bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I Study to Assess the Combination of Afatinib with Trastuzumab in Patients with Advanced or Metastatic HER2-Positive Breast Cancer
Authors: Ring Alistair , Wheatley Duncan , Hatcher Helen , Laing Robert , Plummer Ruth , Uttenreuther-Fischer Martina , Temple Graham , Pelling Katy , Schnell David 
Published: November 2014

Abstract
Purpose: The HER2 mAb, trastuzumab, is a standard therapy for patients with HER2-positive breast cancer before acquired resistance. Afatinib, an irreversible, oral, small-molecule ErbB family blocker, shows clinical activity in trastuzumab-refractory HER2-positive breast cancer.
Experimental Design: This phase I study used a 3+3 dose escalation to determine the MTD of oral once-daily afatinib in combination with the recommended dose of intravenous trastuzumab (4 mg/kg week 1; 2 mg/kg/wk thereafter). Adult women with confirmed advanced/metastatic HER2-positive breast cancer were eligible.
Results: Of 18 patients treated, 16 received daily afatinib 20 mg and two 30 mg. Overall, 4 of 13 and 2 of 2 patients receiving afatinib 20 mg and 30 mg, respectively, experienced dose-limiting toxicity (DLT; all CTCAE grade 3 diarrhea). Most frequent treatment-related adverse events were diarrhea (94%), rash (56%), and fatigue (56%). Overall, pharmacokinetic profiles of afatinib and trastuzumab in combination were consistent with the known characteristics of each alone. Overall, objective response and disease control rates were 11% and 39%, respectively, with median progression-free survival 111.0 days (95% confidence interval, 56.0–274.0).
Conclusions: The MTD of afatinib was 20 mg daily combined with the recommended weekly dose of trastuzumab, with 1 of 6 patients showing DLTs in the dose escalation. However, additional DLTs occurred in the dose-expansion phase meaning that this MTD cannot be recommended for phase II development without strict diarrhea management. There was no evidence suggesting relevant pharmacokinetic drug–drug interactions. Signs of clinical activity were seen in trastuzumab-resistant HER2-positive breast cancer, suggesting further investigation with optimal diarrhea management is warranted. Clin Cancer Res; 21(12); 2737–44. ©2014 AACR.
See related commentary by Sledge and Pegram, p. 2663
Culprit Vessel Versus Multivessel Intervention at the Time of Primary Percutaneous Coronary Intervention in Patients With ST-Segment–Elevation Myocardial Infarction and Multivessel Disease
Authors: Iqbal M. Bilal , Ilsley Charles , Kabir Tito , Smith Robert , Lane Rebecca , Mason Mark , Clifford Piers , Crake Tom , Firoozi Sam , Kalra Sundeep , Knight Charles , Lim Pitt , Malik Iqbal S. , Mathur Anthony , Meier Pascal , Rakhit Roby D. , Redwood Simon , Whitbread Mark , Bromage Dan , Rathod Krishna , MacCarthy Philip , Dalby Miles 
Published: November 2014

Background—
It is estimated that up to two thirds of patients presenting with ST-segment–elevation myocardial infarction have multivessel disease. The optimal strategy for treating nonculprit disease is currently under debate. This study provides a real-world analysis comparing a strategy of culprit-vessel intervention (CVI) versus multivessel intervention at the time of primary percutaneous coronary intervention in patients with ST-segment–elevation myocardial infarction.

