bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ultrasound Increases Nanoparticle Delivery by Reducing Intratumoral Pressure and Increasing Transport in Epithelial and Epithelial–Mesenchymal Transition Tumors
Authors: Watson Katherine D. , Lai Chun-Yen , Qin Shengping , Kruse Dustin E. , Lin Yueh-Chen , Seo Jai Woong , Cardiff Robert D. , Mahakian Lisa M. , Beegle Julie , Ingham Elizabeth S. , Curry Fitz-Roy , Reed Rolf K. , Ferrara Katherine W. 
Published: January 2012

Abstract
Acquisition of the epithelial–mesenchymal transition (EMT) tumor phenotype is associated with impaired chemotherapeutic delivery and a poor prognosis. In this study, we investigated the application of therapeutic ultrasound methods available in the clinic to increase nanotherapeutic particle accumulation in epithelial and EMT tumors by labeling particles with a positron emission tomography tracer. Epithelial tumors were highly vascularized with tight cell–cell junctions, compared with EMT tumors where cells displayed an irregular, elongated shape with loosened cell–cell adhesions and a reduction in E-cadherin and cytokeratins 8/18 and 19. Without ultrasound, the accumulation of liposomal nanoparticles administered to tumors in vivo was approximately 1.5 times greater in epithelial tumors than EMT tumors. When ultrasound was applied, both nanoaccumulation and apparent tumor permeability were increased in both settings. Notably, ultrasound effects differed with thermal and mechanical indices, such that increasing the thermal ultrasound dose increased nanoaccumulation in EMT tumors. Taken together, our results illustrate how ultrasound can be used to enhance nanoparticle accumulation in tumors by reducing their intratumoral pressure and increasing their vascular permeability. Cancer Res; 72(6); 1485–93. ©2012 AACR.
Direct Therapeutic Applications of Calcium Electroporation to Effectively Induce Tumor Necrosis
Authors: Frandsen Stine Krog , Gissel Hanne , Hojman Pernille , Tramm Trine , Eriksen Jens , Gehl Julie 
Published: January 2012

Abstract
Electroporation of cells with short, high-voltage pulses causes a transient permeabilization of cell membranes that permits passage of otherwise nonpermeating ions and molecules. In this study, we illustrate how electroporation with isotonic calcium can achieve highly effective cancer cell kill in vivo. Calcium electroporation elicited dramatic antitumor responses in which 89% of treated tumors were eliminated. Histologic analyses indicated complete tumor necrosis. Mechanistically, calcium electroporation caused acute ATP depletion likely due to a combination of increased cellular use of ATP, decreased production of ATP due to effects on the mitochondria, as well as loss of ATP through the permeabilized cell membrane. Taken together, our findings offer a preclinical proof of concept for the use of electroporation to load cancer cells with calcium as an efficient anticancer treatment. Electroporation equipment is already used clinically to enhance the delivery of chemotherapy to superficial tumors, with trials on internal tumors in progress, enabling the introduction of calcium electroporation to clinical use. Moreover, the safety profile, availability, and low cost of calcium facilitate access to this technology for many cancer patients in developed and developing countries. Cancer Res; 72(6); 1336–41. ©2012 AACR.
Ribosome Biogenesis and Control of Cell Proliferation: p53 Is Not Alone
Authors: Donati Giulio , Montanaro Lorenzo , Derenzini Massimo 
Published: January 2012

Abstract
Cell growth is a prerequisite for cell proliferation, and ribosome biogenesis is a limiting factor for cell growth. In mammalian cells, the tumor suppressor p53 has been shown to induce cell-cycle arrest in response to impaired ribosome biogenesis. Recently, p53-independent mechanisms of cell-cycle arrest in response to alterations of ribosome biogenesis have been described. These findings provide a rational basis for the use of drugs that specifically impact ribosome biogenesis for the treatment of cancers lacking active p53 and extend the scenario of mechanisms involved in the relationship between cell growth and cell proliferation. Cancer Res; 72(7); 1602–7. ©2012 AACR.
Eribulin Mesylate for the Treatment of Patients with Refractory Metastatic Breast Cancer: Use of a “Physician's Choice” Control Arm in a Randomized Approval Trial
Authors: Donoghue Martha , Lemery Steven J. , Yuan Weishi , He Kun , Sridhara Rajeshwari , Shord Stacy , Zhao Hong , Marathe Anshu , Kotch Lori , Jee Josephine , Wang Ying , Zhou Liang , Adams William M. , Jarral Vaishali , Pilaro Anne , Lostritto Richard , Gootenberg Joseph E. , Keegan Patricia , Pazdur Richard 
Published: January 2012

