Mammalian organs are challenging to study as they are fairly inaccessible to experimental manipulation and optical observation. Recent advances in three-dimensional (3D) culture techniques, coupled ...with the ability to independently manipulate genetic and microenvironmental factors, have enabled the real-time study of mammalian tissues. These systems have been used to visualize the cellular basis of epithelial morphogenesis, to test the roles of specific genes in regulating cell behaviours within epithelial tissues and to elucidate the contribution of microenvironmental factors to normal and disease processes. Collectively, these novel models can be used to answer fundamental biological questions and generate replacement human tissues, and they enable testing of novel therapeutic approaches, often using patient-derived cells.
Background Small randomized trials have demonstrated that radial access reduces access site complications compared to a femoral approach. The objective of this meta-analysis was to determine if ...radial access reduces major bleeding and as a result can reduce death and ischemic events compared to femoral access. Methods MEDLINE, EMBASE, and CENTRAL were searched from 1980 to April 2008. Relevant conference abstracts from 2005 to April 2008 were searched. Randomized trials comparing radial versus femoral access coronary angiography or intervention that reported major bleeding, death, myocardial infarction, and procedural or fluoroscopy time were included. A fixed-effects model was used with a random effects for sensitivity analysis. Results Radial access reduced major bleeding by 73% compared to femoral access (0.05% vs 2.3%, OR 0.27 95% CI 0.16, 0.45, P < .001). There was a trend for reductions in the composite of death, myocardial infarction, or stroke (2.5% vs 3.8%, OR 0.71 95% CI 0.49-1.01, P = .058) as well as death (1.2% vs 1.8% OR 0.74 95% CI 0.42-1.30, P = .29). There was a trend for higher rate of inability to the cross lesion with wire, balloon, or stent during percutaneous coronary intervention with radial access (4.7% vs 3.4% OR 1.29 95% CI 0.87, 1.94, P = .21). Radial access reduced hospital stay by 0.4 days (95% CI 0.2-0.5, P = .0001). Conclusions Radial access reduced major bleeding and there was a corresponding trend for reduction in ischemic events compared to femoral access. Large randomized trials are needed to confirm the benefit of radial access on death and ischemic events.
The mammary epithelium is composed of an inner luminal and surrounding myoepithelial cell layer. The presence of cancer cells beyond the myoepithelium defines invasive breast cancer, yet the role of ...the myoepithelium during invasion remains unclear. We developed a 3D organotypic culture assay to model this process through lineage-specific expression of the prometastatic transcription factor
We sought to distinguish the functional role of the myoepithelium in regulating invasion and local dissemination. Myoepithelial-specific
expression induced cell-autonomous myoepithelial cell escape. Remarkably, luminal-specific
expression was rarely sufficient for escape. Time-lapse microscopy revealed that myoepithelial cells collectively restrain and reinternalize invading Twist1
luminal cells. Barrier function correlated with myoepithelial abundance and required the expression of α-smooth muscle actin and P-cadherin. We next demonstrated that myoepithelial cells can restrain and recapture invasive cancer cells. Our data establish the concept of the myoepithelium as a dynamic barrier to luminal dissemination and implicate both smooth muscle contractility and intercellular adhesion in barrier function.
Diagnostic criteria for coeliac disease (CD) from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) were published in 1990. Since then, the autoantigen in CD, ...tissue transglutaminase, has been identified; the perception of CD has changed from that of a rather uncommon enteropathy to a common multiorgan disease strongly dependent on the haplotypes human leukocyte antigen (HLA)-DQ2 and HLA-DQ8; and CD-specific antibody tests have improved.
A panel of 17 experts defined CD and developed new diagnostic criteria based on the Delphi process. Two groups of patients were defined with different diagnostic approaches to diagnose CD: children with symptoms suggestive of CD (group 1) and asymptomatic children at increased risk for CD (group 2). The 2004 National Institutes of Health/Agency for Healthcare Research and Quality report and a systematic literature search on antibody tests for CD in paediatric patients covering the years 2004 to 2009 was the basis for the evidence-based recommendations on CD-specific antibody testing.
