Targeting epidermal growth factor receptor to recruit newly generated neuroblasts in cortical brain injuries.

BACKGROUND: Neurogenesis is stimulated in the subventricular zone (SVZ) of mice with cortical brain injuries. In most of these injuries, newly generated neuroblasts attempt to migrate toward the injury, accumulating within the corpus callosum not reaching the perilesional area. METHODS: We use a murine model of mechanical cortical brain injury, in which we perform unilateral cortical injuries in the primary motor cortex of adult male mice. We study neurogenesis in the SVZ and perilesional area at 7 and 14 dpi as well as the expression and concentration of the signaling molecule transforming growth factor alpha (TGF-α) and its receptor the epidermal growth factor (EGFR). We use the EGFR inhibitor Afatinib to promote neurogenesis in brain injuries. RESULTS: We show that microglial cells that emerge within the injured area and the SVZ in response to the injury express high levels of TGF-α leading to elevated concentrations of TGF-α in the cerebrospinal fluid. Thus, the number of neuroblasts in the SVZ increases in response to the injury, a large number of these neuroblasts remain immature and proliferate expressing the epidermal growth factor receptor (EGFR) and the proliferation marker Ki67. Restraining TGF-α release with a classical protein kinase C inhibitor reduces the number of these proliferative EGFR+ immature neuroblasts in the SVZ. In accordance, the inhibition of the TGF-α receptor, EGFR promotes migration of neuroblasts toward the injury leading to an elevated number of neuroblasts within the perilesional area. CONCLUSIONS: Our results indicate that in response to an injury, microglial cells activated within the injury and the SVZ release TGF-α, activating the EGFR present in the neuroblasts membrane inducing their proliferation, delaying maturation and negatively regulating migration. The inactivation of this signaling pathway stimulates neuroblast migration toward the injury and enhances the quantity of neuroblasts within the injured area. These results suggest that these proteins may be used as target molecules to regenerate brain injuries.

Targeting Protein Kinase C in Glioblastoma Treatment.

Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor and is associated with a poor prognosis. Despite the use of combined treatment approaches, recurrence is almost inevitable and survival longer than 14 or 15 months after diagnosis is low. It is therefore necessary to identify new therapeutic targets to fight GBM progression and recurrence. Some publications have pointed out the role of glioma stem cells (GSCs) as the origin of GBM. These cells, with characteristics of neural stem cells (NSC) present in physiological neurogenic niches, have been proposed as being responsible for the high resistance of GBM to current treatments such as temozolomide (TMZ). The protein Kinase C (PKC) family members play an essential role in transducing signals related with cell cycle entrance, differentiation and apoptosis in NSC and participate in distinct signaling cascades that determine NSC and GSC dynamics. Thus, PKC could be a suitable druggable target to treat recurrent GBM. Clinical trials have tested the efficacy of PKCß inhibitors, and preclinical studies have focused on other PKC isozymes. Here, we discuss the idea that other PKC isozymes may also be involved in GBM progression and that the development of a new generation of effective drugs should consider the balance between the activation of different PKC subtypes.

Evolution of Experimental Models in the Study of Glioblastoma: Toward Finding Efficient Treatments.

Glioblastoma (GBM) is the most common form of brain tumor characterized by its resistance to conventional therapies, including temozolomide, the most widely used chemotherapeutic agent in the treatment of GBM. Within the tumor, the presence of glioma stem cells (GSC) seems to be the reason for drug resistance. The discovery of GSC has boosted the search for new experimental models to study GBM, which allow the development of new GBM treatments targeting these cells. In here, we describe different strategies currently in use to study GBM. Initial GBM investigations were focused in the development of xenograft assays. Thereafter, techniques advanced to dissociate tumor cells into single-cell suspensions, which generate aggregates referred to as neurospheres, thus facilitating their selective expansion. Concomitantly, the finding of genes involved in the initiation and progression of GBM tumors, led to the generation of mice models for the GBM. The latest advances have been the use of GBM organoids or 3D-bioprinted mini-brains. 3D bio-printing mimics tissue cytoarchitecture by combining different types of cells interacting with each other and with extracellular matrix components. These in vivo models faithfully replicate human diseases in which the effect of new drugs can easily be tested. Based on recent data from human glioblastoma, this review critically evaluates the different experimental models used in the study of GB, including cell cultures, mouse models, brain organoids, and 3D bioprinting focusing in the advantages and disadvantages of each approach to understand the mechanisms involved in the progression and treatment response of this devastating disease.

DnaJ molecules as potential effectors in Meloidogyne arenaria. An unexplored group of proteins in plant parasitic nematodes.

