bluuebunny/crossref_metadata_2025 huggingface dataset:
ONE-PARTICLE DENSITY OF LAUGHLIN STATES AT FINITE N
Authors: CIFTJA ORION , OCKLEBERRY NICOLE , OKOLO CHIKO
Published: August 2011

The most robust fractional quantum Hall states occur in the lowest Landau level at filling factors, 1/3 and 1/5. Such states are very well described by Laughlin's wave function. In this work, we have succeeded in calculating exactly the one-particle density function of the Laughlin states for some finite systems of particles in a disk geometry. The exact results we provide are not only important for the Laughlin states, but also for the general field of numerical calculations because they can serve as benchmarks to test the accuracy of various approaches, numerical schemes and computational methods used in studies of strongly correlated electronic systems.
AN APPROXIMATELY UNIVERSAL SET CONSISTING OF TWO OBSERVABLES
Authors: TAKAHASHI YASUHIRO
Published: August 2011

We consider the problem of minimizing the resources required for approximate universality in measurement-only quantum computation. This problem is important not only for realizing a quantum computer, but also for understanding the computational power of quantum computation. The resources we focus on are observables, which describe projective measurements, and ancillary qubits. We show that, if we are allowed to use two ancillary qubits, the set of observables { cos (π/8)X - sin (π/8)Y ,Z ⊗ X} is approximately universal for quantum computation. This is the first construction of an approximately universal set consisting only of one one-qubit observable and one two-qubit observable. Using the proof of the approximate universality, we also show that, if we are allowed to use two initialized ancillary qubits, one two-qubit observable is sufficient for graph state preparation. The use of only one two-qubit observable is optimal in terms of the number of observables available and the number of qubits to be measured jointly.
RELATION BETWEEN INFORMATION AND DISTURBANCE IN QUANTUM KEY DISTRIBUTION PROTOCOL WITH CLASSICAL ALICE
Authors: MIYADERA TAKAYUKI
Published: August 2011

The "semiquantum" key distribution protocol introduced by Zou et al. is examined. The protocol while using two-way quantum communication requires only Bob to be fully quantum. We derive a trade-off inequality between information gained by Eve and the disturbance observed by legitimate users. It guarantees that Eve cannot obtain large information if the disturbance is sufficiently small.
N-to-M JOINT REMOTE STATE PREPARATION OF 2-LEVEL STATES
Authors: SU YUAN , CHEN XIU-BO , YANG YI-XIAN
Published: August 2011

In this paper, we investigate novel protocols for the joint remote state preparation involving several senders and receivers. The highlight of our paper lies in two aspects. First, we focus on the distribution of information among multiple senders and receivers. Second, each receiver can simultaneously reconstruct a qubit state containing the joint information from all senders. These properties imply that our protocols may have many extensive applications in burgeoning quantum network communication. Our protocols cover a variety of class, i.e. two-to-three, N-to-three, and N-to-M. Through introducing the quantum fourier transform, the set of orthogonal basis in the M-dimensional Hilbert space is ingeniously constructed. Moreover, we present all the recovery operations in details. The success probability and the classical communication costs are also given.
SUPER REVIVALS AND SUB-PLANCK SCALE STRUCTURES OF A SLIGHTLY RELATIVISTIC PARTICLE IN A BOX
Authors: GHOSH SURANJANA , MARZOLI IRENE
Published: August 2011

The time evolution of a particle, caught in an infinitely deep square well, displays unexpected features, when one includes tiny relativistic effects. Indeed, even the smallest corrections to the non-relativistic quadratic spectrum manifest themselves in a dramatic way. Our theoretical analysis brings to light a completely new time scale, at which the system exhibits surprisingly perfect revivals. This longer time scale rules the system dynamics and replaces the original revival time of the unperturbed system. The early manifestation of such phenomenon is captured by the sensitivity of sub-Planck structures for different values of the relativistic corrections.
The trisubstituted-triazole approach to extended functional naphthalocyanines
Authors: Juríček Michal , Stout Kathleen , Kouwer Paul H.J. , Rowan Alan E.
Published: August 2011