In group 1, the diagnosis of CD is based on symptoms, positive serology, and histology that is consistent with CD. If immunoglobulin A anti-tissue transglutaminase type 2 antibody titers are high (>10 times the upper limit of normal), then the option is to diagnose CD without duodenal biopsies by applying a strict protocol with further laboratory tests. In group 2, the diagnosis of CD is based on positive serology and histology. HLA-DQ2 and HLA-DQ8 testing is valuable because CD is unlikely if both haplotypes are negative.
The aim of the new guidelines was to achieve a high diagnostic accuracy and to reduce the burden for patients and their families. The performance of these guidelines in clinical practice should be evaluated prospectively.
Long-term continuous electrocardiographic monitoring shows a substantial prevalence of asymptomatic, subclinical atrial fibrillation (SCAF) in patients with pacemakers and patients with cryptogenic ...stroke. Whether SCAF is also common in other patients without these conditions is unknown.
We implanted subcutaneous electrocardiographic monitors (St. Jude CONFIRM-AF) in patients ≥65 years of age attending cardiovascular or neurology outpatient clinics if they had no history of atrial fibrillation but had any of the following: CHA
DS
-VASc score of ≥2, sleep apnea, or body mass index >30 kg/m
. Eligibility also required either left atrial enlargement (≥4.4 cm or volume ≥58 mL) or increased (≥290 pg/mL) serum NT-proBNP (N-terminal pro-B-type natriuretic peptide). Patients were monitored for SCAF lasting ≥5 minutes.
Two hundred fifty-six patients were followed up for 16.3±3.8 months. Baseline age was 74±6 years; mean CHA
DS
-VASc score was 4.1±1.4; left atrial diameter averaged 4.7±0.8 cm; and 48% had a prior stroke, transient ischemic attack, or systemic embolism. SCAF ≥5 minutes was detected in 90 patients (detection rate, 34.4%/y; 95% confidence interval CI, 27.7-42.3). Baseline predictors of SCAF were increased age (hazard ratio HR per decade, 1.55; 95% CI, 1.11-2.15), left atrial dimension (HR per centimeter diameter, 1.43; 95% CI, 1.09-1.86), and blood pressure (HR per 10 mm Hg, 0.87; 95% CI, 0.78-0.98), but not prior stroke. The rate of occurrence of SCAF in those with a history of stroke, systemic embolism, or transient ischemic attack was 39.4%/y versus 30.3%/y without (
=0.32). The cumulative SCAF detection rate was higher (51.9%/y) in those with left atrial volume above the median value of 73.5 mL.
SCAF is frequently detected by continuous electrocardiographic monitoring in older patients without a history of atrial fibrillation who are attending outpatient cardiology and neurology clinics. Its clinical significance is unclear.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01694394.
Although autophagy is being pursued as a therapeutic target in clinical oncology trials, its effects on metastasis, the principal cause of cancer mortality, remain unclear. Here, we utilize mammary ...cancer models to temporally delete essential autophagy regulators during carcinoma progression. Though genetic ablation of autophagy strongly attenuates primary mammary tumor growth, impaired autophagy promotes spontaneous metastasis and enables the outgrowth of disseminated tumor cells into overt macro-metastases. Transcriptomic analysis reveals that autophagy deficiency elicits a subpopulation of otherwise luminal tumor cells exhibiting basal differentiation traits, which is reversed upon preventing accumulation of the autophagy cargo receptor, Neighbor to BRCA1 (NBR1). Furthermore, pharmacological and genetic induction of autophagy suppresses pro-metastatic differentiation and metastatic outgrowth. Analysis of human breast cancer data reveal that autophagy gene expression inversely correlates with pro-metastatic differentiation signatures and predicts overall and distant metastasis-free survival. Overall, these findings highlight autophagy-dependent control of NBR1 as a key determinant of metastatic progression.
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•Autophagy promotes primary tumor growth, yet suppresses metastatic outgrowth•Autophagy deficiency elicits a pro-metastatic basal tumor cell subpopulation•NBR1 accumulation mediates the effects of autophagy inhibition on metastasis•Enforced autophagy induction prevents the outgrowth of disseminated tumor cells
Autophagy is a therapeutic target in cancer, but its role during metastasis remains incompletely understood. In mammary cancer models, Marsh et al. demonstrate that autophagic degradation of NBR1 suppresses metastatic outgrowth by restricting an aggressive, basal subpopulation of tumor cells. Enforced autophagy is a potential therapeutic approach to prevent metastases.
