bluuebunny/crossref_metadata_2025_split huggingface dataset:
The miR-30 Family Inhibits Pulmonary Vascular Hyperpermeability in the Premetastatic Phase by Direct Targeting of Skp2
Authors: Qi Feifei , He Ting , Jia Lin , Song Nan , Guo Lifang , Ma Xuhui , Wang Chunying , Xu Min , Fu Yan , Li Lin , Luo Yongzhang 
Published: March 2015

Abstract
Purpose: Before metastasis, primary tumor can create a premetastatic niche in distant organ to facilitate the dissemination of tumor cells. In the premetastatic phase, the permeability of pulmonary vasculatures is increased to accelerate the extravasation of circulating tumor cells. However, it is not clear whether local miRNAs contribute to the vascular hyperpermeability of the premetastatic niche.
Experimental Design: The expression of total miRNAs was determined using microarray in series of premetastatic lungs from tumor-bearing mice. Significantly differentially expressed miRNAs were identified and validated with qRT-PCR. Vascular permeability assays, vascular mimic systems, and orthotopic tumor models were used to investigate roles of selected miRNAs and target genes in premetastatic hyperpermeability.
Results: We identified a miRNA signature in premetastatic lungs. Among these miRNAs, miR-30a, b, c, d, and e were significantly attenuated. Subsequent investigations elucidated that lung fibroblast–derived miR-30s stabilized pulmonary vessels. Overexpression of miR-30s in lungs postponed metastasis and extended overall survival of B16 tumor–bearing mice. Following studies uncovered that Skp2 was directly targeted by miR-30s. Overexpression of Skp2 could disrupt pulmonary vessels, promote lung metastasis, and decrease overall survival of B16 tumor–bearing mice.
Conclusions: These findings illuminate a novel mechanism for the modulation of premetastatic niches by miR-30s, which suggest that miR-30s represent not only promising targets for antimetastasis therapy but also indicators for metastasis. Clin Cancer Res; 21(13); 3071–80. ©2015 AACR.
CDK4 Amplification Reduces Sensitivity to CDK4/6 Inhibition in Fusion-Positive Rhabdomyosarcoma
Authors: Olanich Mary E. , Sun Wenyue , Hewitt Stephen M. , Abdullaev Zied , Pack Svetlana D. , Barr Frederic G. 
Published: March 2015

Abstract
Purpose: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and includes a PAX3– or PAX7–FOXO1 fusion-positive subtype. Amplification of chromosomal region 12q13–q14, which contains the CDK4 proto-oncogene, was identified in an aggressive subset of fusion-positive RMS. CDK4/6 inhibitors have antiproliferative activity in CDK4-amplified liposarcoma and neuroblastoma, suggesting CDK4/6 inhibition as a potential therapeutic strategy in fusion-positive RMS.
Experimental Design: We examined the biologic consequences of CDK4 knockdown, CDK4 overexpression, and pharmacologic CDK4/6 inhibition by LEE011 in fusion-positive RMS cell lines and xenografts.
Results: Knockdown of CDK4 abrogated proliferation and transformation of 12q13–14-amplified and nonamplified fusion-positive RMS cells via G1-phase cell-cycle arrest. This arrest was mediated by reduced RB phosphorylation and E2F-responsive gene expression. Significant differences in E2F target expression, cell-cycle distribution, proliferation, or transformation were not observed in RMS cells overexpressing CDK4. Treatment with LEE011 phenocopied CDK4 knockdown, decreasing viability, RB phosphorylation, and E2F-responsive gene expression and inducing G1-phase cell-cycle arrest. Although all fusion-positive cell lines showed sensitivity to CDK4/6 inhibition, there was diminished sensitivity associated with CDK4 amplification and overexpression. This variable responsiveness to LEE011 was recapitulated in xenograft models of CDK4-amplified and nonamplified fusion-positive RMS.
Conclusions: Our data demonstrate that CDK4 is necessary but overexpression is not sufficient for RB–E2F–mediated G1-phase cell-cycle progression, proliferation, and transformation in fusion-positive RMS. Our studies indicate that LEE011 is active in the setting of fusion-positive RMS and suggest that low CDK4-expressing fusion-positive tumors may be particularly susceptible to CDK4/6 inhibition. Clin Cancer Res; 21(21); 4947–59. ©2015 AACR.
See related commentary by Gatz and Shipley, p. 4750
Targeting Survivin Inhibits Renal Cell Carcinoma Progression and Enhances the Activity of Temsirolimus
Authors: Carew Jennifer S. , Espitia Claudia M. , Zhao Weiguo , Mita Monica M. , Mita Alain C. , Nawrocki Steffan T. 
Published: March 2015

