bluuebunny/crossref_metadata_2025_split huggingface dataset:
18FDG-PET Predicts Pharmacodynamic Response to OSI-906, a Dual IGF-1R/IR Inhibitor, in Preclinical Mouse Models of Lung Cancer
Authors: McKinley Eliot T. , Bugaj Joseph E. , Zhao Ping , Guleryuz Saffet , Mantis Christine , Gokhale Prafulla C. , Wild Robert , Manning H. Charles 
Published: January 2011

Abstract
Purpose: To evaluate 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography imaging (18FDG-PET) as a predictive, noninvasive, pharmacodynamic (PD) biomarker of response following administration of a small-molecule insulin-like growth factor-1 receptor and insulin receptor (IGF-1R/IR) inhibitor, OSI-906.
Experimental Design: In vitro uptake studies of 3H-2-deoxy glucose following OSI-906 exposure were conducted evaluating correlation of dose with inhibition of IGF-1R/IR as well as markers of downstream pathways and glucose metabolism. Similarly, in vivo PD effects were evaluated in human tumor cell line xenografts propagated in athymic nude mice by 18FDG-PET at 2, 4, and 24 hours following a single treatment of OSI-906 for the correlation of inhibition of receptor targets and downstream markers.
Results: Uptake of 3H-2-deoxy glucose and 18FDG was significantly diminished following OSI-906 exposure in sensitive tumor cells and subcutaneous xenografts (NCI-H292) but not in an insensitive model lacking IGF-1R expression (NCI-H441). Diminished PD 18FDG-PET, collected immediately following the initial treatment agreed with inhibition of pIGF-1R/pIR, reduced PI3K (phosphoinositide 3-kinase) and MAPK (mitogen activated protein kinase) pathway activity, and predicted tumor growth arrest as measured by high-resolution ultrasound imaging.
Conclusion: 18FDG-PET seems to serve as a rapid, noninvasive PD marker of IGF-1R/IR inhibition following a single dose of OSI-906 and should be explored clinically as a predictive clinical biomarker in patients undergoing IGF-1R/IR–directed cancer therapy. Clin Cancer Res; 17(10); 3332–40. ©2011 AACR.
A Phase I Clinical Trial of Safingol in Combination with Cisplatin in Advanced Solid Tumors
Authors: Dickson Mark A. , Carvajal Richard D. , Merrill Alfred H , Gonen Mithat , Cane Lauren M. , Schwartz Gary K. 
Published: January 2011

Abstract
Purpose: Sphingosine 1-phosphate (S1P) is an important mediator of cancer cell growth and proliferation. Production of S1P is catalyzed by sphingosine kinase 1 (SphK). Safingol, (l-threo-dihydrosphingosine) is a putative inhibitor of SphK. We conducted a phase I trial of safingol (S) alone and in combination with cisplatin (C).
Experimental Design: A 3 + 3 dose escalation was used. For safety, S was given alone 1 week before the combination. S + C were then administered every 3 weeks. S was given over 60 to 120 minutes, depending on dose. Sixty minutes later, C was given over 60 minutes. The C dose of 75 mg/m2 was reduced in cohort 4 to 60 mg/m2 due to excessive fatigue.
Results: Forty-three patients were treated, 41 were evaluable for toxicity, and 37 for response. The maximum tolerated dose (MTD) was S 840 mg/m2 over 120 minutes C 60 mg/m2, every 3 weeks. Dose-limiting toxicity (DLT) attributed to cisplatin included fatigue and hyponatremia. DLT from S was hepatic enzyme elevation. S pharmacokinetic parameters were linear throughout the dose range with no significant interaction with C. Patients treated at or near the MTD achieved S levels of more than 20 μmol/L and maintained levels greater than and equal to 5 μmol/L for 4 hours. The best response was stable disease in 6 patients for on average 3.3 months (range 1.8–7.2 m). One patient with adrenal cortical cancer had significant regression of liver and lung metastases and another had prolonged stable disease. S was associated with a dose-dependent reduction in S1P in plasma.
Conclusions: Safingol, the first putative SphK inhibitor to enter clinical trials, can be safely administered in combination with cisplatin. Reversible dose-dependent hepatic toxicity was seen, as expected from preclinical data. Target inhibition was achieved with downregulation of S1P. The recommended phase II dose is S 840 mg/m2 and C 60 mg/m2, every 3 weeks. Clin Cancer Res; 17(8); 2484–92. ©2011 AACR.
SST0001, a Chemically Modified Heparin, Inhibits Myeloma Growth and Angiogenesis via Disruption of the Heparanase/Syndecan-1 Axis
Authors: Ritchie Joseph P. , Ramani Vishnu C. , Ren Yongsheng , Naggi Annamaria , Torri Giangiacomo , Casu Benito , Penco Sergio , Pisano Claudio , Carminati Paolo , Tortoreto Monica , Zunino Franco , Vlodavsky Israel , Sanderson Ralph D. , Yang Yang 
Published: January 2011

