ObjectivePancreatic ductal adenocarcinoma (PDA) has among the highest stromal fractions of any cancer and this has complicated attempts at expression-based molecular classification. The goal of this work is to profile purified samples of human PDA epithelium and stroma and examine their respective contributions to gene expression in bulk PDA samples.DesignWe used laser capture microdissection (LCM) and RNA sequencing to profile the expression of 60 matched pairs of human PDA malignant epithelium and stroma samples. We then used these data to train a computational model that allowed us to infer tissue composition and generate virtual compartment-specific expression profiles from bulk gene expression cohorts.ResultsOur analysis found significant variation in the tissue composition of pancreatic tumours from different public cohorts. Computational removal of stromal gene expression resulted in the reclassification of some tumours, reconciling functional differences between different cohorts. Furthermore, we established a novel classification signature from a total of 110 purified human PDA stroma samples, finding two groups that differ in the extracellular matrix-associated and immune-associated processes. Lastly, a systematic evaluation of cross-compartment subtypes spanning four patient cohorts indicated partial dependence between epithelial and stromal molecular subtypes.ConclusionOur findings add clarity to the nature and number of molecular subtypes in PDA, expand our understanding of global transcriptional programmes in the stroma and harmonise the results of molecular subtyping efforts across independent cohorts.

No abstract

No abstract

Objective Cerebrovascular disease is 1 of the possible mechanisms of the previously reported relationship between Mediterranean-type diet (MeDi) and Alzheimer’s disease (AD). We sought to investigate the association between MeDi and MRI infarcts. Methods High-resolution structural MRI was collected on 707 elderly 65 years or older community residents of New York with available dietary assessments administered an average of 5.8 years (3.22 standard deviations [SDs]) before the MRI. Participants were divided into 3 groups of adherence to MeDi (low, middle, and high tertiles). We examined the association of increasing adherence to MeDi with presence of infarcts on MRI. Models were run without adjustment, adjusted for basic demographic and clinical factors, and adjusted for vascular risk factors. Results A total of 222 participants had at least 1 infarct. In the unadjusted model, compared to the low adherence group, those in the moderate MeDi adherence group had a 22% reduced odds of having an infarct (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.55–1.14), while participants in the highest MeDi adherence group had a 36% reduced odds (OR, 0.64; 95% CI, 0.42–0.97; p for trend = 0.04). In adjusted models, the association between MeDi adherence and MRI infarcts remained essentially unchanged. The association of high MeDi adherence with infarcts was comparable to that of hypertension (40% reduced probability), did not vary by infarct size or after excluding patients with dementia (n = 46) or clinical strokes (n = 86). There was no association between MeDi and white matter hyperintensities. Interpretation Higher adherence to the MeDi is associated with reduced cerebrovascular disease burden.

No abstract

No abstract

ObjectiveIntraplaque hemorrhage is an increasingly recognized contributor to plaque instability. Neovascularization of plaque is believed to facilitate the entry of inflammatory and red blood cells (RBC). Under physiological conditions, neovessels are subject to mechanical loading from the deformation of atherosclerotic plaque by blood pressure and flow. Local mechanical environments around neovessels and their relevant pathophysiologic significance have not yet been examined.Methods and resultsFour carotid plaque samples removed at endarcterectomy were collected for histopathological examination. Neovessels and other components were manually segmented to build numerical models for mechanical analysis. Each component was assumed to be non-linear isotropic, piecewise homogeneous and incompressible. The results indicated that local maximum principal stress and stretch and their variations during one cardiac cycle were greatest around neovessels. Neovessels surrounded by RBC underwent a much larger stretch during systole than those without RBCs present nearby (median [inter quartile range]; 1.089 [1.056, 1.131] vs. 1.034 [1.020, 1.067]; p < 0.0001) and much larger stress (5.3 kPa [3.4, 8.3] vs. 3.1 kPa [1.6, 5.5]; p < 0.0001) and stretch (0.0282 [0.0190, 0.0427] vs. 0.0087 [0.0045, 0.0185]; p < 0.0001) variations during the cardiac cycle.ConclusionsLocal critical mechanical conditions may lead to the rupture of neovessels resulting in the formation and expansion of intraplaque hemorrhage.

The in-hospital mortality of severe pulmonary hypertension (PH) with right heart failure (RHF) is high despite the use of vasoactive and PH-specific therapies. We conducted a prospective analysis evaluating the safety and outcomes of fasudil hydrochloride (Chuan Wei) therapy in acute RHF. PH patients hospitalized between April 2009 and November 2010 were treated with 30 mg of i.v. fasudil three times daily over 30 min, until they experienced relief of RHF symptoms. Adverse and serious adverse events were recorded. Odds ratios (ORs) and 95% confidence intervals were calculated for both in-hospital mortality and re-hospitalization. Multivariate adjustments were made for age, gender and World Health Organization functional class. There were no significant differences between the fasudil group and the control group in demographics, hemodynamics, and PH-specific and vasoactive therapies. Of the 209 study patients, 3 of the 74 patients (4.1%) in the fasudil arm died, and 19 of the 135 patients (14.1%) in the control arm died (P=0.005). Fasudil decreased both in-hospital mortality (OR=0.258 (0.074-0.903); P=0.034) and 30-day re-hospitalization (OR=0.200 (0.059-0.681); P=0.010). Fasudil was well tolerated; one patient discontinued treatment. Intravenous fasudil may be given safely in patients with PH and acute RHF, and may reduce the rates of both in-hospital mortality and 30-day re-hospitalization.