Monotherapy with a P2Y
inhibitor after a minimum period of dual antiplatelet therapy is an emerging approach to reduce the risk of bleeding after percutaneous coronary intervention (PCI).
In a ...double-blind trial, we examined the effect of ticagrelor alone as compared with ticagrelor plus aspirin with regard to clinically relevant bleeding among patients who were at high risk for bleeding or an ischemic event and had undergone PCI. After 3 months of treatment with ticagrelor plus aspirin, patients who had not had a major bleeding event or ischemic event continued to take ticagrelor and were randomly assigned to receive aspirin or placebo for 1 year. The primary end point was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. We also evaluated the composite end point of death from any cause, nonfatal myocardial infarction, or nonfatal stroke, using a noninferiority hypothesis with an absolute margin of 1.6 percentage points.
We enrolled 9006 patients, and 7119 underwent randomization after 3 months. Between randomization and 1 year, the incidence of the primary end point was 4.0% among patients randomly assigned to receive ticagrelor plus placebo and 7.1% among patients assigned to receive ticagrelor plus aspirin (hazard ratio, 0.56; 95% confidence interval CI, 0.45 to 0.68; P<0.001). The difference in risk between the groups was similar for BARC type 3 or 5 bleeding (incidence, 1.0% among patients receiving ticagrelor plus placebo and 2.0% among patients receiving ticagrelor plus aspirin; hazard ratio, 0.49; 95% CI, 0.33 to 0.74). The incidence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke was 3.9% in both groups (difference, -0.06 percentage points; 95% CI, -0.97 to 0.84; hazard ratio, 0.99; 95% CI, 0.78 to 1.25; P<0.001 for noninferiority).
Among high-risk patients who underwent PCI and completed 3 months of dual antiplatelet therapy, ticagrelor monotherapy was associated with a lower incidence of clinically relevant bleeding than ticagrelor plus aspirin, with no higher risk of death, myocardial infarction, or stroke. (Funded by AstraZeneca; TWILIGHT ClinicalTrials.gov number, NCT02270242.).
In patients with ST-segment elevation myocardial infarction (STEMI), percutaneous coronary intervention (PCI) of the culprit lesion reduces the risk of cardiovascular death or myocardial infarction. ...Whether PCI of nonculprit lesions further reduces the risk of such events is unclear.
We randomly assigned patients with STEMI and multivessel coronary artery disease who had undergone successful culprit-lesion PCI to a strategy of either complete revascularization with PCI of angiographically significant nonculprit lesions or no further revascularization. Randomization was stratified according to the intended timing of nonculprit-lesion PCI (either during or after the index hospitalization). The first coprimary outcome was the composite of cardiovascular death or myocardial infarction; the second coprimary outcome was the composite of cardiovascular death, myocardial infarction, or ischemia-driven revascularization.
At a median follow-up of 3 years, the first coprimary outcome had occurred in 158 of the 2016 patients (7.8%) in the complete-revascularization group as compared with 213 of the 2025 patients (10.5%) in the culprit-lesion-only PCI group (hazard ratio, 0.74; 95% confidence interval CI, 0.60 to 0.91; P = 0.004). The second coprimary outcome had occurred in 179 patients (8.9%) in the complete-revascularization group as compared with 339 patients (16.7%) in the culprit-lesion-only PCI group (hazard ratio, 0.51; 95% CI, 0.43 to 0.61; P<0.001). For both coprimary outcomes, the benefit of complete revascularization was consistently observed regardless of the intended timing of nonculprit-lesion PCI (P = 0.62 and P = 0.27 for interaction for the first and second coprimary outcomes, respectively).
Among patients with STEMI and multivessel coronary artery disease, complete revascularization was superior to culprit-lesion-only PCI in reducing the risk of cardiovascular death or myocardial infarction, as well as the risk of cardiovascular death, myocardial infarction, or ischemia-driven revascularization. (Funded by the Canadian Institutes of Health Research and others; COMPLETE ClinicalTrials.gov number, NCT01740479.).
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