bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age constraints and geochemistry of the Ordovician Tyrone Igneous Complex, Northern Ireland: implications for the Grampian orogeny
Authors: Cooper M.R. , Crowley Q.G. , Hollis S.P. , Noble S.R. , Roberts S. , Chew D. , Earls G. , Herrington R. , Merriman R.J. 
Published: June 2011

Abstract:

The Tyrone Igneous Complex is one of the largest areas of ophiolitic and arc-related rocks exposed along the northern margin of Iapetus within the British and Irish Caledonides. New U–Pb zircon data and regional geochemistry suggest that the Tyrone Plutonic Group represents the uppermost portions of a
c
. 480 Ma suprasubduction-zone ophiolite accreted onto an outboard segment of Laurentia prior to 470.3 ± 1.9 Ma. The overlying Tyrone Volcanic Group formed as an island arc that collided with the Laurentian margin during the Grampian phase of the Caledonidan orogeny. Early magmatism is characterized by transitional to calc-alkaline, light REE (LREE)-enriched island-arc signatures, with an increasing component of continentally derived material up sequence. Tholeiitic rhyolites with flat to U-shaped REE profiles and LREE-depleted basalts, located stratigraphically below a
c
. 473 Ma rhyolite of the upper Tyrone Volcanic Group, suggest initiation of intra-arc rifting at
c
. 475 Ma. Metamorphic cooling ages from the Tyrone Central Inlier imply arc–continent collision before 468 ± 1.4 Ma, with the emplacement of the Tyrone Volcanic Group onto the margin. A suite of 470.3 ± 1.9 Ma to 464.3 ± 1.5 Ma calc-alkaline intrusions are associated with the continued closure of Iapetus.

Supplementary material:

Geochemical data and petrography are available at
http://www.geolsoc.org.uk/SUP18467
.
A Low Carbohydrate, High Protein Diet Slows Tumor Growth and Prevents Cancer Initiation
Authors: Ho Victor W. , Leung Kelvin , Hsu Anderson , Luk Beryl , Lai June , Shen Sung Yuan , Minchinton Andrew I. , Waterhouse Dawn , Bally Marcel B. , Lin Wendy , Nelson Brad H. , Sly Laura M. , Krystal Gerald 
Published: June 2011

Abstract
Since cancer cells depend on glucose more than normal cells, we compared the effects of low carbohydrate (CHO) diets to a Western diet on the growth rate of tumors in mice. To avoid caloric restriction–induced effects, we designed the low CHO diets isocaloric with the Western diet by increasing protein rather than fat levels because of the reported tumor-promoting effects of high fat and the immune-stimulating effects of high protein. We found that both murine and human carcinomas grew slower in mice on diets containing low amylose CHO and high protein compared with a Western diet characterized by relatively high CHO and low protein. There was no weight difference between the tumor-bearing mice on the low CHO or Western diets.
Additionally, the low CHO-fed mice exhibited lower blood glucose, insulin, and lactate levels. Additive antitumor effects with the low CHO diets were observed with the mTOR inhibitor CCI-779 and especially with the COX-2 inhibitor Celebrex, a potent anti-inflammatory drug. Strikingly, in a genetically engineered mouse model of HER-2/neu–induced mammary cancer, tumor penetrance in mice on a Western diet was nearly 50% by the age of 1 year whereas no tumors were detected in mice on the low CHO diet. This difference was associated with weight gains in mice on the Western diet not observed in mice on the low CHO diet. Moreover, whereas only 1 mouse on the Western diet achieved a normal life span, due to cancer-associated deaths, more than 50% of the mice on the low CHO diet reached or exceeded the normal life span. Taken together, our findings offer a compelling preclinical illustration of the ability of a low CHO diet in not only restricting weight gain but also cancer development and progression. Cancer Res; 71(13); 4484–93. ©2011 AACR.
BMP4 Promotes Prostate Tumor Growth in Bone through Osteogenesis
Authors: Lee Yu-Chen , Cheng Chien-Jui , Bilen Mehmet A. , Lu Jing-Fang , Satcher Robert L. , Yu-Lee Li-Yuan , Gallick Gary E. , Maity Sankar N. , Lin Sue-Hwa 
Published: June 2011

