bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting CXCR1/2 Significantly Reduces Breast Cancer Stem Cell Activity and Increases the Efficacy of Inhibiting HER2 via HER2-Dependent and -Independent Mechanisms
Authors: Singh Jagdeep K. , Farnie Gillian , Bundred Nigel J. , Simões Bruno M , Shergill Amrita , Landberg Göran , Howell Sacha J. , Clarke Robert B. 
Published: November 2012

Abstract
Purpose: Breast cancer stem-like cells (CSC) are an important therapeutic target as they are predicted to be responsible for tumor initiation, maintenance, and metastases. Interleukin (IL)-8 is upregulated in breast cancer and is associated with poor prognosis. Breast cancer cell line studies indicate that IL-8 via its cognate receptors, CXCR1 and CXCR2, is important in regulating breast CSC activity. We investigated the role of IL-8 in the regulation of CSC activity using patient-derived breast cancers and determined the potential benefit of combining CXCR1/2 inhibition with HER2-targeted therapy.
Experimental Design: CSC activity of metastatic and invasive human breast cancers (n = 19) was assessed ex vivo using the mammosphere colony-forming assay.
Results: Metastatic fluid IL-8 level correlated directly with mammosphere formation (r = 0.652; P &lt; 0.05; n = 10). Recombinant IL-8 directly increased mammosphere formation/self-renewal in metastatic and invasive breast cancers (n = 17). IL-8 induced activation of EGFR/HER2 and downstream signaling pathways and effects were abrogated by inhibition of SRC, EGFR/HER2, phosphoinositide 3-kinase (PI3K), or MEK. Furthermore, lapatinib, which targets EGFR/HER2, inhibited the mammosphere-promoting effect of IL-8 in both HER2-positive and negative patient-derived cancers. CXCR1/2 inhibition also blocked the effect of IL-8 on mammosphere formation and added to the efficacy of lapatinib in HER2-positive cancers.
Conclusions: These studies establish a role for IL-8 in the regulation of patient-derived breast CSC activity and show that IL-8/CXCR1/2 signaling is partly mediated via a novel SRC and EGFR/HER2-dependent pathway. Combining CXCR1/2 inhibitors with current HER2-targeted therapies has potential as an effective therapeutic strategy to reduce CSC activity in breast cancer and improve the survival of HER2-positive patients. Clin Cancer Res; 19(3); 643–56. ©2012 AACR.
Interleukin 15 Provides Relief to CTLs from Regulatory T Cell–Mediated Inhibition: Implications for Adoptive T Cell–Based Therapies for Lymphoma
Authors: Perna Serena K. , De Angelis Biagio , Pagliara Daria , Hasan Sayyeda T. , Zhang Lan , Mahendravada Aruna , Heslop Helen E. , Brenner Malcolm K. , Rooney Cliona M. , Dotti Gianpietro , Savoldo Barbara 
Published: November 2012

AbstractPurpose: Systemic administration of recombinant interleukin (IL)-2 is used to support the expansion and persistence of adoptively transferred antigen-specific CTLs in patients with cancer. However, IL-2 also expands regulatory T cells (Treg) that in turn impair the antitumor activity of CTLs. As recombinant IL-15 is approaching clinical applications, we assessed the effects of this cytokine on the proliferation and antitumor activity of CTLs in the presence of Tregs. We used the model of adoptive transfer of Epstein–Barr virus (EBV)-CTLs, as these cells induce responses in patients with EBV-associated Hodgkin lymphoma, and Tregs are frequently abundant in these patients.Experimental Design: Tregs were isolated from the peripheral blood of healthy donors and patients with Hodgkin lymphoma or from Hodgkin lymphoma tumors and assessed for their ability to inhibit the proliferation and antitumor activity of EBV-CTLs in the presence of IL-15 or IL-2. Specific molecular pathways activated by IL-15 were also explored.Results: We found that in the presence of Tregs, IL-15, but not IL-2, promoted the proliferation, effector function, and resistance to apoptosis of effectors T cells and EBV-CTLs. IL-15 did not reverse or block Tregs but instead preferentially supported the proliferation of CTLs and effector T cells as compared with Tregs.Conclusions: IL-15 selectively favors the survival, proliferation, and effector function of antigen-specific CTLs in the presence of Tregs, and thus IL-15, unlike IL-2, would have a significant impact in sustaining expansion and persistence of adoptively transferred CTLs in patients with cancer, including those infused with EBV-CTLs for treatment of EBV-associated malignancies. Clin Cancer Res; 19(1); 106–17. ©2012 AACR.
Myocardial Structural Associations With Local Electrograms
Authors: Sasaki Takeshi , Miller Christopher F. , Hansford Rozann , Yang Juemin , Caffo Brian S. , Zviman Menekhem M. , Henrikson Charles A. , Marine Joseph E. , Spragg David , Cheng Alan , Tandri Harikrishna , Sinha Sunil , Kolandaivelu Aravindan , Zimmerman Stefan L. , Bluemke David A. , Tomaselli Gordon F. , Berger Ronald D. , Calkins Hugh , Halperin Henry R. , Nazarian Saman 
Published: November 2012

