bluuebunny/crossref_metadata_2025 huggingface dataset:
Individual Motile CD4+ T Cells Can Participate in Efficient Multikilling through Conjugation to Multiple Tumor Cells
Authors: Liadi Ivan , Singh Harjeet , Romain Gabrielle , Rey-Villamizar Nicolas , Merouane Amine , Adolacion Jay R T. , Kebriaei Partow , Huls Helen , Qiu Peng , Roysam Badrinath , Cooper Laurence J.N. , Varadarajan Navin
Published: February 2015

T cells genetically modified to express a CD19-specific chimeric antigen receptor (CAR) for the investigational treatment of B-cell malignancies comprise a heterogeneous population, and their ability to persist and participate in serial killing of tumor cells is a predictor of therapeutic success. We implemented Timelapse Imaging Microscopy in Nanowell Grids (TIMING) to provide direct evidence that CD4+CAR+ T cells (CAR4 cells) can engage in multikilling via simultaneous conjugation to multiple tumor cells. Comparisons of the CAR4 cells and CD8+CAR+ T cells (CAR8 cells) demonstrate that, although CAR4 cells can participate in killing and multikilling, they do so at slower rates, likely due to the lower granzyme B content. Significantly, in both sets of T cells, a minor subpopulation of individual T cells identified by their high motility demonstrated efficient killing of single tumor cells. A comparison of the multikiller and single-killer CAR+ T cells revealed that the propensity and kinetics of T-cell apoptosis were modulated by the number of functional conjugations. T cells underwent rapid apoptosis, and at higher frequencies, when conjugated to single tumor cells in isolation, and this effect was more pronounced on CAR8 cells. Our results suggest that the ability of CAR+ T cells to participate in multikilling should be evaluated in the context of their ability to resist activation-induced cell death. We anticipate that TIMING may be used to rapidly determine the potency of T-cell populations and may facilitate the design and manufacture of next-generation CAR+ T cells with improved efficacy. Cancer Immunol Res; 3(5); 473–82. ©2015 AACR.

See related commentary by June, p. 470
TH2-Polarized CD4+ T Cells and Macrophages Limit Efficacy of Radiotherapy
Authors: Shiao Stephen L. , Ruffell Brian , DeNardo David G. , Faddegon Bruce A. , Park Catherine C. , Coussens Lisa M.
Published: February 2015

Radiotherapy and chemotherapy following surgery are mainstays of treatment for breast cancer. Although multiple studies have recently revealed the significance of immune cells as mediators of chemotherapy response in breast cancer, less is known regarding roles for leukocytes as mediating outcomes following radiotherapy. To address this question, we utilized a syngeneic orthotopic murine model of mammary carcinogenesis to investigate if response to radiotherapy could be improved when select immune cells or immune-based pathways in the mammary microenvironment were inhibited. Treatment of mammary tumor–bearing mice with either a neutralizing mAb to colony-stimulating factor-1 (CSF-1) or a small-molecule inhibitor of the CSF-1 receptor kinase (i.e., PLX3397), resulting in efficient macrophage depletion, significantly delayed tumor regrowth following radiotherapy. Delayed tumor growth in this setting was associated with increased presence of CD8+ T cells and reduced presence of CD4+ T cells, the main source of the TH2 cytokine IL4 in mammary tumors. Selective depletion of CD4+ T cells or neutralization of IL4 in combination with radiotherapy phenocopied results following macrophage depletion, whereas depletion of CD8+ T cells abrogated improved response to radiotherapy following these therapies. Analogously, therapeutic neutralization of IL4 or IL13, or IL4 receptor alpha deficiency, in combination with the chemotherapy paclitaxel, resulted in slowed primary mammary tumor growth by CD8+ T-cell–dependent mechanisms. These findings indicate that clinical responses to cytotoxic therapy in general can be improved by neutralizing dominant TH2-based programs driving protumorigenic and immune-suppressive pathways in mammary (breast) tumors to improve outcomes. Cancer Immunol Res; 3(5); 518–25. ©2015 AACR.
Mass Cytometry Analysis Shows That a Novel Memory Phenotype B Cell Is Expanded in Multiple Myeloma
Authors: Hansmann Leo , Blum Lisa , Ju Chia-Hsin , Liedtke Michaela , Robinson William H. , Davis Mark M.
Published: February 2015

It would be very beneficial if the status of cancers could be determined from a blood specimen. However, peripheral blood leukocytes are very heterogeneous between individuals, and thus high-resolution technologies are likely required. We used cytometry by time-of-flight and next-generation sequencing to ask whether a plasma cell cancer (multiple myeloma) and related precancerous states had any consistent effect on the peripheral blood mononuclear cell phenotypes of patients. Analysis of peripheral blood samples from 13 cancer patients, 9 precancer patients, and 9 healthy individuals revealed significant differences in the frequencies of the T-cell, B-cell, and natural killer–cell compartments. Most strikingly, we identified a novel B-cell population that normally accounts for 4.0% ± 0.7% (mean ± SD) of total B cells and is up to 13-fold expanded in multiple myeloma patients with active disease. This population expressed markers previously associated with both memory (CD27+) and naïve (CD24loCD38+) phenotypes. Single-cell immunoglobulin gene sequencing showed polyclonality, indicating that these cells are not precursors to the myeloma, and somatic mutations, a characteristic of memory cells. SYK, ERK, and p38 phosphorylation responses, and the fact that most of these cells expressed isotypes other than IgM or IgD, confirmed the memory character of this population, defining it as a novel type of memory B cells. Cancer Immunol Res; 3(6); 650–60. ©2015 AACR.
Thyroid Volume and Its Relation to Anthropometric Measures in a Healthy Cuban Population
Authors: Turcios Silvia , Lence-Anta Juan J. , Santana Jose-Luis , Pereda Celia M. , Velasco Milagros , Chappe Mae , Infante Idalmis , Bustillo Marlene , García Anabel , Clero Enora , Maillard Stephane , Rodriguez Regla , Xhaard Constance , Ren Yan , Rubino Carole , Ortiz Rosa M. , de Vathaire Florent
Published: February 2015