Methods and Results—

We compared CVI versus multivessel intervention in 3984 patients with multivessel disease undergoing primary percutaneous coronary intervention between 2004 and 2011 at all 8 tertiary cardiac centers in London. Multivariable-adjusted models were built to determine independent predictors for in-hospital major adverse cardiovascular events (MACEs) and all-cause mortality at 1 year. To reduce confounding and bias, propensity score methods were used. CVI was associated with reduced in-hospital MACE (4.6% versus 7.2%;
P
=0.010) and mortality at 1 year (7.4% versus 10.1%;
P
=0.031). CVI was an independent predictor for reduced in-hospital MACE (odds ratio, 0.49; 95% confidence interval [CI], 0.32–0.75;
P
<0.001) and survival at 1 year (hazard ratio, 0.65; 95% CI, 0.47–0.91;
P
=0.011) in the complete cohort; and in 2821 patients in propensity-matched cohort (in-hospital MACE: odds ratio, 0.49; 95% CI, 0.32–0.76;
P
=0.002; and 1-year survival: hazard ratio, 0.64; 95% CI, 0.45–0.90;
P
=0.010). Inverse probability treatment weighted analyses also confirmed CVI as an independent predictor for reduced in-hospital MACE (odds ratio, 0.38; 95% CI, 0.15–0.96;
P
=0.040) and survival at 1 year (hazard ratio, 0.44; 95% CI, 0.21–0.93;
P
=0.033).

Conclusions—
In this observational analysis of patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention, CVI was associated with increased survival at 1 year. Acknowledging the limitations with observational analyses, our findings support current recommended practice guidelines.
Endovascular Treatment of Mycotic Aortic Aneurysms
Authors: Sörelius Karl , Mani Kevin , Björck Martin , Sedivy Petr , Wahlgren Carl-Magnus , Taylor Peter , Clough Rachel E. , Lyons Oliver , Thompson Matt , Brownrigg Jack , Ivancev Krassi , Davis Meryl , Jenkins Michael P. , Jaffer Usman , Bown Matt , Rancic Zoran , Mayer Dieter , Brunkwall Jan , Gawenda Michael , Kölbel Tilo , Jean-Baptiste Elixène , Moll Frans , Berger Paul , Liapis Christos D. , Moulakakis Konstantinos G. , Langenskiöld Marcus , Roos Håkan , Larzon Thomas , Pirouzram Artai , Wanhainen Anders 
Published: November 2014

Background—
Mycotic aortic aneurysm (MAA) is a rare and life-threatening disease. The aim of this European multicenter collaboration was to study the durability of endovascular aortic repair (EVAR) of MAA, by assessing late infection–related complications and long-term survival.

Methods and Results—
All EVAR treated MAAs, between 1999 and 2013 at 16 European centers, were retrospectively reviewed. One hundred twenty-three patients with 130 MAAs were identified. Mean age was 69 years (range 39–86), 87 (71%) were men, 58 (47%) had immunodeficiency, and 47 (38%) presented with rupture. Anatomic locations were ascending/arch (n=4), descending (n=34), paravisceral (n=15), infrarenal aorta (n=63), and multiple (n=7). Treatments were thoracic EVAR (n=43), fenestrated/branched EVAR (n=9), and infrarenal EVAR (n=71). Antibiotic was administered for mean 30 weeks. Mean follow-up was 35 months (range 1 week to 149 months). Six patients (5%) were converted to open repair during follow-up. Survival was 91% (95% confidence interval, 86% to 96%), 75% (67% to 83%), 55% (44% to 66%), and 41% (28% to 54%) after 1, 12, 60, and 120 months, respectively. Infection-related death occurred in 23 patients (19%), 9 after discontinuation of antibiotic treatment. A Cox regression analysis demonstrated non-Salmonella–positive culture as predictors for late infection–related death.

Conclusions—
Endovascular treatment of MAA is feasible and for most patients a durable treatment option. Late infections do occur, are often lethal, and warrant long-term antibiotic treatment and follow-up. Patients with non-Salmonella–positive blood cultures were more likely to die from late infection.
Carabin Protects Against Cardiac Hypertrophy by Blocking Calcineurin, Ras, and Ca
2+
/Calmodulin-Dependent Protein Kinase II Signaling
Authors: Bisserier Malik , Berthouze-Duquesnes Magali , Breckler Magali , Tortosa Florence , Fazal Loubina , de Régibus Annélie , Laurent Anne-Coline , Varin Audrey , Lucas Alexandre , Branchereau Maxime , Marck Pauline , Schickel Jean-Nicolas , Deloménie Claudine , Cazorla Olivier , Soulas-Sprauel Pauline , Crozatier Bertrand , Morel Eric , Heymes Christophe , Lezoualc’h Frank 
Published: November 2014

Background—
Cardiac hypertrophy is an early hallmark during the clinical course of heart failure and is regulated by various signaling pathways. However, the molecular mechanisms that negatively regulate these signal transduction pathways remain poorly understood.

