bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Cell-Cycle Regulator CDK4: An Emerging Therapeutic Target in Melanoma
Authors: Sheppard Karen E. , McArthur Grant A. 
Published: October 2013

Abstract
The recent clinical success of targeted therapies in melanoma directed at the oncogene BRAF validates the concept of targeting oncogenes. The p16-cyclin D-CDK4/6-retinoblastoma protein pathway (CDK4 pathway) is dysregulated in 90% of melanomas, and is, therefore, an obvious therapeutic target for this disease. The main outcome of CDK4 activation is the phosphorylation and, thus, inhibition of the retinoblastoma protein leading to G1–S cell-cycle transition. In addition, CDK4 directly phosphorylates other proteins that promote cell-cycle progression and inhibit both cell senescence and apoptosis. In preclinical studies, the response to CDK4 inhibition correlates with genomic changes that increase CDK4 activity, most notably where the tumor suppressor CDKN2A (p16INK4A) is deleted. A central question is whether melanomas with activating events in the CDK4 pathway have become “addicted” to this signaling pathway, in which case inhibition of CDK4 would not simply induce cell-cycle arrest but induce cell death and tumor regression. Recently, a number of selective CDK4/6 inhibitors have entered clinical trials, and these compounds are showing great promise in that they are well tolerated and show clinical benefit. This review discusses the CDK4 pathway, its dysregulation in melanoma, the consequences of CDK4 pathway inhibition, and potential novel combinational strategies for the treatment of melanoma. Clin Cancer Res; 19(19); 5320–8. ©2013 AACR.
The Intersection of Immune-Directed and Molecularly Targeted Therapy in Advanced Melanoma: Where We Have Been, Are, and Will Be
Authors: Sullivan Ryan J. , LoRusso Patricia M. , Flaherty Keith T. 
Published: October 2013

AbstractIn three years, four drugs have gained regulatory approval for the treatment of metastatic and unresectable melanoma, with at least seven other drugs having recently completed, currently in, or soon to be in phase III clinical testing. This amazing achievement has been made following a remarkable increase of knowledge in molecular biology and immunology that led to the identification of high-valued therapeutic targets and the clinical development of agents that effectively engage and inhibit these targets. The discovery of either effective molecularly targeted therapies or immunotherapies would have led to dramatic improvements to the standard-of-care treatment of melanoma. However, through parallel efforts that have showcased the efficacy of small-molecule BRAF and MAP–ERK kinase (MEK) inhibitors, as well as the immune checkpoint inhibitors, namely ipilimumab and the anti-PD1/PDL1 antibodies (lambrolizumab, nivolumab, MPDL3280), an opportunity exists to transform the treatment of melanoma specifically and cancer generally by exploring rational combinations of molecularly targeted therapies, immunotherapies, and molecular targeted therapies with immunotherapies. This overview presents the historical context to this therapeutic revolution, reviews the benefits and limitations of current therapies, and provides a look ahead at where the field is headed. Clin Cancer Res; 19(19); 5283–91. ©2013 AACR.
Persistent enhanced platelet activation in patients with acute myocardial infarction and coronary microvascular obstruction: clinical implications
Authors: Aurigemma Cristina , Scalone Giancarla , Tomai Fabrizio , Altamura Luca , Persio Giovanni De , Stazi Alessandra , Crea Filippo , Lanza Gaetano A. 
Published: October 2013

