Endothelial heme dynamics drive cancer cell metabolism by shaping the tumor microenvironment

The crosstalk among cancer cells (CCs) and stromal cells within the tumor microenvironment (TME) has a prominent role in cancer progression. The significance of endothelial cells (ECs) in this scenario relies on multiple vascular functions. By forming new blood vessels, ECs support tumor growth. In addition to their angiogenic properties, tumor-associated ECs (TECs) establish a unique vascular niche that actively modulates cancer development by shuttling a selected pattern of factors and metabolites to the CC. The profile of secreted metabolites is strictly dependent on the metabolic status of the cell, which is markedly perturbed in TECs. Recent evidence highlights the involvement of heme metabolism in the regulation of energy metabolism in TECs. The present study shows that interfering with endothelial heme metabolism by targeting the cell membrane heme exporter Feline Leukemia Virus subgroup C Receptor 1a (FLVCR1a) in TECs, resulted in enhanced fatty acid oxidation (FAO). Moreover, FAO-derived acetyl-CoA was partly consumed through ketogenesis, resulting in ketone bodies (KBs) accumulation in FLVCR1a-deficient TECs. Finally, the results from this study also demonstrate that TECs-derived KBs can be secreted in the extracellular environment, inducing a metabolic rewiring in the CC. Taken together, these data may contribute to finding new metabolic vulnerabilities for cancer therapy

The heme synthesis-export system regulates the tricarboxylic acid cycle flux and oxidative phosphorylation

Heme is an iron-containing porphyrin of vital importance for cell energetic metabolism. High rates of heme synthesis are commonly observed in proliferating cells. Moreover, the cell-surface heme exporter feline leukemia virus subgroup C receptor 1a (FLVCR1a) is overexpressed in several tumor types. However, the reasons why heme synthesis and export are enhanced in highly proliferating cells remain unknown. Here, we illustrate a functional axis between heme synthesis and heme export: heme efflux through the plasma membrane sustains heme synthesis, and implementation of the two processes down-modulates the tricarboxylic acid (TCA) cycle flux and oxidative phosphorylation. Conversely, inhibition of heme export reduces heme synthesis and promotes the TCA cycle fueling and flux as well as oxidative phosphorylation. These data indicate that the heme synthesis-export system modulates the TCA cycle and oxidative metabolism and provide amechanistic basis for the observation that both processes are enhanced in cells with high-energy demand

A prospective evaluation of the safety and efficacy of the TAXUS Element paclitaxel-eluting coronary stent system for the treatment of de novo coronary artery lesions: Design and statistical methods of the PERSEUS clinical program

<p>Abstract</p> <p>Background</p> <p>Paclitaxel-eluting stents decrease angiographic and clinical restenosis following percutaneous coronary intervention compared to bare metal stents. TAXUS Element is a third-generation paclitaxel-eluting stent which incorporates a novel, thinner-strut, platinum-enriched metal alloy platform. The stent is intended to have enhanced radiopacity and improved deliverability compared to other paclitaxel-eluting stents. The safety and efficacy of the TAXUS Element stent are being evaluated in the pivotal PERSEUS clinical trials.</p> <p>Methods/Design</p> <p>The PERSEUS trials include two parallel studies of the TAXUS Element stent in single, de novo coronary atherosclerotic lesions. The PERSEUS Workhorse study is a prospective, randomized (3:1), single-blind, non-inferiority trial in subjects with lesion length ≤28 mm and vessel diameter ≥2.75 mm to ≤4.0 mm which compares TAXUS Element to the TAXUS Express²paclitaxel-eluting stent system. The Workhorse study employs a novel Bayesian statistical approach that uses prior information to limit the number of study subjects exposed to the investigational device and thus provide a safer and more efficient analysis of the TAXUS Element stent. PERSEUS Small Vessel is a prospective, single-arm, superiority trial in subjects with lesion length ≤20 mm and vessel diameter ≥2.25 mm to <2.75 mm that compares TAXUS Element with a matched historical bare metal Express stent control.</p> <p>Discussion</p> <p>The TAXUS PERSEUS clinical trial program uses a novel statistical approach to evaluate whether design and metal alloy iterations in the TAXUS Element stent platform provide comparable safety and improved procedural performance compared to the previous generation Express stent. PERSEUS trial enrollment is complete and primary endpoint data are expected in 2010. PERSEUS Workhorse and Small Vessel are registered at <url>http://www.clinicaltrials.gov</url>, identification numbers NCT00484315 and NCT00489541.</p

