bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of Fatty Acid Oxidation Modulates Immunosuppressive Functions of Myeloid-Derived Suppressor Cells and Enhances Cancer Therapies
Authors: Hossain Fokhrul , Al-Khami Amir A. , Wyczechowska Dorota , Hernandez Claudia , Zheng Liqin , Reiss Krzystoff , Valle Luis Del , Trillo-Tinoco Jimena , Maj Tomasz , Zou Weiping , Rodriguez Paulo C. , Ochoa Augusto C. 
Published: May 2015

Abstract
Myeloid-derived suppressor cells (MDSC) promote tumor growth by inhibiting T-cell immunity and promoting malignant cell proliferation and migration. The therapeutic potential of blocking MDSC in tumors has been limited by their heterogeneity, plasticity, and resistance to various chemotherapy agents. Recent studies have highlighted the role of energy metabolic pathways in the differentiation and function of immune cells; however, the metabolic characteristics regulating MDSC remain unclear. We aimed to determine the energy metabolic pathway(s) used by MDSC, establish its impact on their immunosuppressive function, and test whether its inhibition blocks MDSC and enhances antitumor therapies. Using several murine tumor models, we found that tumor-infiltrating MDSC (T-MDSC) increased fatty acid uptake and activated fatty acid oxidation (FAO). This was accompanied by an increased mitochondrial mass, upregulation of key FAO enzymes, and increased oxygen consumption rate. Pharmacologic inhibition of FAO blocked immune inhibitory pathways and functions in T-MDSC and decreased their production of inhibitory cytokines. FAO inhibition alone significantly delayed tumor growth in a T-cell–dependent manner and enhanced the antitumor effect of adoptive T-cell therapy. Furthermore, FAO inhibition combined with low-dose chemotherapy completely inhibited T-MDSC immunosuppressive effects and induced a significant antitumor effect. Interestingly, a similar increase in fatty acid uptake and expression of FAO-related enzymes was found in human MDSC in peripheral blood and tumors. These results support the possibility of testing FAO inhibition as a novel approach to block MDSC and enhance various cancer therapies. Cancer Immunol Res; 3(11); 1236–47. ©2015 AACR.
Loss of Function Mutations in
NNT
Are Associated With Left Ventricular Noncompaction
Authors: Bainbridge Matthew N. , Davis Erica E. , Choi Wen-Yee , Dickson Amy , Martinez Hugo R. , Wang Min , Dinh Huyen , Muzny Donna M. , Pignatelli Ricardo , Katsanis Nicholas , Boerwinkle Eric , Gibbs Richard A. , Jefferies John L. 
Published: May 2015

Background—
Left ventricular noncompaction (LVNC) is an autosomal-dominant, genetically heterogeneous cardiomyopathy with variable severity, which may co-occur with cardiac hypertrophy.

Methods and Results—

Here, we generated whole exome sequence data from multiple members from 5 families with LVNC. In 4 of 5 families, the candidate causative mutation segregates with disease in known LVNC genes
MYH7
and
TPM1
. Subsequent sequencing of
MYH7
in a larger LVNC cohort identified 7 novel likely disease causing variants. In the fifth family, we identified a frameshift mutation in
NNT
, a nuclear-encoded mitochondrial protein, not implicated previously in human cardiomyopathies. Resequencing of
NNT
in additional LVNC families identified a second likely pathogenic missense allele. Suppression of
nnt
in zebrafish caused early ventricular malformation and contractility defects, probably driven by altered cardiomyocyte proliferation. In vivo complementation studies showed that mutant human
NNT
failed to rescue
nnt
morpholino-induced heart dysfunction, indicating a probable haploinsufficiency mechanism.

Conclusions—
Together, our data expand the genetic spectrum of LVNC and demonstrate how the intersection of whole exome sequence with in vivo functional studies can accelerate the identification of genes that drive human genetic disorders.
Myosin Activator Omecamtiv Mecarbil Increases Myocardial Oxygen Consumption and Impairs Cardiac Efficiency Mediated by Resting Myosin ATPase Activity
Authors: Bakkehaug Jens Petter , Kildal Anders Benjamin , Engstad Erik Torgersen , Boardman Neoma , Næsheim Torvind , Rønning Leif , Aasum Ellen , Larsen Terje Steinar , Myrmel Truls , How Ole-Jakob 
Published: May 2015

Background—
Omecamtiv mecarbil (OM) is a novel inotropic agent that prolongs systolic ejection time and increases ejection fraction through myosin ATPase activation. We hypothesized that a potentially favorable energetic effect of unloading the left ventricle, and thus reduction of wall stress, could be counteracted by the prolonged contraction time and ATP-consumption.