Plant pathogenic organisms secrete proteins called effectors that recognize, infect and promote disease within host cells. Bacteria, like Pseudomona syringae, use effectors with DnaJ function to disrupt plant defenses. DnaJ proteins (also called Hsp40) are a group of co-chaperone molecules, which assist in the folding of proteins. Despite the described role of DnaJs as effectors in several groups of pathogens, this group of proteins has never been correlated with the infection process in plant parasitic nematodes. In this study, we analyze the importance of DnaJ for plant parasitic nematodes. To do that, we compare the number of DnaJ proteins in nematodes with different lifestyles. Then, we predict the secreted DnaJ proteins in order to detect effector candidates. We found that Meloidogyne species have more secreted DnaJs than the rest of the nematodes analyzed in the study. Particularly, M. arenaria possess the highest proportion of secreted DnaJ sequences in comparison to total DnaJ proteins. Furthermore, we found in this species at least five sequences with a putative nuclear localization signal, three of them with a serine rich region with an unknown function. Then, we chose one of these sequences (MG599854) to perform an expression analysis. We found that MG599854 is over-expressed from 3 days post inoculation onwards in tomato plants. Moreover, MG599854 seems to be enough to produce cell death in Nicotiana benthamiana under transient expression conditions. In concordance with our results, we propose that DnaJ proteins are a potential source of effector proteins in plant parasitic nematodes.

Protein Kinase C: Targets to Regenerate Brain Injuries?

Acute or chronic injury to the central nervous system (CNS), causes neuronal death and irreversible cognitive deficits or sensory-motor alteration. Despite the capacity of the adult CNS to generate new neurons from neural stem cells (NSC), neuronal replacement following an injury is a restricted process, which does not naturally result in functional regeneration. Therefore, potentiating endogenous neurogenesis is one of the strategies that are currently being under study to regenerate damaged brain tissue. The insignificant neurogenesis that occurs in CNS injuries is a consequence of the gliogenic/non-neurogenic environment that inflammatory signaling molecules create within the injured area. The modification of the extracellular signals to generate a neurogenic environment would facilitate neuronal replacement. However, in order to generate this environment, it is necessary to unearth which molecules promote or impair neurogenesis to introduce the first and/or eliminate the latter. Specific isozymes of the protein kinase C (PKC) family differentially contribute to generate a gliogenic or neurogenic environment in injuries by regulating the ADAM17 mediated release of growth factor receptor ligands. Recent reports describe several non-tumorigenic diterpenes isolated from plants of the Euphorbia genus, which specifically modulate the activity of PKC isozymes promoting neurogenesis. Diterpenes with 12-deoxyphorbol or lathyrane skeleton, increase NPC proliferation in neurogenic niches in the adult mouse brain in a PKCß dependent manner exerting their effects on transit amplifying cells, whereas PKC inhibition in injuries promotes neurogenesis. Thus, compounds that balance PKC activity in injuries might be of use in the development of new drugs and therapeutic strategies to regenerate brain injuries.

Results of endoscopic nasal surgery in the treatment of invasive fungal sinusitis in children with cancer and immunosuppression. / Resultados de cirugía endoscópica nasal en el tratamiento de sinusitis fúngica invasiva en niños con cáncer e inmunosupresión.

BACKGROUND AND OBJECTIVE: to describe the results of the treatment of invasive fungal sinusitis with nasal endoscopic surgery in an immunocompromised paediatric oncological population. METHODS: retrospective study of all patients diagnosed with invasive fungal sinusitis operated in the National Paediatric Oncology Unit between 2012 and 2016. Data taken from their medical history included: epidemiological characteristics, oncological diagnosis, haematological data, symptoms, tomographic studies, surgical interventions, results of pathology and cultures, medications received, complications, evolution and survival. RESULTS: 18 patients were identified, 7 male and 11 female. The average age was 12 years, 13 had a diagnosis of acute lymphocytic leukemia and 5 of acute myeloid leukemia. Seventeen patients presented severe neutropenia at the time of diagnosis. The most frequently identified aetiological agent was Aspergillus in 13 patients. In 16 patients (89%) the disease was controlled with nasal endoscopic surgery. Ten patients died due to unrelated causes throughout the study. DISCUSSION AND CONCLUSIONS: Invasive fungal sinusitis should be considered a medical emergency due to its high mortality. The diagnosis is based on a high index of suspicion in patients with predisposing factors (leukaemia, neutropenia, persistent fever, nasogastric tube) and endoscopic nasal evaluation. Antifungal medical treatment and aggressive nasal endoscopic surgery is indicated regardless of the patient's condition to reduce the fungal burden and associated high mortality. The treatment must be provided by a multidisciplinary team that includes paediatrics, haemato-oncology, infectology and otorhinolaryngology.

