bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Vigorous Immune Microenvironment of Microsatellite Instable Colon Cancer Is Balanced by Multiple Counter-Inhibitory Checkpoints
Authors: Llosa Nicolas J. , Cruise Michael , Tam Ada , Wicks Elizabeth C. , Hechenbleikner Elizabeth M. , Taube Janis M. , Blosser Richard L. , Fan Hongni , Wang Hao , Luber Brandon S. , Zhang Ming , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Sears Cynthia L. , Anders Robert A. , Pardoll Drew M. , Housseau Franck 
Published: October 2014

AbstractWe examined the immune microenvironment of primary colorectal cancer using immunohistochemistry, laser capture microdissection/qRT-PCR, flow cytometry, and functional analysis of tumor-infiltrating lymphocytes. A subset of colorectal cancer displayed high infiltration with activated CD8+ cytotoxic T lymphocyte (CTL) as well as activated Th1 cells characterized by IFNγ production and the Th1 transcription factor TBET. Parallel analysis of tumor genotypes revealed that virtually all of the tumors with this active Th1/CTL microenvironment had defects in mismatch repair, as evidenced by microsatellite instability (MSI). Counterbalancing this active Th1/CTL microenvironment, MSI tumors selectively demonstrated highly upregulated expression of multiple immune checkpoints, including five—PD-1, PD-L1, CTLA-4, LAG-3, and IDO—currently being targeted clinically with inhibitors. These findings link tumor genotype with the immune microenvironment, and explain why MSI tumors are not naturally eliminated despite a hostile Th1/CTL microenvironment. They further suggest that blockade of specific checkpoints may be selectively efficacious in the MSI subset of colorectal cancer.Significance: The findings reported in this article are the first to demonstrate a link between a genetically defined subtype of cancer and its corresponding expression of immune checkpoints in the tumor microenvironment. The mismatch repair–defective subset of colorectal cancer selectively upregulates at least five checkpoint molecules that are targets of inhibitors currently being clinically tested. Cancer Discov; 5(1); 43–51. ©2014 AACR.See related commentary by Xiao and Freeman, p. 16This article is highlighted in the In This Issue feature, p. 1
Lenition of Intervocalic Alveolar Fricatives in Catalan and Spanish
Authors: Hualde José Ignacio , Prieto Pilar 
Published: October 2014

Abstract
We offer an acoustic study of variation in the realization of intervocalic alveolar fricatives in Catalan and Spanish. We consider the effects of phonological inventory (Catalan has a distinction between /s/ and /z/ that Spanish lacks) and position in word (i.e. effects of word boundaries). An analysis of a corpus of Map Task interviews in Catalan and Spanish revealed that Spanish word-medial and initial intervocalic /s/ segments are shorter than in Catalan. Whereas our results are consistent with the predictions of theories incorporating functional principles (i.e. contrast preservation), we also consider other possible explanations of the facts. The analysis also revealed that Spanish word-final intervocalic /s/ segments are weaker along the two dimensions that we examined (duration and voicing) than their initial and medial counterparts. We suggest that this apparently morphological effect on lenition has an articulatory explanation in terms of gestural coordination. © 2014 S. Karger AG, Basel
Prospective Association of Polycystic Ovary Syndrome With Coronary Artery Calcification and Carotid-Intima-Media Thickness
Authors: Calderon-Margalit Ronit , Siscovick David , Merkin Sharon S. , Wang Erica , Daviglus Martha L. , Schreiner Pamela J. , Sternfeld Barbara , Williams O. Dale , Lewis Cora E. , Azziz Ricardo , Schwartz Stephen M. , Wellons Melissa F. 
Published: October 2014

Objective—
To study the independent associations of polycystic ovary syndrome (PCOS), and its 2 components, hyperandrogenism and anovulation, with coronary artery calcification (CAC) and carotid artery intima-media thickness (IMT).

Approach and Results—
At the year 20 of the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based multicenter cohort of young adults, women (mean age, 45 years) with information on menses and hirsutism in their twenties were assessed for CAC (n=982) and IMT (n=988). We defined PCOS as women who had both irregular menses and hyperandrogenism (n=55); isolated oligomenorrhea (n=103) as women who only had irregular menses; and isolated hyperandrogenism (n=156) as women who had either hirsutism or increased testosterone levels. Logistic regressions and general linear models were used to estimate the associations between components of PCOS and subclinical CVD. The prevalence of CAC was 10.3% overall. Women with PCOS had a multivariable adjusted odds ratio of 2.70 (95% confidence interval, 1.31–5.60) for CAC. Women with either isolated oligomenorrhea or isolated hyperandrogenism had no increased risk of CAC when compared with unexposed women. Women with PCOS had significantly increased bulb and internal carotid-IMT measurements; however, no significant differences were noted in bulb or internal carotid artery IMT among women with either isolated oligomenorrhea or isolated hyperandrogenism when compared with unexposed women. There were no differences in common carotid-IMT among the 4 study groups.