Abstract
This work describes the considerations that led to the approval by the U.S. Food and Drug Administration (FDA), on November 15, 2010, of eribulin mesylate (Halaven; Eisai, Inc.) for the treatment of patients with refractory metastatic breast cancer. The FDA review focused primarily on the results of a single randomized, open-label, multicenter trial of 762 patients with refractory locally advanced or metastatic breast cancer. The patients were randomized to receive eribulin or any single-agent treatment of the physician's choice, selected prior to randomization. The FDA's approval of eribulin mesylate was based on demonstration of a statistically significant prolongation of overall survival (OS) in patients who had been randomized to receive eribulin. The median OS was 13.1 months in the eribulin arm compared with 10.6 months in the control arm [HR 0.81 (95% CI, 0.66–0.99); P = 0.041]. Treatment with eribulin did not show a statistically significant treatment effect [HR 0.87 (95% CI, 0.71–1.05)] on progression-free survival as determined by independent review. This approval highlights the appropriate use of an innovative trial design and shows that improvement in OS is an achievable endpoint in the setting of advanced breast cancer. On the basis of the different conclusions arising from the OS and progression-free survival results, investigators should consider using OS as a primary endpoint in clinical trials for refractory breast cancer. Clin Cancer Res; 18(6); 1496–505. ©2012 AACR.
KRAS and BRAF Mutations Predict Primary Resistance to Imatinib in Gastrointestinal Stromal Tumors
Authors: Miranda Claudia , Nucifora Martina , Molinari Francesca , Conca Elena , Anania Maria Chiara , Bordoni Andrea , Saletti Piercarlo , Mazzucchelli Luca , Pilotti Silvana , Pierotti Marco A. , Tamborini Elena , Greco Angela , Frattini Milo 
Published: January 2012

Abstract
Purpose: Gastrointestinal stromal tumors (GIST) are characterized by gain-of-function mutations in KIT/PDGFRA genes leading to a constitutive receptor activation which is well counteracted by imatinib. However, cases in which imatinib as first-line treatment has no effects are reported (primary resistance). Our purpose is to investigate alterations in downstream effectors, not reported so far in mutated GIST, possibly explaining the primary resistance to targeted treatments.
Experimental Design: Two independent naive GIST cohorts have been analyzed for KIT, PDGFRA, KRAS, and BRAF mutations by direct sequencing. Cell lines expressing a constitutively activated and imatinib-responding KIT, alone or in combination with activated KRAS and BRAF, were produced and treated with imatinib. KIT receptor and its downstream effectors were analyzed by direct Western blotting.
Results: In naive GISTs carrying activating mutations in KIT or PDGFRA a concomitant activating mutation was detected in KRAS (5%) or BRAF (about 2%) genes. In vitro experiments showed that imatinib was able to switch off the mutated receptor KIT but not the downstream signaling triggered by RAS–RAF effectors.
Conclusions: These data suggest the activation of mitogen—activated protein kinase pathway as a possible novel mechanism of primary resistance to imatinib in GISTs and could explain the survival curves obtained from several clinical studies where 2% to 4% of patients with GIST treated with imatinib, despite carrying KIT-sensitive mutations, do not respond to the treatment. Clin Cancer Res; 18(6); 1769–76. ©2012 AACR.
Genome-Wide miRNA Expression Profiling Identifies miR-9-3 and miR-193a as Targets for DNA Methylation in Non–Small Cell Lung Cancers
Authors: Heller Gerwin , Weinzierl Marlene , Noll Christian , Babinsky Valerie , Ziegler Barbara , Altenberger Corinna , Minichsdorfer Christoph , Lang György , Döme Balazs , End-Pfützenreuter Adelheid , Arns Britt-Madeleine , Grin Yuliya , Klepetko Walter , Zielinski Christoph C. , Zöchbauer-Müller Sabine 
Published: January 2012