Phytophthora infestans effector AVRblb2 prevents secretion of a plant immune protease at the haustorial interface.

In response to pathogen attack, plant cells secrete antimicrobial molecules at the site of infection. However, how plant pathogens interfere with defense-related focal secretion remains poorly known. Here we show that the host-translocated RXLR-type effector protein AVRblb2 of the Irish potato famine pathogen Phytophthora infestans focally accumulates around haustoria, specialized infection structures that form inside plant cells, and promotes virulence by interfering with the execution of host defenses. AVRblb2 significantly enhances susceptibility of host plants to P. infestans by targeting the host papain-like cysteine protease C14 and specifically preventing its secretion into the apoplast. Plants altered in C14 expression were significantly affected in susceptibility to P. infestans in a manner consistent with a positive role of C14 in plant immunity. Our findings point to a unique counterdefense strategy that plant pathogens use to neutralize secreted host defense proteases. Effectors, such as AVRblb2, can be used as molecular probes to dissect focal immune responses at pathogen penetration sites.

In planta expression screens of Phytophthora infestans RXLR effectors reveal diverse phenotypes, including activation of the Solanum bulbocastanum disease resistance protein Rpi-blb2.

The Irish potato famine pathogen Phytophthora infestans is predicted to secrete hundreds of effector proteins. To address the challenge of assigning biological functions to computationally predicted effector genes, we combined allele mining with high-throughput in planta expression. We developed a library of 62 infection-ready P. infestans RXLR effector clones, obtained using primer pairs corresponding to 32 genes and assigned activities to several of these genes. This approach revealed that 16 of the 62 examined effectors cause phenotypes when expressed inside plant cells. Besides the well-studied AVR3a effector, two additional effectors, PexRD8 and PexRD36(45-1), suppressed the hypersensitive cell death triggered by the elicitin INF1, another secreted protein of P. infestans. One effector, PexRD2, promoted cell death in Nicotiana benthamiana and other solanaceous plants. Finally, two families of effectors induced hypersensitive cell death specifically in the presence of the Solanum bulbocastanum late blight resistance genes Rpi-blb1 and Rpi-blb2, thereby exhibiting the activities expected for Avrblb1 and Avrblb2. The AVRblb2 family was then studied in more detail and found to be highly variable and under diversifying selection in P. infestans. Structure-function experiments indicated that a 34-amino acid region in the C-terminal half of AVRblb2 is sufficient for triggering Rpi-blb2 hypersensitivity and that a single positively selected AVRblb2 residue is critical for recognition by Rpi-blb2.

Mecanismo de presentación antigénica en el tejido pulpar / Mechanism of antigenic presentation in the pulp tissue

La infección multimicrobiana de la pulpa dental desencadena respuetas inflamatorias. Bacterias y sustancias nocivas pueden alcanzar acceso directo a la pulpa por medio de los túbulos dentinarios. En años recientes, la investigación en biología pulpar ha brindado profundo entendimiento de los mecanismos básicos que gobiernan la defensa y reparación pulpar. Células dendríticas (células profesionales presentadoras de antígeno) son tanto sensoras como mensajeras que forman una red de advertencia inicial de diferentes tejidos y expresan antígenos Clase II que indican la capacidad para presentar antígenos a células T helper. Estas células están localizadas en la capa odontoblástica, así como en la porción central del tejido pulpar y juegan un papel importante en la captura de antígenos, migración al nódulo linfático regional. Sin embargo, la presencia de células T en tejido pulpar normal demuestra que éste es provisto con células inmunocompetentes esenciales para la iniciación de la respuesta inmune. Las células dendríticas pueden interactual también con vasos y nervios pulpares. De este modo la respueta neuroinmunológica de la pulpa puede ser la primera reacción de defensa en el órgano dentinopulpar

Un desafío emergente para la salud de la comunidad: Promoción de la salud / An emerging challenge for community health: health promotion

En este artículo se presenta una conceptualización de la promoción de la salud analizando, en la práctica, los obstáculos que los equipos de salud, y en especial enfermería, enfrentan para lograr aplicar el enfoque de promoción de la salud actual. Así mismo, se discute la medición de la promoción de la salud desde la perspectiva de los indicadores sociales que se proponen y su operacionalización de acuerdo con la realidad.

Desnutriçäo: triagem e diagnóstico / Malnutrition: selection and diagnosis

É mostrada a dificuldade de diagnóstico da desnutriçäo e propöe critérios para triagem do desnutrido tendo por base o Estudo Antropométrico - Santo André 1978 (Marcondes, E. - Pediatria (SP-1982). Desta forma, pode-se incluir num programa de atençäo às crianças, todas aquelas que se apresentem desnutridas e também aquelas em risco de desnutrir-se