Methods and Results—
Postischemic left ventricular dysfunction was created by repetitive left coronary occlusions in 7 pigs (7 healthy pigs also included). In both groups, systolic ejection time and ejection fraction increased after OM (0.75 mg/kg loading for 10 minutes, followed by 0.5 mg/kg/min continuous infusion). Cardiac efficiency was assessed by relating myocardial oxygen consumption to the cardiac work indices, stroke work, and pressure–volume area. To circumvent potential neurohumoral reflexes, cardiac efficiency was additionally assessed in ex vivo mouse hearts and isolated myocardial mitochondria. OM impaired cardiac efficiency; there was a 31% and 23% increase in unloaded myocardial oxygen consumption in healthy and postischemic pigs, respectively. Also, the oxygen cost of the contractile function was increased by 63% and 46% in healthy and postischemic pigs, respectively. The increased unloaded myocardial oxygen consumption was confirmed in OM-treated mouse hearts and explained by an increased basal metabolic rate. Adding the myosin ATPase inhibitor, 2,3-butanedione monoxide abolished all surplus myocardial oxygen consumption in the OM-treated hearts.

Conclusions—
Omecamtiv mecarbil, in a clinically relevant model, led to a significant myocardial oxygen wastage related to both the contractile and noncontractile function. This was mediated by that OM induces a continuous activation in resting myosin ATPase.
Cluster-Randomized Clinical Trial Examining the Impact of Platelet Function Testing on Practice
Authors: Wang Tracy Y. , Henry Timothy D. , Effron Mark B. , Honeycutt Emily , Hess Connie N. , Zettler Marjorie E. , Cohen David J. , Baker Brian A. , Berger Peter B. , Anstrom Kevin J. , Angiolillo Dominick J. , Peterson Eric D. 
Published: May 2015

Background—
Little is known about how clinicians use platelet function testing to guide choice and dosing of adenosine diphosphate receptor inhibitor (ADPri) therapy in routine community practice.

Methods and Results—

The Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (ACS)—Prospective, Open Label, Antiplatelet Therapy Study (TRANSLATE-POPS) was a cluster-randomized trial in which 100 hospitals were assigned access to no-cost platelet function testing versus usual care for acute myocardial infarction patients treated with percutaneous coronary intervention. In both arms, ADPri treatment decisions were left up to the care team. The primary end point was the frequency of ADPri therapy adjustment before discharge. Secondary end points included 30-day rates of major adverse cardiovascular events and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries–defined bleeding events. Platelet function testing was performed in 66.9% of patients treated in intervention sites versus 1.4% of patients in usual care sites. Intervention arm patients were more likely to have ADPri therapy adjustment than usual care patients (14.8% versus 10.5%,
P
=0.004; odds ratio 1.68, 95% confidence interval 1.18–2.40); however, there were no significant differences in 30-day major adverse cardiovascular events (4.8% versus 5.4%,
P
=0.73; odds ratio 0.94, 95% confidence interval 0.66–1.34) or bleeding (4.3% versus 4.2%,
P
=0.33; odds ratio 0.86, 95% confidence interval 0.55–1.34). One-year outcomes were also not significantly different between groups. An as-treated analysis showed higher incidence of ADPri therapy adjustment among intervention arm patients who received platelet function testing than untested usual care arm (16.4% versus 10.2%,
P
<0.0001), but no significant differences in major adverse cardiovascular events or bleeding.

Conclusions—
TRANSLATE-POPS found that when clinicians routinely used platelet function testing, they were more likely to adjust their choice or dosing of ADPri therapy; yet with few changes in therapy overall, significant differences in clinical outcomes were not seen.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01088503.
Change in Coronary Blood Flow After Percutaneous Coronary Intervention in Relation to Baseline Lesion Physiology
Authors: Nijjer Sukhjinder S. , Petraco Ricardo , van de Hoef Tim P. , Sen Sayan , van Lavieren Martijn A. , Foale Rodney A. , Meuwissen Martijn , Broyd Christopher , Echavarria-Pinto Mauro , Al-Lamee Rasha , Foin Nicolas , Sethi Amarjit , Malik Iqbal S. , Mikhail Ghada W. , Hughes Alun D. , Mayet Jamil , Francis Darrel P. , Di Mario Carlo , Escaned Javier , Piek Jan J. , Davies Justin E. 
Published: May 2015

Background—
Percutaneous coronary intervention (PCI) aims to increase coronary blood flow by relieving epicardial obstruction. However, no study has objectively confirmed this and assessed changes in flow over different phases of the cardiac cycle. We quantified the change in resting and hyperemic flow velocity after PCI in stenoses defined physiologically by fractional flow reserve and other parameters.

