bluuebunny/crossref_metadata_2025_split huggingface dataset:
Toward Concurrent Testing for Somatic and Germline Variants in Cancer Patients
Authors: Mandelker Diana 
Published: June 2016

Abstract
Sequencing for somatic alterations in patients' tumors is being increasingly clinically implemented to detect mutations that may guide therapy. Germline analysis of a cohort of patients undergoing tumor sequencing with matched normal has revealed that a small but significant percentage of these patients have germline variants that confer cancer susceptibility. Clin Cancer Res; 22(16); 3987–8. ©2016 AACR.
See related article by Seifert et al., p. 4087
Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma
Authors: Carlsten Mattias , Korde Neha , Kotecha Ritesh , Reger Robert , Bor Simona , Kazandjian Dickran , Landgren Ola , Childs Richard W. 
Published: June 2016

Abstract
Purpose: Immune checkpoint inhibitors have recently revolutionized cancer immunotherapy. On the basis of data showing KIR-ligand mismatched natural killer (NK) cells reduce the risk of leukemia and multiple myeloma relapse following allogeneic hematopoietic stem cell transplantation, investigators have developed a checkpoint inhibition antibody that blocks KIR on NK cells. Although in vitro studies suggest the KIR2D-specific antibody IPH2101 induces KIR-ligand mismatched tumor killing by NK cells, our single-arm phase II clinical trial in patients with smoldering multiple myeloma was prematurely terminated due to lack of clinical efficacy. This study aimed at unveiling the underlying mechanisms behind the lack of clinical efficacy.
Experimental Design: Treatment-naïve patients received an intravenous infusion of 1 mg/kg IPH2101 every other month for up to a year. Peripheral blood was collected at baseline and 24 hours after first infusion, followed by weekly samples for the first month and monthly samples thereafter. NK cell phenotype and function was analyzed using high-resolution flow cytometry.
Results: Unexpectedly, infusion of IPH2101 resulted in rapid reduction in both NK cell responsiveness and KIR2D expression on the NK cell surface. In vitro assays revealed KIR2D molecules are removed from the surface of IPH2101-treated NK cells by trogocytosis, with reductions in NK cell function directly correlating with loss of free KIR2D surface molecules. Although IPH2101 marginally augmented the antimyeloma cytotoxicity of remaining KIR2Ddull patient NK cells, the overall response was diminished by significant contraction and reduced function of KIR2D-expressing NK cells.
Conclusions: These data raise concerns that the unexpected biological events reported in this study could compromise antibody-based strategies designed at augmenting NK cell tumor killing via checkpoint inhibition. Clin Cancer Res; 22(21); 5211–22. ©2016 AACR.
See related commentary by Felices and Miller, p. 5161
miR-146a Exerts Differential Effects on Melanoma Growth and Metastatization
Authors: Raimo Monica , Orso Francesca , Grassi Elena , Cimino Daniela , Penna Elisa , De Pittà Cristiano , Stadler Michael B. , Primo Luca , Calautti Enzo , Quaglino Pietro , Provero Paolo , Taverna Daniela 
Published: June 2016

AbstractMalignant melanoma is the most aggressive form of skin cancer; therefore, it is crucial to disclose its underlying molecular mechanisms. MicroRNAs (miRNAs) are small endogenous noncoding RNAs able to posttranscriptionally downregulate the expression of direct target genes. Using a melanoma progression model, miR-146a was identified as a key double-acting player in melanoma malignancy. In fact, miR-146a is able to enhance tumor growth, while it suppresses dissemination. It was determined that miR-146a coordinated melanoma cell growth by its direct targets lunatic fringe (LFNG) and NUMB, which operate on the NOTCH/PTEN/Akt pathway; while inhibition of metastasis formation was linked to decreased expression of ITGAV and ROCK1. Relevantly, miR-146a expression correlated with melanoma recurrence and was enriched in both patient-derived melanoma and cutaneous metastasis specimens, while its direct targets were depleted. However, miR-146a levels drop in circulating tumor cells (CTCs), suggesting the necessity for miR-146a expression to fluctuate during tumor progression in order to favor tumor growth and allow dissemination. This study reconciles the contradictory biologic functions of miR-146a in melanoma progression and unravels distinct molecular mechanisms that need to be considered for therapeutic interventions.Implications: miR-146a controls melanoma progression in a dual way, promoting growth and inhibiting dissemination; however, it is poorly expressed in CTCs, resulting in overall tumor spreading and distant-site colonization. Mol Cancer Res; 14(6); 548–62. ©2016 AACR.
Simvastatin induces the apoptosis of normal vascular smooth muscle through the disruption of actin integrity via the impairment of RhoA/ Rac-1 activity
Authors: Kang Seojin , Kim Keunyoung , Noh Ji-Yoon , Jung Yeryeon , Bae Ok-Nam , Lim Kyung-Min , Chung Jin-Ho 
Published: June 2016

