Search

En este ensayo se afirma que las investigaciones desarrolladas en Chile sobre la enseñanza del derecho no han reparado suficientemente en las cuestiones referidas al cambio de modelo universitario y su influencia en la enseñanza y aprendizaje del derecho. Esto, a su vez, ha impedido a los teóricos nacionales ejercer una mayor influencia en los procesos de reforma al sistema universitario en general y a las modificaciones y proyecciones de la enseñanza del derecho en particular.

Este artículo pretende precisar la noción de constructivismo ético tal como aparece en la filosofía de John Rawls. Para tal efecto, esta investigación avanza en la determinación conceptual de la idea de constructivismo ético desde una perspectiva metodológica general, para luego vincular los elementos de la teoría general con la propuesta de la justicia como equidad. Hecho lo anterior, muestra someramente los desplazamientos que experimenta la propuesta rawlsiana desde el constructivismo kantiano al político. Termina este trabajo con una consideración crítica de la estrategia de Rawls.

In prostate cancer, androgen deprivation therapy (ADT) enhances the cytotoxic effects of radiotherapy. This effect is associated with weakening of the DNA damage response (DDR) normally supported by the androgen receptor. As a significant number of patients will fail combined ADT and radiotherapy, we hypothesized that DDR may be driven by androgen receptor splice variants (ARV) induced by ADT. Investigating this hypothesis, we found that ARVs increase the clonogenic survival of prostate cancer cells after irradiation in an ADT-independent manner. Notably, prostate cancer cell irradiation triggers binding of ARV to the catalytic subunit of the critical DNA repair kinase DNA-PK. Pharmacologic inhibition of DNA-PKc blocked this interaction, increased DNA damage, and elevated prostate cancer cell death after irradiation. Our findings provide a mechanistic rationale for therapeutic targeting of DNA-PK in the context of combined ADT and radiotherapy as a strategy to radiosensitize clinically localized prostate cancer. Cancer Res; 77(18); 4745-54. ©2017 AACR.

Background and purpose: To simulate patient-level costs, analyze the economic potential of telemedicine-based mobile stroke units for acute prehospital stroke care, and identify major determinants of cost-effectiveness, based on two recent prospective trials from the United States and Germany. Methods: A Markov decision model was developed to simulate lifetime costs and outcomes of mobile stroke unit. The model compares diagnostic and therapeutic pathways of ischemic stroke, hemorrhagic stroke, and stroke mimic patients by conventional care or by mobile stroke units. The treatment outcomes were derived from the B_PROUD and the BEST-mobile stroke unit trials and further input parameters were derived from recent literature. Uncertainty was addressed by deterministic and probabilistic sensitivity analyses. A lifetime horizon based on the US healthcare system was adopted to evaluate different cost thresholds for mobile stroke unit and the resulting cost-effectiveness. Willingness-to-pay thresholds were set at 1x and 3x gross domestic product per capita, as recommended by the World Health Organization. Results: In the base case scenario, mobile stroke unit care yielded an incremental gain of 0.591 quality-adjusted life years per dispatch. Mobile stroke unit was highly cost-effective up to a maximum average cost of 43,067 US dollars per patient. Sensitivity analyses revealed that MSU cost-effectiveness is mainly affected by reduction of long-term disability costs. Also, among other parameters, the rate of stroke mimics patients diagnosed by MSU plays an important role. Conclusion: This study demonstrated that mobile stroke unit can possibly be operated on an excellent level of cost-effectiveness in urban areas in North America with number of stroke mimic patients and long-term stroke survivor costs as major determinants of lifetime cost-effectiveness. [ABSTRACT FROM AUTHOR]

The ratio of elements such as carbon:nitrogen:phosphorus (C:N:P) in phytoplankton is known to vary substantially within single isolates and across environmental gradients. In addition, C:N:P is known to vary throughout the day due to diel patterns in nutrient acquisition and storage. It has been hypothesized that small phytoplankton such as marine cyanobacteria have relatively invariable elemental ratios during a 24 h period, whereas larger phytoplankton have a greater capacity to store elements and thus a wider diel range of C:N:P. To test this hypothesis, we examined diel variability in cellular C:N:P, using a chemostat culturing system, for one of the most abundant marine cyanobacteria, Synechococcus (WH8102) during two 24 h periods. The cellular C quota nearly doubled during the 14 h light period and was subsequently reduced during the dark period. The cellular N quota also varied considerably, whereas the P quota remained relatively stable. These daily changes in elemental quotas led to highly variable C:Ncell and C:Pcell. Furthermore, the magnitude of variability in cellular elemental stoichiometry of Synechococcus was positively related to the growth rate. We constructed a model to test the extent to which variation in C:Ncell and C:Pcell is related to reserve carbon accumulation and depletion over each light-dark cycle. Results imply that, in addition to growth-related respiratory losses, Synechococcus also purges excess C during the dark period in order to maintain a nutritive balance within cells. Our data suggest that diel variation in C:Ncell and C:Pcell of Synechococcus is of the same order of magnitude as stoichiometric variation within plankton communities between major ocean environments.

BackgroundProstate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.MethodsWe conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies.ResultsOverall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib.ConclusionsTreatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.).

PurposeProgression-free survival (PFS) in metastatic castration-resistant prostate cancer (mCRPC) trials has been inconsistently defined and poorly associated with overall survival (OS). A reproducible quantitative definition of radiographic PFS (rPFS) was tested for association with a coprimary end point of OS in a randomized trial of abiraterone in patients with mCRPC.Patients and methodsrPFS was defined as ≥ two new lesions on an 8-week bone scan plus two additional lesions on a confirmatory scan, ≥ two new confirmed lesions on any scan ≥ 12 weeks after random assignment, and/or progression in nodes or viscera on cross-sectional imaging, or death. rPFS was assessed by independent review at 15% of deaths and by investigator review at 15% and 40% of deaths. rPFS and OS association was evaluated by Spearman's correlation.ResultsA total of 1,088 patients were randomly assigned to abiraterone plus prednisone or prednisone alone. At first interim analysis, the hazard ratio (HR) by independent review was 0.43 (95% CI, 0.35 to 0.52; P < .001; abiraterone plus prednisone: median rPFS, not estimable; prednisone: median rPFS, 8.3 months). Similar HRs were obtained by investigator review at the first two interim analyses (HR, 0.49; 95% CI, 0.41 to 0.60; P < .001 and HR, 0.53; 95% CI, 0.45 to 0.62; P < .001, respectively), validating the imaging data assay used. Spearman's correlation coefficient between rPFS and OS was 0.72.ConclusionrPFS was highly consistent and highly associated with OS, providing initial prospective evidence on further developing rPFS as an intermediate end point in mCRPC trials.