Background—
The association of scar on late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) with local electrograms on electroanatomic mapping has been investigated. We aimed to quantify these associations to gain insights regarding LGE-CMR image characteristics of tissues and critical sites that support postinfarct ventricular tachycardia (VT).

Methods and Results—
LGE-CMR was performed in 23 patients with ischemic cardiomyopathy before VT ablation. Left ventricular wall thickness and postinfarct scar thickness were measured in each of 20 sectors per LGE-CMR short-axis plane. Electroanatomic mapping points were retrospectively registered to the corresponding LGE-CMR images. Multivariable regression analysis, clustered by patient, revealed significant associations among left ventricular wall thickness, postinfarct scar thickness, and intramural scar location on LGE-CMR, and local endocardial electrogram bipolar/unipolar voltage, duration, and deflections on electroanatomic mapping. Anteroposterior and septal/lateral scar localization was also associated with bipolar and unipolar voltage. Antiarrhythmic drug use was associated with electrogram duration. Critical sites of postinfarct VT were associated with >25% scar transmurality, and slow conduction sites with >40 ms stimulus-QRS time were associated with >75% scar transmurality.

Conclusions—
Critical sites for maintenance of postinfarct VT are confined to areas with >25% scar transmurality. Our data provide insights into the structural substrates for delayed conduction and VT and may reduce procedural time devoted to substrate mapping, overcome limitations of invasive mapping because of sampling density, and enhance magnetic resonance–based ablation by feature extraction from complex images.
Diagnosis, Treatment, and Outcome of Giant-Cell Myocarditis in the Era of Combined Immunosuppression
Authors: Kandolin Riina , Lehtonen Jukka , Salmenkivi Kaisa , Räisänen-Sokolowski Anne , Lommi Jyri , Kupari Markku 
Published: November 2012

Background—
Giant-cell myocarditis often escapes diagnosis until autopsy or transplantation and has defied proper treatment trials for its rarity and deadly behavior. Current therapy rests on multiple-drug immunosuppression but its prognostic influence remains poorly known. We set out to analyze (1) our experience in diagnosing giant-cell myocarditis and (2) the outcome of patients on combined immunosuppression.

Methods and Results—
We reviewed the histories, diagnostic procedures, details of treatment, and outcome of 32 consecutive patients with histologically verified giant-cell myocarditis treated in our hospital since 1991. Twenty-six patients (81%) were diagnosed by endomyocardial or surgical biopsies and 6 at autopsy or post-transplantation. Twenty-eight (88%) patients underwent endomyocardial biopsy. The sensitivity of transvenous endomyocardial biopsy increased from 68% (19/28 patients) to 93% (26/28) after up to 2 repeat procedures. The 26 biopsy-diagnosed patients were treated with combined immunosuppression (2–4 drugs) including cyclosporine in 20 patients. The Kaplan-Meier estimates of transplant-free survival from symptom onset were 69% at 1 year, 58% at 2 years, and 52% at 5 years. Of the transplant-free survivors, 10/17 (59%) experienced sustained ventricular tachyarrhythmias during follow-up and 3 received intracardiac defibrillator shocks for ventricular tachycardia or fibrillation.