Methods and Results—

Seventy-five stenoses (67 patients) underwent paired flow velocity assessment before and after PCI. Flow velocity was measured over the whole cardiac cycle and the wave-free period. Mean fractional flow reserve was 0.68±0.02. Pre-PCI, hyperemic flow velocity is diminished in stenoses classed as physiologically significant compared with those classed nonsignificant (
P
<0.001). In significant stenoses, flow velocity over the resting wave-free period and hyperemic flow velocity did not differ statistically. After PCI, resting flow velocity over the wave-free period increased little (5.6±1.6 cm/s) and significantly less than hyperemic flow velocity (21.2±3 cm/s;
P
<0.01). The greatest increase in hyperemic flow velocity was observed when treating stenoses below physiological cut points; treating stenoses with fractional flow reserve ≤0.80 gained Δ28.5±3.8 cm/s, whereas those fractional flow reserve >0.80 had a significantly smaller gain (Δ4.6±2.3 cm/s;
P
<0.001). The change in pressure-only physiological indices demonstrated a curvilinear relationship to the change in hyperemic flow velocity but was flat for resting flow velocity.

Conclusions—
Pre-PCI physiology is strongly associated with post-PCI increase in hyperemic coronary flow velocity. Hyperemic flow velocity increases 6-fold more when stenoses classed as physiologically significant undergo PCI than when nonsignificant stenoses are treated. Resting flow velocity measured over the wave-free period changes at least 4-fold less than hyperemic flow velocity after PCI.
High Event Rate After a First Percutaneous Coronary Intervention in Patients With Diabetes Mellitus
Authors: Ritsinger Viveca , Saleh Nawsad , Lagerqvist Bo , Norhammar Anna 
Published: May 2015

Background—
Patients with diabetes mellitus have reduced longevity after acute coronary syndromes and revascularization. However, knowledge of the long-term complication rates and patterns from an everyday life setting is lacking.

Methods and Results—
Consecutive patients undergoing percutaneous coronary intervention included in the Swedish Coronary Angiography Angioplasty Registry (SCAAR) between 2006 and 2010 and with no previous revascularization were prospectively followed up for combined cardiovascular events (first of all-cause mortality, myocardial infarction, stroke, and heart failure) until December 31, 2010. The mean follow-up period was 920 days (SD, 530 days). Differences in background and procedural characteristics were adjusted for in a multivariate Cox regression model. Of 58 891 patients, mean age 67 years, 19% had diabetes mellitus; 27% of them were on diet treatment, 33% on oral glucose lowering, and 40% on insulin treatment. At admission, cardiovascular risk factors, multiple coronary vessel, and left main stem disease were more frequent in patients with diabetes mellitus and their revascularization was less often complete. The adjusted risk for combined cardiovascular events was higher in patients on insulin (hazard ratio [95% confidence interval], 1.63 [1.55–1.72]), on oral treatment (1.23 [1.15–1.31]), and on diet alone (1.21 [1.12–1.29]) compared with patients without diabetes mellitus. Insulin-treated patients ran an increased risk of restenosis (1.54 [1.39–1.71]) and stent thrombosis (1.56 [1.25–1.96]).

Conclusions—
The prognosis after a first percutaneous coronary intervention is more severe in patients with diabetes mellitus, in particular, in patients treated with insulin, with higher rates of mortality, cardiovascular events, and stent thrombosis over the following 5 years.
Magnitude of Troponin Elevation and Long-Term Clinical Outcomes in Acute Coronary Syndrome Patients Treated With and Without Revascularization
Authors: Bagai Akshay , Huang Zhen , Lokhnygina Yuliya , Harrington Robert A. , Armstrong Paul W. , Strony John , White Harvey D. , Leonardi Sergio , Held Claes , Van de Werf Frans , Wallentin Lars , Tricoci Pierluigi , Mahaffey Kenneth W. 
Published: May 2015

Background—
In patients with non–ST-segment–elevation acute coronary syndrome (NSTE ACS), elevated troponin levels identify patients at high risk for adverse outcomes; however, it is unknown whether the magnitude of troponin elevation during hospitalization remains predictive of subsequent events in patients undergoing coronary revascularization.