SummaryAbout 30% of patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing recanalisation of the infarct-related coronary artery do not achieve valid myocardial reperfusion (no-reflow phenomenon or coronary microvascular obstruction [MVO]). The mechanisms of MVO are incompletely understood. In this study we investigated the role platelet activation in the pathogenesis of coronary MVO in STEMI patients. We enrolled 48 STEMI patients (age 56.2 ± 11 years; 31 men), treated by primary percutaneous coronary intervention (PCI) followed by double anti-platelet treatment, and 20 control patients with stable coronary artery disease (CAD) on single antiplatelet treatment (age 57.5 ± 6 years, 12 men). STEMI patients were divided into two groups: 35 patients with complete myocardial reperfusion (MR) and 13 patients with coronary MVO despite successful PCI. Platelet activation was assessed on admission and at one-month follow-up by measuring platelet receptor expression and monocyteplatelet aggregates (MPAs). Platelet receptor expression, platelet receptor conformational change for fibrinogen binding availability and MPA formation were increased in STEMI patients with MVO compared to both STEMI patients with MR and stable CAD patients, both on admission and at one-month follow-up (p<0.05 for all). Among STEMI patients, platelet activation is greater in those who display coronary MVO, compared to those with MR, after successful PCI, both on admission and one month after STEMI, suggesting that enhanced platelet activation might be involved in the pathogenesis of MVO. The persistence of enhanced platelet activation despite double classical anti-platelet therapy suggests that new anti-platelet strategies should be considered in patients with coronary MVO.
Circulating CD45+/CD3+ lymphocyte-derived microparticles map lipid-rich atherosclerotic plaques in familial hypercholesterolaemia patients
Authors: Suades Rosa , Padró Teresa , Alonso Rodrigo , López-Miranda José , Mata Pedro , Badimon Lina 
Published: October 2013

SummaryCirculating microparticles (cMPs) seem to play important roles in vascular function. Beyond markers of activated cells, cMPs may have potential paracrine functions and influence atherosclerosis. Here, our objective was to characterise a) the abundance and phenotype of cMPs in stable statin-treated heterozygous familial hypercholesterolaemia (FH) patients exposed to life-long hypercholesterolaemia and b) the principal phenotype associated to lipid-rich atherosclerotic plaques in hFHpatients with significant atherosclerotic plaque burden. An age/gender/ treatment-matched group of adult-onset non-FH hypercholesterolaemic patients (n=37/group) was comparatively analysed. cMPs were characterised by flow cytometry using annexin-V and cell surface-specific antibodies. Our study shows that LLT-FH patients had higher overall cMP-numbers (p<0.005) than LLT-non-FH patients. Endothelial cellshed cMPs were also significantly higher in FH (p<0.0005). Within the leukocyte-derived cMP-subpopulations, FH-patients had significantly higher lymphocyte- and monocyte-derived cMP-numbers as well as cMPs carrying leukocyte-activation markers. Normalisation of cMPs by LDL levels did not affect cMP number or phenotype, indicating that the proinflammatory effect was derived from chronic vascular damage. Levels of AV+-total, CD45+-pan-leukocyte and CD45+/CD3+-lymphocyte-derived cMPs were significantly higher in FH-patients with subclinical lipid-rich atherosclerotic plaques than fibrous plaques. Levels of CD45+/CD3+-lymphocyte-MPs above 20,000/ml could differentiate between FH-patients with lipidic or non-lipidic plaques (area under the ROC curve of 0.803, 95%CI: 0.641–0.965, p=0.008). In summary, in this snapshot cross-sectional study cMP concentration and phenotype in FH differed markedly from non-FH hypercholesterolaemia. Patients with life-long high LDL exposure have higher endothelial activation and higher proinflammatory profile, even under current state-of-the-art LLT. cMPs carrying lymphocyte-epitopes appear as markers of lipid-rich atherosclerotic plaques in FH.
Intralesional Abciximab and Thrombus Aspiration in Patients With Large Anterior Myocardial Infarction
Authors: Stone Gregg W. , Witzenbichler Bernhard , Godlewski Jacek , Dambrink Jan-Henk E. , Ochala Andrzej , Chowdhary Saqib , El-Omar Magdi , Neunteufl Thomas , Metzger David Christopher , Dizon Jose M. , Wolff Steven D. , Brener Sorin J. , Mehran Roxana , Maehara Akiko , Gibson C. Michael 
Published: October 2013

Background—
Whether intralesional abciximab administration and thrombus aspiration confer clinical benefits to patients undergoing primary percutaneous coronary intervention for ST-segment–elevation myocardial infarction is controversial.