Abstract
Induction of new bone formation is frequently seen in the bone lesions from prostate cancer. However, whether osteogenesis is necessary for prostate tumor growth in bone is unknown. Recently, 2 xenografts, MDA-PCa-118b and MDA-PCa-133, were generated from prostate cancer bone metastases. When implanted subcutaneously in severe combined immunodeficient (SCID) mice, MDA-PCa-118b induced strong ectopic bone formation while MDA-PCa-133 did not. To identify the factors that are involved in bone formation, we compared the expression of secreted factors (secretome) from MDA-PCa-118b and MDA-PCa-133 by cytokine array. We found that the osteogenic MDA-PCa-118b xenograft expressed higher levels of bone morphogenetic protein BMP4 and several cytokines including interleukin-8, growth-related protein (GRO), and CCL2. We showed that BMP4 secreted from MDA-PCa-118b contributed to about a third of the osteogenic differentiation seen in MDA-PCa-118b tumors. The conditioned media from MDA-PCa-118b induced a higher level of osteoblast differentiation, which was significantly reduced by treatment with BMP4 neutralizing antibody or the small molecule BMP receptor 1 inhibitor LDN-193189. BMP4 did not elicit an autocrine effect on MDA-PCa-118b, which expressed low to undetectable levels of BMP receptors. Treatment of SCID mice bearing MDA-PCa-118b tumors with LDN-193189 significantly reduced tumor growth. Thus, these studies support a role of BMP4-mediated osteogenesis in the progression of prostate cancer in bone. Cancer Res; 71(15); 5194–203. ©2011 AACR.
Microvesicles Released from Human Renal Cancer Stem Cells Stimulate Angiogenesis and Formation of Lung Premetastatic Niche
Authors: Grange Cristina , Tapparo Marta , Collino Federica , Vitillo Loriana , Damasco Christian , Deregibus Maria Chiara , Tetta Ciro , Bussolati Benedetta , Camussi Giovanni 
Published: June 2011

Abstract
Recent studies suggest that tumor-derived microvesicles (MV) act as a vehicle for exchange of genetic information between tumor and stromal cells, engendering a favorable microenvironment for cancer development. Within the tumor mass, all cell types may contribute to MV shedding, but specific contributions to tumor progression have yet to be established. Here we report that a subset of tumor-initiating cells expressing the mesenchymal stem cell marker CD105 in human renal cell carcinoma releases MVs that trigger angiogenesis and promote the formation of a premetastatic niche. MVs derived only from CD105-positive cancer stem cells conferred an activated angiogenic phenotype to normal human endothelial cells, stimulating their growth and vessel formation after in vivo implantation in immunocompromised severe combined immunodeficient (SCID) mice. Furthermore, treating SCID mice with MVs shed from CD105-positive cells greatly enhanced lung metastases induced by i.v. injection of renal carcinoma cells. Molecular characterization of CD105-positive MVs defines a set of proangiogenic mRNAs and microRNAs implicated in tumor progression and metastases. Our results define a specific source of cancer stem cell–derived MVs that contribute to triggering the angiogenic switch and coordinating metastatic diffusion during tumor progression. Cancer Res; 71(15); 5346–56. ©2011 AACR.
ERK1/2 and p38α/β Signaling in Tumor Cell Quiescence: Opportunities to Control Dormant Residual Disease
Authors: Sosa Maria Soledad , Avivar-Valderas Alvaro , Bragado Paloma , Wen Huei-Chi , Aguirre-Ghiso Julio A. 
Published: June 2011