AbstractPurpose: Heparanase promotes myeloma growth, dissemination, and angiogenesis through modulation of the tumor microenvironment, thus highlighting the potential of therapeutically targeting this enzyme. SST0001, a nonanticoagulant heparin with antiheparanase activity, was examined for its inhibition of myeloma tumor growth in vivo and for its mechanism of action.Experimental Design: The ability of SST0001 to inhibit growth of myeloma tumors was assessed using multiple animal models and a diverse panel of human and murine myeloma cell lines. To investigate the mechanism of action of SST0001, pharmacodynamic markers of angiogenesis, heparanase activity, and pathways downstream of heparanase were monitored. The potential use of SST0001 as part of a combination therapy was also evaluated in vivo.Results: SST0001 effectively inhibited myeloma growth in vivo, even when confronted with an aggressively growing tumor within human bone. In addition, SST0001 treatment causes changes within tumors consistent with the compound's ability to inhibit heparanase, including downregulation of HGF, VEGF, and MMP-9 expression and suppressed angiogenesis. SST0001 also diminishes heparanase-induced shedding of syndecan-1, a heparan sulfate proteoglycan known to be a potent promoter of myeloma growth. SST0001 inhibited the heparanase-mediated degradation of syndecan-1 heparan sulfate chains, thus confirming the antiheparanase activity of this compound. In combination with dexamethasone, SST0001 blocked tumor growth in vivo presumably through dual targeting of the tumor and its microenvironment.Conclusions: These results provide mechanistic insight into the antitumor action of SST0001 and validate its use as a novel therapeutic tool for treating multiple myeloma. Clin Cancer Res; 17(6); 1382–93. ©2011 AACR.
Pentraxin-3 Is a Novel Biomarker of Lung Carcinoma
Authors: Diamandis Eleftherios P. , Goodglick Lee , Planque Chris , Thornquist Mark D. 
Published: January 2011

Abstract
Purpose: Our objective was to validate the performance of three new candidate lung cancer biomarkers, pentraxin-3 (PTX3), human kallikrein 11 (KLK11), and progranulin.
Experimental Design: We analyzed by commercial ELISA, and with a blinded protocol, 422 samples from 203 patients with lung carcinoma, 180 individuals with high risk for lung cancer (heavy smokers), and 43 individuals with cancers other than lung. All samples were obtained from the Early Detection Research Network (Reference set A).
Results: We found that progranulin and KLK11 were not informative lung cancer biomarkers, with areas under the receiver operating characteristic curve (AUC; ROC), close to 0.50. However, PTX3 was an informative lung cancer biomarker, with considerable ability to separate lung cancer patients from high-risk controls. At 90% and 80% specificity, the sensitivities versus the high-risk control group were 37% and 48%, respectively. The discriminatory ability of PTX3 was about the same with all major subtypes and histotypes of lung cancer. The AUC of the ROC curves increased according to the disease stage, from 0.64 (stage I) to 0.72 (stage IV).
Conclusion: PTX3, but not KLK11 or progranulin, is a new serum biomarker for lung carcinoma. Its diagnostic sensitivity and specificity is similar to other clinically used lung cancer biomarkers. More studies are needed to establish if PTX3 has clinical utility for lung cancer diagnosis and management. Clin Cancer Res; 17(8); 2395–9. ©2011 AACR.
Mouse Snail Is a Target Gene for HIF
Authors: Luo Daochun , Wang Jinxia , Li Jeff , Post Martin 
Published: January 2011