Abstract
Purpose: The major aim of this study was to investigate the role of DNA methylation (referred to as methylation) on miRNA silencing in non–small cell lung cancers (NSCLC).
Experimental Design: We conducted microarray expression analyses of 856 miRNAs in NSCLC A549 cells before and after treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (Aza-dC) and with a combination of Aza-dC and the histone deacetylase inhibitor trichostatin A. miRNA methylation was determined in 11 NSCLC cell lines and in primary tumors and corresponding nonmalignant lung tissue samples of 101 patients with stage I–III NSCLC.
Results: By comparing microarray data of untreated and drug-treated A549 cells, we identified 33 miRNAs whose expression was upregulated after drug treatment and which are associated with a CpG island. Thirty (91%) of these miRNAs were found to be methylated in at least 1 of 11 NSCLC cell lines analyzed. Moreover, miR-9-3 and miR-193a were found to be tumor specifically methylated in patients with NSCLC. We observed a shorter disease-free survival of patients with miR-9-3 methylated lung squamous cell carcinoma (LSCC) than patients with miR-9-3 unmethylated LSCC by multivariate analysis [HR = 3.8; 95% confidence interval (CI), 1.3–11.2, P = 0.017] and a shorter overall survival of patients with miR-9-3 methylated LSCC than patients with miR-9-3 unmethylated LSCC by univariate analysis (P = 0.013).
Conclusions: Overall, our results suggest that methylation is an important mechanism for inactivation of certain miRNAs in NSCLCs and that miR-9-3 methylation may serve as a prognostic parameter in patients with LSCC. Clin Cancer Res; 18(6); 1619–29. ©2012 AACR.
ARC15105 Is a Potent Antagonist of Von Willebrand Factor Mediated Platelet Activation and Adhesion
Authors: Siller-Matula Jolanta M. , Merhi Yahye , Tanguay Jean-François , Duerschmied Daniel , Wagner Denisa D. , McGinness Kathleen E. , Pendergrast P. Shannon , Chung Jou-Ku , Tian Xianbin , Schaub Robert G. , Jilma Bernd 
Published: January 2012

Objective—

We investigated the stability, pharmacokinetic, and pharmacodynamic profile of the 2
nd
generation anti-von Willeband factor aptamer ARC15105.

Methods and Results—

Platelet plug formation was measured by collagen/adenosine diphosphate-induced closure time with the platelet function analyzer-100 and platelet aggregation by multiple electrode aggregometry. Platelet adhesion was measured on denuded porcine aortas and in a flow chamber. Aptamer stability was assessed by incubation in nuclease rich human, monkey, and rat serum for up to 72 hours. Pharmacokinetic and pharmacodynamic profiles were tested in cynomolgus monkeys after IV and SC administration. The median IC
100
and IC
50
to prolong collagen/adenosine diphosphate-induced closure timewere 27 nmol/L and 12 nmol/L, respectively. ARC15105 (1.3 μmol/L) completely inhibited ristocetin-induced platelet aggregation in whole blood (
P
<0.001), but also diminished collagen, ADP, arachidonic acid, and thrombin receptor activating peptide-induced platelet aggregation to some extent (
P
<0.05). ARC15105 (40 nmol/L) decreased platelet adhesion by >90% on denuded porcine aortas (
P
<0.001), which was comparable to the degree of inhibition obtained with abciximab. ARC15105 (100 nmol/L) also inhibited platelet adhesion to collagen under arterial shear in a flow chamber by >90% (
P
<0.001). The IV and SC terminal half-lives in cynomolgus monkeys were 67 and 65 hours, respectively, and the SC bioavailability was ≈98%. Allometric scaling estimates the human T
1/2
would be ≈217 hours. Pharmacodynamic analysis confirms that ARC15105 inhibits von Willeband factor activity >90% in blood samples taken 300 hours after a 20 mg/kg IV or SC dose in monkeys.

Conclusion—
The potency, pharmacokinetic profile, and SC bioavailability of ARC15105 support its clinical investigation for chronic inhibition of von Willeband factor -mediated platelet activation.
HNF4α Increases Liver-Specific Human ATP-Binding Cassette Transporter A1 Expression and Cholesterol Efflux to Apolipoprotein A-I in Response to Cholesterol Depletion
Authors: Ohoka Nobumichi , Okuhira Keiichiro , Cui Hongyan , Wu Weijia , Sato Ryuichiro , Naito Mikihiko , Nishimaki-Mogami Tomoko 
Published: January 2012

Objective—

Hepatic ATP-binding cassette transporter A1 (ABCA1) plays the major role in maintaining plasma high-density lipoprotein levels by producing cholesterol-accepting nascent high-density lipoprotein, whereas peripheral ABCA1 is responsible for releasing cellular cholesterol. We previously reported that in rodents, cholesterol depletion reduces ABCA1 expression in peripheral but not hepatic cells by increasing a liver-specific
ABCA1
transcript via the sterol regulatory element-binding protein-2 system. However, the regulatory element is not conserved in humans. Here we investigated the mechanism of sterol-regulated human hepatic
ABCA1
gene expression.

