Intravital Microscopy of the Mouse Brain Microcirculation using a Closed Cranial Window

This experimental model was designed to assess the mouse pial microcirculation during acute and chronic, physiological and pathophysiological hemodynamic, inflammatory and metabolic conditions, using in vivo fluorescence microscopy. A closed cranial window is placed over the left parieto-occipital cortex of the mice. Local microcirculation is recorded in real time through the window using epi and fluorescence illumination, and measurements of vessels diameters and red blood cell (RBC) velocities are performed. RBC velocity is measured using real-time cross-correlation and/or fluorescent-labeled erythrocytes. Leukocyte and platelet adherence to pial vessels and assessment of perfusion and vascular leakage are made with the help of fluorescence-labeled markers such as Albumin-FITC and anti-CD45-TxR antibodies. Microcirculation can be repeatedly video-recorded over several days. We used for the first time the close window brain intravital microscopy to study the pial microcirculation to follow dynamic changes during the course of Plasmodium berghei ANKA infection in mice and show that expression of CM is associated with microcirculatory dysfunctions characterized by vasoconstriction, profound decrease in blood flow and eventually vascular collapse

Partial Response to Platinum Doublets in Refractory EGFR-Positive Non-Small Cell Lung Cancer Patients after RRx-001: Evidence of Episensitization.

RRx-001, an experimental systemically non-toxic epi-immunotherapeutic agent, which potentiates the resensitization of resistant cancer cells to formerly effective therapies, is under active investigation in several clinical trials that are based on sequential or concomitant rechallenge to resistant first- or second-line regimens. One of these trials is designated TRIPLE THREAT (NCT02489903), because it explores the conditioning or priming effect of RRx-001 on three tumor types - non-small cell lung cancer (NSCLC), small cell lung cancer and high-grade neuroendocrine tumors - prior to re-administration of platinum doublets. In follow-up to a recent case study, which describes early monotherapeutic benefit with RRx-001 in a refractory EGFR-mutated NSCLC tumor, we present subsequent evidence of a radiological partial response to reintroduced platinum doublets after RRx-001. For the 50% of patients with EGFR-mutated NSCLC who progress on EGFR-tyrosine kinase inhibitors (without evidence of a T790M mutations) as well as platinum doublets and pemetrexed/taxane, no other clinically established treatment options exist. A retrial of these therapies in EGFR-positive NSCLC patients via priming with epigenetic agents such as RRx-001 constitutes a strategy to 'episensitize' tumors (i.e. reverse resistance by epigenetic means) and to extend overall survival

Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge's disease.

In this study, because excessive polycythemia is a predominant trait in some high-altitude dwellers (chronic mountain sickness [CMS] or Monge's disease) but not others living at the same altitude in the Andes, we took advantage of this human experiment of nature and used a combination of induced pluripotent stem cell technology, genomics, and molecular biology in this unique population to understand the molecular basis for hypoxia-induced excessive polycythemia. As compared with sea-level controls and non-CMS subjects who responded to hypoxia by increasing their RBCs modestly or not at all, respectively, CMS cells increased theirs remarkably (up to 60-fold). Although there was a switch from fetal to adult HgbA0 in all populations and a concomitant shift in oxygen binding, we found that CMS cells matured faster and had a higher efficiency and proliferative potential than non-CMS cells. We also established that SENP1 plays a critical role in the differential erythropoietic response of CMS and non-CMS subjects: we can convert the CMS phenotype into that of non-CMS and vice versa by altering SENP1 levels. We also demonstrated that GATA1 is an essential downstream target of SENP1 and that the differential expression and response of GATA1 and Bcl-xL are a key mechanism underlying CMS pathology

La visión técnica del arquitecto: Francisco Hernández-Rubio y el hormigón armado

El presente artículo ofrece el comentario de una conferencia inédita del arquitecto jerezano Francisco Hernández-Rubio, analizando su apreciación de los diversos estilos artísticos y, sobre todo, su profundo conocimiento en una fecha relativamente temprana en España de la técnica del hormigón armado. Se trata con ello de reivindicar la figura de un profesional desconocido y no desprovisto de interés y de acometer un estudio esquemático y preliminar del problema de la introducción en España del hormigón armado como ramificación tardía de la generalizada polémica ingenieros/arquitectos, en la que Hernández-Rubio demuestra ser una interesante excepción y un ejemplo notable de aquellos arquitectos que no olvidaban el papel de lo técnico en su arte.The author comments on an unpublihed lecture given by the Jerez architect Francisco Hernández-Rubio. Hernández-Rubio 's views on a variety of artistic styles are discussed, as is his deep undersanding -relatively early in the history of Spanish architecture- of the technique of using reinforced concrete. This is, then, an attempt t do justice to a seriours professional of interest study of the late introduction in Spain of reinforced concrete, and of the polemical discussions between engineers and architects: in this respect, Hernández-Rubio was a remarkable exception, in that he, together with sorne other architets, did not neglect the role played in his art by technical materials and methods

The engineer as a martyr to modernity in Doña Perfecta

El artículo da cuenta de la visión estética de Pérez Galdós al elegir como protagonista de una de sus primeras obras importantes a un ingeniero. El autor toma partido en la polémica ingenieros-arquitectos y Pepe Rey, el personaje central de Doña Perfecta se alza como víctima de una serie de prejuicios políticos y provincianos que convierten a Orbajosa, la ciudad en la que sitúa la trama, en el ejemplo ideal de una España rancia e intolerante. El análisis incide sobre la validez de la narrativa como fuente de la historia y de la subjetividad de cada época.In one of his first important works Pérez Galdos presents an engineer as protagonist, and takes sides in the polemical discussions which took place between engineers and architects. Pepe Rey, the central character of Doña Perfecta, becomes the victim of the political and provincial feuds that occur in Orbajosa, which is presented as a representative illustration of an intolerant and old-fashioned Spain. Our analysis also deals with the narrative as historical source material and reflects on the role played by subjectivity in every historical period