TASK DEFINITION: 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.
PROBLEM: Context: Growth-differentiation factor-15 (GDF-15) is emerging as an independent prognostic biomarker in patients with cardiovascular (CV) disease. Little is known about the pathophysiological basis for the close association of GDF-15 to future CV events. We hypothesized that GDF-15 is related to underlying CV pathologies.', 'To relate the levels of GDF-15 to indices of CV dysfunction and disease in elderly individuals, serum levels of GDF-15 were measured in 1004 subjects aged 70 years from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Carotid intima-media thickness and plaque burden, and left ventricular (LV) geometry and function were assessed by ultrasound. Endothelial function was evaluated in forearm resistance vessels and in the brachial artery by venous occlusion plethysmography and ultrasound imaging, respectively. Elevated levels of GDF-15 were related to several CV risk factors (male gender, current smoking, body mass index, waist circumference, diabetes, fasting glucose, triglycerides, and low HDL cholesterol). After adjustment for CV risk factors, increased levels of GDF-15 were associated with reduced endothelium-dependent vasodilation in resistance vessels, plaque burden, LV mass and concentric LV hypertrophy, reduced LV ejection fraction, and clinical manifestations of coronary artery disease and heart failure.
Answer: GDF-15 carries information on CV dysfunction and disease that is not captured by traditional CV risk factors in elderly individuals.

SOLUTION: Is growth-differentiation factor-15 an independent marker of cardiovascular dysfunction and disease in the elderly : results from the Prospective Investigation of the Vasculature in Uppsala Seniors ( PIVUS ) Study?

PROBLEM: Context: Cilostazol, a potent type 3 phosphodiesterase inhibitor, is found to reduce neointimal formation by inhibiting vascular smooth muscle cell (VSMC) proliferation. The aim of this study is to investigate whether the inhibitory effect of cilostazol on VSMC proliferation is operated via heme oxygenase-1 (HO-1).', 'In rat carotid arteries, cilostazol up-regulated HO-1 in the neointima of balloon-injured arteries. Treatment of human VSMCs with cilostazol enhanced the expression of HO-1, which was mainly regulated at the transcriptional level. Small interfering RNA knock-down of HO-1 attenuated the inhibitory effect of cilostazol on VSMC proliferation, suggesting the critical role of HO-1 in cilostazol effect. The transcriptional responsiveness of HO-1 to cilostazol was inversely correlated with the length of GT-repeat in human HO-1 promoter. Deletion and mutational analysis of HO-1 promoter along with chromatin immunoprecipitation showed that cyclic AMP response element (CRE)-binding protein (CREB) participated in cilostazol-induced HO-1 transcription. Furthermore, cilostazol triggered a linkage between the CRE and GT-repeat regions in the HO-1 promoter. The promoting effect of cilostazol on HO-1 expression, proliferation inhibition, and chromatin conformation in the HO-1 promoter was greater in VSMCs from subjects with shorter GT-repeat alleles than those with longer alleles.
Answer: Cilostazol inhibits VSMC proliferation involving an association between CREB and HO-1. The length polymorphism of GT-repeat in human HO-1 promoter determines the effect of cilostazol.

SOLUTION: Does gT-repeat length polymorphism in heme oxygenase-1 promoter determine the effect of cilostazol on vascular smooth muscle cells?

PROBLEM: Context: Cancer stem cell-tumor microenvironment ecosystem is proposed to drive tumor heterogeneity. Tumor-infiltrating lymphocytes (TILs) in breast cancer ecosystem were demonstrated to indicate better prognosis and benefit from chemotherapy. This study sought to detect the association between breast cancer stem cells and TILs.', '92 patients with breast cancer were enrolled. Matched cancerous and paracancerous tissues were assembled in a tissue microarray and immunohistochemistry was employed to test expression of breast cancer stem cells (BCSCs) markers. TILs counts were estimated with global hematoxylin-eosin staining. The association between TILs and BCSCs phenotypes was analysed by multivariate analysis.', 'Although it was unable to find direct significant association between BCSCs phenotypes and TILs, the BCSCs phenotype with CD44(+)CD24(-)ALDH1A1(+)EpCAM(+)CD49f(+) was proved to be associated with worse DFS and OS (P=0.037 and 0.001). This result was confirmed by cox proportional-hazards regression model (for DFS and OS respectively, HR=2.438 and 3.383, P=0.019 [95%CI 1.418-3.457] and 0.025 [95%CI 1.162-9.843]). Additionally, in results of TILs, plasma cell-predominant breast cancer (PPBC) was unexpectedly found to indicate worse OS and HR was 2.686 (P=0.038 [95%CI 1.582-3.789]).
Answer: The BCSCs phenotype and PPBC may be helpful stratified factors in future clinical trials. The underlying mechanism needs further research.

SOLUTION:
Do breast cancer stem cells phenotype and plasma cell-predominant breast cancer independently indicate poor survival?