Methods and Results—

ABCA1 mRNA
variant
type L3
is a novel and human-liver-specific transcript accounting for ≈25% of total
ABCA1
mRNA in the liver and is induced by cellular cholesterol depletion. Specific knockdown or forced expression revealed that
type L3
produces functional ABCA1 protein in cholesterol efflux. We identified a regulatory enhancer element for
L3
expression lying within intron 3 of the human
ABCA1
gene, to which hepatocyte nuclear factor (HNF) 4α binds in response to cholesterol depletion. HNF4α knockdown abolished induction of liver-specific
L3
and
L2b
transcripts (and consequently the liver-type response of ABCA1 expression to cellular cholesterol status) and diminished cholesterol efflux activity.

Conclusion—
These findings indicate that HNF4α regulates human hepatic ABCA1 expression in response to cholesterol depletion.
Flow Cytometric Identification and Functional Characterization of Immature and Mature Circulating Endothelial Cells
Authors: Mund Julie A. , Estes Myka L. , Yoder Mervin C. , Ingram David A. , Case Jamie 
Published: January 2012

Objective—
We sought to identify and characterize 2 distinct populations of bona fide circulating endothelial cells, including the endothelial colony-forming cell (ECFC), by polychromatic flow cytometry (PFC), colony assays, immunomagnetic selection, and electron microscopy.

Methods and Results—
Mononuclear cells from human umbilical cord blood and peripheral blood were analyzed using our recently published PFC protocol. A population of cells containing both ECFCs and mature circulating endothelial cells was determined by varying expressions of CD34, CD31, and CD146 but not AC133 and CD45. After immunomagnetic separation, these cells failed to form hematopoietic colonies, yet clonogenic endothelial colonies with proliferative potential were obtained, thus verifying their identity as ECFCs. The frequency of ECFCs were increased in cord blood and were extremely rare in the peripheral blood of healthy adults. We also detected another mature endothelial cell population in the circulation that was apoptotic. Finally, when comparing this new protocol with a prior method, we determined that the present protocol identifies circulating endothelial cells, whereas the earlier protocol identified extracellular vesicles.

Conclusion—
Two populations of circulating endothelial cells, including the functionally characterized ECFC, are now identifiable in human cord blood and peripheral blood by PFC.
Nonesterified Fatty Acids and Risk of Sudden Cardiac Death in Older Adults
Authors: Djoussé Luc , Biggs Mary L. , Ix Joachim H. , Kizer Jorge R. , Lemaitre Rozenn N. , Sotoodehnia Nona , Zieman Susan J. , Mozaffarian Dariush , Tracy Russell P. , Mukamal Kenneth J. , Siscovick David S. 
Published: January 2012

Background—
Although nonesterified fatty acids (NEFA) have been positively associated with coronary heart disease risk factors, limited and inconsistent data are available on the relation between NEFA and sudden cardiac death.

Methods and Results—
Using a prospective design, we studied 4657 older men and women (mean age, 75 years) from the Cardiovascular Health Study (1992–2006) to evaluate the association between plasma NEFA and the risk of sudden cardiac death in older adults. Plasma concentrations of NEFA were measured using established enzymatic methods, and sudden death was adjudicated using medical records, death certificates, proxy interview, and autopsy reports. We used Cox proportional hazard models to estimate multivariable-adjusted relative risks. During a median follow-up of 10.0 years, 221 new cases of sudden cardiac death occurred. In a multivariable model adjusting for age, sex, race, clinic site, alcohol intake, smoking, prevalent coronary heart disease and heart failure, and self-reported health status, relative risks (95% confidence interval) for sudden cardiac death were 1.0 (ref), 1.15 (0.81–1.64), 1.06 (0.72–1.55), and 0.91 (0.60–1.38) across consecutive quartiles of NEFA concentration. In secondary analyses restricted to the first 5 years of follow-up, we also did not observe a statistically significant association between plasma NEFA and sudden cardiac death.

