A conceptually new treatment approach for relapsed glioblastoma: Coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care

Kast, Richard E. et al.To improve prognosis in recurrent glioblastoma we developed a treatment protocol based on a combination of drugs not traditionally thought of as cytotoxic chemotherapy agents but that have a robust history of being well-tolerated and are already marketed and used for other non-cancer indications. Focus was on adding drugs which met these criteria: a) were pharmacologically well characterized, b) had low likelihood of adding to patient side effect burden, c) had evidence for interfering with a recognized, well-characterized growth promoting element of glioblastoma, and d) were coordinated, as an ensemble had reasonable likelihood of concerted activity against key biological features of glioblastoma growth. We found nine drugs meeting these criteria and propose adding them to continuous low dose temozolomide, a currently accepted treatment for relapsed glioblastoma, in patients with recurrent disease after primary treatment with the Stupp Protocol. The nine adjuvant drug regimen, Coordinated Undermining of Survival Paths, CUSP9, then are aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir, sertraline, to be added to continuous low dose temozolomide. We discuss each drug in turn and the specific rationale for use- how each drug is expected to retard glioblastoma growth and undermine glioblastoma’s compensatory mechanisms engaged during temozolomide treatment. The risks of pharmacological interactions and why we believe this drug mix will increase both quality of life and overall survival are reviewed.Peer Reviewe

Soil Water Movement in a Watershed in the Chilean Patagonia

Magallanes region, located southern Chile, contains about 1.9 million sheep heads, in about 5 million hectares of rangelands. However, forage production is concentrated in small wetlands meadows called locally “Vegas” that only represent about 300.000 hectares. Those ecosystems that sustain patagonian ranches, produce 20 times more forage biomass than the surrounding natural rangelands. Patagonian vegas have concave topography with a hydrophyte (wet) center, and mesic slopes and xeric highlands of Festuca gracillima. Although the moisture content is controled by topography, there is scarce information about the movement of water through this concave topography. Also, the spatial variability of the soil between the Xeric to the Hydrophyte parts must be taking in account. It is essential to evaluate the movement of water inside the soil, to define agronomic managements to promote the storage and conduction of water. The study was conducted in a watershed dominated by vegas at the Kampenaike Experimental Station in Magallanes region, in Chilean Patagonia (-52,7 ° Lat.; -70.97° Long). Soil was monitored by instruments in five pits, two at East and West of Xeric side; two at East and West of mesic side; and the last at the middle of the vega. Soil moisture sensors (n = 2) and water tension (n = 1) were placed in three soil horizons (5, 30 and 80 cm deep). A weather station was set up in the middle of the vega. Differences in the physical properties that govern the storage and conduction of water between all the sectors were founded. The differences were due to the great spatial variability of the type of soil, because the topography and the genesis

Betulinic Acid Hydroxamate is Neuroprotective and Induces Protein Phosphatase 2A-Dependent HIF-1α Stabilization and Post-transcriptional Dephosphorylation of Prolyl Hydrolase 2

Huntington’s disease (HD) is a neurodegenerative disorder characterized by unwanted choreatic movements, behavioral and psychiatric disturbances, and dementia. The activation of the hypoxic response pathway through the pharmacological inhibition of hypoxia-inducing factor (HIF) prolyl-hydroxylases (PHDs) is a promising approach for neurodegenerative diseases, including HD. Herein, we have studied the mechanism of action of the compound Betulinic acid hydroxamate (BAH), a hypoximimetic derivative of betulinic acid, and its efficacy against striatal neurodegeneration using complementary approaches. Firstly, we showed the molecular mechanisms through which BAH modifies the activity of the PHD2 prolyl hydroxylase, thus directly affecting HIF-1α stability. BAH treatment reduces PHD2 phosphorylation on Ser-125 residue, responsible for the control of its hydrolase activity. HIF activation by BAH is inhibited by okadaic acid and LB-100 indicating that a protein phosphatase 2A (PP2A) is implicated in the mechanism of action of BAH. Furthermore, in striatal cells bearing a mutated form of the huntingtin protein, BAH stabilized HIF-1α protein, induced Vegf and Bnip3 gene expression and protected against mitochondrial toxin-induced cytotoxicity. Pharmacokinetic analyses showed that BAH has a good brain penetrability and experiments performed in a mouse model of striatal neurodegeneration induced by 3-nitropropionic acid showed that BAH improved the clinical symptoms. In addition, BAH also prevented neuronal loss, decreased reactive astrogliosis and microglial activation, inhibited the upregulation of proinflammatory markers, and improved antioxidant defenses in the brain. Taken together, our results show BAH’s ability to activate the PP2A/PHD2/HIF pathway, which may have important implications in the treatment of HD and perhaps other neurodegenerative diseases

Las termas y el Suburbium marítimo de Baelo Claudia. Avance de un reciente descubrimiento