Methods and Results—

Here, we characterized Carabin, a protein expressed in cardiomyocytes that was downregulated in cardiac hypertrophy and human heart failure. Four weeks after transverse aortic constriction, Carabin-deficient (Carabin
−/−
) mice developed exaggerated cardiac hypertrophy and displayed a strong decrease in fractional shortening (14.6±1.6% versus 27.6±1.4% in wild type plus transverse aortic constriction mice;
P
<0.0001). Conversely, compensation of Carabin loss through a cardiotropic adeno-associated viral vector encoding Carabin prevented transverse aortic constriction–induced cardiac hypertrophy with preserved fractional shortening (39.9±1.2% versus 25.9±2.6% in control plus transverse aortic constriction mice;
P
<0.0001). Carabin also conferred protection against adrenergic receptor–induced hypertrophy in isolated cardiomyocytes. Mechanistically, Carabin carries out a tripartite suppressive function. Indeed, Carabin, through its calcineurin-interacting site and Ras/Rab GTPase–activating protein domain, functions as an endogenous inhibitor of calcineurin and Ras/extracellular signal-regulated kinase prohypertrophic signaling. Moreover, Carabin reduced Ca
2+
/calmodulin-dependent protein kinase II activation and prevented nuclear export of histone deacetylase 4 after adrenergic stimulation or myocardial pressure overload. Finally, we showed that Carabin Ras–GTPase–activating protein domain and calcineurin-interacting domain were both involved in the antihypertrophic action of Carabin.

Conclusions—

Our study identifies Carabin as a negative regulator of key prohypertrophic signaling molecules, calcineurin, Ras, and Ca
2+
/calmodulin-dependent protein kinase II and implicates Carabin in the development of cardiac hypertrophy and failure.
Renal Dysfunction Is Associated With a Reduced Contribution of Nitric Oxide and Enhanced Vasoconstriction After a Congenital Renal Mass Reduction in Sheep
Authors: Lankadeva Yugeesh R. , Singh Reetu R. , Moritz Karen M. , Parkington Helena C. , Denton Kate M. , Tare Marianne 
Published: November 2014

Background—
Children born with reduced congenital renal mass have an increased risk of hypertension and chronic kidney disease in adulthood, although the mechanisms are poorly understood. Similar sequelae occur after fetal uninephrectomy (uni-x) in sheep, leading to a 30% nephron deficit. We hypothesized that renal dysfunction is underpinned by a reduced contribution of nitric oxide (NO) and vascular dysfunction in uni-x sheep.

Methods and Results—

In 5-year-old female uni-x and sham sheep, mean arterial pressure, glomerular filtration rate, and renal blood flow were measured before and during NO inhibition (
N
ω
-nitro-
l
-arginine methyl ester [L-NAME]). Reactivity was assessed in resistance arteries, including renal lobar and arcuate arteries. Basal mean arterial pressure was 15 mm Hg higher and glomerular filtration rate and renal blood flow were ≈30% lower (
P
<0.001) in uni-x animals. L-NAME increased mean arterial pressure by ≈17 mm Hg in both groups, whereas glomerular filtration rate and renal blood flow were decreased less in uni-x sheep (
P
Interaction
<0.01). Endothelial NO synthase and Ser-1177–phosphorylated endothelial NO synthase protein levels were upregulated in renal cortex of uni-x sheep (
P
<0.05). Lobar arteries of uni-x sheep had enhanced responsiveness to phenylephrine and nitrotyrosine staining and reduced sensitivity to endothelial stimulation. Vasodilator prostanoid contribution to endothelium-dependent relaxation was reduced in lobar arteries of uni-x sheep, accompanied by reduced cyclooxygenase-1 and -2 gene expression (
P
<0.05). Neurovascular constriction was enhanced ≈1.5-fold in renal arteries of uni-x sheep (
P
<0.05).