Methods and Results—

A total of 452 patients with ST-segment–elevation myocardial infarction caused by proximal or mid left anterior descending artery occlusion undergoing primary percutaneous coronary intervention with bivalirudin anticoagulation were randomized in a 2×2 factorial design to bolus abciximab delivered locally at the infarct lesion site versus no abciximab and to manual thrombus aspiration versus no aspiration. Treatment with intralesional abciximab, thrombus aspiration, or both therapies compared with no active therapy before stent implantation resulted in lower 1-year rates of death (4.5% versus 10.4%;
P
=0.03), severe heart failure (4.2% versus 10.3%;
P
=0.02), and stent thrombosis (0.9% versus 3.8%;
P
=0.046). Between 30 days and 1 year of follow-up, treatment with intralesional abciximab compared with no abciximab was associated with a lower rate of death (1.4% versus 4.9%;
P
=0.04) and composite major adverse ischemic events (3.3% versus 7.8%;
P
=0.04), with nonsignificantly different overall 1-year rates of mortality, composite ischemic events, and heart failure–related events. Thrombus aspiration compared with no aspiration was associated with lower rates of new-onset severe heart failure between 30 days and 1 year (0.9% versus 4.5%;
P
=0.02) and of rehospitalization for heart failure from randomization to 1 year (0.9% versus 5.4%;
P
=0.0008), with nonsignificantly different rates of mortality.

Conclusions—
Intralesional abciximab and thrombus aspiration may have long-term benefits in patients with anterior ST-segment–elevation myocardial infarction presenting early after symptom onset and undergoing primary percutaneous coronary intervention with bivalirudin anticoagulation.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00976521.
Long-Term Evolution and Prognostic Stratification of Biopsy-Proven Active Myocarditis
Authors: Anzini Marco , Merlo Marco , Sabbadini Gastone , Barbati Giulia , Finocchiaro Gherardo , Pinamonti Bruno , Salvi Alessandro , Perkan Andrea , Di Lenarda Andrea , Bussani Rossana , Bartunek Jozef , Sinagra Gianfranco 
Published: October 2013

Background—
Active myocarditis is characterized by large heterogeneity of clinical presentation and evolution. This study describes the characteristics and the long-term evolution of a large sample of patients with biopsy-proven active myocarditis, looking for accessible and valid early predictors of long-term prognosis.

Methods and Results—

From 1981 to 2009, 82 patients with biopsy-proven active myocarditis were consecutively enrolled and followed-up for 147±107 months. All patients underwent clinical and echocardiographic evaluation at baseline and at 6 months. At this time, improvement/normality of left ventricular ejection fraction (LVEF), defined as a LVEF increase > 20 percentage points or presence of LVEF≥50%, was assessed. At baseline, left ventricular dysfunction (LVEF<50%) and left atrium enlargement were independently associated with long-term heart transplantation–free survival, regardless of the clinical pattern of disease onset. At 6 months, improvement/normality of LVEF was observed in 53% of patients. Persistence of New York Heart Association III to IV classes, left atrium enlargement, and improvement/normality of LVEF at 6 months emerged as independent predictors of long-term outcome. Notably, the short-term reevaluation showed a significant incremental prognostic value in comparison with the baseline evaluation (baseline model versus 6 months model: area under the curve 0.79 versus 0.90,
P
=0.03).

Conclusions—
Baseline left ventricular function is a marker for prognosis regardless of the clinical pattern of disease onset, and its reassessment at 6 months appears useful for assessing longer-term outcome.
Migraine and Hemorrhagic Stroke
Authors: Sacco Simona , Ornello Raffaele , Ripa Patrizia , Pistoia Francesca , Carolei Antonio 
Published: October 2013

Background and Purpose—
Several studies have assessed the possible increased risk of hemorrhagic stroke in migraineurs, drawing differing conclusions. No meta-analysis on the topic has been published to date.

Methods—
Multiple electronic databases (MEDLINE, EMBASE, Science Citation Index, and the Cochrane Library) were systematically searched up to March 2013 for studies dealing with migraine and hemorrhagic stroke. We selected case–control and cohort studies with a clear definition of the diagnostic criteria for migraine and hemorrhagic stroke, using an adjusted model or a matching procedure that could control for potential confounders, and reporting effect estimates with 95% confidence intervals (CIs) or enough data to allow calculation of those numbers. Adjusted odds ratios and hazard ratios were used to estimate effect size.