Recently, a novel modular approach to octatriazole-derived phthalocyanines (Pcs; 1) was developed and optimized in our group; herein, the pool of the functional Pc materials was expanded for an additional candidate (2), a fused derivative of 1. Compared with 1, the aromaticity in 2 is extended by an additional four benzene and eight triazole rings and, in addition, the triazole units and the Pc core co-create four functional, in-plane cavities. Various methods to link the unsubstituted carbon atoms of the neighboring triazoles in 1 to afford atomically flat naphthalocyanine (Nc) analogs (2), containing eight fused triazole moieties, were studied. Several synthetic routes were designed, among them the trisubstituted-triazole approach, which was found to be the most suitable route. The crucial steps of this approach, the copper-catalyzed azide-haloalkyne cycloaddition and the intramolecular homocoupling reactions, were first studied on a model system; subsequently, this methodology was applied in the synthesis of the desired Nc 2. The increased core size and the π-electron deficient structure predict this class of Ncs to possess very strong aggregation properties. Moreover, owing to the presence of four tridentate half-cavities, the final properties of the molecule or the assembly can, in principle, be further tuned by doping with metals or guest molecules.
Syntheses, properties and cellular studies of metallo-isoporphyrins
Authors: Mwakwari Sandra C. , Wang Haijun , Jensen Timothy J. , Vicente M. Graça H. , Smith Kevin M.
Published: August 2011

b-Bilene hydrochlorides are shown to be improved intermediates for the synthesis of metallo-isoporphyrins in enhanced yields (28% vs. 6%). Several new diamagnetic zinc(II) and a novel paramagnetic copper(II) isoporphyrin salts were also obtained using this approach. Metal-free isoporphyrins were also isolated. In vitro studies using human carcinoma HEp2 cells show that all metallo-isoporphyrins accumulate within cells and localize partially in the mitochondria. The zinc-isoporphyrins were found to be moderately phototoxic while the copper complex showed the lowest phototoxicity, maybe as a result of its paramagnetic nature.
INVESTIGATION OF GdBaCo2-xFexO5.5-δ AS A CATHODE MATERIAL FOR INTERMEDIATE TEMPERATURE SOLID OXIDE FUEL CELLS
Authors: KULKA ANDRZEJ , HU YANG , DEZANNEAU GUILHEM , MOLENDA JANINA
Published: August 2011

In this work, we present an evaluation of the layered perovskite materials with chemical composition GdBaCo 2-x Fe x O 5.5-δ (x = 0.0, 0.3, 0.6) as a cathode materials for intermediate temperature solid oxide fuel cell (IT-SOFC). We first present results concerning their crystal structure and oxygen nonstoichiometry, and then give results concerning their electrical conductivity and performance in button-type SOFCs.
Thiamin uptake by pancreatic acinar cells: effect of chronic alcohol feeding/exposure
Authors: Subramanya Sandeep B. , Subramanian Veedamali S. , Sekar V. Thillai , Said Hamid M.
Published: August 2011

Thiamin is important for normal function of pancreatic acinar cells, but little is known about its mechanism of uptake and about the effect of chronic alcohol use on the process. We addressed these issues using freshly isolated rat primary and rat-derived cultured AR42J pancreatic acinar cells as models. Results showed thiamin uptake by both primary and cultured AR42J pancreatic acinar cells to be via a specific carrier-mediated mechanism and that both of the thiamin transporters 1 and 2 (THTR-1 and THTR-2) are expressed in these cells. Chronic alcohol feeding of rats was found to lead to a significant inhibition of carrier-mediated thiamin uptake by pancreatic acinar cells and was associated with a significant reduction in level of expression of THTR-1 and THTR-2 at the protein and mRNA levels. Chronic exposure (96 h) of AR42J cells to alcohol also led to a significant decreased carrier-mediated thiamin uptake, an effect that was associated with a significant decrease in the activity of the human SLC19A2 and SLC19A3 promoters expressed in these cells. We also examined the effect of chronic alcohol feeding of rats on level of expression of key thiamin metabolizing enzymes (thiamin phosphokinase and thiamin pyrophosphatase) as well as on level of expression of the mitochondrial thiamin pyrophosphate transporter of pancreatic acinar cells and observed a significant inhibition in all these parameters. These results demonstrate for the first time that thiamin uptake by pancreatic acinar cells is via a carrier-mediated process and that both the THTR-1 as well as THTR-2 are expressed in these cells. Also, chronic alcohol feeding/exposure inhibits thiamin uptake process and the inhibition is, at least in part, being exerted at the transcriptional level. Furthermore, chronic alcohol feeding also negatively impacts intracellular parameters of thiamin metabolism in pancreatic acinar cells.
Characteristics of Kcnn4 channels in the apical membranes of an intestinal epithelial cell line
Authors: Basalingappa Kanthesh M. , Rajendran Vazhaikkurichi M. , Wonderlin William F.
Published: August 2011