SummaryStatins, lipid-lowering agents for the prevention of atherosclerosis and fatal coronary heart diseases, have pleiotropic modalities on the function and physiology of vascular smooth muscle that include anti-contractile and pro-apoptotic effects. These effects were suggested to stem from the inhibition of small GTPase Rho A, but they are largely regarded as distinct and unrelated. Recently, we discovered that simvastatin causes both contractile dysfunction and apoptosis of vascular smooth muscle cells (VSMCs), reflecting that they may be closely related, yet their connecting link remains unexplained. Here, we elaborated the mechanism underlying simvastatin-induced apoptosis of normal VSMCs in connection with contractile dysfunction. Repeated oral administration of simvastatin to rats in vivo resulted in contractile dysfunction and apoptosis of vascular smooth muscle, of which pattern was well reproduced in rat VSMCs in vitro. Of note, contractile dysfunction and apoptosis occurred in concerted manners both in vivo and in vitro in the aspects of time course and dose of exposure. In rat VSMCs, simvastatin impaired the activation of small GTPases, RhoA along with Rac-1, which resulted in the disruption of actin integrity, a pivotal factor both for the generation of contractile force and survival of VSMCs. In line with the disruption of actin integrity, Bmf, a pro-apoptotic factor bound to intact actin, dissociated and translocated into mitochondria, which corresponded well with the dissipation of mitochondrial membrane potential, caspase-3 activation and ultimately apoptosis. These events were all rescued by an actin stabilisation agent, jasplakinolide as well as geranylgeraniol, indicating that damages of the actin integrity from disrupted activation of RhoA/ Rac-1 lies at the center of simvastatin-induced contractile dysfunction and apoptosis in vascular smooth muscle.Supplementary Material to this article is available online at www.thrombosis-online.com.
Oxidative stress and thromboxane-dependent platelet activation in inflammatory bowel disease: effects of anti-TNF-α treatment
Authors: Guerci Marco , Simeone Paola , Ardizzone Sandro , Massari Alessandro , Giuffrida Paolo , Tripaldi Romina , Malara Alessandro , Liani Rossella , Gurini Evelyn , Aronico Nicola , Balduini Alessandra , Sabatino Antonio Di , Santilli Francesca , Corazza Gino Roberto , Davì Giovanni 
Published: June 2016

SummaryPatients with inflammatory bowel disease (IBD) are at higher risk of venous thromboembolism and coronary artery disease despite having a lower burden of traditional risk factors. Platelets from IBD patients release more soluble CD40 ligand (CD40L), and this has been implicated in IBD platelet hyper-activation. We here measured the urinary F2-isoprostane 8-iso-prostaglandin (PG)2α (8-iso-PGF2α), urinary 11–dehydro–thromboxane (TX) B2 (11-dehydro–TXB2) and plasma CD40L in IBD patients, and explored the in vitro action of anti-tumour necrosis factor (TNF)–α antibody infliximab on IBD differentiating megakaryocytes. Urinary and blood samples were collected from 124 IBD patients and 37 healthy subjects. Thirteen IBD patients were also evaluated before and after 6–week infliximab treatment. The in vitro effect of infliximab on patient-derived megakaryocytes was evaluated by immunoflorescence microscopy and by flow cytometry. IBD patients had significantly (p<0.0001) higher urinary 8–iso–PGF2α and 11–dehydro–TXB2 as well as plasma CD40L levels than controls, with active IBD patients displaying higher urinary and plasma values when compared to inactive patients in remission. A 6-week treatment with infliximab was associated with a significant reduction of the urinary excretion of 8–iso–PGF2α and 11–dehydro–TXB2 (p=0.008) and plasma CD40L (p=0.001). Infliximab induced significantly rescued pro-platelet formation by megakaryocytes derived from IBD patients but not from healthy controls. Our findings provide evidence for enhanced in vivo TX–dependent platelet activation and lipid peroxidation in IBD patients. Anti-TNF–α therapy with infliximab down-regulates in vivo isoprostane generation and TX biosynthesis in responder IBD patients. Further studies are needed to clarify the implication of infliximab induced-proplatelet formation from IBD megakaryocytes.Supplementary Material to this article is available online at www.thrombosis-online.com.
Cost-Effectiveness of Percutaneous Closure of the Left Atrial Appendage in Atrial Fibrillation Based on Results From PROTECT AF Versus PREVAIL
Authors: Freeman James V. , Hutton David W. , Barnes Geoffrey D. , Zhu Ruo P. , Owens Douglas K. , Garber Alan M. , Go Alan S. , Hlatky Mark A. , Heidenreich Paul A. , Wang Paul J. , Al-Ahmad Amin , Turakhia Mintu P. 
Published: June 2016