Abstract
Elevated expression of the antiapoptotic factor survivin has been implicated in cancer cell survival and disease progression. However, its specific contribution to renal cell carcinoma (RCC) pathogenesis is not well defined. We investigated the roles of survivin in RCC tumor progression, resistance to mTOR inhibitors, and evaluated the therapeutic activity of the survivin suppressant YM155 in RCC models. Here, we report that survivin expression levels were significantly higher in RCC cell lines compared with normal renal cells. Stable targeted knockdown of survivin completely abrogated the ability of 786-O RCC tumors to grow in mice, thus demonstrating its importance as a regulator of RCC tumorigenesis. We next explored multiple strategies to therapeutically inhibit survivin function in RCC. Treatment with the mTOR inhibitor temsirolimus partially diminished survivin levels and this effect was augmented by the addition of YM155. Further analyses revealed that, in accordance with their combined anti-survivin effects, YM155 significantly improved the anticancer activity of temsirolimus in a panel of RCC cell lines in vitro and in xenograft models in vivo. Similar to pharmacologic inhibition of survivin, shRNA-mediated silencing of survivin expression not only inhibited RCC tumor growth, but also significantly sensitized RCC cells to temsirolimus therapy. Subsequent experiments demonstrated that the effectiveness of this dual survivin/mTOR inhibition strategy was mediated by a potent decrease in survivin levels and corresponding induction of apoptosis. Our findings establish survivin inhibition as a novel approach to improve RCC therapy that warrants further investigation. Mol Cancer Ther; 14(6); 1404–13. ©2015 AACR.
Efficacy and spatial distribution of ultrasound-mediated clot lysis in the absence of thrombolytics
Authors: Lindner Jonathan R. , Zhao Yan , Porter Thomas , Siegel Robert , Kaul Sanjiv , Ammi Azzdine Y. 
Published: March 2015

SummaryUltrasound and microbubble (MB) contrast agents accelerate clot lysis, yet clinical trials have been performed without defining optimal acoustic conditions. Our aim was to assess the effect of acoustic pressure and frequency on the extent and spatial location of clot lysis. Clots from porcine blood were created with a 2-mm central lumen for infusion of lipid-shelled perfluorocarbon MBs (1×107 ml-1) or saline. Therapeutic ultrasound at 0.04, 0.25, 1.05, or 2.00 MHz was delivered at a wide range of peak rarefactional acoustic pressure amplitudes (PRAPAs). Ultrasound was administered over 20 minutes grouped on-off cycles to allow replenishment of MBs. The region of lysis was quantified using contrast-enhanced ultrasound imaging. In the absence of MBs, sonothrombolysis did not occur at any frequency. Sonothrombolysis was also absent in the presence of MBs despite their destruction at 0.04 and 2.00 MHz. It occurred at 0.25 and 1.05 MHz in the presence of MBs for PRAPAs > 1.2 MPa and increased with PRAPA. At 0.25 MHz the clot lysis was located in the far wall. At 1.05 MHz, however, there was a transition from far to near wall as PRAPA was increased. The area of clot lysis measured by ultrasound imaging correlated with that by micro-CT and quantification of debris in the effluent. In conclusion, sonothrombolysis with MBs was most efficient at 0.25 MHz. The spatial location of sonothrombolysis varies with pressure and frequency indicating that the geometric relation between therapeutic probe and vascular thrombosis is an important variable for successful lysis clinically.Supported by grant (NIH R01-HL-095868).
NR4A receptors up-regulate the antiproteinase alpha-2 macroglobulin (A2M) and modulate MMP-2 and MMP-9 in vascular smooth muscle cells
Authors: Rodríguez-Calvo Ricardo , Ferrán Beatriz , Alonso Judith , Martí-Pàmies Ingrid , Aguiló Silvia , Calvayrac Olivier , Rodríguez Cristina , Martínez-González José 
Published: March 2015