Conclusions—
In this study, women with PCOS, manifested as both anovulation and hyperandrogenism, but not women with one of these manifestations alone, were at increased risk for the development of subclinical CVD.
Association Between Physical Activity and Peripheral Artery Disease and Carotid Artery Stenosis in a Self-Referred Population of 3 Million Adults
Authors: Stein Richard A. , Rockman Caron B. , Guo Yu , Adelman Mark A. , Riles Thomas , Hiatt William R. , Berger Jeffrey S. 
Published: October 2014

Objective—
Although the relationship between physical activity and coronary heart disease is well characterized, a paucity of data exists on physical activity and vascular disease in other arterial territories. This study examined the prevalence of peripheral artery disease (PAD) and carotid artery stenosis (CAS) in association with physical activity.

Approach and Results—

The association between physical activity and vascular disease was examined in >3 million self-referred US participants in the United States from 2003 to 2008 who completed a medical and lifestyle questionnaire in the Life Line screening program. All subjects were evaluated by screening ankle brachial indices <0.90 for PAD and ultrasound imaging for CAS >50%. Multivariable logistic regression modeling was used to estimate odds of disease. Among 3 250 350 subjects, 63% of the population engaged in some leisure time vigorous physical activity. After adjustment for age, sex, race/ethnicity, hypertension, hypercholesterolemia, smoking status, diabetes mellitus, body mass index, and family history of cardiovascular disease, subjects who reported any physical activity had a significantly lower odds of PAD (odds ratio, 0.64; 95% confidence interval, 0.63–0.65) and CAS (odds ratio, 0.80; 95% confidence interval, 0.79–0.81). The association between physical activity with PAD and CAS was robust when stratified by sex, race, and age categories. Physical activity intensity frequency was associated with lower PAD and CAS in a graded manner (
P
trend <0.0001 for both). Findings seemed unaffected by confounding by comorbidity or indication.

Conclusions—
In a large population-based study, higher levels of physical activity were independently associated with lower odds of vascular disease in the lower extremities and carotid arteries.
Laminar Shear Stress Inhibits Endothelial Cell Metabolism via KLF2-Mediated Repression of PFKFB3
Authors: Doddaballapur Anuradha , Michalik Katharina M. , Manavski Yosif , Lucas Tina , Houtkooper Riekelt H. , You Xintian , Chen Wei , Zeiher Andreas M. , Potente Michael , Dimmeler Stefanie , Boon Reinier A. 
Published: October 2014

Objective—
Cellular metabolism was recently shown to regulate endothelial cell phenotype profoundly. Whether the atheroprotective biomechanical stimulus elicited by laminar shear stress modulates endothelial cell metabolism is not known.

Approach and Results—
Here, we show that laminar flow exposure reduced glucose uptake and mitochondrial content in endothelium. Shear stress–mediated reduction of endothelial metabolism was reversed by silencing the flow-sensitive transcription factor Krüppel-like factor 2 (KLF2). Endothelial-specific deletion of KLF2 in mice induced glucose uptake in endothelial cells of perfused hearts. KLF2 overexpression recapitulates the inhibitory effects on endothelial glycolysis elicited by laminar flow, as measured by Seahorse flux analysis and glucose uptake measurements. RNA sequencing showed that shear stress reduced the expression of key glycolytic enzymes, such as 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3 (PFKFB3), phosphofructokinase-1, and hexokinase 2 in a KLF2-dependent manner. Moreover, KLF2 represses PFKFB3 promoter activity. PFKFB3 knockdown reduced glycolysis, and overexpression increased glycolysis and partially reversed the KLF2-mediated reduction in glycolysis. Furthermore, PFKFB3 overexpression reversed KLF2-mediated reduction in angiogenic sprouting and network formation.

