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.

Ex Input:
Context: Monocytes are cellular components of wound repair, arteriogenesis, and atherogenesis. Vascular endothelial growth factor (VEGF)-A and placental growth factor recruit monocytes to sites of arteriogenesis via stimulation of VEGF receptor-1 (VEGFR-1). The chemotactic response of monocytes to VEGF-A is attenuated in individuals with diabetes mellitus (DM). This VEGF resistance correlates with impaired collateral growth. The aim of this study is to elucidate the molecular basis of VEGF resistance and impaired monocyte response in DM.', 'Phosphorylation of Akt, p38, and extracellular signal-regulated kinase 1/2 (ERK1/2) could be stimulated with either placental growth factor-1 or VEGF-A in monocytes from non-DM but not DM individuals. In contrast, formyl-methionyl-leucyl-phenylalanine caused a comparable activation of these molecules in both DM and non-DM monocytes. Baseline phosphorylation of Akt, p38, and ERK1/2 was significantly elevated in monocytes from DM compared with non-DM subjects. Of note, H(2)O(2) activated Akt, p38, and ERK1/2 in non-DM monocytes ex vivo. Protein tyrosine phosphatases had stronger oxidative modifications in monocytes from DM than from non-DM individuals, which reflects functional protein tyrosine phosphatase inhibition, similar to that seen after H(2)O(2) challenge. Overall, protein tyrosine phosphatase and protein tyrosine phosphatase-1B activity were reduced in DM monocytes. DM monocytes revealed higher expression of the receptor for advanced glycation end products. Stimulation with advanced glycation end products ligands resulted in activation of non-DM monocytes and inhibition of VEGFR-1-mediated chemotaxis. The elevated baseline phosphorylation/activation of Akt, p38, and ERK1/2 in DM monocytes likely causes the resistance to further stimulation with specific stimuli such as VEGF-A, revealing a molecular explanation of the DM-related signal transduction defect.\Question: Does diabetes mellitus activate signal transduction pathways resulting in vascular endothelial growth factor resistance of human monocytes?

Ex Output:
We propose that elevated advanced glycation end products expression and increased oxidative stress in diabetic monocytes lead to activation of VEGFR-1-related signaling pathways and to desensitization of VEGFR-1 responses. These data establish VEGF resistance as a novel molecular concept for DM-related cellular dysfunction.


Ex Input:
Context: Esophageal eosinophilia can be proton pump inhibitor (PPI) resistant or responsive, representing 2 entities known as eosinophilic esophagitis (EoE) and PPI-responsive esophageal eosinophilia (PPI-REE), respectively. Although they present with similar clinical features, EoE is accepted to be an antigen-driven, TH2-associated allergic disorder, whereas the cause of PPI-REE remains a mystery.', 'In this study, our aim was to investigate the pathogenesis of PPI-REE by using a recently described EoE diagnostic panel (EDP) composed of a set of 94 esophageal transcripts and to determine whether PPI therapy reverses any esophageal transcriptional abnormalities.', 'We evaluated the EDP signature in biopsy samples obtained from adult and pediatric patients with PPI-REE from 4 institutions and compared the pre- and post-PPI therapy expression profiles of these subjects with those of patients with active EoE.', 'The EDP differentiated patients with EoE from control subjects with 100% accuracy among the 4 clinical sites. Bioinformatics analysis revealed largely overlapping transcriptomes between patients with PPI-REE and those with EoE, including the genes for eosinophil chemotaxis (eotaxin 3, CCL26), barrier molecules (desmoglein 1, DSG1), tissue remodeling (periostin, POSTN), and mast cells (carboxypeptidase A, CPA3). PPI monotherapy alone almost completely reversed the allergic inflammatory transcriptome of patients with PPI-REE. Furthermore, we identified a set of candidate genes to differentiate patients with EoE from those with PPI-REE before treatment.\Question: Does transcriptome analysis of proton pump inhibitor-responsive esophageal eosinophilia reveal proton pump inhibitor-reversible allergic inflammation?

Ex Output:
These findings provide definitive evidence that PPI-REE is a disease entity with significant molecular overlap with EoE, suggesting that many patients with PPI-REE represent a continuum of the same pathogenic allergic mechanisms that underlie EoE and thus might constitute a subphenotype of patients with EoE. The ability of PPI therapy to nearly entirely reverse gene expression associated with PPI-REE, particularly that associated with classic features of allergic inflammation, provides new insight into potential disease etiology and management strategies for patients with significant esophageal eosinophilia.


Ex Input:
Context: Setting treatment goals in the intensive care unit (ICU) often involves resuscitation decisions. Our objective was to study the rate of establishing do-not-resuscitate (DNR) directives, determinants, and outcomes of those directives for mechanically ventilated patients.', 'In a multicentre observational study, we included consecutive adults with no DNR directives within 24 hr of ICU admission who were mechanically ventilated for at least 48 hr. We identified the rate with which DNR directives were established, and factors associated with these directives.', 'Among 765 patients, DNR directives were established for 231 (30.2%) patients; 143 (62.1%) of these were established within the first week. Factors independently associated with a DNR directive were: patient age [> or = 75 yr (hazard ratio [HR] 2.3, 95% confidence interval 1.5-3.4], 65 to 74 yr (HR 1.8, 1.2-2.7), 50 to 64 yr (HR 1.4, 1.0-2.2) relative to < 50 yr); medical rather than surgical diagnosis (HR 1.8, 1.3-2.5); multiple organ dysfunction score (HR 1.7 for each five-point increment, 1.4-2.0); physician prediction of ICU survival [< 10% (HR 15.0, 6.7-33.6)], 10 to 40% [(HR 5.0, 2.3-11.2), 41 to 60% (HR 4.0, 1.8-9.0) relative to > 90%]; and physician perception of patient preference to limit life support (no advanced life support [(HR 5.8, 3.6-9.4) or partial advanced life support (HR 3.2, 2.2-4.6) compared to full measures].\Question: Are dNR directives established early in mechanically ventilated intensive care unit patients?

Ex Output:

One third of mechanically ventilated patients had DNR directives established early during their ICU stay after the first 24 hr of admission. The strongest predictors of DNR directives were physician prediction of low probability of survival, physician perception of patient preference to limit life support, organ dysfunction, medical diagnosis and age.