Intermediate-conductance K+ (Kcnn4) channels in the apical and basolateral membranes of epithelial cells play important roles in agonist-induced fluid secretion in intestine and colon. Basolateral Kcnn4 channels have been well characterized in situ using patch-clamp methods, but the investigation of Kcnn4 channels in apical membranes in situ has been hampered by a layer of mucus that prevents seal formation. In the present study, we used patch-clamp methods to characterize Kcnn4 channels in the apical membrane of IEC-18 cells, a cell line derived from rat small intestine. A monolayer of IEC-18 cells grown on a permeable support is devoid of mucus, and tight junctions enable selective access to the apical membrane. In inside-out patches, Ca2+-dependent K+ channels observed with iberiotoxin (a Kcnma1/large-conductance, Ca2+-activated K+ channel blocker) and apamin (a Kcnn1–3/small-conductance, Ca2+-activated K+ channel blocker) present in the pipette solution exhibited a single-channel conductance of 31 pS with inward rectification. The currents were reversibly blocked by TRAM-34 (a Kcnn4 blocker) with an IC50 of 8.7 ± 2.0 μM. The channels were not observed when charybdotoxin, a peptide inhibitor of Kcnn4 channels, was added to the pipette solution. TRAM-34 was less potent in inhibiting Kcnn4 channels in patches from apical membranes than in patches from basolateral membranes, which was consistent with a preferential expression of Kcnn4c and Kcnn4b isoforms in apical and basolateral membranes, respectively. The expression of both isoforms in IEC-18 cells was confirmed by RT-PCR and Western blot analyses. This is the first characterization of Kcnn4 channels in the apical membrane of intestinal epithelial cells.
Pharmacological curve fitting to analyze cutaneous adrenergic responses
Authors: Wenner Megan M. , Wilson Thad E. , Davis Scott L. , Stachenfeld Nina S.
Published: August 2011

Although dose-response curves are commonly used to describe in vivo cutaneous α-adrenergic responses, modeling parameters and analyses methods are not consistent across studies. The goal of the present investigation was to compare three analysis methods for in vivo cutaneous vasoconstriction studies using one reference data set. Eight women (22 ± 1 yr, 24 ± 1 kg/m2) were instrumented with three cutaneous microdialysis probes for progressive norepinephrine (NE) infusions (1 × 10−8, 1 × 10−6, 1 × 10−5, 1 × 10−4, and 1 × 10−3 logM). NE was infused alone, co-infused with NG-monomethyl-l-arginine (l-NMMA, 10 mM) or Ketorolac tromethamine (KETO, 10 mM). For each probe, dose-response curves were generated using three commonly reported analyses methods: 1) nonlinear modeling without data manipulation, 2) nonlinear modeling with data normalization and constraints, and 3) percent change from baseline without modeling. Not all data conformed to sigmoidal dose-response curves using analysis 1, whereas all subjects' curves were modeled using analysis 2. When analyzing only curves that fit the sigmoidal model, NE + KETO induced a leftward shift in ED50 compared with NE alone with analyses 1 and 2 ( F test, P < 0.05) but only tended to shift the response leftward with analysis 3 (repeated-measures ANOVA, P = 0.08). Neither maximal vasoconstrictor capacity (Emax) in analysis 1 nor %change CVC change from baseline in analysis 3 were altered by blocking agents. In conclusion, although the overall detection of curve shifts and interpretation was similar between the two modeling methods of curve fitting, analysis 2 produced more sigmoidal curves.
Huntington's Disease: An Immune Perspective
Authors: Nayak Annapurna , Ansar Rafia , Verma Sunil K. , Bonifati Domenico Marco , Kishore Uday
Published: August 2011