Entre los años 2010 y 2012, la Universidad de Cádiz y la Junta de Andalucía han desarrollado investigaciones arqueológicas en la zona extramuros de la ciudad hispanorromana, en el marco del Proyecto General de Investigación “La economía marítima y las actividades haliéuticas en Baelo Claudia”. Se presentan en esta sede los primeros resultados, que han permitido identificar la existencia de un suburbium occidental en la ciudad, entre el cauce del arroyo de las Villas, la playa y la necrópolis oeste, cuya existencia se ha podido confirmar por datos geofísicos y arqueológicos. En él han podido ser excavadas parcialmente unas estructuras que se han identificado con unas termas suburbanas, activas entre el s. II y el V d.C., habiéndose excavado una piscina del frigidarium y algunas estancias calefactadas, con hallazgos muy significativos como parte de la decoración marmórea y escultórica del complejo, que en época tardorromana fue amortizado intencionalmente por motivos posiblemente religiosos. Estos hallazgos son de gran interés, pues además de verificar la existencia de un segundo complejo balneario público en la ciudad plantean la importancia del poblamiento periurbano, una línea de investigación totalmente inédita hasta la fechaBetween the year 2010 and 2012, the University of Cadiz and the Regional Government (Junta de Andalucía) have developed archaeological activities in the zone outside the hispano-roman city, in the frame of the General Project of Research titled “The maritime economy and the halieutic activities in Baelo Claudia”. We are presenting in this paper the first results, which have allowed to identify the existence of a western suburbium outside the city, between the riverbed of the so called “arroyo de las Villas”, the beach and the western necropolis, whose remains have been confirmed by geophysical and archaeological techniques. Inside this area a few structures have been excavated, identified as a Roman baths complex, active from the 2nd up to the 5th century a.D. A big pool, part of the frigidarium and some heated rooms have been unearthed, with very significant findings as part of the marmoreal and sculptural decoration of the complex, which in late roman times was intentionally broken into pieces possibly by religious motives. These findings are of great interest, since beside confirming the existence of the second public thermae of the city they raise the importance of the peri-urban buildings, a new line of research up to dat

Influencia de la fertilización nitrogenada sobre las concentraciones de K+, Mg2+ y Ca2+ y sus bioindicadores en raíces y hojas de plantas de judía

The pyruvate kinase (PK) and ATPase activities taking part in nitrogen (N) assimilation is essential for the growth and development of plants. Studies on the kinetics of these enzymes reveal that its activities are dependent of the cofactors K+, Ca2+, and Mg2+. Therefore, the objective of the present work was to determine the effect of different doses of N on enzymatic activities of ATPase and PK as potentials biochemical indicators of the levels of K+, Mg2+, and Ca2+ in the roots and leaves of green bean plants. The N was applied to the nutrient solution as NH4NO3 at the following rates: 1.5, 3.0, 6.0, 12.0, 18.0, and 24.0 mM of N. These results indicate that deficient conditions of N (N1 and N2) were characterized by the lowest accumulation of K+, Mg2+ and Ca2+ in both total and soluble forms, and also minimum activities of PK and ATPase induced by K+, Mg2+ and Ca2+, with respect to the activity of basal PK and ATPase; this could mean near optimum conditions for these cations. On the contrary, high-N treatments (N4, N5 and N6) were characterized by presenting decreasing concentrations of total and soluble K+, Mg2+ and Ca2+ in roots and leaves of green bean plants; however, the activities of PK and ATPase induced with K+, Mg2+ and Ca2+ were increased reaching their maximum activity with respect to basal PK and ATPase, both enzymes reflecting the level of cations in roots and leaves, hence being considered as good physiological bioindicators of these cations.Las actividades piruvato kinasa (PK) y ATPasa participan en la asimilación de nitrógeno (N), la cual es esencial para el crecimiento y desarrollo de las plantas. Estudios sobre cinéticas de estas enzimas revelan que sus actividades son dependientes de los cofactores K+, Ca2+ y Mg2+. Por lo tanto, el objetivo del presente trabajo fue determinar el efecto de diferentes dosis de N sobre las actividades de la ATPasa y PK como posibles bioindicadores de los niveles de K+, Mg2+ y Ca2+ en raíces y hojas de plantas de judía (Phaseolus vulgaris L. cv. Strike). Se aplicó N a la solución nutritiva como NH4NO3 en las siguientes dosis: N1=1,5 mM, N2=3,0 mM, N3=6,0 mM, N4=12,0 mM, N5=18,0 mM y N6=24,0 mM. Los resultados indican que bajo condiciones deficientes de N (N1 y N2), las plantas presentaron menor acumulación de K+, Mg2+ y Ca2+ en su forma total y soluble, así como mínimas actividades PK y ATPasa inducidas por K+, Mg2+ y Ca2+ respecto a la actividad PK y ATPasa basal; lo cual indica condiciones cercanas a las óptimas de estos cationes. Por el contrario, en los tratamientos elevados de N (N4, N5 y N6) las plantas presentaron concentraciones decrecientes de K+, Mg2+ y Ca2+ total y soluble tanto en raíces como en hojas; sin embargo, las actividades PK y ATPasa inducidas con K+, Mg2+ y Ca2+ se incrementaron alcanzando sus máximas actividades con respecto a la PK y ATPasa basal, lo que indica una mayor necesidad fisiológica de estos cationes en los tratamientos elevados de N. Finalmente, la actividad ATPasa basal y la inducida con K+, Mg2+ y Ca2+ se comportaron de forma similar a la actividad PK, lo que refleja el nivel de cationes en raíces y en hojas, por lo que se consideran buenos bioindicadores fisiológicos de estos cationes