Abstract
Systemic minimal residual disease after primary tumor treatment can remain asymptomatic for decades. This is thought to be due to the presence of dormant disseminated tumor cells (DTC) or micrometastases in different organs. DTCs lodged in brain, lungs, livers, and/or bone are a major clinical problem because they are the founders of metastasis, which ultimately kill cancer patients. The problem is further aggravated by our lack of understanding of DTC biology. In consequence, there are almost no rational therapies to prevent dormant DTCs from surviving and expanding. Several cancers, including melanoma as well as breast, prostate, and colorectal carcinomas, undergo dormant periods before metastatic recurrences develop. Here we review our experience in studying the cross-talk between ERK1/2 and p38α/β signaling in models of early cancer progression, dissemination, and DTC dormancy. We also provide some potential translational and clinical applications of these findings and describe how some currently used therapies might be useful to control dormant disease. Finally, we draw caution on the use of p38 inhibitors currently in clinical trials for different diseases as these may accelerate metastasis development. Clin Cancer Res; 17(18); 5850–7. ©2011 AACR.
Fibroblast Growth Factor Receptors Are Components of Autocrine Signaling Networks in Head and Neck Squamous Cell Carcinoma Cells
Authors: Marshall Marianne E. , Hinz Trista K. , Kono Scott A. , Singleton Katherine R. , Bichon Brady , Ware Kathryn E. , Marek Lindsay , Frederick Barbara A. , Raben David , Heasley Lynn E. 
Published: June 2011

AbstractPurpose: We previously reported that a fibroblast growth factor (FGF) receptor (FGFR) signaling pathway drives growth of lung cancer cell lines of squamous and large cell histologies. Herein, we explored FGFR dependency in cell lines derived from the tobacco-related malignancy, head and neck squamous cell carcinoma (HNSCC).Experimental Design: FGF and FGFR mRNA and protein expression was assessed in nine HNSCC cell lines. Dependence on secreted FGF2 for cell growth was tested with FP-1039, an FGFR1-Fc fusion protein. FGFR and epidermal growth factor receptor (EGFR) dependence was defined by sensitivity to multiple inhibitors selective for FGFRs or EGFR.Results: FGF2 was expressed in eight of the nine HNSCC cell lines examined. Also, FGFR2 and FGFR3 were frequently expressed, whereas only two lines expressed FGFR1. FP-1039 inhibited growth of HNSCC cell lines expressing FGF2, identifying FGF2 as an autocrine growth factor. FGFR inhibitors selectively reduced in vitro growth and extracellular signal-regulated kinase signaling in three HNSCC cell lines, whereas three distinct lines exhibited responsiveness to both EGFR and FGFR inhibitors. Combinations of these drugs yielded additive growth inhibition. Finally, three cell lines were highly sensitive to EGFR tyrosine kinase inhibitors (TKI) with no contribution from FGFR pathways.Conclusions: FGFR signaling was dominant or codominant with EGFR in six HNSCC lines, whereas three lines exhibited little or no role for FGFRs and were highly EGFR dependent. Thus, the HNSCC cell lines can be divided into subsets defined by sensitivity to EGFR and FGFR-specific TKIs. FGFR inhibitors may represent novel therapeutics to deploy alone or in combination with EGFR inhibitors in HNSCC. Clin Cancer Res; 17(15); 5016–25. ©2011 AACR.
Why Is This Effective HSP90 Inhibitor Not Being Developed in HER2+ Breast Cancer?
Authors: Arteaga Carlos L. 
Published: June 2011

Abstract
Inhibition of the HSP90 chaperone leads to degradation of the HER2 receptor. The HSP90 inhibitor tanespimycin in combination with trastuzumab is active in patients with HER2-overexpressing metastatic breast cancer. This combination is one of several HER2-targeted therapies that will significantly improve the outcome of patients with this subtype of breast cancer. Clin Cancer Res; 17(15); 4919–21. ©2011 AACR.
Neutralizing Monoclonal Antibody to Periostin Inhibits Ovarian Tumor Growth and Metastasis
Authors: Zhu Min , Saxton Romaine E. , Ramos Lillian , Chang David D. , Karlan Beth Y. , Gasson Judith C. , Slamon Dennis J. 
Published: June 2011