Huntington's disease (HD) is a progressive neurodegenerative disorder that is caused by abnormal expansion of CAG trinucleotide repeats. Neuroinflammation is a typical feature of most neurodegenerative diseases that leads to an array of pathological changes within the affected areas in the brain. The neurodegeneration in HD is also caused by aberrant immune response in the presence of aggregated mutant huntingtin protein. The effects of immune activation in HD nervous system are a relatively unexplored area of research. This paper summarises immunological features associated with development and progression of HD.
Imiquimod 3.75% Cream Applied Daily to Treat Anogenital Warts: Combined Results from Women in Two Randomized, Placebo-Controlled Studies
Authors: Baker David A. , Ferris Daron G. , Martens Mark G. , Fife Kenneth H. , Tyring Stephen K. , Edwards Libby , Nelson Anita , Ault Kevin , Trofatter Kenneth F. , Liu Tiepu , Levy Sharon , Wu Jason
Published: August 2011

Objective. To evaluate if new imiquimod formulations using a shorter treatment duration are safe and efficacious to treat anogenital warts.Methods. In two studies 534 women ≥12 years of age (mean 33.4) with 2–30 warts (mean 7.9) and total wart area≥10 mm2(mean 166.3) were randomized (1 : 2 : 2) to placebo (106), imiquimod 2.5% (212) or 3.75% (216) creams applied once daily until complete clearance or a maximum of 8 weeks.Results. For placebo, imiquimod 2.5% and 3.75%, respectively, complete clearance of all warts was achieved in 14.2%, 28.3%, and 36.6% of women (intent-to-treat,P=0.008imiquimod 2.5%, andP<0.0013.75% versus placebo). Mean changes in wart counts were −10.7%, −50.9%, and −63.5% (per-protocol,P<0.001each active versus placebo) and safety-related discontinuation rates 0.9%, 1.4%, and 2.3%.Conclusions. Imiquimod 3.75% applied daily for up to 8 weeks was well tolerated and superior to placebo in treating women with external anogenital warts.
Celecoxib Promotes c-FLIP Degradation through Akt-Independent Inhibition of GSK3
Authors: Chen Shuzhen , Cao Wei , Yue Ping , Hao Chunhai , Khuri Fadlo R. , Sun Shi-Yong
Published: August 2011

Celecoxib is a COX-2 inhibitor that reduces the risk of colon cancer. However, the basis for its cancer chemopreventive activity is not fully understood. In this study, we defined a mechanism of celecoxib action based on degradation of cellular FLICE-inhibitory protein (c-FLIP), a major regulator of the death receptor pathway of apoptosis. c-FLIP protein levels are regulated by ubiquitination and proteasome-mediated degradation. We found that celecoxib controlled c-FLIP ubiquitination through Akt-independent inhibition of glycogen synthase kinase-3 (GSK3), itself a candidate therapeutic target of interest in colon cancer. Celecoxib increased the levels of phosphorylated GSK3, including the α and β forms, even in cell lines, where phosphorylated Akt levels were not increased. Phosphoinositide 3-kinase inhibitors abrogated Akt phosphorylation as expected but had no effect on celecoxib-induced GSK3 phosphorylation. In contrast, protein kinase C (PKC) inhibitors abolished celecoxib-induced GSK3 phosphorylation, implying that celecoxib influenced GSK3 phosphorylation through a mechanism that relied upon PKC and not Akt. GSK3 blockade either by siRNA or kinase inhibitors was sufficient to attenuate c-FLIP levels. Combining celecoxib with GSK3 inhibition enhanced attenuation of c-FLIP and increased apoptosis. Proteasome inhibitor MG132 reversed the effects of GSK3 inhibition and increased c-FLIP ubiquitination, confirming that c-FLIP attenuation was mediated by proteasomal turnover as expected. Our findings reveal a novel mechanism through which the regulatory effects of c-FLIP on death receptor signaling are controlled by GSK3, which celecoxib acts at an upstream level to control independently of Akt. Cancer Res; 71(19); 6270–81. ©2011 AACR.
Loss of Transcription Factor KLF5 in the Context of p53 Ablation Drives Invasive Progression of Human Squamous Cell Cancer
Authors: Yang Yizeng , Nakagawa Hiroshi , Tetreault Marie-Pier , Billig Janelle , Victor Noel , Goyal Abha , Sepulveda Antonia R. , Katz Jonathan P.
Published: August 2011

