TASK DEFINITION: In this task, you are given a passage which has a question and the context. You have to generate an answer to the question based on the information present in the context.
PROBLEM: Context: To evaluate pazopanib eye drops in subjects with active subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD).', 'Multicountry, randomized, parallel-group, double-masked, active and placebo-controlled, dose-ranging study of eye drops.', 'A total of 510 subjects (93% white; 58% female; mean age, 75.3 years) whose AMD was previously managed by anti-vascular endothelial growth factor intravitreal injections.', 'Treatments administered for 52 weeks included placebo eye drops instilled 4 times daily (n=73); pazopanib 5 mg/ml instilled 3 (n=72) or 4 times daily (n=74); pazopanib 10 mg/ml instilled 2 (n=73), 3 (n=73), or 4 times daily (n=72); or ranibizumab injection administered once every 4 weeks (n=73). In addition, for all eye drop treatment groups, open-label ranibizumab was administered as needed.', 'The main outcome measures were best-corrected visual acuity (BCVA) and injection frequency assessed at week 52. Safety was assessed every 4 weeks and pazopanib plasma concentrations were determined at weeks 4 and 24.', 'At week 52, pazopanib, with allowance for as-needed ranibizumab injections, was noninferior to monthly ranibizumab as well as to as-needed ranibizumab administered with placebo eye drops in maintaining BCVA (estimated BCVA gains of 0.3-1.8 vs. 1.4 vs. 0.2 letters, respectively). Pazopanib treatment did not reduce as-needed ranibizumab injections by ≥50% (prespecified efficacy criterion). At week 52, there were no clinically meaningful changes from baseline in retinal thickness or morphology, CNV size, or lesion characteristics on optical coherence tomography or fluorescein angiography. Complement factor H genotype had no effect on the responses to pazopanib and/or ranibizumab (BCVA, injection rate, or optical coherence tomography/fluorescein angiography changes). Steady-state concentrations of pazopanib in plasma seemed to be reached by week 4. The most common ocular adverse events related to pazopanib and ranibizumab were application site pain (3%) and injection site hemorrhage (1%), respectively. No treatment-related serious adverse events were reported.\Question: Does clinical evaluation of pazopanib eye drop versus ranibizumab intravitreal injections in subjects with neovascular age-related macular degeneration?

SOLUTION: Pazopanib was well tolerated. Daily pazopanib eye drops in neovascular AMD subjects did not result in therapeutic benefit beyond that obtained with ranibizumab alone.

PROBLEM: Context: The pulmonary endothelium plays an important role in the metabolism of the amino acid arginine, the exclusive precursor molecule for nitric oxide (NO). Despite decreased circulating arginine levels, endothelial NO production is elevated during endotoxemia. However, the regulation of pulmonary artery endothelial arginine transport has not been studied. We hypothesized that endotoxin stimulates carrier-mediated arginine transport by the pulmonary endothelium.', 'The relative contributions of the various transport systems to total arginine transport by porcine pulmonary artery endothelial cells (PAECs) was determined by assaying the uptake of 3H-L-arginine in the presence or absence of Na+. PAECs were then incubated with various concentrations of Escherichia coli endotoxin, and y(+)-mediated arginine transport was measured at different time points thereafter. Kinetic studies were performed over a range of arginine concentrations to determine changes in transport affinity and maximum rate of metabolism. To address the role of RNA and protein synthesis in the increased transport, uptake was measured after exposure of cells to the transcriptional inhibitor actinomycin D and the protein synthesis inhibitor cycloheximide.', 'Most (75%) of arginine transport by PAECs was mediated by the high-affinity Na(+)-independent transport system y+. Endotoxin stimulated y(+)-mediated arginine transport by PAECs twofold to fivefold, a response that was time and dose dependent. The accelerated transport was detectable within 2 hours and maximal at 12 hours. Kinetic studies revealed that the accelerated arginine transport was the result of a 68% increase in the maximal transport velocity (1519 +/- 65 pmol/mg protein/30 sec in endotoxin-treated cells vs 903 +/- 96 in control cells; p < 0.01) without a change in transport affinity. The endotoxin-mediated increase in arginine uptake was abrogated by actinomycin D and cycloheximide.\Question: Does endotoxin stimulate arginine transport in pulmonary artery endothelial cells?

SOLUTION: Endotoxin stimulates Na(+)-independent arginine transport by PAECs through a process that requires de novo RNA and protein synthesis, possibly of the transporter itself. This response may be designed to support arginine-dependent biosynthetic pathways in the lung during septic states.

PROBLEM: Context: Prostaglandin D2 (PGD2) and cysteinyl leukotrienes (cysLTs) are lipid mediators derived from mast cells, which activate TH2 cells. The combination of PGD2 and cysLTs (notably cysteinyl leukotriene E4 [LTE4]) enhances TH2 cytokine production. However, the synergistic interaction of cysLTs with PGD2 in promoting TH2 cell activation is still poorly understood. The receptors for these mediators are drug targets in the treatment of allergic diseases, and hence understanding their interaction is likely to have clinical implications.', 'We aimed to comprehensively define the roles of PGD2, LTE4, and their combination in activating human TH2 cells and how such activation might allow the TH2 cells to engage downstream effectors, such as neutrophils, which contribute to the pathology of allergic responses.', 'The effects of PGD2, LTE4, and their combination on human TH2 cell gene expression were defined by using a microarray, and changes in specific inflammatory pathways were confirmed by means of PCR array, quantitative RT-PCR, ELISA, Luminex, flow cytometry, and functional assays, including analysis of downstream neutrophil activation. Blockade of PGD2 and LTE4 was tested by using TM30089, an antagonist of chemoattractant receptor-homologous molecule expressed on TH2 cells, and montelukast, an antagonist of cysteinyl leukotriene receptor 1.', 'PGD2 and LTE4 altered the transcription of a wide range of genes and induced diverse functional responses in TH2 cells, including cell adhesion, migration, and survival and cytokine production. The combination of these lipids synergistically or additively enhanced TH2 responses and, strikingly, induced marked production of diverse nonclassical TH2 inflammatory mediators, including IL-22, IL-8, and GM-CSF, at concentrations sufficient to affect neutrophil activation.\Question: Do prostaglandin D2 and leukotriene E4 synergize to stimulate diverse TH2 functions and TH2 cell/neutrophil crosstalk?

SOLUTION:
PGD2 and LTE4 activate TH2 cells through different pathways but act synergistically to promote multiple downstream effector functions, including neutrophil migration and survival. Combined inhibition of both PGD2 and LTE4 pathways might provide an effective therapeutic strategy for allergic responses, particularly those involving interaction between TH2 cells and neutrophils, such as in patients with severe asthma.