Methods and Results—

We studied 12 635 patients with NSTE ACS in the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) study with at least 1 troponin measurement during index hospitalization. Cox proportional hazards regression was used to examine the relationship between peak troponin level (standardized as the ratio of peak troponin value measured during hospitalization and local laboratory upper reference limit [URL]) and revascularization on all-cause mortality at 2 years. Revascularization (percutaneous coronary intervention or coronary artery bypass graft) was performed during index hospitalization in 8586 patients (68.0%); revascularized patients had higher peak troponin ratios (median, 23 versus 9.5× URL). Among patients that did not undergo revascularization, the mortality rate at 2 years increased in a curvilinear fashion with increasing levels of peak troponin. In contrast, the mortality rate at 2 years remained constant irrespective of peak troponin levels among revascularized patients (
P
for interaction=0.004). This relationship was unchanged after multivariable adjustment.

Conclusions—
There is a differential relationship between the magnitude of troponin elevation and long-term mortality in ACS patients treated with and without revascularization. Although prognostically important in patients treated without revascularization, the prognostic implications of peak troponin level seem to be minimal in revascularized patients.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00527943.
Transvenous Implantable Cardioverter‐Defibrillator Lead Reliability: Implications for Postmarket Surveillance
Authors: Kramer Daniel B. , Hatfield Laura A. , McGriff Deepa , Ellis Christopher R. , Gura Melanie T. , Samuel Michelle , Retel Linda Kallinen , Hauser Robert G. 
Published: May 2015

Background
As implantable cardioverter‐defibrillator technology evolves, clinicians and patients need reliable performance data on current transvenous implantable cardioverter‐defibrillator systems. In addition, real‐world reliability data could inform postmarket surveillance strategies directed by regulators and manufacturers.

Methods and Results

We evaluated Medtronic Sprint Quattro, Boston Scientific Endotak, and St Jude Medical Durata and Riata
ST
Optim leads implanted by participating center physicians between January 1, 2006 and September 1, 2012. Our analytic sample of 2653 patients (median age 65, male 73%) included 445 St Jude, 1819 Medtronic, and 389 Boston Scientific leads. After a median of 3.2 years, lead failure was 0.28% per year (95%
CI
, 0.19 to 0.43), with no statistically significant difference among manufacturers. Simulations based on these results suggest that detecting performance differences among generally safe leads would require nearly 10 000 patients or very long follow‐up.

Conclusions
Currently marketed implantable cardioverter‐defibrillator leads rarely fail, which may be reassuring to clinicians advising patients about risks and benefits of transvenous implantable cardioverter‐defibrillator systems. Regulators should consider the sample size implications when designing comparative effectiveness studies and evaluating new technology for preventing sudden cardiac death.
The Mayo Clinic Arizona Spasmodic Dysphonia Experience
Authors: Patel Alpen B. , Bansberg Stephen F. , Adler Charles H. , Lott David G. , Crujido Lisa 
Published: May 2015

Objective: Analyze demographic data collected over a 25-year experience of 718 patients with spasmodic dysphonia (SD) who have been treated with botulinum toxin-A (BoNT-A) and compare our data with previously published studies. Methods: Seven hundred eighteen patients with SD were treated with 6621 BoNT-A injections at Mayo Clinic Arizona between 1989 and 2014. All patients were treated by the same physician team. Background demographic data for each patient were recorded. Results: Of 718 patients, 557 patients were female (77.6%). Six hundred sixty of 718 (91.8%) patients had adductor SD (AdSD), and 58 of 718 (8.1%) patients had abductor SD (AbSD). Average age of onset was 51 years. Of 718 patients, 378 (52.6%) had vocal tremor (VT); VT was present in 54.4% of AdSD patients and 32.1% of AbSD patients. Thirty-seven of 718 (5.2%) patients had other dystonias, including cervical dystonia (2.3%), blepharospasm (1.4%), limb dystonia (1.1%), and oromandibular dystonia (0.3%). A positive family history of SD was present in only 6 of 718 patients (0.8%) and of other dystonias in 11 of 718 patients (1.5%). Conclusions: Spasmodic dysphonia is a chronic and potentially disabling focal laryngeal dystonia. The Mayo Clinic Arizona SD experience compares to prior reports and reveals a female preponderance, onset in middle age, infrequent hereditary pattern, high co-occurrence of VT, and low co-occurrence of other dystonias.
Average Ambulatory Measures of Sound Pressure Level, Fundamental Frequency, and Vocal Dose Do Not Differ Between Adult Females With Phonotraumatic Lesions and Matched Control Subjects
Authors: Van Stan Jarrad H. , Mehta Daryush D. , Zeitels Steven M. , Burns James A. , Barbu Anca M. , Hillman Robert E. 
Published: May 2015