Results—

Of 11 264 records, we identified 8 studies (4 case–control and 4 cohort studies) involving a total of 1600 hemorrhagic strokes, which were included in the meta-analysis. The overall pooled adjusted effect estimate of hemorrhagic stroke in subjects with any migraine versus control subjects was 1.48 (95% CI, 1.16–1.88;
P
=0.002), with moderate statistical heterogeneity (I
2
=54.7%;
P
value for Q test=0.031). The risk of hemorrhagic stroke in subjects with migraine with aura (1.62; 95% CI, 0.87–3.03;
P
=0.129) was not significant. Compared with control subjects, the risk of hemorrhagic stroke was greater in females with any migraine (1.55; 95% CI, 1.16–2.07;
P
=0.003) and in female migraineurs aged less than 45 years (1.57; 95% CI, 1.10–2.24;
P
=0.012).

Conclusions—
Available studies suggest that subjects with migraine have an increased risk of hemorrhagic stroke. Further studies are needed to address the hemorrhagic stroke risk according to migraine type, age, sex, and hemorrhagic stroke type.
Raffaele Pettazzoni from the Perspective of the Anglophone Academy
Authors: Rennie Bryan 
Published: October 2013

AbstractThere should be no need to emphasize the significance of Raffaele Pettazzoni (1883–1959) to historians of religions. However, there are only two books by Pettazzoni available in the English language: the monographThe All-knowing God(1956; original:L’onniscienza di Dio, 1955) and an anthology ofEssays on the History of Religions(1954), which is “a collection of sundry writings on various subjects connected with the History of Religions, which have been already published on different occasions in Italian and foreign periodicals” (Pettazzoni 1954).2 Added to this is a tiny collection of articles in English (in fact, the American Theological Libraries Association database references only three). This seems to constitute a serious neglect of such a productive scholar, who has been called an “exemplary historian of religions.” This paper will attempt to assess the reception of the work of Raffaele Pettazzoni in the Anglophone Academy, to question the adequacy and accuracy of that reception, and to indicate what might be learned from it.
1 Corinthians 2:14
Authors: Lambrecht Jan 
Published: October 2013

Abstract
Can we accept the translation of the second half of 1 Cor 2:14 as proposed by L.B. Dingeldein: (The “psychic” man) is unable to know “that he is pneumatically examined”? An analysis of the preceding and following context of the verse indicates that the traditional causal version is to be preferred: (The “psychic” man) cannot know them (= the things of God’s spirit), “because they are spiritually discerned.”
Suprabenthic amphipods from the littoral zone of Barlovento, Venezuela: spatial distribution and seasonal variation
Authors: Ortega I. , Martin A. 
Published: October 2013

Peracarid crustaceans are a very diverse benthic group and one of the dominant taxa within the suprabenthic community. The Barlovento beaches in Venezuela are characterised by large inputs of organic matter and an important assemblage of amphipods has been observed to thrive in this area. In this paper we describe the species composition of this amphipod assemblage along with their spatial and temporal variation and relationship with some environmental variables on four beaches (Agua Sal, Los Timones, Las Cabañas, Valle Seco). Results showed no significant differences in the amphipod community structure and total density of organisms regardless of the season (rainy and dry). From the 7569 amphipods collected, a total of 20 species were identified within 14 families and 17 genera. The speciesApohyale media(Dana, 1953),Metatiron tropakis(J. L. Barnard, 1972) andNototropis minikoi(A. O. Walker, 1905) were the most abundant species in terms of density, and the last two also in terms of frequency of occurrence. Differences in biomass were not significant at any level (season, beach and their interactions); however, the highest amphipod biomass throughout the year was observed at Valle Seco Beach with peaks in January, August and December coinciding with large accumulations of bryozoans and wood debris. Amphipod density and biomass had low correlation values with the environmental variables; the material caught in the suprabenthos net being the most common variable influencing the community.
Biomechanics of the Monopedicle Skin Flap
Authors: Lovald Scott T. , Topp Shelby G. , Ochoa Jorge A. , Gaball Curtis W. 
Published: October 2013