Abstract
Periostin, an extracellular matrix protein, is reported to be overexpressed in a variety of human cancers and its functions seem to be linked to tumor metastasis. Our previous results show that engineered periostin overexpression promotes ovarian tumor growth and dissemination in vivo. In this study, we developed a neutra-lizing monoclonal antibody to periostin, named MZ-1, and investigated its effects on human ovarian tumor growth and metastasis. Our in vivo studies showed significant growth inhibition by MZ-1 on both subcutaneous and intraperitoneal (i.p.) tumors derived from the periostin-expressing ovarian cancer cell line A2780. In addition, MZ-1 treatment led to a reduction of the metastatic potential of these A2780 i.p. tumors. The in vivo antitumor effects of MZ-1 were linked to its specific inhibition of anchorage-independent growth and survival of periostin-expressing cells, as well as its neutralizing effects on periostin-induced cancer cell migration and invasion. The data suggest that blocking periostin expression may be a novel approach for treating the subset of invasive ovarian tumors that overexpress periostin protein. Mol Cancer Ther; 10(8); 1500–8. ©2011 AACR.
A Pilot Clinical Study of Treatment Guided by Personalized Tumorgrafts in Patients with Advanced Cancer
Authors: Hidalgo Manuel , Bruckheimer Elizabeth , Rajeshkumar N.V. , Garrido-Laguna Ignacio , De Oliveira Elizabeth , Rubio-Viqueira Belen , Strawn Steven , Wick Michael J. , Martell James , Sidransky David 
Published: June 2011

Abstract
Patients with many advanced solid cancers have very poor prognosis, and improvements in life expectancy are measured only in months. We have recently reported the remarkable clinical outcome of a patient with advanced, gemcitabine-resistant, pancreatic cancer who was later treated with DNA-damaging agents, on the basis of the observation of significant activity of this class of drugs against a personalized tumorgraft generated from the patient's surgically resected tumor. Here, we extend the approach to patients with other advanced cancers. Tumors resected from 14 patients with refractory advanced cancers were propagated in immunodeficient mice and treated with 63 drugs in 232 treatment regimens. An effective treatment regimen in the xenograft model was identified for 12 patients. One patient died before receiving treatment, and the remaining 11 patients received 17 prospectively guided treatments. Fifteen of these treatments resulted in durable partial remissions. In 2 subjects, no effective treatments were found. Overall, there was a remarkable correlation between drug activity in the model and clinical outcome, both in terms of resistance and sensitivity. The data support the use of the personalized tumorgraft model as a powerful investigational platform for therapeutic decision making and to efficiently guide cancer treatment in the clinic. Mol Cancer Ther; 10(8); 1311–6. ©2011 AACR.
Loss of Methyl-CpG–Binding Domain Protein 2 Enhances Endothelial Angiogenesis and Protects Mice Against Hind-Limb Ischemic Injury
Authors: Rao Xiaoquan , Zhong Jixin , Zhang Shu , Zhang Yushan , Yu Qilin , Yang Ping , Wang Mong-Heng , Fulton David J. , Shi Huidong , Dong Zheng , Wang Daowen , Wang Cong-Yi 
Published: June 2011

Background—
Despite intensive investigation, how DNA methylation influences endothelial function remains poorly understood. We used methyl-CpG–binding domain protein 2 (MBD2), an interpreter for DNA methylome–encoded information, to dissect the impact of DNA methylation on endothelial function in both physiological and pathophysiological states.