Objectives: Clinical management of phonotraumatic vocal fold lesions (nodules, polyps) is based largely on assumptions that abnormalities in habitual levels of sound pressure level (SPL), fundamental frequency (f0), and/or amount of voice use play a major role in lesion development and chronic persistence. This study used ambulatory voice monitoring to evaluate if significant differences in voice use exist between patients with phonotraumatic lesions and normal matched controls. Methods: Subjects were 70 adult females: 35 with vocal fold nodules or polyps and 35 age-, sex-, and occupation-matched normal individuals. Weeklong summary statistics of voice use were computed from anterior neck surface acceleration recorded using a smartphone-based ambulatory voice monitor. Results: Paired t tests and Kolmogorov-Smirnov tests resulted in no statistically significant differences between patients and matched controls regarding average measures of SPL, f0, vocal dose measures, and voicing/voice rest periods. Paired t tests comparing f0 variability between the groups resulted in statistically significant differences with moderate effect sizes. Conclusions: Individuals with phonotraumatic lesions did not exhibit differences in average ambulatory measures of vocal behavior when compared with matched controls. More refined characterizations of underlying phonatory mechanisms and other potentially contributing causes are warranted to better understand risk factors associated with phonotraumatic lesions.
Upplevelse av trygghet och otrygghet bland patienter med hjärtsvikt som får avancerad sjukvård i hemmet
Authors: Söderberg AnneCharlotte , Karlsson Monica Rydell , Löfvenmark Caroline 
Published: May 2015

Aim The aim of this study was to describe the experience of security and insecurity in patients with chronic heart failure who were treated by Advanced Home Care (AHC) in a city in Sweden. Background It is common for patients with heart failure to have frequent readmissions to hospital due to deterioration. The patients have various symptoms such as breathing problems, oedema and fatigue. Being cared for by AHC has become more common for patients with heart failure to reduce deterioration of heart failure and prevent hospitalization. Method A qualitative method with semi-structured interviews was used. Eight patients with heart failure participated in the study. The interviews were analysed by content analysis. Findings Three categories were identified: ‘home care’, ‘the social network’ and ‘internal and external resources’. Conclusion The experience was complex and depended on several factors both within and outside the health care situation. The need for access to a multidisciplinary team was great and it was important that the nursing staff had time to listen. It was important that the care had focus on the patient’s perspective to create security and avoid insecurity.
Muligheder og barrierer for udvikling af den kommunale palliative indsats: Evaluering af et aktionsforskningsinspireret projekt
Authors: Raunkiær Mette 
Published: May 2015

Aim This study is based on a project inspired by action research with the aim to elucidate possibilities and barriers for the organizational and professional development of community palliative care services. Background Many people with life-threatening diseases want to stay in their own homes as long as possible. Therefore, community palliative care services are significant. Experience concurrently shows several interdisciplinary and inter-sectorial challenges between professions and different organizations. Method The evaluation consisted of continuous reflections of practice by the involved professionals, an interview study with 21 professionals and a questionnaire survey among 88 professionals and 13 relatives. Results The evaluation showed that the guideline system The Gold Standard Framework and EORTC-QLQ-C15-PAL in combination with more locally-developed interventions, according to the professionals, had improved the community palliative care services. However, the results also showed barriers for improvement and change of practice: such as mainly insufficient management, lack of commitment among some of the professionals to work with the new interventions, insufficient information technology, reorganization, cost-cutting, and differently structured organizations. Conclusion The interventions encouraged the community development palliative care, but also showed that there were barriers for the change process. There is a need for research and development of how to lead and manage change processes and methods of cooperation in community palliative care.