ObjectiveThe design and implementation of skin flaps remains a puzzle for the reconstructive surgeon. The objective of the present study is to use finite element (FE) analysis to characterize and understand the biomechanics of the monopedicle skin flap design.Study DesignThe current study uses a nonlinear hyperelastic FE model of the human skin to understand the biomechanics of monopedicle‐based flap designs as geometric flap parameters are varied.SettingIn silico.Subjects and MethodsThe simulation included the displacement loading, stitching, and relaxation of various forms of the flap design. Stress and strain outcomes, previously correlated with scarring, necrosis, and blood perfusion, are reported for a basic monopedicle design as well as a number of modifications to this design.ResultsThe results suggest that the length of the monopedicle flap should not exceed 3 times the size of the defect, as the benefit in reducing principal strain (deformation) is diminished beyond this point. Further, to minimize skin strain, the ideal Burrow's triangle size can be described as proportional to flap length and inversely proportional to defect height, according to a linear function.ConclusionThe ideal flap design should attempt to minimize not only the stress in the skin, but the size of the incisions and the degree of undermining. The results of our analyses provide guidance to increase the general understanding of monopedicle flap mechanics and provide context for the clinician and insight into designing a better monopedicle flap for individual situations.
Consensus and Cooperation on State Supreme Courts
Authors: Leonard Meghan E. , Ross Joseph V. 
Published: October 2013

AbstractThe opinion-writing process is a vital yet understudied aspect of judicial decision making on state supreme courts. We argue that this process is influenced by the political context and particularly by institutional rules that serve to reactivate and reinforce divisions among justices, leading to less cooperation on the court. We test our theory with original data comprising all education cases decided from 1995 to 2005 in all 50 states and find evidence to support our theory. Specifically, we find that elections lead to fewer unanimous decisions and more separate written opinions, indicating that judicial elections may have a more pervasive effect on the daily work of these courts than previously thought.
Atherosclerotic plaque identification by virtual histology intravascular ultrasound in a rabbit abdominal aorta model of vulnerable plaque
Authors: Lin Qing-Fei , Luo Yu-Kun , Zhao Zi-Wen , Cai Wei , Zhen Xing-Chun , Chen Liang-Long 
Published: October 2013

This study aimed to evaluate the utility of virtual histology intravascular ultrasound (VH-IVUS) for recognizing vulnerable plaque compared to histological pathological analysis. Four-month-old New Zealand rabbits ( n = 16) were randomly divided into two groups: one fed a high-fat diet and subjected to balloon injury (experimental, n = 10) and one fed a high-fat diet alone (control, n = 6). Blood lipid profiles of overnight-fasted rabbits were measured at week 2 (beginning of study) and week 12 (end of study). At week 12, experimental group rabbits underwent IVUS under anaesthesia. Rabbits were sacrificed and a 5-cm segment of the abdominal aorta was removed. Arterial sections were subjected to pathological and immunohistochemical analyses. Serum lipid levels increased in all rabbits fed with high-fat diet, with low-density lipid cholesterol (LDL-C) levels increasing the most. Levels of six biomarkers (high sensitivity C-reactive protein, matrix metalloproteinase-3, interleukin [IL]-1, IL-10, tumour necrosis factor-α, and oxidized [ox]-LDL) showed no differences between the two groups at week 2, but were higher in the experimental group at week 12. A total of 276 atherosclerotic plaques in the experimental group were analysed. VH-IVUS had sensitivities of 87% and 92% for detection of noncalcified and calcified thin-cap fibroatheromas, respectively. VH-IVUS correctly identified 85% and 89% of noncalcified and calcified fibroatheromas, respectively. For detection of pathological intimal thickening, VH-IVUS showed a sensitivity of 79% and positive predictive value of 78%. Linear regression analysis showed a strong correlation between histology and VH-IVUS for the percent area of fibrous fibro-fatty tissue, necrotic calcified tissue, and confluent necrotic core. The intra-observer and inter-observer variability of the intimal and medial-adventitial boundaries was low. Endothelial injury followed by a high-fat diet in rabbits is a viable method for inducing atheroma, and VH-IVUS is a feasible, reproducible, and valuable means of vulnerable plaque identification in vivo.
Exome sequencing reveals a thrombopoietin ligand mutation in a Micronesian family with autosomal recessive aplastic anemia
Authors: Dasouki Majed J. , Rafi Syed K. , Olm-Shipman Adam J. , Wilson Nathan R. , Abhyankar Sunil , Ganter Brigitte , Furness L. Mike , Fang Jianwen , Calado Rodrigo T. , Saadi Irfan 
Published: October 2013

Key Points
Recessive mutations in the thrombopoietin gene are a novel cause of aplastic anemia. Such patients may benefit from treatment with eltrombopag or romiplostim.