SummaryMatrix metalloproteinases (MMPs) are associated with tissue remodelling and repair. In non-vascular tissues, NR4A receptors have been involved in the regulation of MMPs by transcriptional repression mechanisms. Here, we analyse alternative mechanisms involving NR4A receptors in the modulation of MMP activity in vascular smooth muscle cells (VSMC). Lentiviral overexpression of NR4A receptors (NOR-1, Nurr1 and Nur77) in human VSMC strongly decreased MMP-2 and MMP-9 activities (analysed by zymography and DQ-gelatin assays) and protein levels. NR4A receptors also down-regulated MMP-2 mRNA levels. Real-time PCR analysis evidenced that alpha-2-macroglobulin (A2M), but not other MMP inhibitors (TIMP-1 and TIMP-2) were up-regulated in NR4A-transduced cells. Interestingly, A2M was expressed in human vascular tissues including the smooth muscle media layer. While NR4A receptors increased A2M expression and secretion in VSMC, NR4A knockdown significantly reduced basal A2M expression in these cells. The direct transcriptional regulation of the human A2M promoter by NR4A receptors was characterised in luciferase reporter assays, electrophoretic mobility shift assays and by chromatin immunoprecipitation, identifying a NGFI-B response element (NBRE-71/-64) essential for the NR4A-mediated induction. The blockade of A2M partially prevented the reduction of MMPs activity observed in NR4A-transduced cells. Although mouse A2M promoter was unresponsive to NR4A receptors, vascular MMP expression was attenuated in transgenic mice over-expressing human NOR-1 in VSMC challenged with lipopolysaccharide. Our results show that the panproteinase inhibitor A2M is expressed in the vasculature and that NR4A receptors modulate VSMC MMP activity by several mechanisms including the up-regulation of A2M.
Blood coagulation and fibrinolysis in aortic valve stenosis: links with inflammation and calcification
Authors: Natorska Joanna , Undas Anetta 
Published: March 2015

SummaryAortic valve stenosis (AS) increasingly afflicts our aging population. However, the pathobiology of the disease is still poorly understood and there is no effective pharmacotherapy for treating those at risk for clinical progression. The progression of AS involves complex inflammatory and fibroproliferative processes that resemble to some extent atherosclerosis. Accumulating evidence indicates that several coagulation proteins and its inhibitors, including tissue factor, tissue factor pathway inhibitor, prothrombin, factor XIII, von Willebrand factor, display increased expression within aortic stenotic valves, predominantly on macrophages and myofibroblasts around calcified areas. Systemic impaired fibrinolysis, along with increased plasma and valvular expression of plasminogen activator inhibitor-1, has also been observed in patients with AS in association with the severity of the disease. There is an extensive cross-talk between inflammation and coagulation in stenotic valve tissue which contributes to the calcification and mineralisation of the aortic valve leaflets. This review summarises the available data on blood coagulation and fibrinolysis in AS with the emphasis on their interactions with inflammation and calcification.
Cardiac Electrophysiological Substrate Underlying the ECG Phenotype and Electrogram Abnormalities in Brugada Syndrome Patients
Authors: Zhang Junjie , Sacher Frédéric , Hoffmayer Kurt , O’Hara Thomas , Strom Maria , Cuculich Phillip , Silva Jennifer , Cooper Daniel , Faddis Mitchell , Hocini Mélèze , Haïssaguerre Michel , Scheinman Melvin , Rudy Yoram 
Published: March 2015

Background—
Brugada syndrome (BrS) is a highly arrhythmogenic cardiac disorder, associated with an increased incidence of sudden death. Its arrhythmogenic substrate in the intact human heart remains ill-defined.

Methods and Results—

Using noninvasive ECG imaging, we studied 25 BrS patients to characterize the electrophysiological substrate and 6 patients with right bundle-branch block for comparison. Seven healthy subjects provided control data. Abnormal substrate was observed exclusively in the right ventricular outflow tract with the following properties (in comparison with healthy controls;
P
<0.005): (1) ST-segment elevation and inverted T wave of unipolar electrograms (2.21±0.67 versus 0 mV); (2) delayed right ventricular outflow tract activation (82±18 versus 37±11 ms); (3) low-amplitude (0.47±0.16 versus 3.74±1.60 mV) and fractionated electrograms, suggesting slow discontinuous conduction; (4) prolonged recovery time (381±30 versus 311±34 ms) and activation-recovery intervals (318±32 versus 241±27 ms), indicating delayed repolarization; (5) steep repolarization gradients (Δrecovery time/Δx=96±28 versus 7±6 ms/cm, Δactivation-recovery interval/Δx=105±24 versus 7±5 ms/cm) at right ventricular outflow tract borders. With increased heart rate in 6 BrS patients, reduced ST-segment elevation and increased fractionation were observed. Unlike BrS, right bundle-branch block had delayed activation in the entire right ventricle, without ST-segment elevation, fractionation, or repolarization abnormalities on electrograms.