Conclusions—
Our data demonstrate that shear stress–mediated repression of endothelial cell metabolism via KLF2 and PFKFB3 controls endothelial cell phenotype.
Heme Oxygenase-1 Gene Promoter Microsatellite Polymorphism Is Associated With Progressive Atherosclerosis and Incident Cardiovascular Disease
Authors: Pechlaner Raimund , Willeit Peter , Summerer Monika , Santer Peter , Egger Georg , Kronenberg Florian , Demetz Egon , Weiss Günter , Tsimikas Sotirios , Witztum Joseph L. , Willeit Karin , Iglseder Bernhard , Paulweber Bernhard , Kedenko Lyudmyla , Haun Margot , Meisinger Christa , Gieger Christian , Müller-Nurasyid Martina , Peters Annette , Willeit Johann , Kiechl Stefan 
Published: October 2014

Objective—
The enzyme heme oxygenase-1 (HO-1) exerts cytoprotective effects in response to various cellular stressors. A variable number tandem repeat polymorphism in the HO-1 gene promoter region has previously been linked to cardiovascular disease. We examined this association prospectively in the general population.

Approach and Results—

Incidence of stroke, myocardial infarction, or vascular death was registered between 1995 and 2010 in 812 participants of the Bruneck Study aged 45 to 84 years (49.4% males). Carotid atherosclerosis progression was quantified by high-resolution ultrasound. HO-1 variable number tandem repeat length was determined by polymerase chain reaction. Subjects with ≥32 tandem repeats on both HO-1 alleles compared with the rest of the population (recessive trait) featured substantially increased cardiovascular disease risk (hazard ratio [95% confidence interval], 5.45 [2.39, 12.42];
P
<0.0001), enhanced atherosclerosis progression (median difference in atherosclerosis score [interquartile range], 2.1 [0.8, 5.6] versus 0.0 [0.0, 2.2] mm;
P
=0.0012), and a trend toward higher levels of oxidized phospholipids on apolipoprotein B-100 (median oxidized phospholipids/apolipoprotein B level [interquartile range], 11364 [4160, 18330] versus 4844 [3174, 12284] relative light units;
P
=0.0554). Increased cardiovascular disease risk in those homozygous for ≥32 repeats was also detected in a pooled analysis of 7848 participants of the Bruneck, SAPHIR, and KORA prospective studies (hazard ratio [95% confidence interval], 3.26 [1.50, 7.33];
P
=0.0043).

Conclusions—
This study found a strong association between the HO-1 variable number tandem repeat polymorphism and cardiovascular disease risk confined to subjects with a high number of repeats on both HO-1 alleles and provides evidence for accelerated atherogenesis and decreased antioxidant defense in this vascular high-risk group.
Vitamin D Therapy in Individuals With Prehypertension or Hypertension
Authors: Arora Pankaj , Song Yanna , Dusek Jeffery , Plotnikoff Gregory , Sabatine Marc S. , Cheng Susan , Valcour Andre , Swales Heather , Taylor Beth , Carney Erin , Guanaga Derek , Young Joseph R. , Karol Courtney , Torre Michael , Azzahir Atum , Strachan Semerit M. , O’Neill Dillon C. , Wolf Myles , Harrell Frank , Newton-Cheh Christopher , Wang Thomas J. 
Published: October 2014

Background—
A large body of epidemiological and experimental evidence suggests that vitamin D deficiency may promote hypertension. This raises the possibility that vitamin D supplementation could be a simple intervention to reduce blood pressure, but data from prospective, randomized trials are limited.

Methods and Results—

A double-blind, randomized, controlled trial was conducted at 4 sites in the United States. We enrolled 534 individuals 18 to 50 years of age with low vitamin D status (25-hydroxyvitamin D levels ≤25 ng/mL) and systolic blood pressure of 120 to 159 mm Hg. Participants were randomized to high-dose (4000 IU/d) versus low-dose (400 IU/d) oral vitamin D
3
for 6 months. The primary end point was change in mean 24-hour systolic blood pressure. Secondary end points included change in ambulatory diastolic blood pressure and clinic systolic and diastolic blood pressures. The median age was 38 years, and 62% of participants were men. Forty-six percent of participants were white, and 48% were black. The median 25-hydroxyvitamin D level at baseline was 15.3 ng/mL. Four-hundred fifty-five participants (85%) had at least 1 follow-up blood pressure measurement; 383 participants (72%) completed the full 6-month study. At the end of the study, there was no significant difference in the primary end point (change in mean 24-hour systolic blood pressure, −0.8 versus −1.6 mm Hg in the high-dose and low-dose arms;
P
=0.71) or in any of the secondary end points. Furthermore, there was no evidence of association between change in 25-hydroxyvitamin D and change in 24-hour systolic blood pressure at 6 months (Spearman correlation coefficient, −0.05,
P
=0.34). Results were consistent across prespecified subgroups.

