bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Aldehyde Dehydrogenase-3 Activator (Alda-89) Protects Submandibular Gland Function from Irradiation without Accelerating Tumor Growth
Authors: Xiao Nan , Cao Hongbin , Chen Che-Hong , Kong Christina S. , Ali Rehan , Chan Cato , Sirjani Davud , Graves Edward , Koong Albert , Giaccia Amato , Mochly-Rosen Daria , Le Quynh-Thu 
Published: June 2013

Abstract
Purpose: To determine the effect of Alda-89 (an ALDH3 activitor) on (i) the function of irradiated (radiotherapy) submandibular gland (SMG) in mice, (ii) its toxicity profile, and (iii) its effect on the growth of head and neck cancer (HNC) in vitro and in vivo.
Experimental Design: Adult mice were infused with Alda-89 or vehicle before, during, and after radiotherapy. Saliva secretion was monitored weekly. Hematology, metabolic profile, and postmortem evaluation for toxicity were examined at the time of sacrifice. Alda-89 or vehicle was applied to HNC cell lines in vitro, and severe combined immunodeficient (SCID) mice transplanted with HNC in vivo with or without radiation; HNC growth was monitored. The ALDH3A1 and ALDH3A2 protein expression was evaluated in 89 patients with HNC and correlated to freedom from relapse (FFR) and overall survival (OS).
Results: Alda-89 infusion significantly resulted in more whole saliva production and a higher percentage of preserved acini after radiotherapy compared with vehicle control. There was no difference in the complete blood count, metabolic profile, and major organ morphology between the Alda-89 and vehicle groups. Compared with vehicle control, Alda-89 treatment neither accelerated HNC cell proliferation in vitro, nor did it affect tumor growth in vivo with or without radiotherapy. Higher expression of ALDH3A1 or ALDH3A2 was not significantly associated with worse FFR or OS in either human papillomavirus (HPV)-positive or HPV-negative group.
Conclusion: Alda-89 preserves salivary function after radiotherapy without affecting HNC growth or causing measurable toxicity in mice. It is a promising candidate to mitigate radiotherapy-related xerostomia. Clin Cancer Res; 19(16); 4455–64. ©2013 AACR.
Development and Preclinical Characterization of a Humanized Antibody Targeting CXCL12
Authors: Zhong Cuiling , Wang Jianyong , Li Bing , Xiang Hong , Ultsch Mark , Coons Mary , Wong Terence , Chiang Nancy Y. , Clark Suzy , Clark Robyn , Quintana Leah , Gribling Peter , Suto Eric , Barck Kai , Corpuz Racquel , Yao Jenny , Takkar Rashi , Lee Wyne P. , Damico-Beyer Lisa A. , Carano Richard D. , Adams Camellia , Kelley Robert F. , Wang Weiru , Ferrara Napoleone 
Published: June 2013

Abstract
Purpose: Our goal was to develop a potent humanized antibody against mouse/human CXCL12. This report summarized its in vitro and in vivo activities.
Experimental Design: Cell surface binding and cell migration assays were used to select neutralizing hamster antibodies, followed by testing in several animal models. Monoclonal antibody (mAb) 30D8 was selected for humanization based on its in vitro and in vivo activities.
Results: 30D8, a hamster antibody against mouse and human CXCL12α, CXCL12β, and CXCL12γ, was shown to dose-dependently block CXCL12α binding to CXCR4 and CXCR7, and CXCL12α-induced Jurkat cell migration in vitro. Inhibition of primary tumor growth and/or metastasis was observed in several models. 30D8 alone significantly ameliorated arthritis in a mouse collagen-induced arthritis model (CIA). Combination with a TNF-α antagonist was additive. In addition, 30D8 inhibited 50% of laser-induced choroidal neovascularization (CNV) in mice. Humanized 30D8 (hu30D8) showed similar in vitro and in vivo activities as the parental hamster antibody. A crystal structure of the hu30D8 Fab/CXCL12α complex in combination with mutational analysis revealed a “hot spot” around residues Asn44/Asn45 of CXCL12α and part of the RFFESH region required for CXCL12α binding to CXCR4 and CXCR7. Finally, hu30D8 exhibited fast clearance in cynomolgus monkeys but not in rats.
Conclusion: CXCL12 is an attractive target for treatment of cancer and inflammation-related diseases; hu30D8 is suitable for testing this hypothesis in humans. Clin Cancer Res; 19(16); 4433–45. ©2013 AACR.
The Potential Role of miR-451 in Cancer Diagnosis, Prognosis, and Therapy
Authors: Pan Xuan , Wang Rui , Wang Zhao-Xia 
Published: June 2013

