Carbonic anhydrase IX expression, a novel surrogate marker of tumor hypoxia, is associated with a poor prognosis in non-small-cell lung cancer

Purpose To evaluate carbonic anhydrase (CA) IX as a surrogate marker of hypoxia and investigate the prognostic significance of different patterns of expression in non-small-cell lung cancer (NSCLC). Methods Standard immunohistochemical techniques were used to study CA IX expression in 175 resected NSCLC tumors. CA IX expression was determined by Western blotting in A549 cell lines grown under normoxic and hypoxic conditions. Measurements from microvessels to CA IX positivity were obtained. Results CA IX immunostaining was detected in 81.8% of patients. Membranous (m) (P = .005), cytoplasmic (c) (P = .018), and stromal (P < .001) CA IX expression correlated with the extent of tumor necrosis (TN). The mean distance from vascular endothelium to the start of tumor cell positivity was 90 μm, which equates to an oxygen pressure of 5.77 mmHg. The distance to blood vessels from individual tumor cells or tumor cell clusters was greater if they expressed mCA IX than if they did not (P < .001). Hypoxic exposure of A549 cells for 16 hours enhanced CAIX expression in the nuclear and cytosolic extracts. Perinuclear (p) CA IX (P = .035) was associated with a poor prognosis. In multivariate analysis, pCA IX (P = .004), stage (P = .001), platelet count (P = .011), sex (P = .027), and TN (P = .035) were independent poor prognostic factors. Conclusion These results add weight to the contention that mCA IX is a marker of tumor cell hypoxia. The absence of CA IX staining close to microvessels suggests that these vessels are functionally active. pCA IX expression is representative of an aggressive phenotype. © 2003 by American Society of Clinical Oncology.

Control social y familia en el siglo XIX colombiano : una aproximación a distintas prácticas de regulación estatal

This article explores a number of social control strategies on individuals and families actioned by the newly created state-national project during the first decades of Colombian XIX century. With special attention on the discourse of urbanity, also named 'civility or good manners', this paper analyses literary sources produced in the time for molding citizens behaviors in order to incorporate the society into the new paradigm of Modernity.

A H-1-NMR STUDY OF BILIRUBIN IX-ALPHA SOLUBILIZATION BY CHOLATE MICELLES - APPLICATION OF NUCLEAR OVERHAUSER EFFECTS

The solubilization of bilirubin IX-Alpha in aqueous solution by sodium cholate micelles has been examined by 270 MHz 1H-NMR spectroscopy. Incorporation of bilirubin into the micelles is accompanied by specific shifts of bilirubin vinyl and bridgehead protons and the C18 and C19 methyl groups of the steroid. The observed chemical shifts show a monotonic concentration dependence suggesting that changes in aggregation size are continuous. Nuclear Overhauser effects (NOE) have been shown to be a useful probe or micellization. A 4:1 cholate/bilirubin mixture has been investigated by difference NOE spectroscopy. The observation of intermolecular nuclear Overhauser effects between peripheral protons of bilirubin and cholate are diagnostic of spatially proximate groups. Inter-cholate nuclear Overhauser effects increase in magnitude upon bilirubin incorporation suggesting closer packing of steroid molecules on solubilization of the pigment. Intramolecular nuclear Overhauser effects observed for solubilized bilirubin are consistent with a compact intramolecularly hydrogen-bonded conformation resembling that determined for bilirubin in the solid state.

Long-term trends in fertility of soils under continuous cultivation and cereal cropping in southern Queensland. IX. Simulation of soil carbon and nitrogen pools using CENTURY model

Cultivation and cropping of soils results in a decline in soil organic carbon and soil nitrogen, and can lead to reduced crop yields. The CENTURY model was used to simulate the effects of continuous cultivation and cereal cropping on total soil organic matter (C and N), carbon pools, nitrogen mineralisation, and crop yield from 6 locations in southern Queensland. The model was calibrated for each replicate from the original datasets, allowing comparisons for each replicate rather than site averages. The CENTURY model was able to satisfactorily predict the impact of long-term cultivation and cereal cropping on total organic carbon, but was less successful in simulating the different fractions and nitrogen mineralisation. The model firstly over-predicted the initial (pre-cropping) soil carbon and nitrogen concentration of the sites. To account for the unique shrinking and swelling characteristics of the Vertosol soils, the default annual decomposition rates of the slow and passive carbon pools were doubled, and then the model accurately predicted initial conditions. The ability of the model to predict carbon pool fractions varied, demonstrating the difficulty inherent in predicting the size of these conceptual pools. The strength of the model lies in the ability to closely predict the starting soil organic matter conditions, and the ability to predict the impact of clearing, cultivation, fertiliser application, and continuous cropping on total soil carbon and nitrogen.