Abstract
The transcriptional inhibitor Snail is a critical regulator for epithelial–mesenchymal transition (EMT). Although low oxygen induces Snail transcription, thereby stimulating EMT, a direct role of hypoxia-inducible factor (HIF) in this process remains to be demonstrated. Here we show that hypoxia induces the expression of Snail via HIF. In silico analysis identified a potential hypoxia-response element (HRE) close to the minimal promoter of the human and mouse genome of the snail gene. Gel shift assays demonstrated that a specific hypoxia-inducible complex is formed with the putative HRE and that the complex contains HIF proteins. ChIP assays confirmed the interaction of HIF proteins with the putative HRE in vivo. Reporter gene analyses showed that the putative HRE responds to hypoxia in its natural position as well as in front of a heterologous promoter and that the HRE is directly activated by HIF-1α or HIF-2α. HIF knockdown with siRNA at 2% oxygen and overexpression of an oxygen-insensitive HIF (HIF-ΔODD) mutant at 21% oxygen showed that HIF regulates Snail activation and subsequent cell migration. Our findings identify snail as a HIF target gene and provide novel insights into the regulation of snail and hypoxia-induced EMT. Mol Cancer Res; 9(2); 234–45. ©2011 AACR.
An Image-Based, High-Throughput Screening Assay for Molecules that Induce Excess DNA Replication in Human Cancer Cells
Authors: Zhu Wenge , Lee Chrissie Y. , Johnson Ronald L. , Wichterman Jennifer , Huang Ruili , DePamphilis Melvin L. 
Published: January 2011

Abstract
Previous studies have shown DNA re-replication can be induced in cells derived from human cancers under conditions in which it is not possible for cells derived from normal tissues. Because DNA re-replication induces cell death, this strategy could be applied to the discovery of potential anticancer therapeutics. Therefore, an imaging assay amenable to high-throughput screening was developed that measures DNA replication in excess of four genomic equivalents in the nuclei of intact cells and indexes cell proliferation. This assay was validated by screening a library of 1,280 bioactive molecules on both normal and tumor-derived cells where it proved more sensitive than current methods for detecting excess DNA replication. This screen identified known inducers of excess DNA replication, such as inhibitors of microtubule dynamics, and novel compounds that induced excess DNA replication in both normal and cancer cells. In addition, two compounds were identified that induced excess DNA replication selectively in cancer cells and one that induced endocycles selectively in cancer cells. Thus, this assay provides a new approach to the discovery of compounds useful for investigating the regulation of genome duplication and for the treatment of cancer. Mol Cancer Res; 9(3); 294–310. ©2011 AACR.
Effect of Chronic and Intermittent Calorie Restriction on Serum Adiponectin and Leptin and Mammary Tumorigenesis
Authors: Rogozina Olga P. , Bonorden Melissa J.L. , Seppanen Christine N. , Grande Joseph P. , Cleary Margot P. 
Published: January 2011

Abstract
The effect of chronic (CCR) and intermittent (ICR) caloric restriction on serum adiponectin and leptin levels was investigated in relation to mammary tumorigenesis. 10-wks old MMTV-TGF-α female mice were assigned to ad libitum fed (AL; AIN-93M diet), ICR (3-week 50% caloric restriction, AIN-93M-mod diet, 2× protein, fat, vitamins, and minerals followed by 3-wks 100% AL consumption of AIN-93M), and CCR (calorie and nutrient intake matched for each 6-wks ICR cycle, ∼75% of AL) groups. Mice were sacrificed at 79 (end of restriction) or 82 (end of refeeding) wks of age. Serum was obtained in cycles 1, 3, 5, 8, 11, and terminal. Mammary tumor incidence was 71.0%, 35.4%, and 9.1% for AL, CCR, and ICR mice, respectively. Serum adiponectin levels were similar among groups with no impact of either CCR or ICR. Serum leptin level rose in AL mice with increasing age but was significantly reduced by long-term CCR and ICR. The ICR protocol was also associated with an elevated adiponectin/leptin ratio. In addition, ICR-restricted mice had increased mammary tissue AdipoR1 expression and decreased leptin and ObRb expression compared with AL mice. Mammary fat pads from tumor-free ICR-mice had higher adiponectin expression than AL and CCR mice whereas all tumor-bearing mice had weak adiponectin signal in mammary fat pad. Although we did not show an association of either adiponectin or leptin with individual mice in relation to mammary tumorigenesis, we did find that reduced serum leptin and elevated adiponectin/leptin ratio were associated with the protective effect of intermittent calorie restriction. Cancer Prev Res; 4(4); 568–81. ©2011 AACR.
Enlargement of Catheter Ablation Lesions in Infant Hearts With Cryothermal Versus Radiofrequency Energy
Authors: Khairy Paul , Guerra Peter G. , Rivard Lena , Tanguay Jean-François , Landry Evelyn , Guertin Marie-Claude , Macle Laurent , Thibault Bernard , Tardif Jean-Claude , Talajic Mario , Roy Denis , Dubuc Marc 
Published: January 2011

Background—
Radiofrequency catheter ablation in immature hearts has been associated with marked enlargement of lesions over time, with potential for related late adverse events. It remains unknown whether cryothermal ablation lesions display a similar pattern of growth.