Conclusions—
Vitamin D supplementation did not reduce blood pressure in individuals with prehypertension or stage I hypertension and vitamin D deficiency. Our findings suggest that the association between vitamin D status and elevated blood pressure noted in observational studies is not causal.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01240512.
Cardiovascular, Bleeding, and Mortality Risks in Elderly Medicare Patients Treated With Dabigatran or Warfarin for Nonvalvular Atrial Fibrillation
Authors: Graham David J. , Reichman Marsha E. , Wernecke Michael , Zhang Rongmei , Southworth Mary Ross , Levenson Mark , Sheu Ting-Chang , Mott Katrina , Goulding Margie R. , Houstoun Monika , MaCurdy Thomas E. , Worrall Chris , Kelman Jeffrey A. 
Published: October 2014

Background—
The comparative safety of dabigatran versus warfarin for treatment of nonvalvular atrial fibrillation in general practice settings has not been established.

Methods and Results—
We formed new-user cohorts of propensity score–matched elderly patients enrolled in Medicare who initiated dabigatran or warfarin for treatment of nonvalvular atrial fibrillation between October 2010 and December 2012. Among 134 414 patients with 37 587 person-years of follow-up, there were 2715 primary outcome events. The hazard ratios (95% confidence intervals) comparing dabigatran with warfarin (reference) were as follows: ischemic stroke, 0.80 (0.67–0.96); intracranial hemorrhage, 0.34 (0.26–0.46); major gastrointestinal bleeding, 1.28 (1.14–1.44); acute myocardial infarction, 0.92 (0.78–1.08); and death, 0.86 (0.77–0.96). In the subgroup treated with dabigatran 75 mg twice daily, there was no difference in risk compared with warfarin for any outcome except intracranial hemorrhage, in which case dabigatran risk was reduced. Most patients treated with dabigatran 75 mg twice daily appeared not to have severe renal impairment, the intended population for this dose. In the dabigatran 150-mg twice daily subgroup, the magnitude of effect for each outcome was greater than in the combined-dose analysis.

Conclusions—
In general practice settings, dabigatran was associated with reduced risk of ischemic stroke, intracranial hemorrhage, and death and increased risk of major gastrointestinal hemorrhage compared with warfarin in elderly patients with nonvalvular atrial fibrillation. These associations were most pronounced in patients treated with dabigatran 150 mg twice daily, whereas the association of 75 mg twice daily with study outcomes was indistinguishable from warfarin except for a lower risk of intracranial hemorrhage with dabigatran.
Acute Hospital, Community, and Indirect Costs of Stroke Associated With Atrial Fibrillation
Authors: Hannon Niamh , Daly Leslie , Murphy Sean , Smith Samantha , Hayden Derek , Ní Chróinín Danielle , Callaly Elizabeth , Horgan Gillian , Sheehan Órla , Honari Bahman , Duggan Joseph , Kyne Lorraine , Dolan Eamon , Williams David , Wiley Miriam , Kelly Peter J. 
Published: October 2014

Background and Purpose—
No economic data from population-based studies exist on acute or late hospital, community, and indirect costs of stroke associated with atrial fibrillation (AF-stroke). Such data are essential for policy development, service planning, and cost-effectiveness analysis of new therapeutic agents.

Methods—
In a population-based prospective study of incident and recurrent stroke treated in hospital and community settings, we investigated direct (healthcare related) and indirect costs for a 2-year period. Survival, disability, poststroke residence, and healthcare use were determined at 90 days, 1 year, and 2 years. Acute hospital cost was determined using a case-mix approach, and other costs using a bottom-up approach (2007 prices).

Results—

In 568 patients ascertained in 1 year (2006), the total estimated 2-year cost was $33.84 million. In the overall sample, AF-stroke accounted for 31% (177) of patients, but a higher proportion of costs (40.5% of total and 45% of nursing home costs). On a per-patient basis compared with non–AF-stroke, AF-stroke was associated with higher total (
P
<0.001) and acute hospital costs (
P
<0.001), and greater nursing home (
P
=0.001) and general practitioner (
P
<0.001) costs among 90-day survivors. After stratification by stroke severity in survivors, AF was associated with 2-fold increase in costs in patients with mild-moderate (National Institutes of Health Stroke Scale, 0–15) stroke (
P
<0.001) but not in severe stroke (National Institutes of Health Stroke Scale ≥16;
P
=0.7).