Methods and Results—

Human umbilical vein endothelial cells under normal conditions express moderate levels of MBD2, but knockdown of MBD2 by siRNA significantly enhanced angiogenesis and provided protection against H
2
O
2
-induced apoptosis. Remarkably,
Mbd2
−/−
mice were protected against hind-limb ischemia evidenced by the significant improvement in perfusion recovery, along with increased capillary and arteriole formation. Loss of MBD2 activated endothelial survival and proangiogenic signals downstream of vascular endothelial growth factor signaling characterized by an increase in endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor receptor 2 expression, along with enhanced extracellular signal-regulated kinase 1/2 activation and BCL-2 expression. Mechanistic studies confirmed the methylation of CpG elements in the eNOS and vascular endothelial growth factor receptor 2 promoter. MBD2 binds to these methylated CpG elements and suppresses eNOS promoter activity. On ischemic insult, key endothelial genes such as eNOS and vascular endothelial growth factor receptor 2 undergo a DNA methylation turnover, and MBD2 interprets the changes of DNA methylation to suppress their expressions. Moreover, MBD2 modulation of eNOS expression is likely confined to endothelial cells because nonendothelial cells such as splenocytes fail to express eNOS after loss of MBD2.

Conclusions—
We provided direct evidence supporting that DNA methylation regulates endothelial function, which forms the molecular basis for understanding how environmental insults (epigenetic factor) affect the genome to modify disease susceptibility. Because MBD2 itself does not affect the methylation of DNA and is dispensable for normal physiology in mice, it could be a viable epigenetic target for modulating endothelial function in disease states.
Mitral Valve Abnormalities Identified by Cardiovascular Magnetic Resonance Represent a Primary Phenotypic Expression of Hypertrophic Cardiomyopathy
Authors: Maron Martin S. , Olivotto Iacopo , Harrigan Caitlin , Appelbaum Evan , Gibson C. Michael , Lesser John R. , Haas Tammy S. , Udelson James E. , Manning Warren J. , Maron Barry J. 
Published: June 2011

Background—
Whether morphological abnormalities of the mitral valve represent part of the hypertrophic cardiomyopathy (HCM) disease process is unresolved. Therefore, we applied cardiovascular magnetic resonance to characterize mitral valve morphology in a large HCM cohort.

Methods and Results—

Cine cardiac magnetic resonance images were obtained in 172 HCM patients (age, 42±18 years; 62% men) and 172 control subjects. In addition, 15 HCM gene-positive/phenotype-negative relatives were studied. Anterior mitral leaflet (AML) and posterior mitral leaflet lengths were greater in HCM patients than in control subjects (26±5 versus 19±5 mm,
P
<0.001; and 14±4 versus 10±3 mm,
P
<0.001, respectively), including 59 patients (34%) in whom AML length alone, posterior mitral leaflet length alone, or both were particularly substantial (>2 SDs above controls). Leaflet length was increased compared with controls in virtually all HCM age groups, including young patients 15 to 20 years of age (AML, 26±5 versus 21±4 mm;
P
=0.0002) and those ≥60 years of age (AML, 26±4 versus 19±2 mm;
P
<0.001). No relation was evident between mitral leaflet length and LV thickness or mass index (
P
=0.09 and
P
=0.16, respectively). A ratio of AML length to LV outflow tract diameter of >2.0 was associated with subaortic obstruction (
P
=0.001). In addition, AML length in 15 genotype-positive relatives without LV hypertrophy exceeded that of matched control subjects (21±3 versus 18±3 mm;
P
<0.01).

Conclusions—
In HCM, mitral valve leaflets are elongated independently of other disease variables, likely constituting a primary phenotypic expression of this heterogeneous disease, and are an important morphological abnormality responsible for LV outflow obstruction in combination with small outflow tract dimension. These findings suggest a novel role for cardiac magnetic resonance in the assessment of HCM.
Nonmuscle Myosin Light-Chain Kinase Deficiency Attenuates Atherosclerosis in Apolipoprotein E–Deficient Mice via Reduced Endothelial Barrier Dysfunction and Monocyte Migration
Authors: Sun Chongxiu , Wu Mack H. , Yuan Sarah Y. 
Published: June 2011

Background—
Endothelial dysfunction and monocyte migration are key events in the pathogenesis of atherosclerosis. Nonmuscle myosin light-chain kinase (nmMLCK), the predominant MLCK isoform in endothelial cells, has been shown to contribute to vascular inflammation by altering endothelial barrier function. However, its impact on atherogenesis remains unknown.