Objectives: The aim of this study was to describe the thyroid volume in healthy adults by ultrasound and to correlate this volume with some anthropometric measures and other differentiated thyroid cancer risk factors. Study Design: Thyroid volume and anthropometric measures were recorded in a sample of 100 healthy adults, including 21 men and 79 women aged 18-50 years, living in a non-iodine-deficient area of Havana city. Results: The average thyroid volume was 6.6 ± 0.26 ml; it was higher in men (7.3 ml) than in women (6.4 ml; p = 0.15). In the univariate analysis, thyroid volume was correlated with all anthropometric measures, but in the multivariate analysis, body surface area was found to be the only significant anthropometric parameter. Thyroid volume was also higher in current or former smokers and in persons with blood group AB or B. Conclusion: Specific reference values of thyroid volume as a function of body surface area could be used for evaluating thyroid volume in clinical practice. The relation between body surface area and thyroid volume is coherent with what is known about the relation of thyroid volume to thyroid cancer risk, but the same is not true about the relation between thyroid volume and smoking habit.
Combination of Matrine and Sorafenib Decreases the Aggressive Phenotypes of Hepatocellular Carcinoma Cells
Authors: Lin Yan , Lin Lianjie , Jin Yu , Zhang Ying , Wang Dongxu , Tan Yue , Zheng Changqing
Published: February 2015

Background: The aim of this study was to determine the effects of matrine (a natural alkaloid) on sorafenib-induced cytotoxicty against hepatocellular carcinoma (HCC) cells, and to explore the molecular mechanisms involved. Methods: HepG2 and Hep3B cells were treated with matrine alone or in combination with sorafenib, and cell viability and apoptosis were assessed. The involvement of micro (mi)RNA-21 in the action of matrine was examined. Results: Matrine significantly augmented the antiproliferative activity of sorafenib in a dose-dependent manner. Matrine significantly increased apoptosis, coupled with enhanced cleavage of caspase-3 and poly (ADP-ribose) polymerase. miRNA-21-overexpressing HCC cells showed a marked decrease in matrine-induced growth suppression and the expression of phosphatase and tensin homolog (PTEN). The suppressive effect of combining matrine and sorafenib was significantly reduced by miRNA-21 overexpression or PTEN inhibition. Conclusion: Matrine in combination with sorafenib leads to increased cytotoxic effects against HCC cells, at least partially, via the suppression of miRNA-21 and the subsequent induction of PTEN.
Management of Gastrointestinal Stromal Tumour: Current Practices and Visions for the Future
Authors: Blay Jean-Yves , Casali Paolo G. , Dei Tos Angelo Paolo , Le Cesne Axel , Reichardt Peter
Published: February 2015

Gastrointestinal stromal tumour (GIST), while relatively rare, is the most common mesenchymal tumour of the gastrointestinal tract. These tumours are largely resistant to cytotoxic chemotherapy and, in the past, were typically managed surgically. However, as a result of the identification of activating mutations in the proto-oncogene KIT and the development of compounds that inhibit the KIT receptor tyrosine kinase, GISTs have, in the last 14 years, become the archetype of a targeted agent-responsive tumour. Due to the almost continual emergence of new data from clinical trials and other studies on GIST diagnosis and treatment, the management of this disease requires regular review. The 2013 ArcheoloGIST summit was convened in Prague, Czech Republic. Interaction between attending physicians and the expert faculty was a core component of the summit. The current article is based on discussions held during two interactive sessions at ArcheoloGIST 2013 in which the authors aimed to: (1) reach a consensus on the current management of GIST and (2) provide a vision for the future diagnosis and treatment of this disease.
Resting Energy Expenditure in Patients with Stroke during the Subacute Phases - Relationships with Stroke Types, Location, Severity of Paresis, and Activities of Daily Living
Authors: Kawakami Michiyuki , Liu Meigen , Wada Ayako , Otsuka Tomoyoshi , Nishimura Atsuko
Published: February 2015

Background: The energy demands in patients with stroke during the subacute phases are unclear. However, this information is essential for appropriate clinical and nutritional management. The aims of this study were to determine the resting energy expenditure (REE) during the subacute phases, examine its relationships with stroke types, location, severity of hemiparesis, and activities of daily living (ADL), and evaluate whether estimation of REE from the Harris-Benedict equation (HB) requires the addition of a ‘stress factor' to capture possible additional REE imposed by stroke. Methods: We measured REE in 95 patients with subacute stroke (53.5 ± 16.6 days post-stroke) with indirect calorimetry, and compared it with predicted values of energy expenditure estimated from the HB (expressed as percentage). Patients were admitted for rehabilitation of their first ischemic or nonsurgical hemorrhagic stroke. The severity of hemiparesis was assessed with the motor items of the Stroke Impairment Assessment Set (SIAS). The ADL was assessed with the Functional Independence Measure (FIM). We compared REE and %HB of the two groups divided by hemiparesis severity and ADL limitation using the Student's t-test, and those of the five groups divided by stroke location. The correlations between REE and the motor items of the SIAS and the FIM score were assessed with the Spearman rank correlation test. A multiple regression analysis for REE was conducted. Results: The average body weight (BW) was 57.1 ± 11.3 kg. The average body mass index (BMI) was 22.5 ± 4.0. The mean REE (%HB) was 1,271 ± 284 kcal/day (106.0 ± 17.3%). REE and %HB of the low ADL group was less than that of the high ADL group (p < 0.05). The REE had a positive correlation with the FIM score (rs = 0.51, p < 0.01). The motor items of the SIAS were not significantly correlated with REE. BW, FIM, and stroke location were independent predictors of REE. Conclusions: Analysis of energy expenditure suggests that stroke patients are not hypermetabolic during the subacute phase. The ‘stress factor' in stroke patients during the subacute phase was 1.0-1.1. This finding provides important information for improving nutritional management during the subacute phase in patients with stroke.
Differential effects of platelets and platelet inhibition by ticagrelor on TLR2- and TLR4-mediated inflammatory responses
Authors: van der Ven Andre J. , Riksen Niels , Rongen Gerard , Tacke Sabine , van den Berg T. N. A. , Fijnheer Rob , Gomes Marc E. , Dinarello Charles A. , van de Veerdonk Frank L. , Gasem M. Hussein , Netea Mihai G. , Joosten Leo A. B. , de Groot Philip G. , de Mast Quirijn , Tunjungputri Rahajeng N.
Published: February 2015

