Un ejemplo es el benceno, relacionado con aplasia medular y leucemia. Algunos metales que también están en las partículas inhaladas son hematotóxicos. Uno de ellos es el vanadio, que nuestro grupo ha identificado como un agente inductor de alteraciones en la megacariopoyesis, lo que motivó esta revisión. Las plaquetas desempeñan un papel muy importante en la hemostasia y derivan de la célula más grande de la médula ósea: el megacariocito. Hasta hace algunos años desconocíamos casi todo del megacariocito, pero con la clonación de la trombopoyetina, en 1994, la principal hormona reguladora de la producción plaquetaria, ha existido un desarrollo acelerado en el conocimiento de la megacariopoyesis. Este artículo hace una revisión de la megacariopoyesis y su regulación, con énfasis en las vías de señalización implicadas. Además, se mencionan algunas enfermedades relacionadas y se discuten las perspectivas de investigación de este proceso, con énfasis en la toxicología.

Hematotoxicology has been studied with less interest than other fields associated with atmospheric pollution. There is limited knowledge about on the effects that certain atmospheric pollutants may provoke in the blood and bone marrow. Suspended particle pollution has become an area of scientific inquiry due to the contaminants adhering to its surface. We have identified the association of inhaled vanadium and variations in megakaryopoyesis and thrombopoyesis. Platelets are the smallest elements in the blood, but they play a strategic role in hemostasis. They are derived from the largest cell of the bone marrow, the megakaryocite. This cell size is about 150 microm, with apolyploid nucleus and unknown origin until few years ago. When TPO was cloned in 1994 the knowledge about megakaryocyte began to growth exponentially, elucidating the mechanisms of proliferation, differentiation and release of platelets. More information is still needed in order to translate knowledge into clinical application for diseases such as thrombocytopenia or thrombocytosis. A review of the current concepts of megakaryopoiesis and its regulation, with emphasis on signaling pathways are presented in this paper; a classification in TPO-dependent and TPO-independent is also detailed. In addition, we review some diseases associated with changes in the signaling pathway of megakaryopoyesis, as well as possible perspectives in this field, including toxicology.