Conclusions—
The results indicate that both slow discontinuous conduction and steep dispersion of repolarization are present in the right ventricular outflow tract of BrS patients. ECG imaging could differentiate between BrS and right bundle-branch block.
Risk of Stroke in Chronic Heart Failure Patients Without Atrial Fibrillation
Authors: Abdul-Rahim Azmil H. , Perez Ana-Cristina , Fulton Rachael L. , Jhund Pardeep S. , Latini Roberto , Tognoni Gianni , Wikstrand John , Kjekshus John , Lip Gregory Y.H. , Maggioni Aldo P. , Tavazzi Luigi , Lees Kennedy R. , McMurray John J.V. 
Published: March 2015

Background—
Our aim was to describe the incidence and predictors of stroke in patients who have heart failure without atrial fibrillation (AF).

Methods and Results—

We pooled 2 contemporary heart failure trials, the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza cardiaca-Heart Failure trial (GISSI-HF). Of the 9585 total patients, 6054 did not have AF. Stroke occurred in 165 patients (4.7%) with AF and in 206 patients (3.4%) without AF (rates 16.8/1000 patient-years and 11.1/1000 patient-years, respectively). Using Cox proportional-hazards models, we identified the following independent predictors of stroke in patients without AF (ranked by χ
2
value): age (hazard ratio, 1.34; 95% confidence interval, 1.18–1.63 per 10 years), New York Heart Association class (1.60, 1.21–2.12 class III/IV versus II), diabetes mellitus treated with insulin (1.87, 1.22–2.88), body mass index (0.74, 0.60–0.91 per 5 kg/m
2
up to 30), and previous stroke (1.81, 1.19–2.74). N-terminal pro B-type natriuretic peptide (available in 2632 patients) was also an independent predictor of stroke (hazard ratio, 1.31; 1.11–1.57 per log unit) when added to this model. With the use of a risk score formulated from these predictors, we found that patients in the upper third of risk had a rate of stroke that approximated the risk in patients with AF.

Conclusions—
A small number of demographic and clinical variables identified a subset of patients who have heart failure without AF at a high risk of stroke.
The Contribution of Attentional Lapses to Individual Differences in Visual Working Memory Capacity
Authors: Adam Kirsten C. S. , Mance Irida , Fukuda Keisuke , Vogel Edward K. 
Published: March 2015

Abstract
Attentional control and working memory capacity are important cognitive abilities that substantially vary between individuals. Although much is known about how attentional control and working memory capacity relate to each other and to constructs like fluid intelligence, little is known about how trial-by-trial fluctuations in attentional engagement impact trial-by-trial working memory performance. Here, we employ a novel whole-report memory task that allowed us to distinguish between varying levels of attentional engagement in humans performing a working memory task. By characterizing low-performance trials, we can distinguish between models in which working memory performance failures are caused by either (1) complete lapses of attention or (2) variations in attentional control. We found that performance failures increase with set-size and strongly predict working memory capacity. Performance variability was best modeled by an attentional control model of attention, not a lapse model. We examined neural signatures of performance failures by measuring EEG activity while participants performed the whole-report task. The number of items correctly recalled in the memory task was predicted by frontal theta power, with decreased frontal theta power associated with poor performance on the task. In addition, we found that poor performance was not explained by failures of sensory encoding; the P1/N1 response and ocular artifact rates were equivalent for high- and low-performance trials. In all, we propose that attentional lapses alone cannot explain individual differences in working memory performance. Instead, we find that graded fluctuations in attentional control better explain the trial-by-trial differences in working memory that we observe.
p16INK4a Status and Response to Induction Low-Dose Fractionated Radiation in Advanced Head and Neck Cancer
Authors: Silver Natalie L. , Arnold Susanne M. , Gleason John F. , Kudrimoti Mahesh , Brill Yolanda , Dressler Emily V. , Valentino Joseph 
Published: March 2015