Protoporphyrinogen IX oxidase from Plasmodium falciparum is anaerobic and is localized to the mitochondrion

Earlier studies in this laboratory had shown that the malarial parasite can synthesize heme de novo and inhibition of the pathway leads to death of the parasite. It has been proposed that the pathway for the biosynthesis of heme in Plasmodium falciparum is unique involving three different cellular compartments, namely mitochondrion, apicoplast and cytosol. Experimental evidences are now available for the functionality and localization of all the enzymes of this pathway, except protoporphyrinogen IX oxidase (PfPPO), the penultimate enzyme. In the present study. PfPPO has been cloned, expressed and shown to be localized to the mitochondrion by immunofluorescence microscopy. Interestingly, the enzyme has been found to be active only under anaerobic conditions and is dependent on electron transport chain (ETC) acceptors for its activity. The native enzyme present in the parasite is inhibited by the ETC inhibitors, atovaquone and antimycin. Atovaquone, a well known inhibitor of parasite dihydroorotate dehydrogenase, dependent on the ETC, inhibits synthesis of heme as well in P. falciparum culture. A model is proposed to explain the ETC dependence of both the pyrimidine and heme-biosynthetic pathways in P. falciparum. (C) 2010 Elsevier B.V. All rights reserved.

Organometallic chemistry of diphosphazanes. Part IX: Syntheses and spectroscopic studies of molybdenum and tungsten tetracarbonyl complexes of unsymmetrical diphosphazanes

The unsymmetrical diphosphazanes X2PN(Pr(i))PYY'(1a-1h) {X = Ph, YY' = O2 C6H4 (1a) or YY' = O2C12H8 (1b); X = Ph, Y = Ph, Y' = OC6H4Me-4 (1c), OC6H4Br-4 (1d), OC6H3Me2-3,5 (1e), OC5H4N-2 (1f), N2C3HMe2-3,5 (1g) or Cl (1h)} react with [M(CO)4(NHC5H10)2] (M = Mo, W) to yield the cis-chelate complexes [M(CO)4{X2PN(Pr(i)) PYY'}] {M = Mo (2a-2h); M = W (3-f,3-g)}. These complexes have been characterized by H-1, P-31 and C-13 NMR and IR spectroscopic studies.

A novel adeno-associated virus serotype (AAV)-8 capsid mutant improves human coagulation factor IX expression in vivo

Recombinant AAV-8 vectors have shown significant promise for hepatic gene therapy of hemophilia B. However, the theme of AAV vector dose dependent immunotoxicity seen with AAV2 vectors earlier seem to re-emerge with AAV8 vectors as well. It is therefore important to develop novel AAV8 vectors that provide enhanced gene expression at significantly less vector doses. We hypothesized that AAV8 during its intracellular trafficking, are targeted for destruction in the cytoplasm by the host-cellular kinase/ubiquitination/proteasomal degradation machinery and modification of specific serine/threonine kinase or ubiquitination targets on AAV8 capsid (Fig.1A) may improve its transduction efficiency. To test this, point mutations at specific serine (S)/threonine (T) > alanine (A) or lysine (K)>arginine (R) residues were generated on AAV8 capsid. scAAV8-EGFP vectors containing the wild-type (WT) and each one of the 5 S/T/K-mutant(S276A, S501A, S671A, T251A and K137R) capsids were evaluated for their liver transduction efficiency at a dose of 5 X 1010 vgs/ animal in C57BL/6 mice in vivo. The best performing mutant was found to be the K137R vector in terms of either the gene expression (46-fold) or the vector copy numbers in the hepatocytes (22-fold) compared to WT-AAV8 (Fig.1B). The K137R-AAV8 vector that showed significantly decreased ubiquitination of the viral capsid had reduced activation of markers of innate immune response [IL-6, IL-12, tumor necrosis factor α, Kupffer cells and TLR-9]. In addition, animals injected with the K137R mutant also demonstrated decreased (2-fold) levels of cross-neutralizing antibodies when compared to animals that received the WT-AAV8 vector. To study further the utility of the novel AAV8-K137R mutant in a therapeutic setting, we delivered human coagulation factor IX (h.FIX) under the control of liver specific promoters (LP1 or hAAT) at two different doses (2.5x10^10 and 1x10^11 vgs per mouse) in 8-12 weeks old male C57BL/6 mice. As can be seen in Fig.1C/D, the circulating levels of h.FIX were higher in all the K137R-AAV8 treated groups as compared to the WT-AAV8 treated groups either at 2 weeks (62% vs 37% for hAAT constructs and 47% vs 21% for LP1 constructs) or 4 weeks (78% vs 56% for hAAT constructs and 64% vs 30% for LP1 constructs) post hepatic gene transfer. These studies demonstrate the feasibility of the use of this novel vector for potential gene therapy of hemophilia B.