Squamous cell cancers account for more than half of all human cancers, and esophageal cancer is the sixth leading cause of cancer death worldwide. The majority of esophageal squamous cell carcinomas have identifiable p53 mutations, yet the same p53 mutations are found at comparable frequencies in precancerous dysplasia, indicating that transformation requires additional somatic changes yet to be defined. Here, we show that the zinc finger transcription factor Krüppel-like factor 5 (KLF5) transactivates NOTCH1 in the context of p53 mutation or loss. KLF5 loss limited NOTCH1 activity and was sufficient on its own to transform primary human keratinocytes harboring mutant p53, leading to the formation of invasive tumors. Restoration of NOTCH1 blocked transformation of KLF5-deficient and p53-mutant keratinocytes. Although human dysplastic epithelia accumulated KLF5, KLF5 expression was lost concurrently with NOTCH1 in squamous cell cancers. Taken together, these results define KLF5 loss as a critical event in squamous cell transformation and invasion. Our findings suggest that KLF5 may be a useful diagnostic and therapeutic target in esophageal squamous carcinomas and possibly more generally in other cancers associated with p53 loss of function. Cancer Res; 71(20); 6475–84. ©2011 AACR.
Assembly and Initial Characterization of a Panel of 85 Genomically Validated Cell Lines from Diverse Head and Neck Tumor Sites
Authors: Zhao Mei , Sano Daisuke , Pickering Curtis R. , Jasser Samar A. , Henderson Ying C. , Clayman Gary L. , Sturgis Erich M. , Ow Thomas J. , Lotan Reuben , Carey Thomas E. , Sacks Peter G. , Grandis Jennifer R. , Sidransky David , Heldin Nils Erik , Myers Jeffrey N.
Published: August 2011

Purpose: Human cell lines are useful for studying cancer biology and preclinically modeling cancer therapy, but can be misidentified and cross-contamination is unfortunately common. The purpose of this study was to develop a panel of validated head and neck cell lines representing the spectrum of tissue sites and histologies that could be used for studying the molecular, genetic, and phenotypic diversity of head and neck cancer.

Methods: A panel of 122 clinically and phenotypically diverse head and neck cell lines from head and neck squamous cell carcinoma, thyroid cancer, cutaneous squamous cell carcinoma, adenoid cystic carcinoma, oral leukoplakia, immortalized primary keratinocytes, and normal epithelium was assembled from the collections of several individuals and institutions. Authenticity was verified by carrying out short tandem repeat analysis. Human papillomavirus (HPV) status and cell morphology were also determined.

Results: Eighty-five of the 122 cell lines had unique genetic profiles. HPV-16 DNA was detected in 2 cell lines. These 85 cell lines included cell lines from the major head and neck primary tumor sites, and close examination shows a wide range of in vitro phenotypes.

Conclusions: This panel of 85 genomically validated head and neck cell lines represents a valuable resource for the head and neck cancer research community that can help advance understanding of the disease by providing a standard reference for cell lines that can be used for biological as well as preclinical studies. Clin Cancer Res; 17(23); 7248–64. ©2011 AACR.
Polymeric Nanoparticle-Encapsulated Hedgehog Pathway Inhibitor HPI-1 (NanoHHI) Inhibits Systemic Metastases in an Orthotopic Model of Human Hepatocellular Carcinoma
Authors: Xu Yang , Chenna Venugopal , Hu Chaoxin , Sun Hai-Xiang , Khan Mehtab , Bai Haibo , Yang Xin-Rong , Zhu Qing-Feng , Sun Yun-Fan , Maitra Anirban , Fan Jia , Anders Robert A.
Published: August 2011

Purpose: To illustrate the prognostic significance of hedgehog (Hh) signaling in patients with hepatocellular carcinoma (HCC) and to evaluate the efficacy of a novel nanoparticle-encapsulated inhibitor of the Hh transcription factor, Gli1 (NanoHHI) using in vitro and in vivo models of human HCCs.