Platelets and platelet-monocyte interaction play an important role in inflammation. Both pro- and anti-inflammatory effects of platelet inhibition have been reported in animal models. This study aimed to investigate the effect of platelets and platelet inhibition by the new P2Y12 receptor antagonist ticagrelor on monocyte function, as assessed by cytokine responses to Toll-like Receptor (TLR) ligands. In a set of in vitro experiments, peripheral blood mononuclear cells (PBMC) incubated with the TLR2 ligand Pam3CSK4 produced less cytokines in the presence of platelets, whereas platelets increased the production of cytokines when PBMC were exposed to TLR4 ligand lipopolysaccharide (LPS). These effects of platelets were dependent on direct platelet-leukocyte aggregation and for the Pam3CSK4-induced response, on phagocytosis of platelets by monocytes. In a double blind, placebo-controlled crossover trial in healthy volunteers, a single oral dosage of 180 mg ticagrelor reduced platelet-monocyte complex (PMC) formation. This was associated with an increase in pro-inflammatory cytokines in blood exposed to Pam3CSK4, but a decrease in these cytokines in blood exposed to LPS. These findings show that platelets differentially modulate TLR2- and TLR4-mediated cytokine responses of PBMC. Through inhibition of platelet-leukocyte interaction, P2Y12 receptor antagonists may either exert a pro- or anti-inflammatory effect during infections depending on the TLR primarily involved.
Safety and efficacy of well managed warfarin
Authors: Sjögren Vilhelm , Grzymala-Lubanski Bartosz , Renlund Henrik , Friberg Leif , Lip Gregory Y. H. , Svensson Peter J. , Själander Anders
Published: February 2015

The safety and efficacy of warfarin in a large, unselected cohort of warfarin-treated patients with high quality of care is comparable to that reported for non-vitamin K antagonists. Warfarin is commonly used for stroke prevention in atrial fibrillation, as well as for treatment and prevention of venous thromboembolism. While reducing risk of thrombotic/embolic incidents, warfarin increases the risk of bleeding. The aim of this study was to elucidate risks of bleeding and thromboembolism for patients on warfarin treatment in a large, unselected cohort with rigorously controlled treatment. This was a retrospective, registry-based study, covering all patients treated with warfarin in the Swedish national anticoagulation register Auricula, which records both primary and specialised care. The study included 77,423 unselected patients with 100,952 treatment periods of warfarin, constituting 217,804 treatment years. Study period was January 1, 2006 to December 31, 2011. Atrial fibrillation was the most common indication (68%). The mean time in therapeutic range of the international normalised ratio (INR) 2.0-3.0 was 76.5%. The annual incidence of severe bleeding was 2.24% and of thromboembolism 2.65%. The incidence of intracranial bleeding was 0.37% per treatment year in the whole population, and 0.38% among patients with atrial fibrillation. In conclusion, warfarin treatment where patients spend a high proportion of time in the therapeutic range is safe and effective, and will continue to be a valid treatment option in the era of newer oral anticoagulants.

Note: The review process for this paper was fully handled by Christian Weber, Editor in Chief.
Three-Dimensional
123
I-
Meta
-Iodobenzylguanidine Cardiac Innervation Maps to Assess Substrate and Successful Ablation Sites for Ventricular Tachycardia
Authors: Klein Thomas , Abdulghani Mohammed , Smith Mark , Huang Rui , Asoglu Ramazan , Remo Benjamin F. , Turgeman Aharon , Mesubi Olurotimi , Sidhu Sunjeet , Synowski Stephen , Saliaris Anastasios , See Vincent , Shorofsky Stephen , Chen Wengen , Dilsizian Vasken , Dickfeld Timm
Published: February 2015

Background—

Innervation is a critical component of arrhythmogenesis and may present an important trigger/substrate modifier not used in current ventricular tachycardia (VT) ablation strategies.

Methods and Results—

Fifteen patients referred for ischemic VT ablation underwent preprocedural cardiac
123
I-
meta
-iodobenzylguanidine (
123
I-
m
IBG) imaging, which was used to create 3-dimensional (3D) innervation models and registered to high-density voltage maps. 3D
123
I-
m
IBG innervation maps demonstrated areas of complete denervation and
123
I-
m
IBG transition zone in all patients, which corresponded to 0% to 31% and 32% to 52% uptake.
123
I-
m
IBG denervated areas were ≈2.5-fold larger than bipolar voltage–defined scar (median, 24.6% [Q1–Q3, 18.3%–34.4%] versus 10.6% [Q1–Q3, 3.9%–16.4%];
P
<0.001) and included the inferior wall in all patients, with no difference in the transition/border zone (11.4% [Q1–Q3, 9.5%–13.2%] versus 16.6% [Q1–Q3, 12.0%–18.8%];
P
=0.07). Bipolar/unipolar voltages varied widely within areas of denervation (0.8 mV [Q1–Q3, 0.3–1.7 mV] and 4.0 mV [Q1–Q3, 2.9–5.6 mV]) and
123
I-
m
IBG transition zones (0.8 mV [Q1–Q3, 0.4–1.8 mV] and 4.6 mV [Q1–Q3, 3.2–6.3 mV]). Bipolar voltages in denervated areas and
123
I-
m
IBG transition zones were <0.5 mV, 0.5 to 1.5 mV, and >1.5 mV in 35%, 36%, and 29%, as well as 35%, 35%, and 30%, respectively (
P
>0.05). Successful ablation sites were within bipolar voltage–defined scar (7%), border zone (57%), and areas of normal voltage (36%), but all ablation sites were abnormally innervated (denervation/
123
I-
m
IBG transition zone in 50% each).

