The Combination of Gefitinib With ATRA and ATO Induces Myeloid Differentiation in Acute Promyelocytic Leukemia Resistant Cells

In approximately 15% of patients with acute myeloid leukemia (AML), total and phosphorylated EGFR proteins have been reported to be increased compared to healthy CD34(+) samples. However, it is unclear if this subset of patients would benefit from EGFR signaling pharmacological inhibition. Pre-clinical studies on AML cells provided evidence on the pro-differentiation benefits of EGFR inhibitors when combined with ATRA or ATO in vitro. Despite the success of ATRA and ATO in the treatment of patients with acute promyelocytic leukemia (APL), therapy-associated resistance is observed in 5-10% of the cases, pointing to a clear need for new therapeutic strategies for those patients. In this context, the functional role of EGFR tyrosine-kinase inhibitors has never been evaluated in APL. Here, we investigated the EGFR pathway in primary samples along with functional in vitro and in vivo studies using several APL models. We observed that total and phosphorylated EGFR (Tyr992) was expressed in 28% and 19% of blast cells from APL patients, respectively, but not in healthy CD34(+) samples. Interestingly, the expression of the EGF was lower in APL plasma samples than in healthy controls. The EGFR ligand AREG was detected in 29% of APL patients at diagnosis, but not in control samples. In vitro, treatment with the EGFR inhibitor gefitinib (ZD1839) reduced cell proliferation and survival of NB4 (ATRA-sensitive) and NB4-R2 (ATRA-resistant) cells. Moreover, the combination of gefitinib with ATRA and ATO promoted myeloid cell differentiation in ATRA- and ATO-resistant APL cells. In vivo, the combination of gefitinib and ATRA prolonged survival compared to gefitinib- or vehicle-treated leukemic mice in a syngeneic transplantation model, while the gain in survival did not reach statistical difference compared to treatment with ATRA alone. Our results suggest that gefitinib is a potential adjuvant agent that can mitigate ATRA and ATO resistance in APL cells. Therefore, our data indicate that repurposing FDA-approved tyrosine-kinase inhibitors could provide new perspectives into combination therapy to overcome drug resistance in APL patients

Evaluación de la enseñanza a través de la guía docente en la UPCT

[SPA]Este trabajo presenta una propuesta de metodología para la evaluación de guías docentes basada en un conjunto de tres criterios principales (utilidad, coherencia e idoneidad), once subcriterios y una serie de indicadores cuyos valores se obtienen a través de cuestionarios dirigidos a centros, departamentos, estudiantes y profesorado. Los cuestionarios parten del modelo de Guía Docente adoptado por la UPCT y contemplan todos los apartados de la misma. El método propuesto puede aplicarse también para mejorar los programas de evaluación del profesorado, pues aporta las evidencias que se necesitan para valorar la labor de planificación desarrollada por el mismo, la cual se plasma en la guía docente. [ENG]This paper presents a methodological proposal for the evaluation of teaching guides based on three main criteria, i.e. usefulness, consistency, and suitability, and eleven subcriteria. It is also based on different indicators obtained through questionnaires aimed at Educational Centres, Departments, Students and Professors. These questionnnaires have been prepared from the teaching guide model adopted by the Technical University of Cartagena (UPCT), and considering all the sections included in that guide. The proposed methodology can be also used to improve the teaching staff evaluation program, because of the inclusion of planning task carried out by the professor, an aspect considered in the teaching guide.Campus Mare Nostrum, Universidad Politécnica de Cartagena, Universidad de Murcia, Región de Murcia

Effects of intrauterine food restriction and long-term dietary supplementation with L-arginine on age-related changes in renal function and structure of rats

We have previously demonstrated that restricting intrauterine food by 50% in 3-mo-old rats produced lower nephron numbers and early-onset hypertension, the latter being normalized by L-arginine administration. in 18-mo-old rats, such restriction increased glomerulosclerosis. in this study, we expanded our investigation, evaluating functional, morphologic, and immunohistochemical parameters in intrauterine-food-restricted 18-mo-old rats, either receiving L-arginine (RA18) or not (R18). Age-matched, non-food-restricted controls were assigned to similar groups with L-arginine (CA18) and without (C18). After weaning, L-arginine was given daily for 17 mo. No functional or morphologic changes were observed in C IS rats. the R18 rats developed early-onset hypertension, which persisted throughout the observation period, as well its significant proteinuria from 12 mo on. in RA18 rats, L-arginine decreased both blood pressure levels and proteinuria, and glomerular diameter was si,significantly smaller than in R18 rats (115.63 +/- 2.2 versus 134.8 +/- 1.0 mu m, p < 0.05). However, in RA18 rats, glomerular filtration rate remained depressed. Although L-arginine prevented glomerulosclerosis (R18 = 14%, RA18 = 4%; p < 0.05), glomerular expression of fibronectin and desmin was still greater in RA18 rats than in controls. Our data show that, although L-arginine prevented hypertension and proteinuria, glomerular injury still occurred, suggesting that intrauterine food restriction may be one of the leading causes of impaired renal function in adult life.Universidade Federal de São Paulo, Dept Physiol, EPM, Dept Physiol, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Physiol, EPM, Dept Morphol,Embrol Div, BR-04023900 São Paulo, BrazilUniv São Paulo, Ribeirao Preto Sch Med, Dept Physiol & Biophys, Brookline, MA 02146 USAUniversidade Federal de São Paulo, Dept Physiol, EPM, Dept Physiol, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Physiol, EPM, Dept Morphol,Embrol Div, BR-04023900 São Paulo, BrazilWeb of Scienc

The spectrum of natural forest disturbances and the Amazon forest carbon balance.

Estimates of the atmospheric accumulation of anthropogenic CO2 emissions indicate a large terrestrial carbon sink in recent decades. Intact tropical forests may contribute a substantial fraction of this. While current estimates are based on data from forest inventory plots, these plot studies have been criticized for failure to represent landscape scale processes especially the frequency of severe natural disturbances. Here we characterize the frequency distribution of disturbance events in natural forests from 0.01 ha to 2,651 ha size throughout Amazonia using a novel combination of forest inventory, airborne lidar and satellite remote sensing data. We find that small-scale mortality events are responsible for aboveground biomass losses of about 88.3% over the entire Amazon region. We also find that intermediate-scale disturbances account for losses around 12.7%, and that the largest-scale disturbances as a result of blow-downs only accounts for losses of around 0.02%. Stochastic simulation of growth and mortality based on data from the forest plot census network and the region-wide disturbance spectrum together indicate that rare large disturbances are outweighed by the net biomass gains measured, supporting the inference of a substantial carbon sink in old-growth Amazon forests