Conclusions—
Renal dysfunction after congenital renal mass reduction is associated with impaired regulation of renal hemodynamics by NO. Reductions in renal blood flow and glomerular filtration rate are underpinned by impaired basal NO contribution, endothelial dysfunction, and enhanced vascular responsiveness to sympathetic nerve stimulation.
Off-Hours Admission and Acute Stroke Care Quality
Authors: Kristiansen Nina Sahlertz , Mainz Jan , Nørgård Bente Mertz , Bartels Paul D. , Andersen Grethe , Johnsen Søren Paaske 
Published: November 2014

Background and Purpose—
Studies have reported higher risks of death and other adverse outcomes in acute stroke patients admitted off-hours; however, little is known about the underlying mechanisms. According to time of admission, our aim was to examine compliance with performance measures for acute stroke care processes, including the effect of a systematic quality improvement program, and to examine 30 days case-fatality.

Methods—
A population-based historical cohort study, including patients admitted to Danish hospitals with a first ever acute stroke (January 1, 2003, to December 31, 2011; N=64 975). Off-hours were weekends and evening and nighttime shifts on weekdays. Compliance with performance measures was compared using general linear modeling, and odds ratios for 30 days case-fatality were obtained using multivariable logistic regression.

Results—
Patients admitted off-hours had a lower chance of compliance with 8 out of 10 performance measures; however, these differences diminished over time. Unadjusted odds ratio for 30 days case-fatality, for patients admitted off-hours compared with patients admitted on-hours, was 1.15 (95% confidence interval, 1.09–1.21). Adjusting for patient characteristics (in particular, stroke severity) decreased the odds ratio to 1.03 (95% confidence interval, 0.97–1.10). Additional adjustment for hospital characteristics and compliance with performance measures had no effect on the odds ratio.

Conclusion—
Patients admitted off-hours received a poorer quality of care. However, the admission time–related differences in care were substantially reduced over time, and the differences in 30 days case-fatality appeared primarily to be explained by differences in stroke severity.
18FDG-PET-CT
Authors: Müller Hubertus Fritz Georg , Viaccoz Aurélien , Fisch Loraine , Bonvin Christophe , Lovblad Karl-Olof , Ratib Osman , Lalive Patrice , Pagano Sabrina , Vuilleumier Nicolas , Willi Jean-Pierre , Sztajzel Roman 
Published: November 2014

Background and Purpose—

We investigated whether uptake of
18
fluoro-2-deoxy-d-glucose (18FDG) positron emission tomography–computed tomography (PET-CT) correlated to clinical symptoms and presence of microembolic signals (MES) detected by transcranial Doppler in patients with carotid stenosis.

Methods—
18FDG-PET-CT and MES detection was performed in consecutive patients with 50% to 99% symptomatic or asymptomatic carotid stenoses. Uptake index was defined by a target to background ratio (TBR) between maximum standardized uptake value of the carotid plaque and the mean standardized uptake value of the jugular veins. End points for analysis were presence of symptoms and presence of MES.

Results—

We included 123 stenosis derived from 110 patients, 60 symptomatic and 63 asymptomatic. MES positive (+) lesions were found in 16%. TBR values were higher in symptomatic compared with asymptomatic (median 2.07 versus 1.78;
P
<0.0018) and in MES+ compared with MES− plaques (median 2.14 versus 1.86;
P
<0.008). TBR values were also higher in asymptomatic MES+ compared with MES− plaques (median 1.97 versus 1.76;
P
<0.03). The best TBR threshold value for symptomatic versus asymptomatic, for MES+ versus MES−, for symptomatic MES+ versus symptomatic or asymptomatic MES−, and for asymptomatic MES+ versus asymptomatic MES− plaques was 1.9. Sensitivity/specificity were, respectively, 56/77%, 73/63%, 79/64%, and 80/77%. We found a strong correlation between number of MES and TBR values (
ρ
0.26;
P
=0.0043).