Conclusions—

123
I-
m
IBG innervation defects are larger than bipolar voltage–defined scar and cannot be detected with standard voltage criteria. Thirty-six percent of successful VT ablation sites demonstrated normal voltages (>1.5 mV), but all ablation sites were within the areas of abnormal innervation.
123
I-
m
IBG innervation maps may provide critical information about triggers/substrate modifiers and could improve understanding of VT substrate and facilitate VT ablation.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique Identifier: NCT01250912.
Catecholaminergic Polymorphic Ventricular Tachycardia in Children
Authors: Roston Thomas M. , Vinocur Jeffrey M. , Maginot Kathleen R. , Mohammed Saira , Salerno Jack C. , Etheridge Susan P. , Cohen Mitchell , Hamilton Robert M. , Pflaumer Andreas , Kanter Ronald J. , Potts James E. , LaPage Martin J. , Collins Kathryn K. , Gebauer Roman A. , Temple Joel D. , Batra Anjan S. , Erickson Christopher , Miszczak-Knecht Maria , Kubuš Peter , Bar-Cohen Yaniv , Kantoch Michal , Thomas Vincent C. , Hessling Gabriele , Anderson Chris , Young Ming-Lon , Cabrera Ortega Michel , Lau Yung R. , Johnsrude Christopher L. , Fournier Anne , Kannankeril Prince J. , Sanatani Shubhayan
Published: February 2015

Background—

Catecholaminergic polymorphic ventricular tachycardia is an uncommon, potentially lethal, ion channelopathy. Standard therapies have high failure rates and little is known about treatment in children. Newer options such as flecainide and left cardiac sympathetic denervation are not well validated. We sought to define treatment outcomes in children with catecholaminergic polymorphic ventricular tachycardia.

Methods and Results—

This is a Pediatric and Congenital Electrophysiology Society multicenter, retrospective cohort study of catecholaminergic polymorphic ventricular tachycardia patients diagnosed before 19 years of age. The cohort included 226 patients, including 170 probands and 56 relatives. Symptomatic presentation was reported in 176 (78%). Symptom onset occurred at 10.8 (interquartile range, 6.8–13.2) years with a delay to diagnosis of 0.5 (0–2.6) years. Syncope (
P
<0.001), cardiac arrest (
P
<0.001), and treatment failure (
P
=0.008) occurred more often in probands. β-Blockers were prescribed in 205 of 211 patients (97%) on medication, and 25% experienced at least 1 treatment failure event. Implantable cardioverter defibrillators were placed in 121 (54%) and was associated with electrical storm in 22 (18%). Flecainide was used in 24% and left cardiac sympathetic denervation in 8%. Six deaths (3%) occurred during a cumulative follow-up of 788 patient-years.

Conclusions—

This study demonstrates a malignant phenotype and lengthy delay to diagnosis in catecholaminergic polymorphic ventricular tachycardia. Probands were typically severely affected. β-Blockers were almost universally initiated; however, treatment failure, noncompliance and subtherapeutic dosing were often reported. Implantable cardioverter defibrillators were common despite numerous device-related complications. Treatment failure was rare in the quarter of patients on flecainide. Left cardiac sympathetic denervation was not uncommon although the indication was variable.
Symptom Recognition and Healthcare Experiences of Young Women With Acute Myocardial Infarction
Authors: Lichtman Judith H. , Leifheit-Limson Erica C. , Watanabe Emi , Allen Norrina B. , Garavalia Brian , Garavalia Linda S. , Spertus John A. , Krumholz Harlan M. , Curry Leslie A.
Published: February 2015

Background—

Prompt recognition of acute myocardial infarction symptoms and timely care-seeking behavior are critical to optimize acute medical therapies. Relatively little is known about the symptom presentation and care-seeking experiences of women aged ≤55 years with acute myocardial infarction, a group shown to have increased mortality risk as compared with similarly aged men. Understanding symptom recognition and experiences engaging the healthcare system may provide opportunities to reduce delays and improve acute care for this population.

Methods and Results—

We conducted a qualitative study using in-depth interviews with 30 women (aged 30–55 years) hospitalized with acute myocardial infarction to explore their experiences with prodromal symptoms and their decision-making process to seek medical care. Five themes characterized their experiences: (1) prodromal symptoms varied substantially in both nature and duration; (2) they inaccurately assessed personal risk of heart disease and commonly attributed symptoms to noncardiac causes; (3) competing and conflicting priorities influenced decisions about seeking acute care; (4) the healthcare system was not consistently responsive to them, resulting in delays in workup and diagnosis; and (5) they did not routinely access primary care, including preventive care for heart disease.