Methods and Results—

We investigated the role of nmMLCK in the development of atherosclerotic lesions in apolipoprotein E–deficient (
apoE
−/−
) mice fed an atherogenic diet for 12 weeks. Histopathological examination demonstrated that nmMLCK deficiency (
apoE
−/−
nmmlck
−/−
) reduced the size of aortic lesions by 53%, lipid contents by 44%, and macrophage deposition by 40%. Western blotting and reverse-transcription polymerase chain reaction revealed the expression of nmMLCK in aortic endothelial cells and peripheral blood monocytes. Measurements of transendothelial electric resistance indicated that nmMLCK deficiency attenuated endothelial barrier dysfunction caused by thrombin, oxidized low-density lipoprotein, and tumor necrosis factor α. In monocytes, nmMLCK deficiency reduced their migration in response to the chemokine monocyte chemoattractant protein-1. Further mechanistic studies showed that nmMLCK acted through both myosin light chain phosphorylation-coupled and -uncoupled pathways; the latter involved Rous sacracoma virus homolog genes-encoded tyrosine kinases (Src) signaling. Moreover, depletion of Src via gene silencing, site-specific mutagenesis, or pharmacological inhibition of Src greatly attenuated nmMLCK-dependent endothelial barrier dysfunction and monocyte migration.

Conclusions—
Nonmuscle myosin light-chain kinase contributes to atherosclerosis by regulating endothelial barrier function and monocyte migration via mechanisms involving not only kinase-mediated MLC phosphorylation but also Src activation.
Extracorporeal Membrane Oxygenation for Bridge to Heart Transplantation Among Children in the United States
Authors: Almond Christopher S. , Singh Tajinder P. , Gauvreau Kimberlee , Piercey Gary E. , Fynn-Thompson Francis , Rycus Peter T. , Bartlett Robert H. , Thiagarajan Ravi R. 
Published: June 2011

Background—
Extracorporeal membrane oxygenation (ECMO) has served for >2 decades as the standard of care for US children requiring mechanical support as a bridge to heart transplantation. Objective data on the safety and efficacy of ECMO for this indication are limited. We describe the outcomes of ECMO as a bridge to heart transplantation to serve as performance benchmarks for emerging miniaturized assist devices intended to replace ECMO.

Methods and Results—
Data from the Extracorporeal Life Support Organization Registry and the Organ Procurement Transplant Network database were merged to identify children supported with ECMO and listed for heart transplantation from 1994 to 2009. Independent predictors of wait-list and posttransplantation in-hospital mortality were identified. Objective performance goals for ECMO were developed. Of 773 children, the median age was 6 months (interquartile range, 1 to 44 months); 28% had cardiomyopathy; and in 38%, a bridge to transplantation was intended at ECMO initiation. Overall, 45% of subjects reached transplantation, although one third of those transplanted died before discharge; overall survival to hospital discharge was 47%. Wait-list mortality was independently associated with congenital heart disease, cardiopulmonary resuscitation before ECMO, and renal dysfunction. Posttransplantation mortality was associated with congenital heart disease, renal dysfunction, ECMO duration of >14 days, and initial ECMO indication as a bridge to recovery. In the objective performance goal cohort (n=485), patients with cardiomyopathy had the highest survival to hospital discharge (63%), followed by patients with myocarditis (59%), 2-ventricle congenital heart disease (44%) and 1-ventricle congenital heart disease (33%).

Conclusion—
Although ECMO is effective for short-term circulatory support, it is not reliable for the long-term circulatory support necessary for children awaiting heart transplantation. Fewer than half of patients bridged with ECMO survive to hospital discharge. More effective modalities for chronic circulatory support in children are urgently needed.