Conclusions—
In our population study, AF-stroke was associated with substantially higher total, acute hospital, nursing home, and general practitioner costs per patient. Targeted programs to identify AF and prevent AF-stroke may have significant economic benefits, in addition to health benefits.
Influence of Age on Clinical and Revascularization Outcomes in the North American Solitaire Stent-Retriever Acute Stroke Registry
Authors: Castonguay Alicia C. , Zaidat Osama O. , Novakovic Roberta , Nguyen Thanh N. , Taqi M. Asif , Gupta Rishi , Sun Chung-Huan J. , Martin Coleman , Holloway William E. , Mueller-Kronast Nils , E. English Joey , Linfante Italo , Dabus Guilherme , Malisch Tim W. , Marden Franklin A. , Bozorgchami Hormozd , Xavier Andrew , Rai Ansaar T. , Froehler Michael T. , Badruddin Aamir , Abraham Michael G. , Janardhan Vallabh , Shaltoni Hashem , Yoo Albert J. , Abou-Chebl Alex , Chen Peng R. , Britz Gavin W. , Kaushal Ritesh , Nanda Ashish , A. Issa Mohammad , Nogueira Raul G. 
Published: October 2014

Background and Purpose—
The Solitaire With the Intention for Thrombectomy (SWIFT) and thrombectomy revascularization of large vessel occlusions in acute ischemic stroke (TREVO 2) trial results demonstrated improved recanalization rates with mechanical thrombectomy; however, outcomes in the elderly population remain poorly understood. Here, we report the effect of age on clinical and angiographic outcome within the North American Solitaire-FR Stent-Retriever Acute Stroke (NASA) Registry.

Methods—
The NASA Registry recruited sites to submit data on consecutive patients treated with Solitaire-FR. Influence of age on clinical and angiographic outcomes was assessed by dichotomizing the cohort into ≤80 and >80 years of age.

Results—

Three hundred fifty-four patients underwent treatment in 24 centers; 276 patients were ≤80 years and 78 were >80 years of age. Mean age in the ≤80 and >80 cohorts was 62.2±13.2 and 85.2±3.8 years, respectively. Of patients >80 years, 27.3% had a 90-day modified Rankin Score ≤2 versus 45.4% ≤80 years (
P
=0.02). Mortality was 43.9% and 27.3% in the >80 and ≤80 years cohorts, respectively (
P
=0.01). There was no significant difference in time to revascularization, revascularization success, or symptomatic intracranial hemorrhage between the groups. Multivariate analysis showed age >80 years as an independent predictor of poor clinical outcome and mortality. Within the >80 cohort, National Institutes of Health Stroke Scale (NIHSS), revascularization rate, rescue therapy use, and symptomatic intracranial hemorrhage were independent predictors of mortality.

Conclusion—
Greater than 80 years of age is predictive of poor clinical outcome and increased mortality compared with younger patients in the NASA registry. However, intravenous tissue-type plasminogen activator use, lower NIHSS, and shorter revascularization time are associated with better outcomes. Further studies are needed to understand the endovascular therapy role in this cohort compared with medical therapy.
Carotid-Bulb Atypical Fibromuscular Dysplasia in Young Afro-Caribbean Patients With Stroke
Authors: Joux Julien , Chausson Nicolas , Jeannin Séverine , Saint-Vil Martine , Mejdoubi Mehdi , Hennequin Jean-Luc , Deschamps Lydia , Smadja Didier , Olindo Stéphane 
Published: October 2014

Background and Purpose—
An atypical form of fibromuscular dysplasia located in the internal carotid-bulb (CaFMD) is thought to be uncommon and is poorly described as a cause of ischemic stroke in the young. This study aimed to obtain a better description of CaFMD in Afro-Caribbean population, who could be particularly affected by it.

Methods—
This study included consecutive patients <55 years consulting at Fort-de-France University Hospital Stroke Center (Martinique, FWI) found to have CaFMD as the only cause after a comprehensive work-up. CaFMD was diagnosed when computed tomographic angiography showed a bulbar spur without calcification.

Results—
Twenty-five patients with stroke and CaFMD were identified. Computed tomographic angiography showed 2 CaFMD patterns: a thin (n=15) or thick (n=10) spur. Three patients initial computed tomographic angiography images showed a mural thrombus overlying the CaFMD. CaFMD was surgically removed from 7 of 25 and 20 of 25 patients who received antiplatelet therapy; after mean follow-up of 25.3±19.5 months, their respective recurrence rates were 0% and 30%.

Conclusions—
CaFMD could be a common condition in young Afro-Caribbeans with carotid-territory ischemic stroke. Recurrences were frequent under antiplatelet treatment, while surgical CaFMD removal seemed more effective.