Conclusions—

Participants did not accurately assess their cardiovascular risk, reported poor preventive health behaviors, and delayed seeking care for symptoms, suggesting that differences in both prevention and acute care may be contributing to young women’s elevated acute myocardial infarction mortality relative to men. Identifying factors that promote better cardiovascular knowledge, improved preventive health care, and prompt care-seeking behaviors represent important target for this population.
Vascular Smooth Muscle Cell Calcification Is Mediated by Regulated Exosome Secretion
Authors: Kapustin Alexander N. , Chatrou Martijn L.L. , Drozdov Ignat , Zheng Ying , Davidson Sean M. , Soong Daniel , Furmanik Malgorzata , Sanchis Pilar , De Rosales Rafael Torres Martin , Alvarez-Hernandez Daniel , Shroff Rukshana , Yin Xiaoke , Muller Karin , Skepper Jeremy N. , Mayr Manuel , Reutelingsperger Chris P. , Chester Adrian , Bertazzo Sergio , Schurgers Leon J. , Shanahan Catherine M.
Published: February 2015

Rationale:

Matrix vesicles (MVs), secreted by vascular smooth muscle cells (VSMCs), form the first nidus for mineralization and fetuin-A, a potent circulating inhibitor of calcification, is specifically loaded into MVs. However, the processes of fetuin-A intracellular trafficking and MV biogenesis are poorly understood.

Objective:

The objective of this study is to investigate the regulation, and role, of MV biogenesis in VSMC calcification.

Methods and Results:

Alexa488-labeled fetuin-A was internalized by human VSMCs, trafficked via the endosomal system, and exocytosed from multivesicular bodies via exosome release. VSMC-derived exosomes were enriched with the tetraspanins CD9, CD63, and CD81, and their release was regulated by sphingomyelin phosphodiesterase 3. Comparative proteomics showed that VSMC-derived exosomes were compositionally similar to exosomes from other cell sources but also shared components with osteoblast-derived MVs including calcium-binding and extracellular matrix proteins. Elevated extracellular calcium was found to induce sphingomyelin phosphodiesterase 3 expression and the secretion of calcifying exosomes from VSMCs in vitro, and chemical inhibition of sphingomyelin phosphodiesterase 3 prevented VSMC calcification. In vivo, multivesicular bodies containing exosomes were observed in vessels from chronic kidney disease patients on dialysis, and CD63 was found to colocalize with calcification. Importantly, factors such as tumor necrosis factor-α and platelet derived growth factor-BB were also found to increase exosome production, leading to increased calcification of VSMCs in response to calcifying conditions.

Conclusions:

This study identifies MVs as exosomes and shows that factors that can increase exosome release can promote vascular calcification in response to environmental calcium stress. Modulation of the exosome release pathway may be as a novel therapeutic target for prevention.
Knockout of
Adamts7
, a Novel Coronary Artery Disease Locus in Humans, Reduces Atherosclerosis in Mice
Authors: Bauer Robert C. , Tohyama Junichiro , Cui Jian , Cheng Lan , Yang Jifu , Zhang Xuan , Ou Kristy , Paschos Georgios K. , Zheng X. Long , Parmacek Michael S. , Rader Daniel J. , Reilly Muredach P.
Published: February 2015

Background—

Genome-wide association studies have established
ADAMTS7
as a locus for coronary artery disease in humans. However, these studies fail to provide directionality for the association between
ADAMTS7
and coronary artery disease. Previous reports have implicated ADAMTS7 in the regulation of vascular smooth muscle cell migration, but a role for and the direction of impact of this gene in atherogenesis have not been shown in relevant model systems.

Methods and Results—

We bred an
Adamts7
whole-body knockout mouse onto both the
Ldlr
and
Apoe
knockout hyperlipidemic mouse models.
Adamts7
−/−
/
Ldlr
−/−
and
Adamts7
−/−
/
Apoe
−/−
mice displayed significant reductions in lesion formation in aortas and aortic roots compared with controls.
Adamts7
knockout mice also showed reduced neointimal formation after femoral wire injury.
Adamts7
expression was induced in response to injury and hyperlipidemia but was absent at later time points, and primary
Adamts7
knockout vascular smooth muscle cells showed reduced migration in the setting of tumor necrosis factor-α stimulation. ADAMTS7 localized to cells positive for smooth muscle cell markers in human coronary artery disease lesions, and subcellular localization studies in cultured vascular smooth muscle cells placed ADAMTS7 at the cytoplasm and cell membrane, where it colocalized with markers of podosomes.

Conclusions—

These data represent the first in vivo experimental validation of the association of
Adamts7
with atherogenesis, likely through modulation of vascular cell migration and matrix in atherosclerotic lesions. These results demonstrate that Adamts7 is proatherogenic, lending directionality to the original genetic association and supporting the concept that pharmacological inhibition of ADAMTS7 should be atheroprotective in humans, making it an attractive target for novel therapeutic interventions.
Optimal Medical Therapy Improves Clinical Outcomes in Patients Undergoing Revascularization With Percutaneous Coronary Intervention or Coronary Artery Bypass Grafting
Authors: Iqbal Javaid , Zhang Yao-Jun , Holmes David R. , Morice Marie-Claude , Mack Michael J. , Kappetein Arie Pieter , Feldman Ted , Stahle Elizabeth , Escaned Javier , Banning Adrian P. , Gunn Julian P. , Colombo Antonio , Steyerberg Ewout W. , Mohr Friedrich W. , Serruys Patrick W.
Published: February 2015

Background—

There is a paucity of data on the use of optimal medical therapy (OMT) in patients with complex coronary artery disease undergoing revascularization with percutaneous coronary intervention or coronary artery bypass grafting (CABG) and its long-term prognostic significance.