Conclusions—
Repeat endomyocardial biopsies are frequently needed to diagnose giant-cell myocarditis. On contemporary immunosuppession, two thirds of patients reach a partial clinical remission characterized by freedom from severe heart failure and need of transplantation but continuing proneness to ventricular tachyarrhythmias.
Impact of Diabetes Mellitus on Vessel Response in the Drug-Eluting Stent Era
Authors: Sakata Kenji , Waseda Katsuhisa , Kume Teruyoshi , Otake Hiromasa , Nakatani Daisaku , Yock Paul G. , Fitzgerald Peter J. , Honda Yasuhiro 
Published: November 2012

Background—
Exaggerated neointimal hyperplasia is considered as the primary mechanism for increased restenosis in patients with diabetes mellitus (DM) treated with bare-metal stent. However, the vessel response in DM and non-DM treated with different drug-eluting stents (DES) has not been systematically evaluated.

Methods and Results—
We investigated 3D intravascular ultrasound (postprocedure and 6 to 9 months) in 971 patients (267 with DM and 704 without DM) treated with sirolimus- (n=104), paclitaxel- (n=303), zotarolimus- (n=391), or everolimus- (n=173) eluting stents. Volumetric data were standardized by length as volume index (VI). At postprocedure, lumen VI at the stented segment was significantly smaller in DM than in non-DM, whereas vessel VI was similar between the 2 groups. At follow-up, neointimal obstruction and maximum cross-sectional narrowing (neointimal area/stent area) were not significantly different between the 2 groups with no interaction for the DES type. Consequently, lumen VI was smaller in DM than in non-DM at follow-up. In the reference segments, residual plaque burden at postprocedure was significantly greater in DM than in non-DM, although change in lumen VI was similar between the 2 groups. The arterial responses at the reference segments also showed no interaction for the DES type.

Conclusions—
DM and non-DM lesions showed similar vessel response in both in-stent and reference segments regardless of the DES type. In the DES era, the follow-up lumen in DM patients seems to be determined primarily by the smaller lumen at postprocedure rather than exaggerated neointima within the stent or plaque proliferation at the reference segments.
Circulating 25-Hydroxy-Vitamin D and Risk of Cardiovascular Disease
Authors: Wang Lu , Song Yiqing , Manson JoAnn E. , Pilz Stefan , März Winfried , Michaëlsson Karl , Lundqvist Annamari , Jassal Simerjot K. , Barrett-Connor Elizabeth , Zhang Cuilin , Eaton Charles B. , May Heidi T. , Anderson Jeffrey L. , Sesso Howard D. 
Published: November 2012

Background—
Vitamin D status has been linked to the risk of cardiovascular disease (CVD). However, the optimal 25-hydroxy-vitamin D (25[OH]-vitamin D) levels for potential cardiovascular health benefits remain unclear.

Methods and Results—
We searched MEDLINE and EMBASE from 1966 through February 2012 for prospective studies that assessed the association of 25(OH)-vitamin D concentrations with CVD risk. A total of 24 articles met our inclusion criteria, from which 19 independent studies with 6123 CVD cases in 65 994 participants were included for a meta-analysis. In a comparison of the lowest with the highest 25(OH)-vitamin D categories, the pooled relative risk was 1.52 (95% confidence interval, 1.30–1.77) for total CVD, 1.42 (95% confidence interval, 1.19–1.71) for CVD mortality, 1.38 (95% confidence interval, 1.21–1.57) for coronary heart disease, and 1.64 (95% confidence interval, 1.27–2.10) for stroke. These associations remained strong and significant when analyses were limited to studies that excluded participants with baseline CVD and were better controlled for season and confounding. We used a fractional polynomial spline regression analysis to assess the linearity of dose–response association between continuous 25(OH)-vitamin D and CVD risk. The CVD risk increased monotonically across decreasing 25(OH)-vitamin D below ≈60 nmol/L, with a relative risk of 1.03 (95% confidence interval, 1.00–1.06) per 25-nmol/L decrement in 25(OH)-vitamin D.

Conclusions—
This meta-analysis demonstrated a generally linear, inverse association between circulating 25(OH)-vitamin D ranging from 20 to 60 nmol/L and risk of CVD. Further research is needed to clarify the association of 25(OH)-vitamin D higher than 60 nmol/L with CVD risk and assess causality of the observed associations.
Attenuating Endoplasmic Reticulum Stress as a Novel Therapeutic Strategy in Pulmonary Hypertension
Authors: Dromparis Peter , Paulin Roxane , Stenson Trevor H. , Haromy Alois , Sutendra Gopinath , Michelakis Evangelos D. 
Published: November 2012

