bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis
Authors: Péqueux Christel , Raymond-Letron Isabelle , Blacher Silvia , Boudou Frédéric , Adlanmerini Marine , Fouque Marie-José , Rochaix Philippe , Noël Agnès , Foidart Jean-Michel , Krust Andrée , Chambon Pierre , Brouchet Laurent , Arnal Jean-François , Lenfant Françoise 
Published: April 2012

Abstract
Estrogens directly promote the growth of breast cancers that express the estrogen receptor α (ERα). However, the contribution of stromal expression of ERα in the tumor microenvironment to the protumoral effects of estrogen has never been explored. In this study, we evaluated the molecular and cellular mechanisms by which 17β-estradiol (E2) impacts the microenvironment and modulates tumor development of ERα-negative tumors. Using different mouse models of ER-negative cancer cells grafted subcutaneously into syngeneic ovariectomized immunocompetent mice, we found that E2 potentiates tumor growth, increases intratumoral vessel density, and modifies tumor vasculature into a more regularly organized structure, thereby improving vessel stabilization to prevent tumor hypoxia and necrosis. These E2-induced effects were completely abrogated in ERα-deficient mice, showing a critical role of host ERα. Notably, E2 did not accelerate tumor growth when ERα was deficient in Tie2-positive cells, even in mice grafted with wild-type bone marrow. These results were extended by clinical evidence of ERα-positive stromal cell labeling in the microenvironment of human breast cancers. Together, our findings therefore show that E2 promotes the growth of ERα-negative cancer cells through the activation of stromal ERα (extra-hematopoietic Tie-2 positive cells), which normalizes tumor angiogenesis and allows an adaptation of blood supply to tumors, thereby preventing hypoxia and necrosis. These findings significantly deepen mechanistic insights into the impact of E2 on tumor development with potential consequences for cancer treatment. Cancer Res; 72(12); 3010–9. ©2012 AACR.
The Proto-oncogene PKCι Regulates the Alternative Splicing of Bcl-x Pre-mRNA
Authors: Shultz Jacqueline C. , Vu Ngoc , Shultz Michael D. , Mba Mba-Uzoma U. , Shapiro Brian A. , Chalfant Charles E. 
Published: April 2012

AbstractTwo splice variants derived from the Bcl-x gene via alternative 5′ splice site selection (5′SS) are proapoptotic Bcl-x(s) and antiapoptotic Bcl-x(L). Previously, our laboratory showed that apoptotic signaling pathways regulated the alternative 5′SS selection via protein phosphatase-1 and de novo ceramide. In this study, we examined the elusive prosurvival signaling pathways that regulate the 5′SS selection of Bcl-x pre-mRNA in cancer cells. Taking a broad-based approach by using a number of small-molecule inhibitors of various mitogenic/survival pathways, we found that only treatment of non–small cell lung cancer (NSCLC) cell lines with the phosphoinositide 3-kinase (PI3K) inhibitor LY294002 (50 μmol/L) or the pan-protein kinase C (PKC) inhibitor Gö6983 (25 μmol/L) decreased the Bcl-x(L)/(s) mRNA ratio. Pan-PKC inhibitors that did not target the atypical PKCs, PKCι and PKCζ, had no effect on the Bcl-x(L)/(s) mRNA ratio. Additional studies showed that downregulation of the proto-oncogene, PKCι, in contrast to PKCζ, also resulted in a decrease in the Bcl-x(L)/(s) mRNA ratio. Furthermore, downregulation of PKCι correlated with a dramatic decrease in the expression of SAP155, an RNA trans-acting factor that regulates the 5′SS selection of Bcl-x pre-mRNA. Inhibition of the PI3K or atypical PKC pathway induced a dramatic loss of SAP155 complex formation at ceramide-responsive RNA cis-element 1. Finally, forced expression of Bcl-x(L) “rescued” the loss of cell survival induced by PKCι siRNA. In summary, the PI3K/PKCι regulates the alternative splicing of Bcl-x pre-mRNA with implications in the cell survival of NSCLC cells. Mol Cancer Res; 10(5); 660–9. ©2012 AACR.
Overexpression of Aurora-A Enhances Invasion and Matrix Metalloproteinase-2 Expression in Esophageal Squamous Cell Carcinoma Cells
Authors: Wang Xiaoxia , Lu Na , Niu Bo , Chen Xianjiu , Xie Jun , Cheng Niuliang 
Published: April 2012

Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers, and metastasis is the principal cause of death in ESCC patients. It has been shown that amplification and overexpression of mitotic serine/threonine kinase Aurora-A occur in several types of human tumors, including ESCC. Moreover, increase in expression levels of Aurora-A has been predicted to correlate with the grades of tumor differentiation and invasive capability. However, the mechanisms by which Aurora-A mediates its invasive effects still remain elusive. In this article, we showed that Aurora-A overexpression significantly increased cell migration and invasion as well as secretion and expression of matrix metalloproteinase-2 (MMP-2). Conversely, siRNA-mediated knockdown of Aurora-A expression in human ESCC cells led to inhibition of cell invasiveness as well as secretion and expression of MMP-2. In addition, Aurora-A overexpression increased phosphorylation levels of p38 mitogen-activated protein kinase (MAPK) and Akt, and the knockdown of Aurora-A by siRNA decreased the activity of p38 MAPK and Akt. Moreover, the blocking of the activity of above kinases using chemical inhibitors suppressed the ability of Aurora-A to induce MMP-2 secretion and expression as well as cell invasion. These data show that overexpression of Aurora-A contributes to the malignancy development of ESCC by enhancing tumor cell invasion as well as MMP-2 activity and expression, which can occur through signaling pathways involving p38 MAPK and Akt protein kinases. Taken together, these studies provide a molecular basis for promoting the role of Aurora-A in malignancy development of ESCC. Mol Cancer Res; 10(5); 588–96. ©2012 AACR.
Genetic Evidence That Lipoprotein(a) Associates With Atherosclerotic Stenosis Rather Than Venous Thrombosis
Authors: Kamstrup Pia R. , Tybjærg­-Hansen Anne , Nordestgaard Børge G. 
Published: April 2012

Objective—
The aim of the present study was to determine whether lipoprotein(a) [Lp(a)], considered a causal risk factor for cardiovascular disease, primarily promotes thrombosis or atherosclerosis.

Methods and Results—

Using a Mendelian randomization study design, we measured plasma Lp(a) and genetically elevated Lp(a) levels through the
LPA
kringle IV type 2 repeat genotype in 41231 individuals. We included 2 general population studies of both venous thrombosis and combined thrombosis and atherosclerosis in coronary arteries (=myocardial infarction), and 3 ­case–­control studies of atherosclerotic stenosis. Neither Lp(a) tertiles nor
LPA
kringle IV type 2 tertiles associated with the risk of venous thrombosis in general population studies (trend:
P
=0.12–0.76), but did each associate with risk of coronary, carotid, and femoral atherosclerotic stenosis in ­case–­control studies (trend:
P
<0.001 to 0.04). Lp(a) and
LPA
kringle IV type 2 tertiles also associated with the risk of myocardial infarction in general population studies (trend:
P
<0.001 to 0.003). For doubling of Lp(a) levels, instrumental variable estimates of hazard/odds ratios were 1.02 (95% CI 0.90–1.15) and 1.04 (0.93–1.16) for venous thrombosis in the 2 general population studies, 1.12 (1.01–1.25), 1.17 (1.05–1.32), and 1.16 (1.01–1.35), respectively, for coronary, carotid, and femoral atherosclerotic stenosis in ­case–control studies, and 1.21 (1.10–1.33) and 1.17 (1.05–1.29) for myocardial infarction in general population studies.

Conclusion—
This supports that Lp(a) primarily promotes atherosclerotic stenosis rather than venous thrombosis.
Thioredoxin-1 Promotes Anti-Inflammatory Macrophages of the M2 Phenotype and Antagonizes Atherosclerosis
Authors: Hadri Khadija El , Mahmood Dler Faieeq Darweesh , Couchie Dominique , Jguirim-Souissi Imene , Genze Felicitas , Diderot Vimala , Syrovets Tatiana , Lunov Oleg , Simmet Thomas , Rouis Mustapha 
Published: April 2012

Objective—
Oxidative stress is believed to play a key role in cardiovascular disorders. Thioredoxin (Trx) is an oxidative stress-limiting protein with anti-inflammatory and antiapoptotic properties. Here, we analyzed whether Trx-1 might exert atheroprotective effects by promoting macrophage differentiation into the M2 anti-inflammatory phenotype.

Methods and Results—

Trx-1 at 1 μg/mL induced downregulation of p16
INK4a
and significantly promoted the polarization of anti-inflammatory M2 macrophages in macrophages exposed to interleukin (IL)-4 at 15 ng/mL or IL-4/IL-13 (10 ng/mL each) in vitro, as evidenced by the expression of the CD206 and IL-10 markers. In addition, Trx-1 induced downregulation of nuclear translocation of activator protein-1 and Ref-1, and significantly reduced the lipopolysaccharide-induced differentiation of inflammatory M1 macrophages, as indicated by the decreased expression of the M1 cytokines, tumor necrosis factor-α and monocyte chemoattractant protein-1. Consistently, Trx-1 administered to hyperlipoproteinemic ApoE2.Ki mice at 30 μg/30 g body weight challenged either with lipopolysaccharide at 30 μg/30 g body weight or with IL-4 at 500 ng/30 g body weight significantly induced the M2 phenotype while inhibiting differentiation of macrophages into the M1 phenotype in liver and thymus. ApoE2.Ki mice challenged once weekly with lipopolysaccharide for 5 weeks developed severe atherosclerotic lesions enriched with macrophages expressing predominantly M1 over M2 markers. In contrast, however, daily injections of Trx-1 shifted the phenotype pattern of lesional macrophages in these animals to predominantly M2 over M1, and the aortic lesion area was significantly reduced (from 100%±18% to 62.8%±9.8%; n=8;
P
<0.01). Consistently, Trx-1 colocalized with M2 but not with M1 macrophage markers in human atherosclerotic vessel specimens.

Conclusion—
The ability of Trx-1 to promote differentiation of macrophages into an alternative, anti-inflammatory phenotype may explain its protective effects in cardiovascular diseases. These data provide novel insight into the link between oxidative stress and cardiovascular diseases.
Attenuation of Early Atherogenesis in Low-Density Lipoprotein Receptor–Deficient Mice by Proteasome Inhibition
Authors: Wilck Nicola , Fechner Mandy , Dreger Henryk , Hewing Bernd , Arias Aimara , Meiners Silke , Baumann Gert , Stangl Verena , Stangl Karl , Ludwig Antje 
Published: April 2012

Objective—
Low and nontoxic proteasome inhibition has anti-inflammatory, antiproliferative, and antioxidative effects on vascular cells in vitro and in vivo. We hypothesized that low-dose inhibition of the proteasome could provide antiatherogenic protection. The present study investigated the effect of low-dose proteasome inhibition on early lesion formation in low-density lipoprotein receptor–deficient mice fed a Western-type diet.

Methods and Results—
Male low-density lipoprotein receptor–deficient mice, 10 weeks old, were fed a Western-type diet for 6 weeks with intraperitoneal injections of bortezomib or solvent. Bortezomib was injected at a dose of 50 μg/kg body weight. Cholesterol plasma levels were not affected by bortezomib treatment. En face Oil Red O staining of aortae and aortic root cryosections demonstrated significant reduction of atherosclerotic lesion coverage in bortezomib-treated animals. Bortezomib significantly reduced vascular cellular adhesion molecule-1 expression and macrophage infiltration as shown by histological analysis. Bortezomib treatment resulted in a significant reduction of superoxide content, lipid peroxidation and protein oxidation products, serum levels of monocyte chemoattractant protein-1, and interleukin-6. Gene expression microarray analysis showed that expressional changes induced by Western-type diet were attenuated by treatment with low-dose bortezomib.

Conclusion—
Low-dose proteasome inhibition exerts antioxidative and anti-inflammatory effects and attenuates development of atherosclerotic lesions in low-density lipoprotein receptor–deficient mice.
Depressive Symptoms, a Time-Dependent Risk Factor for Coronary Heart Disease and Stroke in Middle-Aged Men
Authors: Majed Bilal , Arveiler Dominique , Bingham Annie , Ferrieres Jean , Ruidavets Jean-Bernard , Montaye Michèle , Appleton Katherine , Haas Bernadette , Kee Frank , Amouyel Philippe , Ducimetiere Pierre , Empana Jean-Philippe 
Published: April 2012

Background and Purpose—
To date, the association between depressive symptoms and the risk of cardiovascular diseases remains controversial. We investigated prospectively, within the same population, the time course of the association between baseline depressive symptoms and first stroke or coronary heart disease event.

Methods—
In the Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study, a multicenter, observational, prospective cohort, 9601 men from France and Northern Ireland were surveyed for the occurrence of first coronary heart disease (n=647) and stroke events (n=136) over 10 years. At baseline, the fourth quartile of a 13-item modified Center for Epidemiological Studies questionnaire was used to define the presence of depressive symptoms. We sought the best time-dependent function to assess the association between depressive symptoms and outcomes. Thus, the hazard ratios were estimated by a Cox proportional hazard model after splitting the follow-up before and after 5 years of follow-up time periods.

Results—
Depressive symptoms at baseline were associated with coronary heart disease in the first 5 years of follow-up (hazard ratio, 1.43; 1.10–1.87) and with stroke in the second 5 years of follow up (hazard ratio, 1.96; 1.21–3.19) after adjustment for age, study centers, baseline socioeconomic factors, traditional vascular risk factors, and antidepressant treatment. The association was even stronger for ischemic stroke (n=108; hazard ratio, 2.48; 1.45–4.25).

Conclusions—
The current study suggests that in healthy, European, middle-aged men, baseline depressive symptoms are associated with an increased risk of coronary heart disease in the short-term, and for stroke in the long-term.
Factors Affecting Extension Ladder Angular Positioning
Authors: Simeonov Peter , Hsiao Hongwei , Kim In-Ju , Powers John R. , Kau Tsui-Ying 
Published: April 2012

Objective: The study objectives were to identify factors affecting extension ladders’ angular positioning and evaluate the effectiveness of two anthropometric positioning methods. Background: A leading cause for extension ladder fall incidents is a slide-out event, usually related to suboptimal ladder inclination. An improved ladder positioning method or procedure could reduce the risk of ladder stability failure and the related fall injury. Method: Participants in the study were 20 experienced and 20 inexperienced ladder users. A series of ladder positioning tests was performed in a laboratory environment with 4.88-m (16-ft) and 7.32-m (24-ft) ladders in extended and retracted positions. The setup methods included a no-instruction condition and two anthropometric approaches: the American National Standards Institute A14 and “fireman” methods. Performance measures included positioning angle and time. Results: The results indicated that ladder setup method and ladder effective length, defined by size and extended state, affected ladder positioning angle. On average, both anthropometric methods were effective in improving extension ladder positioning; however, they required 50% more time than did the no-instruction condition and had a 9.5% probability of setting the ladder at a less-than-70° angle. Shorter ladders were consistently positioned at shallower angles. Conclusion: Anthropometric methods may lead to safer ladder positioning than does no instruction when accurately and correctly performed. Workers tended to underperform as compared with their theoretical anthropometric estimates. Specific training or use of an assistive device may be needed to improve ladder users’ performance. Application: The results provide practical insights for employers and workers to correctly set up extension ladders.
Pharmacists’ Impact on Improving Outcomes in Patients With Type 2 Diabetes Mellitus
Authors: Pepper Matthew J. , Mallory Natohya , Coker T. Nicole , Chaki Amber , Sando Karen R. 
Published: April 2012

Purpose The purpose of this study was to evaluate a diabetes education program that includes a pharmacist as a member of the diabetes management team by assessing the change in hemoglobin A1c (A1C), cholesterol, and blood pressure for patients with type 2 diabetes in outpatient clinics. Methods This was a retrospective study in outpatient clinics at Shands Jacksonville Medical Center. The patients were assigned into either the pharmacist group or the nonpharmacist group, according to the presence or the absence of a pharmacist in the clinic. The primary end point was the absolute change in A1C versus baseline. Secondary end points included change in cholesterol and blood pressure and the number of patients to attain American Diabetes Association goals. End points were recorded to correlate within 3 months of the initial visit and final visit with a provider. Results Compared to the nonpharmacist group, patients in the pharmacist group had more advanced and uncontrolled diabetes at baseline. The pharmacist group showed a greater percent change in A1C and improvement between the initial and final clinic visits, after adjusting for baseline confounders. Despite the statistically significant improvement in A1C in the pharmacist group, there was no difference found between the 2 groups for the end points of cholesterol and blood pressure. Conclusion Including a pharmacist as a part of the diabetes management team may result in lower A1C in patients with more advanced and uncontrolled type 2 diabetes mellitus versus a health care team without a pharmacist.
Bone Replacement of Fast-Absorbing Biocomposite Anchors in Arthroscopic Shoulder Labral Repairs
Authors: Milewski Matthew D. , Diduch David R. , Hart Joseph M. , Tompkins Marc , Ma Shen-Ying , Gaskin Cree M. 
Published: April 2012

Background: Newer generation biocomposite anchors are hypothesized to resorb more reliably and faster, while allowing for bone ingrowth and replacement. Purpose: The purposes of this study were to (1) assess anchor resorption and bone ingrowth over time, (2) identify tunnel widening or potential reactions to the implants, (3) compare imaging findings for different sites of labral repair, and (4) determine patient subjective outcomes with the use of biocomposite anchors in glenoid labral repair. Study Design: Case series; Level of evidence, 4. Methods: We enrolled 22 patients to participate in a 24-month outcomes study that included subjective and objective outcome assessments after glenoid labrum repair surgery. Magnetic resonance imaging (MRI) was performed at 6 and 12 months to identify any potential reactions to implants. Computed tomography (CT) scans were performed at 12 and 24 months to determine anchor resorption and bone ingrowth. Sixteen patients and 47 anchors were available for follow-up at 24 months. An independent, fellowship-trained musculoskeletal radiologist read the scans. Subjective outcome scores measured at 24 months postoperatively included Simple Shoulder Test, Tegner activity scale, American Shoulder and Elbow Surgeons (ASES), and University of California, Los Angeles (UCLA) shoulder scores. Results: No adverse events were reported with the use of biocomposite anchors at the end of the study period. At 12 and 24 months, respectively, CT scans demonstrated that an estimated 68% and 98% of combined anchor material had been absorbed, 56% and 78% of the anchor material had been replaced by soft tissue of variable density, and 9% and 20% of total anchor volume was replaced by bone. No obvious mechanical failure of the labral repairs was detected on nonarthrogram MRI. Three of the 47 anchors showed bone cyst formation. Tunnel widening (expansion beyond tunnel diameter of 3 mm; 2.9-mm drill hole utilized) was seen in 55% of the anchors but decreased between 12 and 24 months, consistent with bone replacement. Tunnel widening was seen more in anteroinferior and posterior glenoid anchor locations (84% and 57%, respectively) than in superior labral anchors (13%). Subjective outcome scores at 24 months for ASES and UCLA shoulder scores averaged 88 and 30, respectively. All but one patient were satisfied with their outcome at 24 months. Conclusion: Our imaging evaluation indicates resorption of newer generation biocomposite anchors with progressive bone replacement at 12 and 24 months while maintaining acceptable subjective outcomes.
Anatomic Femoral Tunnel Drilling in Anterior Cruciate Ligament Reconstruction
Authors: Tompkins Marc , Milewski Matthew D. , Brockmeier Stephen F. , Gaskin Cree M. , Hart Joseph M. , Miller Mark D. 
Published: April 2012

Background: During anatomic anterior cruciate ligament (ACL) reconstruction, we have found that the femoral footprint can best be visualized from the anteromedial portal. Independent femoral tunnel drilling can then be performed through an accessory medial portal, medial and inferior to the standard anteromedial portal. Purpose: To compare the accuracy of independent femoral tunnel placement relative to the ACL footprint using an accessory medial portal versus tunnel placement with a traditional transtibial technique. Study Design: Controlled laboratory study. Methods: Ten matched pairs of cadaveric knees were randomized such that within each pair, one knee underwent arthroscopic transtibial (TT) drilling, and the other underwent drilling through an accessory medial portal (AM). All knees underwent computed tomography (CT) both preoperatively and postoperatively with a technique optimized for ligament evaluation (80 keV with maximum mAs). Computed tomography was performed with a dual-energy scanner. Commercially available third-party software was used to fuse the preoperative and postoperative CT scans, allowing anatomic comparison of the ACL footprint to the drilled tunnel. The ACL footprint was marked in consensus by an orthopaedic surgeon and a musculoskeletal radiologist and then compared with the tunnel aperture after drilling. The percentage of tunnel aperture contained within the native footprint as well as the distance from the center of the tunnel aperture to the center of the footprint was measured. Results: The AM technique placed 97.7% ± 5% of the tunnel within the native femoral footprint, significantly more than 61.2% ± 24% for the TT technique ( P = .001). The AM technique placed the center of the femoral tunnel 3.6 ± 1.2 mm from the center of the native footprint, significantly closer than 6.0 ± 1.9 mm for the TT technique ( P = .003). Conclusion: This study demonstrates that use of an accessory medial portal will facilitate more accurate placement of the femoral tunnel in the native ACL femoral footprint. Clinical Relevance: More accurate placement of the femoral tunnel in the native ACL femoral footprint should improve the ability to achieve more anatomic positioning of the ACL graft.
Discomfort glare: What do we actually know?
Authors: Clear RD 
Published: April 2012

Glare models were reviewed with an eye for missing conditions or inconsistencies. Ambiguities were found relating to when to use small source versus large source models and as to what constitutes a glare source in a complex scene. Also, there was surprisingly little information validating the assumed independence of the factors driving glare. A barrier to progress in glare research is the lack of a standardized dependent measure of glare. The glare models were inverted so as to predict luminance and to compare model predictions against the 1949 Luckiesh and Guth data that form the basis of many of them. The models performed surprisingly poorly, particularly with regards to the luminance-size relationship and additivity. Evaluating glare in complex scenes may require fundamental changes to the form of the glare models.