Methods and Results—

The Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery (SYNTAX) trial is a multicenter, randomized, clinical trial of patients (n=1800) with complex coronary disease randomized to revascularization with percutaneous coronary intervention or CABG. Detailed drug history was collected for all patients at discharge and at the 1-month, 6-month, 1-year, 3-year, and 5-year follow-ups. OMT was defined as the combination of at least 1 antiplatelet drug, statin, β-blocker, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. Five-year clinical outcomes were stratified by OMT and non-OMT. OMT was underused in patients treated with coronary revascularization, especially CABG. OMT was an independent predictor of survival. OMT was associated with a significant reduction in mortality (hazard ratio, 0.64; 95% confidence interval, 0.48–0.85;
P
=0.002) and composite end point of death/myocardial infarction/stroke (hazard ratio, 0.73; 95% confidence interval, 0.58–0.92;
P
=0.007) at the 5-year follow-up. The treatment effect with OMT (36% relative reduction in mortality over 5 years) was greater than the treatment effect of revascularization strategy (26% relative reduction in mortality with CABG versus percutaneous coronary intervention over 5 years). On stratified analysis, all the components of OMT were important for reducing adverse outcomes regardless of revascularization strategy.

Conclusions—

The use of OMT remains low in patients with complex coronary disease requiring coronary intervention with percutaneous coronary intervention and even lower in patients treated with CABG. Lack of OMT is associated with adverse clinical outcomes. Targeted strategies to improve OMT use in postrevascularization patients are warranted.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00114972.
Interplay Between Connexin40 and Nitric Oxide Signaling During Hypertension
Authors: Le Gal Loïc , Alonso Florian , Mazzolai Lucia , Meda Paolo , Haefliger Jacques-Antoine
Published: February 2015

Connexins (Cxs) and endothelial nitric oxide synthase (eNOS) contribute to the adaptation of endothelial and smooth muscle cells to hemodynamic changes. To decipher the in vivo interplay between these proteins, we studied Cx40-null mice, a model of renin-dependent hypertension which displays an altered endothelium-dependent relaxation of the aorta because of reduced eNOS levels. These mice, which were either untreated or subjected to the 1-kidney, 1-clip (1K1C) procedure, a model of volume-dependent hypertension, were compared with control mice submitted to either the 1K1C or the 2-kidney, 1-clip (2K1C) procedure, a model of renin-dependent hypertension. All operated mice became hypertensive and featured hypertrophy and altered Cx expression of the aorta. The combination of volume- and renin-dependent hypertension in Cx40−/− 1K1C mice raised blood pressure and cardiac weight index. Under these conditions, all aortas showed increased levels of Cx40 in endothelial cells and of both Cx37 and Cx45 in smooth muscle cells. In the wild-type 1K1C mice, the interactions between Cx40 and Cx37 with eNOS were enhanced, resulting in increased NO release. The Cx40–eNOS interaction could not be observed in mice lacking Cx40, which also featured decreased levels of eNOS. In these animals, the volume overload caused by the 1K1C procedure resulted in increased phosphorylation of eNOS and in a higher NO release. The findings provide evidence that Cx40 and Cx37 play an in vivo role in the regulation of eNOS.
Characteristics and Determinants of the Sublingual Microcirculation in Populations of Different Ethnicity
Authors: Gu Yu-Mei , Wang Shuai , Zhang Lu , Liu Yan-Ping , Thijs Lutgarde , Petit Thibault , Zhang Zhenyu , Wei Fang-Fei , Kang Yuan-Yuan , Huang Qi-Fang , Sheng Chang-Sheng , Struijker-Boudier Harry A.J. , Kuznetsova Tatiana , Verhamme Peter , Li Yan , Staessen Jan A.
Published: February 2015

No previous population study assessed sublingual capillary density (CD) or perfused boundary region (PBR). Lower PBR indicates greater glycocalyx width. In 252 Han and 220 She Chinese and 254 Flemish people (mean age, 51.1 years; 54.7% women), representing random population samples, we measured total and perfused CD and PBR in the sublingual capillary bed, using oblique profiled epi-illumination, and cardiovascular risk factors. In multivariable analyses, we modeled ethnicity as random effect. Significance level was α≤0.05. Compared with Chinese, Flemish had lower total (577 versus 546 n°/mm
2
) and perfused (338 versus 320 n°/mm
2
) CD, but similar perfused-to-total CD ratio (mean, 0.59). Perfused-to-total CD ratio increased with age (effect size per 1–SD increase, +0.015 per year), body mass index (+0.008 per kg/m
2
), total cholesterol (+0.012 per mmol/L), and Framingham risk score (+0.018 per point) with no ethnic differences in these associations. For age and Framingham risk score, associations with perfused-to-total CD ratio were driven by positive relationships with perfused CD, whereas associations with total CD were nonsignificant. Chinese when compared with Flemish had higher hematocrit (43.0 versus 41.1%), PBR (2010 versus 1876 nm), and pulse rate (72.6 versus 63.3 bpm). PBR standardized for hematocrit, perfused CD, and pulse rate decreased with body mass index (–26.7 nm/kg/m2), mean arterial pressure (–30.6 nm/mm Hg), and diastolic pressure (–28.5 nm/mm Hg) with no ethnic differences in these associations. In conclusion, a higher cardiovascular risk profile is associated with functional recruitment of capillaries with preserved glycocalyx that protects the endothelial lining.
Cardiac Energy Dependence on Glucose Increases Metabolites Related to Glutathione and Activates Metabolic Genes Controlled by Mechanistic Target of Rapamycin
Authors: Schisler Jonathan C. , Grevengoed Trisha J. , Pascual Florencia , Cooper Daniel E. , Ellis Jessica M. , Paul David S. , Willis Monte S. , Patterson Cam , Jia Wei , Coleman Rosalind A.
Published: February 2015

Background

Long chain acyl‐CoA synthetases (
ACSL
) catalyze long‐chain fatty acids (
FA
) conversion to acyl‐CoAs. Temporal
ACSL
1 inactivation in mouse hearts (
Acsl1
H−/−
) impaired
FA
oxidation and dramatically increased glucose uptake, glucose oxidation, and
mTOR
activation, resulting in cardiac hypertrophy. We used unbiased metabolomics and gene expression analyses to elucidate the cardiac cellular response to increased glucose use in a genetic model of inactivated
FA
oxidation.