Background—
Randomized trials of left atrial appendage (LAA) closure with the Watchman device have shown varying results, and its cost effectiveness compared with anticoagulation has not been evaluated using all available contemporary trial data.

Methods and Results—
We used a Markov decision model to estimate lifetime quality-adjusted survival, costs, and cost effectiveness of LAA closure with Watchman, compared directly with warfarin and indirectly with dabigatran, using data from the long-term (mean 3.8 year) follow-up of Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation (PROTECT AF) and Prospective Randomized Evaluation of the Watchman LAA Closure Device in Patients With Atrial Fibrillation (PREVAIL) randomized trials. Using data from PROTECT AF, the incremental cost-effectiveness ratios compared with warfarin and dabigatran were $20 486 and $23 422 per quality-adjusted life year, respectively. Using data from PREVAIL, LAA closure was dominated by warfarin and dabigatran, meaning that it was less effective (8.44, 8.54, and 8.59 quality-adjusted life years, respectively) and more costly. At a willingness-to-pay threshold of $50 000 per quality-adjusted life year, LAA closure was cost effective 90% and 9% of the time under PROTECT AF and PREVAIL assumptions, respectively. These results were sensitive to the rates of ischemic stroke and intracranial hemorrhage for LAA closure and medical anticoagulation.

Conclusions—
Using data from the PROTECT AF trial, LAA closure with the Watchman device was cost effective; using PREVAIL trial data, Watchman was more costly and less effective than warfarin and dabigatran. PROTECT AF enrolled more patients and has substantially longer follow-up time, allowing greater statistical certainty with the cost-effectiveness results. However, longer-term trial results and postmarketing surveillance of major adverse events will be vital to determining the value of the Watchman in clinical practice.
Plaque Structural Stress Estimations Improve Prediction of Future Major Adverse Cardiovascular Events After Intracoronary Imaging
Authors: Brown Adam J. , Teng Zhongzhao , Calvert Patrick A. , Rajani Nikil K. , Hennessy Orla , Nerlekar Nitesh , Obaid Daniel R. , Costopoulos Charis , Huang Yuan , Hoole Stephen P. , Goddard Martin , West Nick E.J. , Gillard Jonathan H. , Bennett Martin R. 
Published: June 2016

Background—
Although plaque rupture is responsible for most myocardial infarctions, few high-risk plaques identified by intracoronary imaging actually result in future major adverse cardiovascular events (MACE). Nonimaging markers of individual plaque behavior are therefore required. Rupture occurs when plaque structural stress (PSS) exceeds material strength. We therefore assessed whether PSS could predict future MACE in high-risk nonculprit lesions identified on virtual-histology intravascular ultrasound.

Methods and Results—

Baseline nonculprit lesion features associated with MACE during long-term follow-up (median: 1115 days) were determined in 170 patients undergoing 3-vessel virtual-histology intravascular ultrasound. MACE was associated with plaque burden ≥70% (hazard ratio: 8.6; 95% confidence interval, 2.5–30.6;
P
<0.001) and minimal luminal area ≤4 mm
2
(hazard ratio: 6.6; 95% confidence interval, 2.1–20.1;
P
=0.036), although absolute event rates for high-risk lesions remained <10%. PSS derived from virtual-histology intravascular ultrasound was subsequently estimated in nonculprit lesions responsible for MACE (n=22) versus matched control lesions (n=22). PSS showed marked heterogeneity across and between similar lesions but was significantly increased in MACE lesions at high-risk regions, including plaque burden ≥70% (13.9±11.5 versus 10.2±4.7;
P
<0.001) and thin-cap fibroatheroma (14.0±8.9 versus 11.6±4.5;
P
=0.02). Furthermore, PSS improved the ability of virtual-histology intravascular ultrasound to predict MACE in plaques with plaque burden ≥70% (adjusted log-rank,
P
=0.003) and minimal luminal area ≤4 mm
2
(
P
=0.002). Plaques responsible for MACE had larger superficial calcium inclusions, which acted to increase PSS (
P
<0.05).