Abstract
MicroRNAs (miRNA) are small noncoding RNAs that converge to maintain an intrinsic balance of various processes, including cell proliferation, differentiation, and apoptosis. Recent research efforts have been devoted to translating these basic discoveries into applications that could improve the early diagnosis and therapeutic outcome of patients with cancer. Early studies have shown that miRNA-451 (miR-451) is widely dysregulated in human cancers and plays a critical role in tumorigenesis and tumor progression. In this review, we summarize the potential use of miR-451 for cancer diagnosis, prognosis, and treatment. In addition, we discuss the possible mechanisms of miR-451 dysregulation and future challenges in development of miR-451 as a noninvasive biomarker and a potential therapeutic target in human cancers. Mol Cancer Ther; 12(7); 1153–62. ©2013 AACR.
Dual Inhibition of PI3K and mTOR Mitigates Compensatory AKT Activation and Improves Tamoxifen Response in Breast Cancer
Authors: Chen Xiaosong , Zhao Meizhong , Hao Mingang , Sun Xueqing , Wang Jinglong , Mao Yan , Zu Lidong , Liu Junjun , Shen Yandong , Wang Jianhua , Shen Kunwei 
Published: June 2013

Abstract
Everolimus, an mTOR inhibitor, showed great clinical efficacy in combination with tamoxifen, letrozole, or exemestane for the treatment of estrogen receptor-positive (ER+) breast cancer. However, its antitumor activity was shown to be compromised by a compensatory process involving AKT activation. Here, it was determined whether combining an additional PI3K inhibitor can reverse this phenomenon and improve treatment efficacy. In breast cancer cells (MCF-7 and BT474), everolimus inhibited the mTOR downstream activity by limiting phosphorylation of p70S6K and 4EBP1, which resulted in p-Ser473-AKT activation. However, addition of a LY294002, a PI3K inhibitor, to tamoxifen and everolimus treatment improved the antitumor effect compared with tamoxifen alone or the other two agents in combination. Moreover, LY294002 suppressed the activity of the PI3K/AKT/mTOR axis and mitigated the p-Ser473-AKT activation feedback loop in both cell lines. Critically, this combination scheme also significantly inhibited the expression of HIF-1a, an angiogenesis marker, under hypoxic conditions and reduced blood vessel sprout formation in vitro. Finally, it was shown that the three-agent cocktail had the greatest efficacy in inhibiting MCF-7 xenograft tumor growth and angiogenesis. Taken together, these results suggest that inhibition of PI3K and mTOR may further improve therapy in ER+ breast cancer cells.
Implications: Combinatorial inhibition of the PI3K/AKT/mTOR signaling axis may enhance endocrine-based therapy in breast cancer. Mol Cancer Res; 11(10); 1269–78. ©2013 AACR.
Liver ABCA1 Deletion in LDLrKO Mice Does Not Impair Macrophage Reverse Cholesterol Transport or Exacerbate Atherogenesis
Authors: Bi Xin , Zhu Xuewei , Duong MyNgan , Boudyguina Elena Y. , Wilson Martha D. , Gebre Abraham K. , Parks John S. 
Published: June 2013

Objective—
Hepatic ATP binding cassette transporter A1 (ABCA1) expression is critical for maintaining plasma high-density lipoprotein (HDL) concentrations, but its role in macrophage reverse cholesterol transport and atherosclerosis is not fully understood. We investigated atherosclerosis development and reverse cholesterol transport in hepatocyte-specific ABCA1 knockout (HSKO) mice in the low-density lipoprotein (LDL) receptor KO (LDLrKO) C57BL/6 background.