Methods and Results

Metabolomics analysis identified 60 metabolites altered in
Acsl1
H−/−
hearts, including 6 related to glucose metabolism and 11 to cysteine and glutathione pathways. Concurrently, global cardiac transcriptional analysis revealed differential expression of 568 genes in
Acsl1
H−/−
hearts, a subset of which we hypothesized were targets of
mTOR
; subsequently, we measured the transcriptional response of several genes after chronic
mTOR
inhibition via rapamycin treatment during the period in which cardiac hypertrophy develops. Hearts from
Acsl1
H−/−
mice increased expression of several
Hif1
α‐responsive glycolytic genes regulated by
mTOR
; additionally, expression of
Scl7a5
,
Gsta1/2
,
Gdf15
, and amino acid‐responsive genes,
Fgf21
,
Asns
,
Trib3
,
Mthfd2
, were strikingly increased by
mTOR
activation.

Conclusions

The switch from
FA
to glucose use causes
mTOR
‐dependent alterations in cardiac metabolism. We identified cardiac
mTOR
‐regulated genes not previously identified in other cellular models, suggesting heart‐specific
mTOR
signaling. Increased glucose use also changed glutathione‐related pathways and compensation by
mTOR
. The hypertrophy, oxidative stress, and metabolic changes that occur within the heart when glucose supplants
FA
as a major energy source suggest that substrate switching to glucose is not entirely benign.
Patterns of Use of Angiotensin‐Converting Enzyme Inhibitors/Angiotensin Receptor Blockers Among Patients With Acute Myocardial Infarction in China From 2001 to 2011: China PEACE‐Retrospective AMI Study
Authors: Liu Jiamin , Masoudi Frederick A. , Spertus John A. , Wang Qing , Murugiah Karthik , Spatz Erica S. , Li Jing , Li Xi , Ross Joseph S. , Krumholz Harlan M. , Jiang Lixin ,   China PEACE Collaborative Group
Published: February 2015

Background

Chinese and
U.S.
guidelines recommend angiotensin‐converting enzyme inhibitors (
ACEIs
)/angiotensin receptor blockers (
ARBs
) for all patients with acute myocardial infarction (
AMI
) in the absence of contraindications as either a Class I or Class
II
a recommendation. Little is known about the use and trends of
ACEI
/
ARB
therapy in China over the past decade.

Methods and Results

Using nationally representative data from the China Patient‐centered Evaluative Assessment of Cardiac Events Retrospective Study of Acute Myocardial Infarction (China
PEACE
‐Retrospective
AMI
Study), we assessed use of
ACEI
/
ARB
therapy in 2001, 2006, and 2011, overall and across geographic regions and strata of estimated mortality risk, and predictors of
ACEI
/
ARB
therapy, among patients with Class I indication by Chinese guidelines. The weighted rate of
ACEI
/
ARB
therapy increased from 62.0% in 2001 to 71.4% in 2006, decreasing to 67.6% in 2011. Use was low across all 5 geographic regions. By strata of estimated mortality risk, in 2001, rates of therapy increased with increasing risk; however, by 2011, this reversed and those at higher risk were less likely to be treated (70.7% in lowest‐risk quintile vs. 63.5% in the highest‐risk quintile;
P
<0.001).

Conclusion

One third of Chinese
AMI
patients with Class I indications do not receive
ACEI
/
ARB
therapy during hospitalization, with little improvement in rates over time. Patients at higher mortality risk in 2011 were less likely to be treated, highlighting important opportunities to optimize the use of this cost‐effective therapy.

Clinical Trial Registration

URL: ClinicalTrials.gov. Unique identifier: NCT01624883.
Prognostic Significance of Perihematomal Edema in Acute Intracerebral Hemorrhage
Authors: Yang Jie , Arima Hisatomi , Wu Guojun , Heeley Emma , Delcourt Candice , Zhou Junshan , Chen Guofang , Wang Xia , Zhang Shihong , Yu Sungwook , Chalmers John , Anderson Craig S.
Published: February 2015

Background and Purpose—

Controversy exists over the prognostic significance of perihematomal edema (PHE) in intracerebral hemorrhage. We aimed to determine the association of early PHE and clinical outcome among participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT) studies.

Methods—

Pooled analyses of computed tomographic substudies in the pilot phase (INTERACT1) and main phase (INTERACT2), both international, prospective, open, blinded end point, randomized controlled trials, of patients with spontaneous intracerebral hemorrhage (<6 hours) and elevated systolic blood pressure, randomly assigned to intensive (target systolic blood pressure, <140 mm Hg) or guideline-based (systolic blood pressure, <180 mm Hg) blood-pressure management. Substudy participants (n=1310; 346 INTERACT1, 964 INTERACT2) had blinded central analyses of digital images from standardized baseline and 24-hour computed tomography. Predictors of death or dependency (modified Rankin scale scores, ≥3) at 90 days were assessed in logistic regression models and reported with odds ratios and 95% confidence intervals. INTERACT studies are registered at
ClinicalTrials.gov
(NCT00226096 and NCT00716079).

Results—

Of 1138 (87%) patients with 2 CTs available for edema analysis and outcome information, time from intracerebral hemorrhage onset to baseline computed tomography, baseline hematoma volume, 24-hour hematoma growth, and intraventricular extension were independent predictors of 24-hour PHE growth. Absolute growth in PHE volume was significantly associated with death or dependency (adjusted odds ratio, 1.17; 95% confidence interval, 1.02–1.33 per 5 mL increase from baseline;
P
=0.025) at 90 days after adjustment for demographic, clinical, and hematoma parameter prognostic factors. Associations were consistent across various sensitivity analyses.