Conclusions—
Baseline PSS is increased in plaques responsible for MACE and improves the ability of intracoronary imaging to predict events. Biomechanical modeling may complement plaque imaging for risk stratification of coronary nonculprit lesions.
Three-Dimensional Echocardiography Compared With Computed Tomography to Determine Mitral Annulus Size Before Transcatheter Mitral Valve Implantation
Authors: Mak George J. , Blanke Philipp , Ong Kevin , Naoum Christopher , Thompson Christopher R. , Webb John G. , Moss Robert , Boone Robert , Ye Jian , Cheung Anson , Munt Brad , Leipsic Jonathon , Grewal Jasmine 
Published: June 2016

Background—
Previously, through the use of computed tomography (CT), it has been proposed that D-shaped versus saddle-shaped mitral annulus (MA) segmentation is more biomechanically appropriate to determine transcatheter mitral valve implantation size and eligibility.

Methods and Results—

Forty-one patients with severe mitral regurgitation being considered for transcatheter mitral valve implantation who had undergone cardiac CT and 3-dimensional transesophageal echocardiography (3D-TEE) were retrospectively evaluated. A standardized segmentation protocol for the D-shaped MA was developed using Philips Q-Laboratory mitral valve quantification software. MA dimensions were compared using Spearman’s rank correlation and Bland–Altman analysis. Inter- and intraobserver agreement was quantified by intraclass correlation coefficient and Bland–Altman analysis. Mean age was 77±14 years; 71% male (n=29); mitral regurgitation pathogenesis was functional in 54% (n=22) and myxomatous in 46% (n=19). Mean MA area and circumference by 3D-TEE and CT were 11.3±2.7 versus 11.4±3.0 (
P
=0.67) and 124.1±15.6 versus 123.9±15.5 (
P
=0.79), respectively, with excellent correlation between modalities (
r
=0.84 and
r
=0.86;
P
<0.0001) and no systematic bias (−0.20±1.8 cm
2
[−3.7 cm
2
; 3.3 cm
2
], 0.37±9 mm [−18.0 mm; 17.27 mm]). Mean septal-to-lateral and inter-trigone distances by 3D-TEE and CT were 33.2±4.7 versus 32.5±4.4 (
P
=0.24) and 31.7±3.5 versus 32.6±3.6 (
P
=0.06), respectively, with good correlation (
r
=0.69 and
r
=0.71;
P
<0.0001) and no systematic bias (0.77±3.8 mm [−6.7 mm; 8.2 mm], −1.5±3.1 mm [−4.6 mm; 7.6 mm]). There was excellent intra- and interobserver agreement according to intraclass correlation coefficients >0.90 for all parameters.

Conclusions—
Similar to cardiac CT, 3D-TEE allows for D-shaped MA segmentation with no systematic difference in MA dimensions between modalities. This study supports the utilization of 3D-TEE as a complementary tool to CT assessment of the D-shaped MA to determine transcatheter mitral valve implantation size.
Noninvasive Localization of Accessory Pathways in Wolff–Parkinson–White Syndrome by Three-Dimensional Speckle Tracking Echocardiography
Authors: Ishizu Tomoko , Seo Yoshihiro , Igarashi Miyako , Sekiguchi Yukio , Machino-Ohtsuka Tomoko , Ogawa Kojiro , Kuroki Kenji , Yamamoto Masahiro , Nogami Akihiko , Kawakami Yasushi , Aonuma Kazutaka 
Published: June 2016

Background—
We have developed a noninvasive isochrone activation imaging (AI) system with 3-dimensional (3D) speckle tracking echocardiography (STE), which allows visualization of the wavefront image of mechanical propagation of the accessory pathway (ACP) in Wolff–Parkinson–White syndrome.

Methods and Results—
Patients with manifest Wolff–Parkinson–White syndrome were imaged in 3D-STE AI mode, which quantified the time from QRS onset to regional endocardial deformation. In 2 patients with left- and right-side ACP, we confirmed that intraoperative contact endocardial electric mapping and the 3D-STE AI system showed comparable images pre- and postablation. In normal heart assessment by 3D-echo AI, the earliest activation sites were found at the attachment of the papillary muscles in the left ventricle and midseptum in the right ventricle, and none showed earliest activation at the peri-atrioventricular valve annuli. An analyzer who was unaware of the clinical information assessed 39 ACP locations in 38 Wolff–Parkinson–White syndrome patients using 3D-STE. All showed abnormal perimitral or tricuspid annular activations, and the location of 34 ACP (87%) showed agreement with the successful ablation sites within a 2-o’clock range. Especially for left free wall ACP, 17/18 (94%) showed consistency with the ablation site within a 2 o’clock range. Among 15 ACP at the ventricular septum, 9 (60%) showed early local activation in both right and left sides of the septum.