Objective: To evaluate the impact of p16INK4a (p16) expression on clinical efficacy of induction low-dose fractionated radiation therapy (LDFRT) with concurrent chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Study Design: Historical cohort study. Setting: Tertiary medical center. Methods: A total of 66 Patients with locally advanced SCCHN were enrolled in 2 clinical trials using paclitaxel, carboplatin, and concurrent LDFRT induction therapy. Patients were evaluated for response to induction by a multidisciplinary team and then were given definitive treatment. Adequate tissue samples from the pretreatment biopsies of 42 individuals were identified and analyzed for p16 expression. Expression was correlated with clinical outcomes. Results: Of 42 tumors, 15 (35.7%) were positive for p16. Patients with p16-positive tumors had improved response to induction, but this was not statistically significant ( P = .06). Five-year overall survival was 80% in p16-positive patients and 58% in p16-negative patients ( P = .025). Conclusions: p16 Expression affects treatment response in patients treated with induction LDFRT with concurrent chemotherapy. This is similar to results reported for standard induction chemotherapy.
Inspiratory muscle training improves aerobic capacity and pulmonary function in patients with ankylosing spondylitis: a randomized controlled study
Authors: Drăgoi Răzvan-Gabriel , Amaricai Elena , Drăgoi Mihai , Popoviciu Horatiu , Avram Claudiu 
Published: March 2015

Objective: To evaluate the impact of inspiratory muscle training on aerobic capacity and pulmonary function in patients with ankylosing spondylitis. Design: Randomized controlled study. Setting: Rheumatic Rehabilitation Centre. Subjects: A total of 54 ankylosing spondylitis patients, all males, were randomized to a conventional exercise training associated with an inspiratory muscle training group, or to a conventional exercise training group. Interventions: Group 1 (27 patients) performed eight weeks of conventional exercise training (supervised weekly group sessions followed by a home-based exercise programme) associated with inspiratory muscle training sessions. Group 2 (27 patients) received eight weeks of conventional exercise training only. Main measures: Resting pulmonary function (forced vital capacity − FVC, forced expiratory volume in one second − FEV1); effort ventilatory efficiency (lowest ventilatory equivalent ratio for oxygen and carbon dioxide – VE/VO2 and VE/VCO2) and aerobic capacity (peak oxygen uptake – VO2peak) were assessed at baseline and after eight weeks of exercise-based intervention. Results: After eight weeks follow-up, patients in Group 1 had a significant increased chest expansion and VO2peak compared with Group 2 (3.6 ±0.8 cm vs. 3.2 ±0.5 cm, P = 0.032; 2.0 ±0.5 l/min vs. 1.8 ±0.3 l/min, P = 0.033). There were no significant differences of spirometric measurements, except FVC which significantly improved in patients who performed inspiratory muscle training (82.7 ±5.1% vs. 79.5 ±3.5%, P = 0.014). VE/VCO2 also improved significantly in Group 1 (26.6 ±3.6 vs. 29.2 ±4.7, P = 0.040). Conclusions: Ankylosing spondylitis patients who performed eight weeks of inspiratory muscle training associated to conventional exercise training had an increased chest expansion, a better aerobic capacity, resting pulmonary function and ventilatory efficiency than those who performed conventional exercise training only.
Concordance and discordance between measured and perceived balance and the effect on gait speed and falls following stroke
Authors: Liphart Jodi , Gallichio Joann , Tilson Julie K , Pei Qinglin , Wu Samuel S , Duncan Pamela W 
Published: March 2015

Objective: To ascertain the existence of discordance between perceived and measured balance in persons with stroke and to examine the impact on walking speed and falls. Design: A secondary analysis of a phase three, multicentered randomized controlled trial examining walking recovery following stroke. Subjects: A total of 352 participants from the Locomotor Experience Applied Post-Stroke (LEAPS) trial. Methods: Participants were categorized into four groups: two concordant and two discordant groups in relation to measured and perceived balance. Number and percentage of individuals with concordance and discordance were evaluated at two and 12 months. Walking speed and fall incidence between groups were examined. Main measures: Perceived balance was measured by the Activities-Specific Balance Confidence scale, measured balance was determined by the Berg Balance Scale and gait speed was measured by the 10-meter walk test. Results: Discordance was present for 35.8% of participants at two months post stroke with no statistically significant change in proportion at 12 months. Discordant participants with high perceived balance and low measured balance walked 0.09 m/s faster at two months than participants with concordant low perceived and measured balance ( p < 0.05). Discordant participants with low perceived balance and high measured balance walked 0.15 m/s slower than those that were concordant with high perceived and measured balance ( p ⩽ 0.0001) at 12 months. Concordant participants with high perceived and measured balance walked fastest and had fewer falls. Conclusions: Discordance existed between perceived and measured balance in one-third of individuals at two and 12 months post-stroke. Perceived balance impacted gait speed but not fall incidence.