Conclusion—

PHE growth is an independent prognostic factor in intracerebral hemorrhage.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00226096 and NCT00716079.
Measure of Functional Independence Dominates Discharge Outcome Prediction After Inpatient Rehabilitation for Stroke
Authors: Brown Allen W. , Therneau Terry M. , Schultz Billie A. , Niewczyk Paulette M. , Granger Carl V.
Published: February 2015

Background and Purpose—

Identifying clinical data acquired at inpatient rehabilitation admission for stroke that accurately predict key outcomes at discharge could inform the development of customized plans of care to achieve favorable outcomes. The purpose of this analysis was to use a large comprehensive national data set to consider a wide range of clinical elements known at admission to identify those that predict key outcomes at rehabilitation discharge.

Methods—

Sample data were obtained from the Uniform Data System for Medical Rehabilitation data set with the diagnosis of stroke for the years 2005 through 2007. This data set includes demographic, administrative, and medical variables collected at admission and discharge and uses the FIM (functional independence measure) instrument to assess functional independence. Primary outcomes of interest were functional independence measure gain, length of stay, and discharge to home.

Results—

The sample included 148 367 people (75% white; mean age, 70.6±13.1 years; 97% with ischemic stroke) admitted to inpatient rehabilitation a mean of 8.2±12 days after symptom onset. The total functional independence measure score, the functional independence measure motor subscore, and the case-mix group were equally the strongest predictors for any of the primary outcomes. The most clinically relevant 3-variable model used the functional independence measure motor subscore, age, and walking distance at admission (
r
2
=0.107). No important additional effect for any other variable was detected when added to this model.

Conclusions—

This analysis shows that a measure of functional independence in motor performance and age at rehabilitation hospital admission for stroke are predominant predictors of outcome at discharge in a uniquely large US national data set.
Legitimacy and eu Biofuel Governance: In Search of Greater Coherence
Authors: Romppanen Seita
Published: February 2015

The eu regulatory framework for sustainable biofuels is an example of today’s dynamic European climate and energy governance. The article demonstrates that there are, however, particular internal controversies that continue to undermine the overall credibility of the eu biofuel regime, as well as the effectiveness and legitimacy of the scheme. In connection with the debate on new governance, the article explores the concepts of input and output legitimacy as regards the verification of compliance with biofuel sustainability criteria. The article shows that if the procedural requirements to satisfy input legitimacy are not met, there is a risk that output legitimacy—the credibility of the substantive outcome—will also be diminished. By paying attention to the process and harmonizing the itemized process-related elements we can improve both the appropriate achievement of the substantive outcome as well as the legitimacy of eu biofuel governance.
A survey of Palaearctic Dictynidae (Araneae). 1. Taxonomic notes on
Dictynomorpha Spassky, 1939, Brigittea Lehtinen, 1967 and Lathys Simon, 1884
Authors: MARUSIK YURI M. , ESYUNIN SERGEI L. , TUNEVA TATYANA K.
Published: February 2015

A new species, Dictynomorpha daemonis sp. n. (♂) is described from South Kazakhstan and a new diagnosis is suggested for Dictynomorpha Spassky, 1939. The genus is redelimited and its type species D. strandi Spassky, 1939 redescribed. Three Dictynomorpha species are transferred to Ajmonia Caporiacco, 1934 and three new combinations are suggested: Ajmonia smaragdula (Simon, 1905) comb. n., Ajmonia bedeshai (Tikader, 1966) comb. n. and Ajmonia marakata (Sherriffs, 1927) comb. n. Brigittea Lehtinen, 1967 is removed from the synonymy with Dictyna Sundevall, 1833 and its composition is discussed. The type species of Brigittea, B. latens (Fabricius, 1775) is synonymized with B. latens mutabilis Spassky & Shnitnikov, 1937. Lathys spasskyi Andreeva & Tyshchenko, 1969 is removed from the synonymy with L. stigmatisata (Menge, 1869). New illustrations and distribution data are provided for Lathys truncata Danilov, 1994. Lathys mussooriensis Biswas & Roy, 2008 is transferred from Dictynidae to Amaurobiidae and tentatively placed in Himalmartensus Wang & Zhu, 2008, the new combination is suggested: Himalmartensus mussooriensis (Biswas & Roy, 2008) comb. n.
Regional Variability in New Zealand’s Wind Resource Linked to Synoptic-Scale Circulation: Implications for Generation Reliability
Authors: Gibson Peter B. , Cullen Nicolas J.
Published: February 2015

Even in locations endowed with excellent wind resources, the intermittent nature of wind is perceived as a barrier to reliable generation. However, recent studies have demonstrated that electrically interconnecting wind farms in a meteorologically oriented network can reduce supply variability and the observed frequency of zero-generation conditions. In this study a 5-yr synthetic dataset of 15 wind farms is utilized to investigate the benefits to supply reliability from wind farm interconnection in New Zealand. An examination is carried out primarily through a synoptic climatology framework, hypothesizing that benefits to reliability are primarily related to the degree to which wind farms are influenced differently by the synoptic-scale circulation. Using a weather-typing approach and composite analysis, regionality is observed in the linkages between synoptic-scale circulation and wind resources, particularly between wind farms located in the far northern and far southern regions of the country. Subsequently, and as compared with all other possible combinations, supply reliability is observed to be optimized in a network that includes wind farms connected between far northern and far southern regions, under which the frequency of hours with zero generation is almost eliminated. It is likely that the frequency of hours with zero generation could be further reduced on the basis of a more extensive meteorologically based selection of wind data from a greater number of locations. It is suggested that these findings should be taken into consideration in future planning and site selection of wind farm projects in New Zealand.