Conclusions—
Isochrone AI with 3D-STE may be a promising noninvasive imaging tool to assess cardiac synchronized activation in normal hearts and detect abnormal breakthrough of mechanical activation from both atrioventricular annuli in Wolff–Parkinson–White syndrome.
Helping people with a mental illness obtain work: the Health Optimisation Program for Employment
Authors: Castle David , Crosse Caroline , Morgain Dea , McDowell Caitlin , Rossell Susan , Thomas Neil , Phillipou Andrea , Gilbert Monica , Moore Gaye , Fossey Ellie , Harvey Carol 
Published: June 2016

Objective: Inclusion in work and education remains problematic for many people with a mental illness. We describe a structured programme – the Health Optimisation Program for Employment – that supported people with a mental illness to gain employment or commence studies. Method: Twenty hours of the Health Optimisation Program for Employment were delivered to 600 individuals. Participants were asked to complete an evaluation survey encompassing vocational status and ratings of self-efficacy. Results: Of the 364 participants who completed the baseline assessment, 168 responded to the evaluation survey 6 months after the delivery of the Health Optimisation Program for Employment. Of these, 21.5% had started a new job, while a further 42.8% were either volunteering or studying. Satisfaction with the programme was high and self-efficacy ratings improved significantly over the short term only. Conclusions: The Health Optimisation Program for Employment requires further evaluation using rigorous scientific methodology but these initial results are encouraging in terms of vocational attainment for people with a mental illness, in the Australian context.
Factors Influencing the Choice of Anesthesia as a Career by Undergraduates of the University of Rwanda
Authors: Chan Denise M. , Wong Rex , Runnels Sean , Muhizi Epaphrodite , McClain Craig D. 
Published: June 2016

BACKGROUND:
Rwanda currently faces a severe shortage of trained medical personnel, including physician anesthesiologists. The recruitment of residents into the anesthesia program has been consistently low. This study aimed at determining the factors that influence undergraduates’ decision to pursue anesthesia as a career choice.

METHODS:
A questionnaire was created and administered to final year undergraduate medical students at the University of Rwanda. The questionnaire was created based on factors identified from literature review and key informant interviews. The questionnaire was translated, field-tested, and refined. The final survey questionnaire contains 27 4-point Likert scale items and 4 free-text questions.

RESULTS:
Seventy-nine final year undergraduate medical students responded to the survey. Only 2 students (2.5%) chose anesthesia as their top choice for postgraduate training. The most frequently named factors for not choosing anesthesiology were long work hours and high stress level, insufficient mentorship, and low job opportunity.

CONCLUSIONS:
The issues identified by our survey must be considered when making efforts toward increasing anesthesia recruitment in Rwanda. Factors such as lack of material resources and high workload will not be easily addressed. Others can be addressed through changes in medical student anesthesiology rotations and better mentorship by anesthesiologists during formative years. Focusing on factors that can be changed now may increase enrollment into anesthesiology. Future studies will include broadening the survey population and further investigating the influencing factors elucidated by this study.
No discrimination shock avoidance with sequential presentation of stimuli but shore crabs still reduce shock exposure
Authors: Magee Barry , Elwood Robert W. 
Published: June 2016

ABSTRACTInsights into the potential for pain may be obtained from examination of behavioural responses to noxious stimuli. In particular, prolonged responses coupled with long-term motivational change and avoidance learning cannot be explained by nociceptive reflex but are consistent with the idea of pain. Here, we placed shore crabs alternately in two halves of a test area divided by an opaque partition. Each area had a dark shelter and in one repeated small electric shocks were delivered in an experimental but not in a control group. Crabs showed no specific avoidance of the shock shelter either during these trials or in a subsequent test in which both were offered simultaneously; however they often emerged from the shock shelter during a trial and thus avoided further shock. More crabs emerged in later trials and took less time to emerge than in early trials. Thus, despite the lack of discrimination learning between the two shelters they used other tactics to markedly reduce the amount of shock received. We note that a previous experiment using simultaneous presentation of two shelters demonstrated rapid discrimination and avoidance learning but the paradigm of sequential presentation appears to prevent this. Nevertheless, the data show clearly that the shock is aversive and tactics, other than discrimination learning, are used to avoid it. Thus, the behaviour is only partially consistent with the idea of pain.