instruction:
Given a passage with a context and an answer, construct a question on the basis of the information present in the passage. Construct the question in such a way that (i) it is unambiguous, (ii) it is answerable from the passage, (iii) its answer is unique (iv) it answer uses text phrases from the passage. Avoid creating questions that (i) can't be answered correctly without actually understanding the passage and (ii) uses the same words or phrases given in the passage.
question:
Context: Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with poor prognosis, as a majority of patients present with advanced disease. Current adjuvant strategies for metastatic patients include mitotane or other cytotoxic agents and carry a significant morbidity as well as a low (<10 %) 5-year survival. Withanolides, including withaferin A, are novel chemotherapeutic agents with potent targeted effects in medullary thyroid cancer and a number of solid malignancies with low toxicity in vivo. We hypothesize that novel naturally derived withanolides will have potent targeted anti-cancer activity against ACCs.', 'In vitro cell viability of ACC cell lines (Y1 and SW13) was measured using MTS cell proliferation assay. Cell cycle and apoptotic analysis studied using annexin V/propidium iodide staining on flow cytometry (FC) and targeted molecular mechanisms of withanolide cytotoxicity were assessed using standard Western blot analysis.', 'All the withanolides potently reduced ACC cell viability on MTS assay with 7- to 185-fold higher selectivity than normal fibroblasts. Cell cycle analysis demonstrated a shift in cell cycle arrest from G1/G0 to G2/M with induction of apoptosis at nanomolar concentrations of withanolides. Unlike current ACC therapeutics, withanolides modulated expression of several key oncogenic pathway proteins in ACCs by Western blot, including Jagged 1, MAPK, and Akt/mTOR pathway proteins in a dose-dependent manner after 24 h drug treatment of SW13 cells.
Answer: These results demonstrate the first evidence of the anticancer efficacy of withanolides in ACC cells and provide support for future translational evaluation of these compounds as novel therapeutic agents for ACC patients.
answer:
Are withanolides potent novel targeted therapeutic agents against adrenocortical carcinomas?


question:
Context: Postoperative neurologic deficits after thoracic aortic reconstruction vary widely. Our previous study showed that delayed ischemic preconditioning could prevent spinal cord injury caused by occlusion of the descending thoracic aorta in pigs. We investigated early ischemic preconditioning in the same model.', 'Twenty-eight pigs were divided into 4 groups: group 1 (n = 6) underwent a sham operation, group 2 (n = 6) underwent aortic occlusion for 20 minutes, group 3 (n = 8) underwent aortic occlusion for 35 minutes, and group 4 (n = 8) underwent aortic occlusion for 20 minutes and underwent aortic occlusion 80 minutes later without hypotension for 35 minutes. Aortic occlusion was accomplished by using 2 balloon occlusion catheters placed fluoroscopically at T6 to T8 above the diaphragm and at the aortic bifurcation. Neurologic evaluation was performed by an independent observer according to the Tarlov scale (0-4). The lower thoracic and lumbar spinal cords were harvested at 120 hours and examined histologically with hematoxylin-and-eosin stain. Histologic results (number of neurons and grade of inflammation) were scored (0-4) and were similarly analyzed. Statistical analysis was by means of the Kruskal-Wallis test.', 'Group 4 had a better neurologic outcome at 24, 48, and 120 hours in comparison with group 3 (P <.001). The histologic changes were proportional to the neurologic test scores, with the more severe and extensive gray matter damage in animals of group 3 (number of neurons, P <.001; grade of inflammation, P <.001).
Answer: Early ischemic preconditioning without hypotension protects against spinal cord injury after aortic occlusion, as confirmed by using the Tarlov score and histopathology.
answer:
Does early ischemic preconditioning without hypotension prevent spinal cord injury caused by descending thoracic aortic occlusion?


question:
Context: Apelin plays an important role in the protection against myocardial ischemia-reperfusion (I/R) injury, while the mechanism still remains unclear. In the current study, we aimed to evaluate the protective effect of apelin-13, and the main mechanism.', 'The in vivo I/R injury model (Sprague-Dawley rat) was established, then infarct size, expression levels of phospho-protein kinase B (p-Akt), phospho-extracellular signal-regulated kinase (p-ERK) and phospho-glycogen synthase kinase-3β (p-GSK-3β) were measured. The fluorescence intensity of tetramethylrhodamine ethyl ester perchlorate (TMRE) of the isolated myocardial cells was determined to evaluate the opening of the mitochondrial permeability transition pore (mPTP) caused by oxidant stress and hypoxia/reoxygenation.', 'For the established I/R injury model, apelin-13 and SB216763 (GSK-3β inhibitor) significantly reduced the infarct size (p < 0.05), which could be abolished by LY294002 (PI3K inhibitor), PD98059 (MEK inhibitor) and atractyloside (mPTP accelerator). The enhanced expression levels of p-Akt, p-ERK and p-GSK-3β caused by apelin-13 (p < 0.05) could be counteracted by LY294002 and PD98059. The reduced fluorescence intensity of TMRE in the H2O2/apelin-13 and H2O2/SB216763 treated groups was significantly lower (p < 0.05), indicating that apelin-13 and SB216763 could reduce the decline in mitochondrial membrane potential caused by oxidant stress, and the fluorescence intensity in the hypoxia/reoxygenation + apelin-13 group was significantly lower (p < 0.05), which suggested that apelin-13 could inhibit the mitochondrial membrane potential changes induced by hypoxia/reoxygenation.
Answer: The protective mechanism of apelin-13 might be that inactivation of GSK-3β could inhibit the opening of mPTP by activating PI3K/Akt and ERK1/2 involved in the reperfusion injury salvage kinase (RISK) pathway.
answer:

Does apelin-13 protect the heart against ischemia-reperfusion injury through the RISK-GSK-3β-mPTP pathway?