TASK DEFINITION: Given a passage, 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: P2X1 receptors play an important role in platelet function as they can induce shape change, granule centralization and are also involved in thrombus formation. As platelets have no nuclei, the level of P2X1 expression depends on transcriptional regulation in megakaryocytes, the platelet precursor cell. Since nothing is known about the molecular mechanisms regulating megakaryocytic P2X1 expression, this study aimed to identify and functionally characterize the P2X1 core promoter utilized in the human megakaryoblastic cell line MEG-01.', 'In order to identify cis-acting elements involved in the transcriptional regulation of P2X1 expression, the ability of 4.7 kb P2X1 upstream sequence to drive luciferase reporter gene expression was tested. Low promoter activity was detected in proliferating MEG-01 cells. This activity increased 20-fold after phorbol-12-myristate-13-acetate (PMA) induced differentiation. A transcription start site was detected 365 bp upstream of the start codon by primer extension. Deletion analysis of reporter constructs indicated a core promoter located within the region -68 to +149 bp that contained two Sp1 sites (named Sp1a and Sp1b) and an NF-1 site. Individual mutations of Sp1b or NF-1 binding sites severely reduced promoter activity whereas triple mutation of Sp1a, Sp1b and NF-1 sites completely abolished promoter activity in both untreated and PMA treated cells. Sp1/3 and NF-1 proteins were shown to bind their respective sites by EMSA and interaction of Sp1/3, NF-1 and TFIIB with the endogenous P2X1 core promoter in MEG-01 cells was demonstrated by chromatin immunoprecipitation. Alignment of P2X1 genes from human, chimp, rat, mouse and dog revealed consensus Sp1a, Sp1b and NF-1 binding sites in equivalent positions thereby demonstrating evolutionary conservation of these functionally important sites.

SOLUTION: Do sp1/3 and NF-1 mediate basal transcription of the human P2X1 gene in megakaryoblastic MEG-01 cells?

PROBLEM: Ovarian cancer (OvCa) is the most lethal gynecologic malignancy in the United States because of chemoresistant recurrent disease. Our objective was to investigate the efficacy of inhibiting the Notch pathway with a γ-secretase inhibitor (GSI) in an OvCa patient-derived xenograft model as a single agent therapy and in combination with standard chemotherapy.', 'Immunocompromised mice bearing xenografts derived from clinically platinum-sensitive human ovarian serous carcinomas were treated with vehicle, GSI (MRK-003) alone, paclitaxel and carboplatin (P/C) alone, or the combination of GSI and P/C. Mice bearing platinum-resistant xenografts were given GSI with or without paclitaxel. Gene transcript levels of the Notch pathway target Hes1 were analyzed using RT-PCR. Notch1 and Notch3 protein levels were evaluated. The Wilcoxon rank-sum test was used to assess significance between the different treatment groups.', 'Expression of Notch1 and 3 was variable. GSI alone decreased tumor growth in two of three platinum-sensitive ovarian tumors (p\u2009<\u20090.05), as well as in one of three platinum-sensitive tumors (p\u2009=\u20090.04). The combination of GSI and paclitaxel was significantly more effective than GSI alone and paclitaxel alone in all platinum-resistant ovarian tumors (all p\u2009<\u20090.05). The addition of GSI did not alter the effect of P/C in platinum-sensitive tumors. Interestingly, although the response of each tumor to chronic GSI exposure did not correlate with its endogenous level of Notch expression, GSI did negatively affect Notch signaling in an acute setting.

SOLUTION: Does inhibition of notch signaling in combination with Paclitaxel reduce platinum-resistant ovarian tumor growth?

PROBLEM: Shift-work and a sedentary lifestyle are risk factors for raised blood pressure (BP). Exercise can reduce BP in diurnally-active individuals, but it is unknown whether postexercise hypotension persists when people are active and eating at night. We present the first investigation into the acute effects of exercise on BP monitored during simulated night-work.', 'Nine normotensive participants, aged 20-42 years, completed at least two crossover trials beginning at 1800 hours. Between 1900 and 2000 hours, participants either rested or exercised at 50% peak oxygen uptake (VO(2peak)) and then remained awake throughout the night, completing various tasks until 0515 hours. Six participants completed a total of four trials in which they exercised or rested, whereas either one standardized (60 kJ/kg) meal at 2200 hours or two smaller (30 kJ/kg) meals at 2200 and 0200 hours were eaten. Systolic and diastolic BP, mean arterial pressure (MAP), heart rate (HR), and wrist activity were recorded every 30 min.', 'Following exercise, MAP was significantly (P < 0.0005) lower throughout the night-shift compared with no prior exercise (95% confidence limits for reduction: 4-7 mm Hg). The postexercise reductions in systolic BP and MAP were not moderated by diet, but the reduction in diastolic BP was slightly greater when only one meal was eaten (P < 0.0005). BP was lower even though wrist activity and HR were significantly higher following exercise (P < 0.0005).

SOLUTION:
Does prior exercise lower blood pressure during simulated night-work with different meal schedules?