Approach and Results—

Male and female LDLrKO and HSKO/LDLrKO mice were switched from chow at 8 weeks of age to an atherogenic diet (10% palm oil, 0.2% cholesterol) for 16 weeks. Chow-fed HSKO/LDLrKO mice had HDL concentrations 10% to 20% of LDLrKO mice, but similar very low-density lipoprotein and LDL concentrations. Surprisingly, HSKO/LDLrKO mice fed the atherogenic diet had significantly lower (40% to 60%) very low-density lipoprotein, LDL, and HDL concentrations (50%) compared with LDLrKO mice. Aortic surface lesion area and cholesterol content were similar for both genotypes of mice, but aortic root intimal area was significantly lower (20% to 40%) in HSKO/LDLrKO mice. Although macrophage
3
H-cholesterol efflux to apoB lipoprotein–depleted plasma was 24% lower for atherogenic diet–fed HSKO/LDLrKO versus LDLrKO mice, variation in percentage efflux among individual mice was <2-fold compared with a 10-fold variation in plasma HDL concentrations, suggesting that HDL levels, per se, were not the primary determinant of plasma efflux capacity. In vivo reverse cholesterol transport, resident peritoneal macrophage sterol content, biliary lipid composition, and fecal cholesterol mass were similar between both genotypes of mice.

Conclusions—
The markedly reduced plasma HDL pool in HSKO/LDLrKO mice is sufficient to maintain macrophage reverse cholesterol transport, which, along with reduced plasma very low-density lipoprotein and LDL concentrations, prevented the expected increase in atherosclerosis.
Smad2-Dependent Protease Nexin-1 Overexpression Differentiates Chronic Aneurysms From Acute Dissections of Human Ascending Aorta
Authors: Gomez Delphine , Kessler Ketty , Borges Luciano F. , Richard Benjamin , Touat Ziad , Ollivier Véronique , Mansilla Silvana , Bouton Marie-Christine , Alkoder Soleyman , Nataf Patrick , Jandrot-Perrus Martine , Jondeau Guillaume , Vranckx Roger , Michel Jean-Baptiste 
Published: June 2013

Objective—
Tissue activation of proteolysis is involved in acute intramural rupture (dissections, acute ascending aortic dissection) and in progressive dilation (aneurysms, thoracic aneurysm of the ascending aorta) of human ascending aorta. The translational aim of this study was to characterize the regulation of antiproteolytic serpin expression in normal, aneurysmal, and dissecting aorta.

Approach and Results—
We explored expression of protease nexin-1 (PN-1) and plasminogen activator inhibitor-1 and their regulation by the Smad2 signaling pathway in human tissue and cultured vascular smooth muscle cells (VSMCs) of aneurysms (thoracic aneurysm of the ascending aorta; n=46) and acute dissections (acute ascending aortic dissection; n=10) of the ascending aorta compared with healthy aortas (n=10). Both PN-1 and plasminogen activator inhibitor-1 mRNA and proteins were overexpressed in medial tissue extracts and primary VSMC cultures from thoracic aneurysm of the ascending aorta compared with acute ascending aortic dissection and controls. Transforming growth factor-β induced increased PN-1 expression in control but not in aneurysmal VSMCs. PN-1 and plasminogen activator inhibitor-1 overexpression by aneurysmal VSMCs was associated with increased Smad2 binding on their promoters and, functionally, resulted in VSMC self-protection from plasmin-induced detachment and death. This phenomenon was restricted to aneurysms and not observed in acute dissections.

Conclusions—
These results demonstrate that epigenetically regulated PN-1 overexpression promotes development of an antiproteolytic VSMC phenotype and might favor progressive aneurysmal dilation, whereas absence of this counter-regulation in dissections would lead to acute wall rupture.
Elevated Levels of Circulating DNA and Chromatin Are Independently Associated With Severe Coronary Atherosclerosis and a Prothrombotic State
Authors: Borissoff Julian I. , Joosen Ivo A. , Versteylen Mathijs O. , Brill Alexander , Fuchs Tobias A. , Savchenko Alexander S. , Gallant Maureen , Martinod Kimberly , ten Cate Hugo , Hofstra Leonard , Crijns Harry J. , Wagner Denisa D. , Kietselaer Bas L.J.H. 
Published: July 2013

Objective—
Aberrant neutrophil activation occurs during the advanced stages of atherosclerosis. Once primed, neutrophils can undergo apoptosis or release neutrophil extracellular traps. This extracellular DNA exerts potent proinflammatory, prothrombotic, and cytotoxic properties. The goal of this study was to examine the relationships among extracellular DNA formation, coronary atherosclerosis, and the presence of a prothrombotic state.

Approach and Results—

In a prospective, observational, cross-sectional cohort of 282 individuals with suspected coronary artery disease, we examined the severity, extent, and phenotype of coronary atherosclerosis using coronary computed tomographic angiography. Double-stranded DNA, nucleosomes, citrullinated histone H4, and myeloperoxidase–DNA complexes, considered in vivo markers of cell death and NETosis, respectively, were established. We further measured various plasma markers of coagulation activation and inflammation. Plasma double-stranded DNA, nucleosomes, and myeloperoxidase–DNA complexes were positively associated with thrombin generation and significantly elevated in patients with severe coronary atherosclerosis or extremely calcified coronary arteries. Multinomial regression analysis, adjusted for confounding factors, identified high plasma nucleosome levels as an independent risk factor of severe coronary stenosis (odds ratio, 2.14; 95% confidence interval, 1.26–3.63;
P
=0.005). Markers of neutrophil extracellular traps, such as myeloperoxidase–DNA complexes, predicted the number of atherosclerotic coronary vessels and the occurrence of major adverse cardiac events.

Conclusions—
Our report provides evidence demonstrating that markers of cell death and neutrophil extracellular trap formation are independently associated with coronary artery disease, prothrombotic state, and occurrence of adverse cardiac events. These biomarkers could potentially aid in the prediction of cardiovascular risk in patients with chest discomfort.
Endothelial Cell Sensing of Flow Direction
Authors: Wang Chong , Baker Brendon M. , Chen Christopher S. , Schwartz Martin Alexander 
Published: June 2013

Objective—
Atherosclerosis-prone regions of arteries are characterized by complex flow patterns where the magnitude of shear stress is low and direction rapidly changes, termed disturbed flow. How endothelial cells sense flow direction and how it impacts inflammatory effects of disturbed flow are unknown. We therefore aimed to understand how endothelial cells respond to changes in flow direction.

Approach and Results—
Using a recently developed flow system capable of changing flow direction to any angle, we show that responses of aligned endothelial cells are determined by flow direction relative to their morphological and cytoskeletal axis. Activation of the atheroprotective endothelial nitric oxide synthase pathway is maximal at 180° and undetectable at 90°, whereas activation of proinflammatory nuclear factor-κB is maximal at 90° and undetectable at 180°. Similar effects were observed in randomly oriented cells in naive monolayers subjected to onset of shear. Cells aligned on micropatterned substrates subjected to oscillatory flow were also examined. In this system, parallel flow preferentially activated endothelial nitric oxide synthase and production of nitric oxide, whereas perpendicular flow preferentially activated reactive oxygen production and nuclear factor-κB.

Conclusions—
These data show that the angle between flow and the cell axis defined by their shape and cytoskeleton determines endothelial cell responses. The data also strongly suggest that the inability of cells to align in low and oscillatory flow is a key determinant of the resultant inflammatory activation.
Clinical Profile and Underdiagnosis of Pulmonary Hypertension in US Veteran Patients
Authors: Maron Bradley A. , Choudhary Gaurav , Khan Umar A. , Jankowich Matthew D. , McChesney Hope , Ferrazzani Sarah J. , Gaddam Sainath , Sharma Satish , Opotowsky Alexander R. , Bhatt Deepak L. , Rocco Thomas P. , Aragam Jayashri R. 
Published: June 2013

Background—
Pulmonary hypertension (PH) is a key contributor to cardiovascular morbidity and early mortality; however, reports are lacking on the epidemiology of PH in at-risk patient populations.

Methods and Results—
The echocardiography registries from 2 major Veterans Affairs hospitals were accessed to identify patients with at least moderate PH, defined here as a pulmonary artery systolic pressure ≥60 mm Hg detected echocardiographically. From a total of 10 471 individual patient transthoracic echocardiograms, we identified moderate or severe PH in 340 patients (332 men; mean, 77 years; mean pulmonary artery systolic pressure, 69.4±10.5 mm Hg), of which PH was listed as a diagnosis in the medical record for only 59 (17.3%). At a mean of 832 days (0–4817 days) following echocardiography diagnosing PH, 150 (44.1%) patients were deceased. PH was present without substantial left heart remodeling: the mean left ventricular ejection fraction was 0.50±0.16, left ventricular end-diastolic dimension was 5.0±0.9 cm, and left atrial dimension was 4.4±0.7 cm. Cardiac catheterization (n=122, 36%) demonstrated a mean pulmonary artery pressure of 40.5±11.4 mm Hg, pulmonary capillary wedge pressure of 22.6±8.9 mm Hg, and pulmonary vascular resistance of 4.6±2.9 Wood units. Diagnostic strategies for PH were variable and often incomplete; for example, only 16% of appropriate patients were assessed with a nuclear ventilation/perfusion scan for thromboembolic causes of PH.

Conclusions—
In an at-risk patient population, PH is underdiagnosed and associated with substantial mortality. Enhanced awareness is necessary among practitioners regarding contemporary PH diagnostic strategies.
Validity and Reliability of a Novel Slow Cuff-Deflation System for Noninvasive Blood Pressure Monitoring in Patients With Continuous-Flow Left Ventricular Assist Device
Authors: Lanier Gregg M. , Orlanes Khristine , Hayashi Yacki , Murphy Jennifer , Flannery Margaret , Te-Frey Rosie , Uriel Nir , Yuzefpolskaya Melana , Mancini Donna M. , Naka Yoshifumi , Takayama Hiroo , Jorde Ulrich P. , Demmer Ryan T. , Colombo Paolo C. 
Published: June 2013

Background—
Doppler ultrasound is the clinical gold standard for noninvasive blood pressure (BP) measurement among continuous-flow left ventricular assist device patients. The relationship of Doppler BP to systolic BP (SBP) and mean arterial pressure (MAP) is uncertain and Doppler measurements require a clinic visit. We studied the relationship between Doppler BP and both arterial-line (A-line) SBP and MAP. Validity and reliability of the Terumo Elemano BP Monitor, a novel slow cuff-deflation device that could potentially be used by patients at home, were assessed.

Methods and Results—
Doppler and Terumo BP measurements were made in triplicate among 60 axial continuous-flow left ventricular assist device (HeartMate II) patients (30 inpatients and 30 outpatients) at 2 separate exams (360 possible measurements). A-line measures were also obtained among inpatients. Mean absolute differences (MADs) and correlations were used to determine within-device reliability (comparison of second and third BP measures) and between-device validity. Bland–Altman plots assessed BP agreement between A-line, Doppler BP, and Terumo Elemano. Success rates for Doppler and Terumo Elemano were 100% and 91%. Terumo Elemano MAD for repeat SBP and MAP were 4.6±0.6 and 4.2±0.6 mm Hg; repeat Doppler BP MAD was 2.9±0.2 mm Hg. Mean Doppler BP was lower than A-line SBP by 4.1 (MAD=6.4±1.4) mm Hg and higher than MAP by 9.5 (MAD=11.0±1.2) mm Hg; Terumo Elemano underestimated A-line SBP by 0.3 (MAD=5.6±0.9) mm Hg and MAP by 1.7 (MAD=6.0±1.0) mm Hg.

Conclusions—
Doppler BP more closely approximates SBP than MAP. Terumo Elemano was successful, reliable, and valid when compared with A-line and Doppler.
Longitudinal Changes in Left Ventricular Stiffness
Authors: Borlaug Barry A. , Redfield Margaret M. , Melenovsky Vojtech , Kane Garvan C. , Karon Barry L. , Jacobsen Steven J. , Rodeheffer Richard J. 
Published: June 2013

Background—
Cross-sectional studies suggest that left ventricular (LV) and arterial elastance (stiffness) increase with age, but data examining longitudinal changes within human subjects are lacking. In addition, it remains unknown whether age-related LV stiffening is merely a reaction to arterial stiffening or caused by other processes.

Methods and Results—

Comprehensive echo-Doppler cardiography was performed in 1402 subjects participating in a randomly selected community-based study at 2 examinations separated by 4 years. From this population, 788 subjects had adequate paired data to determine LV end-systolic elastance (Ees), end-diastolic elastance (Eed), and effective arterial elastance. Throughout 4 years, blood pressure, arterial elastance, and LV mass decreased, coupled with significantly greater use of antihypertensive medications. However, despite reductions in arterial load, Ees increased by 14% (2.10±0.67–2.26±0.70 mm Hg/mL;
P
<0.0001) and Eed increased by 8% (0.13±0.03–0.14±0.04 mm Hg/mL;
P
<0.0001). Increases in Eed were greater in women than men, whereas Ees changes were similar. Age-related increases in Ees and Eed were correlated with changes in body weight, but were similar in subjects with or without cardiovascular disease. Changes in Ees were correlated with Eed (
r
=0.5;
P
<0.0001), but not with other measures of contractility, indicating that the increase in Ees was reflective of passive stiffening rather than enhanced systolic function.

Conclusions—
Despite reductions in arterial load with medical therapy, LV systolic and diastolic stiffness increase over time in humans, particularly in women. In addition to blood pressure control, therapies targeting load-independent ventricular stiffening may be effective to treat and prevent age-associated cardiovascular diseases, such as heart failure.
Identification of Nodal Tissue in the Living Heart Using Rapid Scanning Fiber-Optics Confocal Microscopy and Extracellular Fluorophores
Authors: Huang Chao , Kaza Aditya K. , Hitchcock Robert W. , Sachse Frank B. 
Published: June 2013

Background—
Risks associated with pediatric reconstructive heart surgery include injury of the sinoatrial node (SAN) and atrioventricular node (AVN), requiring cardiac rhythm management using implantable pacemakers. These injuries are the result of difficulties in identifying nodal tissues intraoperatively. Here we describe an approach based on confocal microscopy and extracellular fluorophores to quantify tissue microstructure and identify nodal tissue.

Methods and Results—

Using conventional 3-dimensional confocal microscopy we investigated the microstructural arrangement of SAN, AVN, and atrial working myocardium (AWM) in fixed rat heart. AWM exhibited a regular striated arrangement of the extracellular space. In contrast, SAN and AVN had an irregular, reticulated arrangement. AWM, SAN, and AVN tissues were beneath a thin surface layer of tissue that did not obstruct confocal microscopic imaging. Subsequently, we imaged tissues in living rat hearts with real-time fiber-optics confocal microscopy. Fiber-optics confocal microscopy images resembled images acquired with conventional confocal microscopy. We investigated spatial regularity of tissue microstructure from Fourier analysis and second-order image moments. Fourier analysis of fiber-optics confocal microscopy images showed that the spatial regularity of AWM was greater than that of nodal tissues (37.5±5.0% versus 24.3±3.9% for SAN and 23.8±3.7% for AVN;
P
<0.05). Similar differences of spatial regularities were revealed from second-order image moments (50.0±7.3% for AWM versus 29.3±6.7% for SAN and 27.3±5.5% for AVN;
P
<0.05).

Conclusions—
The study demonstrates feasibility of identifying nodal tissue in living heart using extracellular fluorophores and fiber-optics confocal microscopy. Application of the approach in pediatric reconstructive heart surgery may reduce risks of injuring nodal tissues.