Conclusions—
18FDG-PET-CT accurately detected high-risk carotid plaques. Also given its strong correlation to MES, 18FDG-PET-CT may be a useful tool in clinical practice.
Intraluminal Cell Transplantation Prevents Growth and Rupture in a Model of Rupture-Prone Saccular Aneurysms
Authors: Marbacher Serge , Frösén Juhana , Marjamaa Johan , Anisimov Andrey , Honkanen Petri , von Gunten Michael , Abo-Ramadan Usama , Hernesniemi Juha , Niemelä Mika 
Published: November 2014

Background and Purpose—
Aneurysm occlusion by intraluminal thrombus formation is the desired effect of all endovascular treatments. Intraluminal thrombus may, however, recanalize and be absorbed, unless it is infiltrated by cells that turn it into fibrous tissue (neointima). Because ruptured aneurysm walls are characterized by loss of smooth muscle cells, we assessed the impact of mural cell loss on wall remodeling of thrombosed aneurysms and investigated whether neointima formation could be enhanced by direct transplantation of cells into the thrombus.

Methods—
Sidewall aneurysms were microsurgically created in rats (n=81). Certain aneurysms were decellularized. Thrombosis was induced using direct injection of a fibrin polymer into the aneurysm. CM-Dil–labeled smooth muscle cells were injected into 25 of 46 fibrin embolized aneurysms. Recanalization and aneurysm growth were monitored with magnetic resonance angiography. Endoscopy, optical projection tomography, histology, and immunohistochemistry were used to study the fate of transplanted cells, thrombus organization, and neointima formation.

Results—

Decellularized embolized aneurysms demonstrated higher angiographic recurrence compared with decellularized embolized aneurysms with transplanted cells (
P
=0.037). Local cell replacement at the time of thrombosis resulted in better histological neointima formation than both nondecellularized embolized aneurysms (
P
<0.001) and decellularized embolized aneurysms (
P
=0.002). Aneurysm growth and rupture were observed exclusively in decellularized embolized aneurysms.

Conclusions—
Lack of smooth muscle cells in the aneurysm wall promotes wall degradation, aneurysm growth and rupture, even if the aneurysm is occluded by luminal thrombus. Transplantation of smooth muscle cells into the luminal thrombus can reduce this degenerative remodeling.
Effect of Alteplase Within 6 Hours of Acute Ischemic Stroke on All-Cause Mortality (Third International Stroke Trial)
Authors: Whiteley William N. , Thompson Douglas , Murray Gordon , Cohen Geoff , Lindley Richard I. , Wardlaw Joanna , Sandercock Peter 
Published: November 2014

Background and Purpose—
Prompt thrombolytic therapy with intravenous alteplase reduces disability after acute ischemic stroke. In an exploratory analysis, we examined whether long-term survival varied by baseline characteristics after alteplase.

Methods—
In this open-treatment, international, randomized, controlled trial, ischemic stroke patients were randomly allocated <6 hours of onset to intravenous alteplase (0.9 mg/kg) plus standard care (n=1515) or standard care alone (n=1520). We followed patients to death, censoring when last known to be alive. We grouped patients by delay to randomization, and good or poor predicted prognosis (calculated from baseline National Institutes of Health Stroke Scale [NIHSS] score and age). We present absolute mortality differences between treated and control groups at 7 days, 6 months, and 18 months poststroke.

Results—

Alteplase was not associated with a significant increase in mortality within 18 months (0.6% [95% confidence interval (CI), −2.9% to +4.2]
P
=0.72] in all patients with complete vital status (99.9%, 3034/3035). In patients randomized <3 hours of stroke, 18-month mortality was lower in the alteplase-treated group than the control group (40.6% [95% CI, 42.6–52.7] versus 47.8% [95% CI, 35.5–45.3];
P
=0.0434]. The difference in 18-month mortality between alteplase-treated and control patients was greater in patients who were randomized early (<3 hours) compared with late (3–6 hours; +9% [95% CI, 1–17];
P
=0.0317). Alteplase led to a greater improvement in 18-month survival in patients with a poor prognosis than in patients with a good prognosis (+8% [95% CI, 2–14];
P
=0.0091).