La urna (1911) de Enrique Banchs : un cancionero argentino del siglo XX

Integran este número de la revista ponencias presentadas en Studia Hispanica Medievalia VIII : Actas de las X Jornadas Internacionales de Literatura Española Medieval, 2011, y de Homenaje al Quinto Centenario del Cancionero General de Hernando del Castillo.

Pleitos y usurpaciones de tierras realengas en Córdoba a fines del siglo XV : la villa de Las Posadas

Resumen: Analizamos el problema de las apropiaciones ilícitas de tierras en el término jurisdicional de la ciudad de Córdoba a fines de la Edad Media, centrando la atención en la villa de Las Posadas y en los procesos judiciales.

Corporeidad, herencia y educación : la representación de la infancia en tres poemas castellanos del siglo XIII

Resumen: Tomando como punto de partida el gesto inaugural de Philippe Ariès en lo concerniente a los estudios sobre la niñez, el presente artículo se propone abordar las formas de representación de la infancia presentes en los tres poemas que componen el Ms. K-III-4 de la Biblioteca de San Lorenzo de El Escorial (Libro de Apolonio, Vida de Santa María Egipciaca, Libre dels tres reys d’Orient), buscando así, delinearle un espacio de comprensión a los modos de ser niño que se dejan leer en este códice. Modos de ser que, no sólo permiten rectifi car las afi rmaciones fundantes del historiador francés, sino que a su vez, devienen signo del imaginario y los saberes de un siglo XIII propenso a la condición terrena del hombre.

Escepticismo y fideísmo en el giro del siglo XVII

ESCEPTICISMO

Versiones cronísticas de las enfances de Rodrigo: ¿prosificación o reescritura?

Resumen: El estudio de la relación entre poesía épica cidiana y prosa historiográfica ha estado enfocado mayormente en el Poema de Mio Cid. Las conclusiones extraídas del análisis de las versiones cronísticas de las hazañas del héroe en su madurez suelen extrapolarse al caso de la leyenda del héroe joven. Aunque los principales estudiosos, desde Menéndez Pidal hasta Diego Catalán, no han dejado de señalar las particularidades de la épica tardía y de la producción cronística postalfonsí, no ha habido, desde la tesis doctoral de Samuel Armistead hace más de medio siglo, un estudio específico del proceso de escritura que conllevó el aprovechamiento historiográfico del cantar de gesta tardío conocido como Mocedades de Rodrigo. El presente trabajo asume esa tarea y pretende formular nuevas hipótesis sobre la vieja cuestión de la relación textual entre el poema conservado y los relatos incluidos en la Crónica de Castilla y la Crónica General de 1344, así como sobre el discutido punto de la prioridad cronológica de estas versiones

Piketty : la inequidad, el siglo XXI y lecciones para la Argentina

Introducción: Como el Das Kapital de Marx en la segunda mitad del siglo XIX, el libro de Thomas Piketty, El Capital en el Siglo XXI, ha revolucionado el debate económico. Piketty es un economista francés especialista en desigualdad económica y distribución del ingreso, y su trabajo busca poner en el centro del análisis económico la cuestión de la distribución del ingreso y de la riqueza, en contraposición al eje crecimiento-inflación de la visión económica dominante. Su trabajo ha llevado a cuestionar la relación optimista entre el desarrollo económico y la desigualdad postulada por Kuznets en 1954, y a poner de relieve el rol de las instituciones políticas y fiscales en la evolución histórica de la distribución del ingreso y la riqueza. En este artículo se revisan los aspectos centrales del libro, y se identifican propuestas de Piketty para el desarrollo económico y social de largo plazo, que pueden ser muy útiles para un país como la Argentina que encuentra su actual estado de desarrollo lejos de su potencial