Experimental Design: Patched1 (Ptch1) expression was detected in tumor tissue microarrays of 396 patients with HCC who underwent curative surgical resection during February 2000 to December 2002. Prognostic significance was assessed using Kaplan–Meier survival estimates and log-rank tests. The effects of NanoHHI alone and in combination with sorafenib were investigated on HCC cell lines. Primary HCC tumor growth and metastasis were examined in vivo using subcutaneous and orthotopic HCC xenografts in nude mice.

Results: Elevated expression of Ptch1 in HCC tissues was significantly related to disease recurrence, as well as a shorter time to recurrence in patients with HCC. In vitro, NanoHHI significantly inhibited the proliferation and invasion of HCC cell lines. NanoHHI potently suppressed in vivo tumor growth of HCC xenografts in both subcutaneous and orthotopic milieus, and in contrast to sorafenib, resulted in significant attenuation of systemic metastases in the orthotopic setting. Furthermore, NanoHHI significantly decreased the population of CD133-expressing HCC cells, which have been implicated in tumor initiation and metastases.

Conclusion: Downstream Hh signaling has prognostic significance in patients with HCC as it predicts early recurrence. Gli inhibition through NanoHHI has profound tumor growth inhibition and antimetastatic effects in HCC models, which may provide a new strategy in the treatment of patients with HCC and prevention post-operative recurrence. Clin Cancer Res; 18(5); 1291–302. ©2011 AACR.
Randomized Phase II Trial of Letrozole plus Anti-MUC1 Antibody AS1402 in Hormone Receptor–Positive Locally Advanced or Metastatic Breast Cancer
Authors: Ibrahim Nuhad K. , Yariz Kemal O. , Bondarenko Ihor , Manikhas Alexei , Semiglazov Vladimir , Alyasova Anna , Komisarenko Volodymyr , Shparyk Yaroslav , Murray James Lee , Jones David , Senderovich Shai , Chau Albert , Erlandsson Fredrik , Acton Gary , Pegram Mark
Published: August 2011

Purpose: AS1402 is a humanized immunoglobulin G1 antibody that targets the aberrantly glycosylated antigen MUC1, which is overexpressed in 90% of breast tumors and contributes to estrogen-mediated growth and survival of breast cancer cells in vitro by modulating estrogen receptor (ER) activity. Aromatase inhibitors have been reported to enhance antibody-dependent cell-mediated cytotoxicity elicited by antibodies in vitro. We compared the outcomes of patients with breast cancer treated with letrozole with or without AS1402.

Experimental Design: The study population included 110 patients with locally advanced or metastatic hormone receptor–positive breast cancer randomized to receive 2.5 mg letrozole only once daily or with a weekly 9 mg/kg AS1402 infusion. The primary endpoint was overall response rate. Secondary endpoints included progression-free survival, time to progression, and safety. AS1402 exposure and influence of allotypes of FcγRIIIa, FcγRIIa, and MUC1 were evaluated.

Results: The study was stopped early because of a trend toward worse response rates and a higher rate of early disease progression in the AS1402 + letrozole arm. Final analysis revealed no significant difference in efficacy between the study arms. Evaluated gene polymorphisms did not define patient subgroups with improved outcomes. Addition of AS1402 to letrozole was associated with manageable toxicity.

Conclusions: Because adding AS1402 to letrozole did not improve outcomes compared with letrozole only, blocking ER may be a better strategy for harnessing MUC1 modulation of the ER to a clinical advantage. FcγRIIIa, FcγRIIa, and MUC1 allotype did not predict outcome for patients treated with letrozole with or without AS1402. Clin Cancer Res; 17(21); 6822–30. ©2011 AACR.
Prevention of Chemotherapy-Induced Anemia and Thrombocytopenia by Constant Administration of Stem Cell Factor
Authors: Bartucci Monica , Dattilo Rosanna , Martinetti Daniela , Todaro Matilde , Zapparelli Giuseppina , Di Virgilio Antonio , Biffoni Mauro , De Maria Ruggero , Zeuner Ann
Published: August 2011

Purpose: Chemotherapy-induced apoptosis of immature hematopoietic cells is a major cause of anemia and thrombocytopenia in cancer patients. Although hematopoietic growth factors such as erythropoietin and colony-stimulating factors cannot prevent the occurrence of drug-induced myelosuppression, stem cell factor (SCF) has been previously shown to protect immature erythroid and megakaryocytic cells in vitro from drug-induced apoptosis. However, the effect of SCF in vivo as a single myeloprotective agent has never been elucidated.