Methods and Results—

Ablation lesions (n=384) were performed in 32 infant miniature swine in right and left atria, ventricles, and atrioventricular (AV) grooves preselected by a randomized factorial design devised to compare radiofrequency and cryothermal lesions produced by 7F 4-mm electrode-tip catheters. Animals were euthanized acutely or at 1, 6, or 12 months, according to the randomization scheme. The miniature swine weighed 8.8±1.2 kg and were 63±13 days of age at time of ablation. The minimum temperature during cryoablation was −79.8±3.4°C and the average temperature during radiofrequency ablation was 54.4±5.5°C. On morphometric analyses, no differences in the rate of growth of ablation lesions were noted between the 2 energy modalities in atria (
P
=0.44), ventricles (
P
=0.57), or AV grooves (
P
=0.69). Lesion volumes increased 3.3-fold in atria (95% confidence interval [CI], 2.3 to 4.3;
P
=0.001) and 2.2-fold in ventricles (95% CI, 1.4 to 3.0;
P
<0.0001), with the difference between chambers being nonsignificant (
P
=0.22). Whereas the depth of AV groove lesions increased over time (1.9-fold; 95% CI, 1.5 to 2.3;
P
<0.0001), lesion volumes did not enlarge significantly (1.5-fold; 95% CI, 0.4 to 2.6;
P
=0.45).

Conclusions—
Ablation lesions produced by cryothermal energy in immature atrial and ventricular myocardium enlarge to a similar extent to radiofrequency ablation. In contrast, AV groove lesion volumes do not increase significantly with either energy modality.
Associations of Retinal Microvascular Signs and Intracranial Large Artery Disease
Authors: De Silva Deidre A. , Manzano Jennifer J.F. , Woon Fung-Peng , Liu Erica Yang , Lee Moi-Pin , Gan Hui-Yee , Chen Christopher P.L.H. , Chang Hui-Meng , Mitchell Paul , Wang Jie Jin , Lindley Richard I. , Wong Tien-Yin , Wong Meng-Cheong 
Published: January 2011

Background and Purpose—
Intracranial large artery disease (ICLAD) is a major cause of ischemic stroke. Retinal microvascular changes are associated with stroke, including small vessel cerebral disease and extracranial carotid disease. We examined the relationship between ICLAD and retinal microvascular changes.

Methods—
This is a prospective cohort of 802 acute ischemic stroke patients. Retinal changes were assessed from photographs by graders masked to clinical data. ICLAD was evaluated using prespecified criteria.

Results—

ICLAD was not associated with ipsilateral retinal arteriolar/venular caliber, focal arteriolar narrowing, or arteriovenous nicking. Severe enhanced arteriolar light reflex was independently associated with any ICLAD (
P
=0.006) and severe ICLAD (
P
<0.001).

Conclusion—
Enhanced arteriolar light reflex, but not retinal vessel caliber, was related to ICLAD. These data suggest that retinal microvascular signs have specific associations with large cerebral vessel disease.
A Candidate Gene Study Revealed Sex-Specific Association Between the
OLR1
Gene and Carotid Plaque
Authors: Wang Liyong , Yanuck Danielle , Beecham Ashley , Gardener Hannah , Slifer Susan , Blanton Susan H. , Sacco Ralph L. , Rundek Tatjana 
Published: January 2011

Background and Purpose—
Sex differences have been recognized in stroke risk; however, the sex-dependent genetic contribution to stroke is unclear. We sought to examine the sex-dependent associations between genes involved in lipid metabolism and carotid atherosclerotic plaque, a subclinical precursor of stroke.

Methods—

For the Genetic Determinant of Subclinical Carotid Disease study, 287 Dominicans ascertained through the Northern Manhattan Study were examined for carotid plaque using high-resolution ultrasound. Sixty-four single nucleotide polymorphisms (SNPs) in 11 lipid-related genes were genotyped. Plaque presence and plaque subphenotypes, including multiple, thick, irregular, and calcified plaque, were analyzed. First, the interaction between each SNP and sex was evaluated for association with each plaque phenotype using multiple logistic regression and controlling for age, smoking, and the main effects of sex and SNP. For SNPs with suggestive evidence for interaction with sex (
P
<0.1 for the interaction term), stratification analysis by sex was performed to evaluate the sex-specific association between the SNP and plaque phenotypes.