Conclusions—
These exploratory analyses of the third International Stroke Trial (IST-3) trial support improving acute stroke patients’ access to earlier alteplase treatment, treatment of patients with poor prognosis, and further randomized controlled trials in minor stroke to replicate these findings.

Clinical Trial Registration—

URL:
http://www.controlled-trials.com
. Unique identifier: ISRCTN25765518.
Incremental Predictive Value of Carotid Inflammation in Acute Ischemic Stroke
Authors: Toutouzas Konstantinos , Benetos Georgios , Drakopoulou Maria , Deligianni Christina , Spengos Konstantinos , Stefanadis Christodoulos , Siores Elias , Tousoulis Dimitrios 
Published: November 2014

Background and Purpose—

Microwave Radiometry (MWR) allows in vivo noninvasive assessment of internal temperature of tissues. The aim of the present study was to evaluate in patients with ischemic stroke and bilateral carotid plaques (1) whether ipsilateral carotid arteries exhibit higher temperature differences (Δ
T
), as assessed by MWR; (2) the predictive accuracy of MWR in symptomatic carotid artery identification.

Methods—
Consecutive patients with recent acute anterior circulation ischemic stroke because of large artery atherosclerosis were included in the study. Carotid arteries of all patients were evaluated by carotid ultrasound and MWR.

Results—

In total, 50 patients were included in the study. Culprit carotid arteries had higher Δ
T
compared with nonculprit (0.93±0.58 versus 0.58±0.35°C;
P
<0.001). The addition of Δ
T
to a risk prediction model based only on ultrasound plaque characteristics increased its predictive accuracy significantly (c-statistic: 0.691 versus 0.768;
P
dif
=0.05).

Conclusions—
Culprit carotid arteries show higher thermal heterogeneity compared with nonculprit carotid arteries in patients with acute ischemic stroke and bilateral carotid plaques. MWR has incremental value in culprit carotid artery discrimination.
From the Analytical to the Artistic: A Review of Literature on Information Visualization
Authors: Gough Phillip 
Published: November 2014

ABSTRACTEngaging a general audience with scientific research can be effectively assisted by visualization. Visualization art has the potential to engage users with data in a way that gives the audience deep and reflective insights into information. This article reviews relevant literature on different methods and practices of visualization from the analytical to artistic. The literature shows that beautiful presentations of data, in a clarified context, can help an audience with little understanding of the data domain gain deep, meaningful insights into information.
A new species of Cymbasoma (Copepoda, Monstrilloida) from the northern coast of Turkey (Black Sea) with comments on the C. longispinosum species-group
Authors: Üstün F. , Terbiyik Kurt T. , Suárez-Morales E. 
Published: November 2014

Cymbasoma sinopense sp. nov. is described from an adult female collected off the Sinop coast, in the southern Black Sea, Turkey. This is the first species of this genus recorded from the Black Sea coast of Turkey. The new species is a member of the widespread Cymbasoma longispinosum species-group, and it closely resembles C. chelemense Suárez-Morales & Escamilla, 1997 from the Yucatan Peninsula and C. californiense Suárez-Morales & Palomares-García, 1999 from the Gulf of California. This species can be distinguished by a combination of subtle characters, including the body proportions, the structure and armature of the fifth legs, the ornamentation of the genital somite, and the relative length of the ovigerous spines. A previous report of C. longispinosum from the northern Black Sea probably represented a misidentified record of C. sinopense sp. nov. The Mediterranean reports refer to a species that is different from the one of the Black Sea. Comparative comments and data including the main taxonomic characters of members of the Cymbasoma longispinosum species-group are presented. Overall, it is confirmed that records of this species from different geographic areas should be revised carefully because they could represent undescribed species. A key for the identification of the females of the currently known species assigned to the Cymbasoma longispinosum species-group is included.