Background—
Evidence suggestive of endoplasmic reticulum (ER) stress in the pulmonary arteries of patients with pulmonary arterial hypertension has been described for decades but has never been therapeutically targeted. ER stress is a feature of many conditions associated with pulmonary arterial hypertension like hypoxia, inflammation, or loss-of-function mutations. ER stress signaling in the pulmonary circulation involves the activation of activating transcription factor 6, which, via induction of the reticulin protein Nogo, can lead to the disruption of the functional ER-mitochondria unit and the increasingly recognized cancer-like metabolic shift in pulmonary arterial hypertension that promotes proliferation and apoptosis resistance in the pulmonary artery wall. We hypothesized that chemical chaperones known to suppress ER stress signaling, like 4-phenylbutyrate (PBA) or tauroursodeoxycholic acid, will inhibit the disruption of the ER-mitochondrial unit and prevent/reverse pulmonary arterial hypertension.

Methods and Results—
PBA in the drinking water both prevented and reversed chronic hypoxia–induced pulmonary hypertension in mice, decreasing pulmonary vascular resistance, pulmonary artery remodeling, and right ventricular hypertrophy and improving functional capacity without affecting systemic hemodynamics. These results were replicated in the monocrotaline rat model. PBA and tauroursodeoxycholic acid improved ER stress indexes in vivo and in vitro, decreased activating transcription factor 6 activation (cleavage, nuclear localization, luciferase, and downstream target expression), and inhibited the hypoxia-induced decrease in mitochondrial calcium and mitochondrial function. In addition, these chemical chaperones suppressed proliferation and induced apoptosis in pulmonary artery smooth muscle cells in vitro and in vivo.

Conclusions—
Attenuating ER stress with clinically used chemical chaperones may be a novel therapeutic strategy in pulmonary hypertension with high translational potential.
Soluble Urokinase Plasminogen Activator Receptor is Associated With Inflammation in the Vulnerable Human Atherosclerotic Plaque
Authors: Edsfeldt Andreas , Nitulescu Mihaela , Grufman Helena , Grönberg Caitriona , Persson Ana , Nilsson Marie , Persson Margaretha , Björkbacka Harry , Gonçalves Isabel 
Published: November 2012

Background and Purpose—
Recently, plasma soluble urokinase plasminogen activator receptor (suPAR) has gained interest as a marker of cardiovascular risk. suPAR is released through the cleavage of urokinase plasminogen activator receptor (uPAR), which is found in monocytes, activated T-lymphocytes and endothelial cells, all involved in atherosclerosis. suPAR levels have been well studied in plasma, but no studies have focused on suPAR in human atherosclerotic plaques. The aim of this study was to determine whether suPAR measured in the plaque is associated with symptomatic plaques and plaque inflammation.

Methods—
Plasma and carotid plaques from 162 patients were analyzed. Lipids, collagen, uPAR, and macrophages were measured histologically. Cytokines and suPAR were measured in homogenized plaque extracts using multiplex immunoassay and ELISA, respectively. Plasma levels of suPAR were analysed with ELISA. CD3, CD4, as well as uPAR mRNA expression were assessed with quantitative real-time polymerase chain reaction in plaque homogenates from 123 patients.

Results—
Plaque and plasma suPAR levels were higher in symptomatic patients compared with asymptomatic patients. Plaque suPAR levels correlated with plaque content of lipids and macrophages and with proinflammatory chemokines and cytokines monocyte chemoattractant protein 1, tumor necrosis factor α, interleukin 1β, interleukin 6, platelet-derived growth factor AB/BB, monocyte inflammatory protein 1β, regulated on activation normal T-cell expressed and secreted, and s-CD40L. uPAR mRNA and histological staining for uPAR correlated with plaque content of suPAR.

Conclusion—
This study shows that suPAR in human carotid plaques and plasma is associated with the presence of symptoms and that plaque suPAR is associated with the vulnerable inflammatory plaque. These findings strengthen the hypothesis of suPAR as a future marker of vulnerable atherosclerotic plaques.
Impairment of Cerebral Autoregulation Predicts Delayed Cerebral Ischemia After Subarachnoid Hemorrhage
Authors: Budohoski Karol P. , Czosnyka Marek , Smielewski Peter , Kasprowicz Magdalena , Helmy Adel , Bulters Diederik , Pickard John D. , Kirkpatrick Peter J. 
Published: November 2012

Background and Purpose—
Delayed cerebral ischemia (DCI) is a recognized contributor to unfavorable outcome after subarachnoid hemorrhage (SAH). Recent data challenge the concept of vasospasm as the sole cause of ischemia and suggest a multifactorial process with dysfunctional cerebral autoregulation as a component. We tested the hypothesis that early autoregulatory failure, detected using near-infrared spectroscopy–based index, TOxa and transcranial Doppler–based index, Sxa, can predict DCI.