Use of a Repositionable and Fully Retrievable Aortic Valve in Routine Clinical Practice: The RESPOND Study and RESPOND Extension Cohort

Objectives: The authors sought to evaluate 1-year clinical outcomes with the Lotus valve (Boston Scientific, Marlborough, Massachusetts) in a large international, multicenter prospective registry including patients eligible for transcatheter aortic valve replacement (TAVR) based on heart team consensus. Background: TAVR is a safe and effective treatment for severe aortic valve stenosis; however, limited data are available on TAVR with the repositionable and fully retrievable Lotus valve in unrestricted contemporary clinical practice. Methods: The RESPOND (Repositionable Lotus Valve System—Post-Market Evaluation of Real World Clinical Outcomes) study enrolled 1,014 patients; 996 patients were implanted with the Lotus valve (mean age 80.8 years, 50.8% female, mean STS score 6.0 ± 6.9%). The primary endpoint was all-cause mortality in the intent-to-treat population at 30 days and 1 year. An Extension cohort of 50 patients was treated with the Lotus valve with Depth Guard including a modified delivery system. Mortality and stroke were independently adjudicated. An independent core laboratory assessed echocardiographic data. Results: One-year clinical follow-up was available for 99.9% of Lotus valve-treated patients. At 1 year, the all-cause mortality rate was 11.7% and 4.1% of patients had experienced a disabling stroke. The permanent pacemaker implantation rate was 32% (37% among pacemaker-naive patients). Echocardiographic data at 1 year were available for core laboratory assessment in 62.6% of patients. Paravalvular leak was absent or trace in 94.5%, mild in 5.1%, and moderate in 0.4% of patients. Data from the Extension cohort confirmed good clinical outcomes at 30 days with an 18% permanent pacemaker rate (20% among pacemaker-naive patients). Conclusions: One-year outcomes from the RESPOND study confirm the safety and efficacy of the Lotus valve when used in routine clinical practice. (Repositionable Lotus Valve System—Post-Market Evaluation of Real World Clinical Outcomes [RESPOND]; NCT02031302

Constructing Biological Pathways by a Two-Step Counting Approach

Networks are widely used in biology to represent the relationships between genes and gene functions. In Boolean biological models, it is mainly assumed that there are two states to represent a gene: on-state and off-state. It is typically assumed that the relationship between two genes can be characterized by two kinds of pairwise relationships: similarity and prerequisite. Many approaches have been proposed in the literature to reconstruct biological relationships. In this article, we propose a two-step method to reconstruct the biological pathway when the binary array data have measurement error. For a pair of genes in a sample, the first step of this approach is to assign counting numbers for every relationship and select the relationship with counting number greater than a threshold. The second step is to calculate the asymptotic p-values for hypotheses of possible relationships and select relationships with a large p-value. This new method has the advantages of easy calculation for the counting numbers and simple closed forms for the p-value. The simulation study and real data example show that the two-step counting method can accurately reconstruct the biological pathway and outperform the existing methods. Compared with the other existing methods, this two-step method can provide a more accurate and efficient alternative approach for reconstructing the biological network

De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus

Congenital hydrocephalus (CH), featuring markedly enlarged brain ventricles, is thought to arise from failed cerebrospinal fluid (CSF) homeostasis and is treated with lifelong surgical CSF shunting with substantial morbidity. CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 × 10−7), SMARCC1 (p = 8.15 × 10−10), and PTCH1 (p = 1.06 × 10−6). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 × 10−4). Together, these probands account for ∼10% of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate. These results implicate impaired neurogenesis (rather than active CSF accumulation) in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications