bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chromosomal Instability Selects Gene Copy-Number Variants Encoding Core Regulators of Proliferation in ER+ Breast Cancer
Authors: Endesfelder David , Burrell Rebecca A. , Kanu Nnennaya , McGranahan Nicholas , Howell Mike , Parker Peter J. , Downward Julian , Swanton Charles , Kschischo Maik 
Published: June 2014

Abstract
Chromosomal instability (CIN) is associated with poor outcome in epithelial malignancies, including breast carcinomas. Evidence suggests that prognostic signatures in estrogen receptor–positive (ER+) breast cancer define tumors with CIN and high proliferative potential. Intriguingly, CIN induction in lower eukaryotic cells and human cells is context dependent, typically resulting in a proliferation disadvantage but conferring a fitness benefit under strong selection pressures. We hypothesized that CIN permits accelerated genomic evolution through the generation of diverse DNA copy-number events that may be selected during disease development. In support of this hypothesis, we found evidence for selection of gene amplification of core regulators of proliferation in CIN-associated cancer genomes. Stable DNA copy-number amplifications of the core regulators TPX2 and UBE2C were associated with expression of a gene module involved in proliferation. The module genes were enriched within prognostic signature gene sets for ER+ breast cancer, providing a logical connection between CIN and prognostic signature expression. Our results provide a framework to decipher the impact of intratumor heterogeneity on key cancer phenotypes, and they suggest that CIN provides a permissive landscape for selection of copy-number alterations that drive cancer proliferation. Cancer Res; 74(17); 4853–63. ©2014 AACR.
Heparanase Cooperates with Ras to Drive Breast and Skin Tumorigenesis
Authors: Boyango Ilanit , Barash Uri , Naroditsky Inna , Li Jin-Ping , Hammond Edward , Ilan Neta , Vlodavsky Israel 
Published: June 2014

Abstract
Heparanase has been implicated in cancer but its contribution to the early stages of cancer development is uncertain. In this study, we utilized nontransformed human MCF10A mammary epithelial cells and two genetic mouse models [Hpa-transgenic (Hpa-Tg) and knockout mice] to explore heparanase function at early stages of tumor development. Heparanase overexpression resulted in significantly enlarged asymmetrical acinar structures, indicating increased cell proliferation and decreased organization. This phenotype was enhanced by coexpression of heparanase variants with a mutant H-Ras gene, which was sufficient to enable growth of invasive carcinoma in vivo. These observations were extended in vivo by comparing the response of Hpa-Tg mice to a classical two-stage 12-dimethylbenz(a)anthracene (DMBA)/12-o-tetradecanoylphorbol-13-acetate (TPA) protocol for skin carcinogenesis. Hpa-Tg mice overexpressing heparanase were far more sensitive than control mice to DMBA/TPA treatment, exhibiting a 10-fold increase in the number and size of tumor lesions. Conversely, DMBA/TPA-induced tumor formation was greatly attenuated in Hpa-KO mice lacking heparanase, pointing to a critical role of heparanase in skin tumorigenesis. In support of these observations, the heparanase inhibitor PG545 potently suppressed tumor progression in this model system. Taken together, our findings establish that heparanase exerts protumorigenic properties at early stages of tumor initiation, cooperating with Ras to dramatically promote malignant development. Cancer Res; 74(16); 4504–14. ©2014 AACR.
Case–Control Study of Aspirin Use and Risk of Pancreatic Cancer
Authors: Streicher Samantha A. , Yu Herbert , Lu Lingeng , Kidd Mark S. , Risch Harvey A. 
Published: June 2014

Abstract
Background: Pancreas-cancer prognosis is dismal, with 5-year survival less than 5%. Significant relationships between aspirin use and decreased pancreas-cancer incidence and mortality have been shown in four of 13 studies.
Methods: To evaluate further a possible association between aspirin use and risk of pancreatic cancer, we used data from a population-based Connecticut study conducted from January 2005 to August 2009, of 362 pancreas-cancer cases frequency matched to 690 randomly sampled controls.
Results: Overall, regular use of aspirin was associated with reduced risk of pancreatic cancer [odds ratio (OR), 0.52; 95% confidence interval (CI), 0.39–0.69]. Increments of decreasing risk of pancreatic cancer were observed for each year of low-dose or regular-dose aspirin use (OR, 0.94; 95% CI, 0.91–0.98 and OR, 0.98; 95% CI, 0.96–1.01, respectively) and for increasing years in the past that low-dose or regular-dose aspirin use had started (OR, 0.95; 95% CI, 0.92–0.99 and OR, 0.98; 95% CI, 0.96–1.00, respectively). Reduced risk of pancreatic cancer was seen in most categories of calendar time period of aspirin use, for both low-dose aspirin and regular-dose aspirin use. Relative to continuing use at the time of interview, termination of aspirin use within 2 years of interview was associated with increased risk of pancreatic cancer (OR, 3.24; 95% CI, 1.58–6.65).
Conclusions: Our results provide some support that a daily aspirin regimen may reduce risk of developing pancreatic cancer.
Impact: Long-term aspirin use has benefits for both cardiovascular disease and cancer, but appreciable bleeding complications that necessitate risk–benefit analysis for individual applications. Cancer Epidemiol Biomarkers Prev; 23(7); 1254–63. ©2014 AACR.
Detection of Minimal Residual Disease in B Lymphoblastic Leukemia by High-Throughput Sequencing of IGH
Authors: Wu David , Emerson Ryan O. , Sherwood Anna , Loh Mignon L. , Angiolillo Anne , Howie Bryan , Vogt Jennifer , Rieder Mark , Kirsch Ilan , Carlson Christopher , Williamson David , Wood Brent L. , Robins Harlan 
Published: June 2014

Abstract
Purpose: High-throughput sequencing (HTS) of immunoglobulin heavy-chain genes (IGH) in unselected clinical samples for minimal residual disease (MRD) in B lymphoblastic leukemia (B-ALL) has not been tested. As current MRD-detecting methods such as flow cytometry or patient-specific qPCR are complex or difficult to standardize in the clinical laboratory, sequencing may enhance clinical prognostication.
Experimental Design: We sequenced IGH in paired pretreatment and day 29 post-treatment samples using residual material from consecutive, unselected samples from the Children's Oncology Group AALL0932 trial to measure MRD as compared with flow cytometry. We assessed the impact of ongoing recombination at IGH on MRD detection in post-treatment samples. Finally, we evaluated a subset of cases with discordant MRD results between flow cytometry and sequencing.
Results: We found clonal IGH rearrangements in 92 of 98 pretreatment patient samples. Furthermore, while ongoing recombination of IGH was evident, index clones typically prevailed in MRD-positive post-treatment samples, suggesting that clonal evolution at IGH does not contribute substantively to tumor fitness. MRD was detected by sequencing in all flow cytometry–positive cases with no false-negative results. In addition, in a subset of patients, MRD was detected by sequencing, but not by flow cytometry, including a fraction with MRD levels within the sensitivity of flow cytometry. We provide data that suggest that this discordance in some patients may be due to the phenotypic maturation of the transformed cell.
Conclusion: Our results provide strong support for HTS of IGH to enhance clinical prognostication in B-ALL. Clin Cancer Res; 20(17); 4540–8. ©2014 AACR.
Monocytes Are Recruited From Venules During Arteriogenesis in the Murine Spinotrapezius Ligation Model
Authors: Bruce Anthony C. , Kelly-Goss Molly R. , Heuslein Joshua L. , Meisner Joshua K. , Price Richard J. , Peirce Shayn M. 
Published: June 2014

Objective—
Chronic arterial occlusion results in arteriogenesis of collateral blood vessels. This process has been shown to be dependent on the recruitment of growth-promoting macrophages to remodeling collaterals. However, the potential role of venules in monocyte recruitment during microvascular arteriogenesis is not well demonstrated. First, we aim to document that arteriogenesis occurs in the mouse spinotrapezius ligation model. Then, we investigate the temporal and spatial distribution, as well as proliferation, of monocytes/macrophages recruited to collateral arterioles in response to elevated fluid shear stress.

Approach and Results—

Laser speckle flowmetry confirmed a postligation increase in blood velocity within collateral arterioles but not within venules. After 72 hours post ligation, collateral arteriole diameters were increased, proliferating cells were identified in vessel walls of shear-activated collaterals, and perivascular CD206
+
macrophages demonstrated proliferation. A 5-ethynyl-2′-deoxyuridine assay identified proliferation. CD68
+
CD206
+
cells around collaterals were increased 96%, whereas CX3CR1
(+/GFP)
cells were increased 126% in ligated versus sham groups after 72 hours. CX3CR1
(+/GFP)
cells were predominately venule associated at 6 hours after ligation; and CX3CR1
(+/GFP hi)
cells shifted from venule to arteriole associated between 6 and 72 hours after surgery exclusively in ligated muscle. We report accumulation and extravasation of adhered CX3CR1
(+/GFP)
cells in and from venules, but not from arterioles, after ligation.

Conclusions—
Our results demonstrate that arteriogenesis occurs in the murine spinotrapezius ligation model and implicate postcapillary venules as the site of tissue entry for circulating monocytes. Local proliferation of macrophages is also documented. These data open up questions about the role of arteriole–venule communication during monocyte recruitment.
Direct Interaction of Kindlin-3 With Integrin αIIbβ3 in Platelets Is Required for Supporting Arterial Thrombosis in Mice
Authors: Xu Zhen , Chen Xue , Zhi Huiying , Gao Juan , Bialkowska Katarzyna , Byzova Tatiana V. , Pluskota Elzbieta , White Gilbert C. , Liu Junling , Plow Edward F. , Ma Yan-Qing 
Published: June 2014

Objective—
Kindlin-3 is a critical supporter of integrin function in platelets. Lack of expression of kindlin-3 protein in patients impairs integrin αIIbβ3–mediated platelet aggregation. Although kindlin-3 has been categorized as an integrin-binding partner, the functional significance of the direct interaction of kindlin-3 with integrin αIIbβ3 in platelets has not been established. Here, we evaluated the significance of the binding of kindlin-3 to integrin αIIbβ3 in platelets in supporting integrin αIIbβ3–mediated platelet functions.

Approach and Results—
We generated a strain of kindlin-3 knockin (K3KI) mice that express a kindlin-3 mutant that carries an integrin-interaction defective substitution. K3KI mice could survive normally and express integrin αIIbβ3 on platelets similar to their wild-type counterparts. Functional analysis revealed that K3KI mice exhibited defective platelet function, including impaired integrin αIIbβ3 activation, suppressed platelet spreading and platelet aggregation, prolonged tail bleeding time, and absence of platelet-mediated clot retraction. In addition, whole blood drawn from K3KI mice showed resistance to in vitro thrombus formation and, as a consequence, K3KI mice were protected from in vivo arterial thrombosis.

Conclusions—
These observations demonstrate that the direct binding of kindlin-3 to integrin αIIbβ3 is involved in supporting integrin αIIbβ3 activation and integrin αIIbβ3-dependent responses of platelets and consequently contributes significantly to arterial thrombus formation.
Dietary Cholesterol Promotes Adipocyte Hypertrophy and Adipose Tissue Inflammation in Visceral, but Not in Subcutaneous, Fat in Monkeys
Authors: Chung Soonkyu , Cuffe Helen , Marshall Stephanie M. , McDaniel Allison L. , Ha Jung-Heun , Kavanagh Kylie , Hong Cynthia , Tontonoz Peter , Temel Ryan E. , Parks John S. 
Published: June 2014

Objective—
Excessive caloric intake is associated with obesity and adipose tissue dysfunction. However, the role of dietary cholesterol in this process is unknown. The aim of this study was to determine whether increasing dietary cholesterol intake alters adipose tissue cholesterol content, adipocyte size, and endocrine function in nonhuman primates.

Approach and Results—

Age-matched, male African Green monkeys (n=5 per group) were assigned to 1 of 3 diets containing 0.002 (low [Lo]), 0.2 (medium [Med]), or 0.4 (high [Hi]) mg cholesterol/kcal. After 10 weeks of diet feeding, animals were euthanized for adipose tissue, liver, and plasma collection. With increasing dietary cholesterol, free cholesterol (FC) content and adipocyte size increased in a stepwise manner in visceral, but not in subcutaneous fat, with a significant association between visceral adipocyte size and FC content (
r
2
=0.298; n=15;
P
=0.035). In visceral fat, dietary cholesterol intake was associated with (1) increased proinflammatory gene expression and macrophage recruitment, (2) decreased expression of genes involved in cholesterol biosynthesis and lipoprotein uptake, and (3) increased expression of proteins involved in FC efflux.

Conclusions—
Increasing dietary cholesterol selectively increases visceral fat adipocyte size, FC and macrophage content, and proinflammatory gene expression in nonhuman primates. Visceral fat cells seem to compensate for increased dietary cholesterol by limiting cholesterol uptake/synthesis and increasing FC efflux pathways.
Platelet Endothelial Cell Adhesion Molecule-1 Inhibits Platelet Response to Thrombin and von Willebrand Factor by Regulating the Internalization of Glycoprotein Ib via AKT/Glycogen Synthase Kinase-3/Dynamin and Integrin αIIbβ3
Authors: Jones Chris I. , Sage Tanya , Moraes Leonardo A. , Vaiyapuri Sakthivel , Hussain Umara , Tucker Katherine L. , Barrett Natasha E. , Gibbins Jonathan M. 
Published: June 2014

Objective—
Platelet endothelial cell adhesion molecule-1 (PECAM-1) regulates platelet response to multiple agonists. How this immunoreceptor tyrosine-based inhibitory motif–containing receptor inhibits G protein-coupled receptor–mediated thrombin-induced activation of platelets is unknown.

Approach and Results—

Here, we show that the activation of PECAM-1 inhibits fibrinogen binding to integrin αIIbβ3 and P-selectin surface expression in response to thrombin (0.1–3 U/mL) but not thrombin receptor–activating peptides SFLLRN (3×10
−7
–1×10
−5
mol/L) and GYPGQV (3×10
−6
–1×10
−4
mol/L). We hypothesized a role for PECAM-1 in reducing the tethering of thrombin to glycoprotein Ibα (GPIbα) on the platelet surface. We show that PECAM-1 signaling regulates the binding of fluorescein isothiocyanate–labeled thrombin to the platelet surface and reduces the levels of cell surface GPIbα by promoting its internalization, while concomitantly reducing the binding of platelets to von Willebrand factor under flow in vitro. PECAM-1–mediated internalization of GPIbα was reduced in the presence of both EGTA and cytochalasin D or latrunculin, but not either individually, and was reduced in mice in which tyrosines 747 and 759 of the cytoplasmic tail of β3 integrin were mutated to phenylalanine. Furthermore, PECAM-1 cross-linking led to a significant reduction in the phosphorylation of glycogen synthase kinase-3β Ser
9
, but interestingly an increase in glycogen synthase kinase-3α pSer
21
. PECAM-1–mediated internalization of GPIbα was reduced by inhibitors of dynamin (Dynasore) and glycogen synthase kinase-3 (CHIR99021), an effect that was enhanced in the presence of EGTA.

Conclusions—
PECAM-1 mediates internalization of GPIbα in platelets through dual AKT/protein kinase B/glycogen synthase kinase-3/dynamin-dependent and αIIbβ3-dependent mechanisms. These findings expand our understanding of how PECAM-1 regulates nonimmunoreceptor signaling pathways and helps to explains how PECAM-1 regulates thrombosis.
Influence of Steroid Therapy on the Incidence of Pericarditis and Atrial Fibrillation After Percutaneous Epicardial Mapping and Ablation for Ventricular Tachycardia
Authors: Dyrda Katia , Piers Sebastiaan R.D. , van Huls van Taxis Carine F. , Schalij Martin J. , Zeppenfeld Katja 
Published: June 2014

Background—
This study evaluates the influence of 3 therapeutic approaches on the incidence of pericarditis and atrial fibrillation (AF) after percutaneous epicardial mapping and ablation for ventricular tachycardia.

Methods and Results—

Eighty-five consecutive procedures (2006–2011) were retrospectively reviewed. After the first 17 procedures (20.0%), no steroids were administered. For the subsequent 30 procedures (35.3%), systemic steroids were administered intravenously or orally, whereas the last 38 procedures (44.7%) were followed by intrapericardial steroid injection. Compared with no steroids, the incidence of pericarditic chest pain was significantly reduced by intrapericardial steroids (58.8% versus 21.1%;
P
=0.006) but not by intravenous or oral steroids (58.8% versus 43.4%;
P
=0.31). There was no significant difference in the incidence of pericarditic ECG with steroids (36.8%, 30.0%, and 41.2% for intrapericardial, intravenous or oral, and none, respectively). There was a nonsignificant reduced incidence of chest pain with ECG changes with steroids (13.2%, 10.0%, and 29.4% for intrapericardial, intravenous or oral, and none, respectively). Radiofrequency applications (65.9% of procedures) did not affect the incidence of pericarditic ECG changes, pericarditic chest pain, or pericarditis (all
P
>0.05). In 7 (8.3%) patients with no prior history of AF, AF was documented a median 36 hours after procedure. Patients with pericarditic ECG tended to be at greater risk of AF (16.7 versus 3.6%;
P
=0.091).

Conclusions—
There is a high incidence of pericarditic chest pain and ECG changes after epicardial ventricular tachycardia mapping and ablation. Pericarditic chest pain is significantly decreased by intrapericardial steroids. Procedure-related AF is relatively frequent and tends to occur more commonly with pericarditic ECG changes.
Safety of Continuous Periprocedural Rivaroxaban for Patients Undergoing Left Atrial Catheter Ablation Procedures
Authors: Dillier Roger , Ammar Sonia , Hessling Gabriele , Kaess Bernhard , Pavaci Herribert , Buiatti Alessandra , Semmler Verena , Kathan Susanne , Hofmann Monika , Lennerz Carsten , Kolb Christof , Reents Tilko , Deisenhofer Isabel 
Published: June 2014

Background—
This study aimed to evaluate the safety of continuous periprocedural rivaroxaban administration during left atrial radiofrequency ablation (RFA) in comparison with uninterrupted oral vitamin K antagonist administration. Data about the use of rivaroxaban in the setting of left atrial RFA procedures are lacking.

Methods and Results—

The study cohort included 544 patients (mean age, 63±10 years) who underwent left atrial RFA procedures between February 2012 and May 2013. All patients (n=272) receiving uninterrupted periprocedural rivaroxaban 15 or 20 mg/d before the procedure (rivaroxaban) were matched by age, sex, and type of rhythm disorder with an equal number of patients managed with uninterrupted vitamin K antagonist phenprocoumon (international normalized ratio, 2–3). During RFA, heparin was given intravenously to maintain an activated clotting time at 270 to 300 s. The safety end point was a composite of bleeding, thromboembolic events, and death. There were no thromboembolic complications and no deaths in either group. The prevalence of major bleeding complications was similar in both groups (1 tamponade in RivG and 1 groin hematoma requiring transfusion in phenprocoumon). Minor bleeding complications occurred equally in both groups (20 of 272; 7% in the rivaroxaban versus 33 of 272, 12% in the phenprocoumon;
P
=0.08). In multivariable analyses, female sex was associated with a greater risk of complications (odds ratio, 1.96; 95% confidence interval, 1.10–3.49).

Conclusions—
In patients undergoing left atrial RFA, continuous periprocedural rivaroxaban use seems to be as safe as uninterrupted periprocedural phenprocoumon administration.
Effect of Fixed-Dose Combination of Isosorbide Dinitrate and Hydralazine on All Hospitalizations and on 30-Day Readmission Rates in Patients With Heart Failure
Authors: Anand Inder S. , Win Sithu , Rector Thomas S. , Cohn Jay N. , Taylor Anne L. 
Published: June 2014

Background—
Fixed-dose combination of isosorbide dinitrate and hydralazine (FDC-I/H) reduced mortality by 43% and death or first hospitalization for heart failure (HF) by 37% in the African-American Heart Failure Trial (A-HeFT). Reduction in mortality makes it difficult to determine the effect on hospitalizations unless the analysis adjusts for death as a competing risk.

Methods and Results—

In A-HeFT, 1050 self-identified black patients with moderate to severe HF were randomized to FDC-I/H or placebo. The effects of FDC-I/H on first and all hospitalizations and 30-day readmission rates were analyzed. Deaths as competing risks were adjusted using Fine–Gray regression and joint models of hospitalizations and mortality. There were 558 all-cause and 251 HF hospitalizations in placebo compared with 435 and 173 hospitalizations in the FDC-I/H group. Adjusting for deaths as a competing risk, the effect of FDC-I/H on the first hospitalization for HF, expressed in hazard ratio (95% confidence interval), was 0.61 (0.47–0.80;
P
<0.001) and 0.88 (0.72–1.06;
P
=0.18) on the first all-cause hospitalization. The effect of FDC-I/H on all recurrent hospitalizations for HF was 0.66 (0.52–0.83;
P
=0.0005), similar to the effect on the first hospitalizations for HF, whereas the effect on all hospitalizations for any cause was 0.75 (0.63–0.91;
P
=0.003). The 30-day all-cause readmission rate after the first hospitalization for HF was 23.6% (29 of 123) in placebo versus 14.8% (12 of 81) in the FDC-I/H group, but the effect (0.59; 0.30–1.16;
P
=0.12) in this small subgroup was not significant.

Conclusions—
Treatment with FDC-I/H was associated with a substantial reduction in the first and recurrent HF hospitalizations, and in total all-cause hospitalizations, reducing the total burden of costly and distressing hospitalizations.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00047775.
New genus Arxellia with new species of Solariellidae (Gastropoda: Trochoidea) from New Caledonia, Papua New Guinea, Philippines, Western Australia, Vanuatu and Tonga
Authors: VILVENS CLAUDE , WILLIAMS SUZANNE T. , HERBERT DAVID G. 
Published: June 2014

A new genus, Arxellia, is described in the family Solariellidae. Nine species are referred to this taxon, eight of which are new and are described in this paper (Arxellia trochos n. sp., Arxellia boucheti n. sp., Arxellia herosae n. sp., Arxellia helicoides n. sp., Arxellia tracheia n. sp., Arxellia thaumasta n. sp., Arxellia maestratii n. sp. and Arxellia erythrea n. sp.). The previously described species Bathymophila tenorioi Poppe, Tagaro & Dekker, 2006 is reassigned to Arxellia.