Methods—
In this prospective observational study we enrolled consecutive patients with aneurysmal SAH that occurred <5 days from admission. The primary end point was the occurrence of DCI within 21 days of ictus. The predictive value of autoregulatory disturbances detected in the first 5 days was assessed using univarate proportional hazards model and a multivariate model.

Results—
Ninety-eight patients were included. Univariate analysis demonstrated increased odds of developing DCI when early autoregulation failure was detected (odds ratio [OR], 7.46; 95% confidence interval [CI], 3.03–18.40 and OR, 4.52; 95% CI, 1.84–11.07 for Sxa and TOxa, respectively) but not TCD-vasospasm (OR, 1.36; 95% CI, 0.56–3.33). In a multivariate model Sxa and TOxa remained independent predictors of DCI (OR, 12.66; 95% CI, 2.97–54.07 and OR, 5.34; 95% CI, 1.25–22.84 for Sxa and TOxa, respectively).

Conclusions—
Disturbed autoregulation in the first 5 days after SAH significantly increases the risk of DCI. Autoregulatory disturbances can be detected using near-infrared spectroscopy and transcranial Doppler technologies.
Aerosol Impacts on the Microphysical Growth Processes of Orographic Snowfall
Authors: Saleeby Stephen M. , Cotton William R. , Lowenthal Douglas , Messina Joe 
Published: November 2012

AbstractThe Regional Atmospheric Modeling System was used to simulate four winter snowfall events over the Park Range of Colorado. For each event, three hygroscopic aerosol sensitivity simulations were performed with initial aerosol profiles representing clean, moderately polluted, and highly polluted scenarios. Previous work demonstrates that the addition of aerosols can produce a snowfall spillover effect, during events in which riming growth of snow is prevalent in the presence of supercooled liquid water, that is due to a modified orographic cloud containing more numerous but smaller cloud droplets. This study focuses on the detailed microphysical processes that lead to snow growth in each event and how these processes are modulated by the addition of hygroscopic aerosols. A conceptual model of hydrometeor growth processes is presented, along a vertical orographic transect, that reveals zones of vapor deposition of ice and liquid, riming growth, evaporation, sublimation, and regions in which the Wegener–Bergeron–Findeisen (WBF) snow growth process is active. While the aerosol-induced spillover effect is largely determined by the degree of reduction in ice particle riming, an enhancement in the WBF snow growth process under more polluted conditions largely offsets the loss of rime growth, thus leading to a minimal net change in the regional precipitation.
The Modification of Sea Surface Temperature Anomaly Linear Damping Time Scales by Stratocumulus Clouds
Authors: Evan Amato T. , Allen Robert J. , Bennartz Ralf , Vimont Daniel J. 
Published: November 2012

Abstract
Stratocumulus (Sc) cloud cover is a persistent feature of the subtropical North and South Atlantic. It is well known that Sc cloud cover increases with decreasing temperatures of the underlying sea surface and that an increase in cloud cover will cool the surface temperatures via increasing the local albedo, otherwise known as the Sc feedback. In this study observations are used to quantify the magnitude and spatial structure of the Sc feedback in the tropical–extratropical Atlantic Ocean and investigate the role of the Sc feedback in shaping the evolution of coupled modes of variability there. The authors show that in the Atlantic the Sc feedback increases the time scales of Newtonian cooling by 40% and in an idealized linear model of the tropical Atlantic the dominant mode of coupled variability (the Atlantic meridional mode or dipole mode) would experience no transient growth without the influence of the Sc feedback on the surface temperature damping time scales. This study also investigates Atlantic Sc clouds and the Sc feedback in phase 3 of the Coupled Model Intercomparison Project (CMIP3) models. The authors find that most models have negative biases in the mean state of Sc cloud cover and do not reproduce the observed spatial structure of Atlantic Sc clouds. This study also shows that while the majority of models exhibit some agreement with observations in the meridional structure of the Sc feedback, the vast majority of models underestimate the dependence of Sc cloud cover on the underlying SST.