Conclusions—
Our data do not provide evidence for an association between plasma NEFA measured late in life and the risk of sudden cardiac death in older adults.
Outcomes in Advanced Heart Failure Patients With Left Ventricular Assist Devices for Destination Therapy
Authors: Park Soon J. , Milano Carmelo A. , Tatooles Antone J. , Rogers Joseph G. , Adamson Robert M. , Steidley D. Eric , Ewald Gregory A. , Sundareswaran Kartik S. , Farrar David J. , Slaughter Mark S. ,   for the HeartMate II Clinical Investigators†
Published: January 2012

Background—
The HeartMate II (HMII) destination therapy (DT) trial demonstrated significant improvements in outcomes in continuous-flow left ventricular assist devices compared with patients implanted with the pulsatile-flow HeartMate XVE. The primary hypothesis of the current study is that trial patients enrolled after the initial data cohort would have better clinical outcomes.

Methods and Results—

Two hundred eighty-one patients who underwent HMII for DT from May 2007 to March 2009 (Mid Trial [MT] group) were compared with the initial 133 HMII patients from March 2005 to May 2007 (Early Trial [ET] group). Patient entry criteria were the same during the 2 time periods. Survival, adverse events, and quality of life were compared between the 2 groups. Baseline characteristics were similar between the groups. Compared with the ET group, patients in the MT group had reduced adverse event rates for bleeding requiring transfusions (1.66 versus 1.13 events per patient-year,
P
<0.001), sepsis (0.38 versus 0.27,
P
=0.025), device-related infections (0.47 versus 0.27,
P
<0.001), and hemorrhagic stroke (0.07 versus 0.03,
P
=0.01). Other event rates were similar between groups including ischemic stroke (0.06 versus 0.05 events per patient-year,
P
=0.57). Survival at 1 year in the MT group was 73% versus 68% in the ET group (
P
=0.21). Additionally, there was a significant reduction in deaths caused by hemorrhagic stroke (
P
=0.01). Quality of life improvements were significant in both the groups (
P
<0.001).

Conclusions—
The benefit of DT therapy with the HMII is confirmed in subsequent trial patients, with improved adverse event rates and a strong trend for improvements in survival.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00121485.
Thrombus Branching and Vessel Curvature Are Important Determinants of Middle Cerebral Artery Trunk Recanalization With Merci Thrombectomy Devices
Authors: Zhu Liangfu , Liebeskind David S. , Jahan Reza , Starkman Sidney , Salamon Noriko , Duckwiler Gary , Vinuela Fernando , Tateshima Satoshi , Gonzalez Nestor , Villablanca Pablo , Ali Latisha K. , Kim Doojin , Ovbiagele Bruce , Froehler Michael , Tenser Matthew , Saver Jeffrey L. 
Published: January 2012

Background and Purpose—
Determinants of successful recanalization likely differ for Merci thrombectomy and intra-arterial pharmacological fibrinolysis interventions. Although the amount of thrombotic material to be digested is an important consideration for chemical lysis, mechanical debulking may be more greatly influenced by other target lesion characteristics.

Methods—
In consecutive patients with acute ischemic stroke treated with Merci thrombectomy for middle cerebral artery M1 occlusions, we analyzed the influence on recanalization success and clinical outcome of target thrombus size (length) and shape (curvature and branching) on pretreatment T2* gradient echo MRI.

Results—

Among 65 patients, pretreatment MRI showed susceptibility vessel signs in 45 (69%). Thrombus length averaged 13.03 mm (range, 5.56–34.91) and irregular shape (curvature or branching) was present in 17 of 45 (38%). Presence and length of susceptibility vessel signs did not predict recanalization or good clinical outcome. Substantial recanalization (Thrombolysis In Cerebral Infarction 2b or 3) and good clinical outcome (modified Rankin Scale score ≤2) were more frequent with regular than irregular susceptibility vessel signs shape (57% versus 18%,
P
=0.013; 39% versus 6%,
P
=0.017). On multiple regression analysis, the only independent predictor of substantial recanalization was irregular susceptibility vessel signs (OR, 0.16; 95% CI, 0.04–0.69;
P
=0.014); and leading predictors of good clinical outcome were baseline National Institutes of Health Stroke Scale (OR, 1.20; 95% CI, 1.03–1.40;
P
= 0.019) and irregular susceptibility vessel signs (OR, 9.36; 95% CI, 0.98–89.4;
P
=0.052).

Conclusions—
Extension of thrombus into middle cerebral artery division branches and curving shape of the middle cerebral artery stem, but not thrombus length, decrease technical and clinical success of Merci thrombectomy in M1 occlusions.