Results—

The most compelling finding is with the missense SNP rs11053646 (K167N) in the
OLR1
gene, which encodes lectin-like oxidized low-density lipoprotein receptor. Stratification analysis revealed a strong association between rs11053646 and all plaque phenotypes in women (OR, 2.44 to 5.86;
P
=0.0003 to 0.0081) but not in men (OR, 0.85 to 1.22;
P
=0.77 to 0.92).

Conclusions—
Genetic variation in genes involved in lipid metabolism may have sex-dependent effects on carotid plaque burden. Our findings provide a plausible biological basis underlying the sex difference in cardiovascular risk.
Selectin-Mediated Recruitment of Bone Marrow Stromal Cells in the Postischemic Cerebral Microvasculature
Authors: Yilmaz Gokhan , Vital Shantel , Yilmaz Cigdem Erkuran , Stokes Karen Y. , Alexander J. Steven , Granger D. Neil 
Published: January 2011

Background and Purpose—
The therapeutic potential of bone marrow stromal cells (BMSCs) has been demonstrated in different models of stroke. Although it is well established that BMSCs selectively migrate to the site of brain injury, the mechanisms underlying this process are poorly understood. This study addresses the hypothesis that selectins mediate the recruitment of BMSCs into the postischemic cerebral microvasculature.

Methods—
Focal ischemic stroke was induced by middle cerebral artery occlusion and reperfusion. Cell recruitment was monitored using either fluorescent- or radiolabeled BMSCs detected by intravital microscopy or tissue radioactivity. Mice were treated with either a blocking antibody against P- or E-selectin or with the nonselective selectin antagonist, fucoidin. The role of CD44 in cell recruitment was evaluated using BMSCs from CD44 knockout mice.

Results—
Middle cerebral artery occlusion and reperfusion was associated with a significantly increased adhesion of BMSCs in cerebral venules compared with sham mice. Immunoneutralization of either E- or P-selectin blocked the middle cerebral artery occlusion and reperfusion-induced recruitment of adherent BMSCs. An attenuated recruitment response in the postischemic hemisphere was also noted after fucoidin treatment or administration of CD44-deficient BMSCs.

Conclusions—
Cerebral vascular endothelium assume a proadhesive phenotype after ischemic stroke that favors the recruitment of BMSCs, which use both P- and E-selectin to home into the infarct site. CD44 may serve as the critical ligand for selectin-mediated BMSC recruitment.
Pharmacological Deep Vein Thrombosis Prophylaxis Does Not Lead to Hematoma Expansion in Intracerebral Hemorrhage With Intraventricular Extension
Authors: Wu Tzu-Ching , Kasam Mallik , Harun Nusrat , Hallevi Hen , Bektas Hesna , Acosta Indrani , Misra Vivek , Barreto Andrew D. , Gonzales Nicole R. , Lopez George A. , Grotta James C. , Savitz Sean I. 
Published: January 2011

Background and Purpose—
Patients with intracerebral hemorrhage (ICH) are at high risk for development of deep venous thrombosis. Current guidelines state that low-dose subcutaneous low molecular weight heparin or unfractionated heparin may be considered at 3 to 4 days from onset. However, insufficient data exist on hematoma volume in patients with ICH before and after pharmacological deep venous thrombosis prophylaxis, leaving physicians with uncertainty regarding the safety of this practice.

Methods—
We identified patients from our stroke registry (June 2003 to December 2007) who presented with ICH only or ICH+intraventricular hemorrhage and received either low molecular weight heparin subcutaneously or unfractionated heparin within 7 days of admission and had a repeat CT scan performed within 4 days of starting deep venous thrombosis prophylaxis. We calculated the change in hematoma volume from the admission and posttreatment CTs. Hematoma volume was calculated using the ABC/2 method and intraventricular hemorrhage volumes were calculated using a published method of hand drawn regions of interest.

Results—
We identified 73 patients with a mean age of 63 years and median National Institutes of Health Stroke Scale score 11.5. The mean baseline total hematoma volume was 25.8 mL±23.2 mL. There was an absolute change in hematoma volume from pre- and posttreatment CT of −4.3 mL±11.0 mL. Two patients developed hematoma growth. Repeat analysis of patients given pharmacological deep venous thrombosis prophylaxis within 2 or 4 days after ICH found no increase in hematoma size.

Conclusions—
Pharmacological deep venous thrombosis prophylaxis given subcutaneously in patients with ICH and/or intraventricular hemorrhage in the subacute period is generally not associated with hematoma growth.