Multiwavelength monitoring of the nucleus in PBC J2333.9-2343: the giant radio galaxy with a blazar-like core

PBC J2333.9-2343 is a giant radio galaxy at z = 0.047 with a bright central core associated to a blazar nucleus. If the nuclear blazar jet is a new phase of the jet activity, then the small orientation angle suggest a dramatic change of the jet direction. We present observations obtained between September 2018 and January 2019 (cadence larger than three days) with Effeslberg, SMARTS-1.3m, ZTF, ATLAS, Swift, and Fermi-LAT, and between April-July 2019 (daily cadence) with SMARTS-1.3m and ATLAS. Large (>2x) flux increases are observed on timescales shorter than a month, which are interpreted as flaring events. The cross correlation between the SMARTS-1.3m monitoring in the NIR and optical shows that these data do not show significant time lag within the measured errors. A comparison of the optical variability properties between non-blazars and blazars AGN shows that PBC J2333.9-2343 has properties more comparable to the latter. The SED of the nucleus shows two peaks, that were fitted with a one zone leptonic model. Our data and modelling shows that the high energy peak is dominated by External Compton from the dusty torus with mild contribution from Inverse Compton from the jet. The derived jet angle of 3 degrees is also typical of a blazar. Therefore, we confirm the presence of a blazar-like core in the center of this giant radio galaxy, likely a Flat Spectrum Radio Quasar with peculiar properties.Comment: Accepted for publication in MNRAS. 15 pages, 6 figures, 2 appendix including tables and figure

Persistent and occasional: searching for the variable population of the ZTF/4MOST sky using ZTF data release 11

We present a variability, color and morphology based classifier, designed to identify transients, persistently variable, and non-variable sources, from the Zwicky Transient Facility (ZTF) Data Release 11 (DR11) light curves of extended and point sources. The main motivation to develop this model was to identify active galactic nuclei (AGN) at different redshift ranges to be observed by the 4MOST ChANGES project. Still, it serves as a more general time-domain astronomy study. The model uses nine colors computed from CatWISE and PS1, a morphology score from PS1, and 61 single-band variability features computed from the ZTF DR11 g and r light curves. We trained two versions of the model, one for each ZTF band. We used a hierarchical local classifier per parent node approach, where each node was composed of a balanced random forest model. We adopted a 17-class taxonomy, including non-variable stars and galaxies, three transient classes, five classes of stochastic variables, and seven classes of periodic variables. The macro averaged precision, recall and F1-score are 0.61, 0.75, and 0.62 for the g-band model, and 0.60, 0.74, and 0.61, for the r-band model. When grouping the four AGN classes into one single class, its precision, recall, and F1-score are 1.00, 0.95, and 0.97, respectively, for both the g and r bands. We applied the model to all the sources in the ZTF/4MOST overlapping sky, avoiding ZTF fields covering the Galactic bulge, including 86,576,577 light curves in the g-band and 140,409,824 in the r-band. Only 0.73\% of the g-band light curves and 2.62\% of the r-band light curves were classified as stochastic, periodic, or transient with high probability ($P_{init}\geq0.9$). We found that, in general, more reliable results are obtained when using the g-band model. Using the latter, we identified 384,242 AGN candidates, 287,156 of which have $P_{init}\geq0.9$.Comment: Accepted for publication in Astronomy & Astrophysics. Abstract shortened for arXiv. Tables containing the classifications and features for the ZTF g and r bands, and the labeled sets will be available at CDS. Individual catalogs per class and band, as well as the labeled set catalogs, can be downloaded at Zenodo DOI:10.5281/zenodo.782604

Herramienta de coordinación de titulaciones en la E.P.S. Linares

En este trabajo se presenta una plataforma de coordinación de actividades vinculadas con la docencia de todas las asignaturas de las titulaciones de grado y máster impartidas en el centro, organizadas por cursos y títulos, de manera que el profesorado de cada asignatura cuente, para la programación sus tareas (pruebas, entregas de prácticas o relaciones de problemas, visitas, conferencias, seminarios, etc.), de toda la información sobre el resto de asignaturas del título. En este sentido, la plataforma se nutre de la información que el profesorado, usuario principal de la misma, introduce en ella. Debe contener las actividades del trabajo y recursos utilizados: es decir, metodologías, técnicas y tecnología