Experimental Design: The ability of SCF to prevent the occurrence of chemotherapy-induced anemia and thrombocytopenia was tested in a mouse model of cisplatin-induced myelosuppression. To highlight the importance of maintaining a continuous antiapoptotic signal in immature hematopoietic cells, we compared two treatment schedules: in the first schedule, SCF administration was interrupted during chemotherapy treatment and resumed thereafter, whereas in the second schedule, SCF was administered without interruption for 7 days, including the day of chemotherapy treatment.

Results: The administration of SCF to cisplatin-treated mice could preserve bone marrow integrity, inhibit apoptosis of erythroid and megakaryocytic precursors, prevent chemotherapy-induced anemia, and rapidly restore normal platelet production. Treatment with SCF increased the frequency of Bcl-2/Bcl-XL–positive bone marrow erythroid cells and sustained Akt activation in megakaryocytes. Myeloprotection was observed only when SCF was administered concomitantly with cisplatin and kept constantly present during the days following chemotherapy treatment.

Conclusions: SCF treatment can prevent the occurrence of chemotherapy-induced anemia and thrombocytopenia in mice, indicating a potential use of this cytokine in the supportive therapy of cancer patients. Clin Cancer Res; 17(19); 6185–91. ©2011 AACR.
Variants in Inflammation Genes Are Implicated in Risk of Lung Cancer in Never Smokers Exposed to Second-hand Smoke
Authors: Spitz Margaret R. , Gorlov Ivan P. , Amos Christopher I. , Dong Qiong , Chen Wei , Etzel Carol J. , Gorlova Olga Y. , Chang David W. , Pu Xia , Zhang Di , Wang Liang , Cunningham Julie M. , Yang Ping , Wu Xifeng
Published: August 2011

Lung cancer in lifetime never smokers is distinct from that in smokers, but the role of separate or overlapping carcinogenic pathways has not been explored. We therefore evaluated a comprehensive panel of 11,737 single-nucleotide polymorphisms (SNP) in inflammatory-pathway genes in a discovery phase (451 lung cancer cases, 508 controls from Texas). SNPs that were significant were evaluated in a second external population (303 cases, 311 controls from the Mayo Clinic). An intronic SNP in the ACVR1B gene, rs12809597, was replicated with significance and restricted to those reporting adult exposure to environmental tobacco smoke. Another promising candidate was an SNP in NR4A1, although the replication OR did not achieve statistical significance. ACVR1B belongs to the TGFR-β superfamily, contributing to resolution of inflammation and initiation of airway remodeling. An inflammatory microenvironment (second-hand smoking, asthma, or hay fever) is necessary for risk from these gene variants to be expressed. These findings require further replication, followed by targeted resequencing, and functional validation.

Significance: Beyond passive smoking and family history of lung cancer, little is known about the etiology of lung cancer in lifetime never smokers that accounts for about 15% of all lung cancers in the United States. Our two-stage candidate pathway approach examined a targeted panel of inflammation genes and has identified novel structural variants that appear to contribute to risk in patients who report prior exposure to sidestream smoking. Cancer Discovery; 1(5): 420–9. ©2011 AACR.

This article is highlighted in the In This Issue feature, p. 367
Heme Induces Heme Oxygenase 1 via Nrf2
Authors: Boyle Joseph J. , Johns Michael , Lo Jonathan , Chiodini Alessandra , Ambrose Nicola , Evans Paul C. , Mason Justin C. , Haskard Dorian O.
Published: August 2011

Objective—

Intraplaque hemorrhage (IPH) is an important progression event in advanced atherosclerosis, in large part because of the delivery of prooxidant hemoglobin in erythrocytes. We have previously defined a novel macrophage phenotype (hemorrhage-associated-mac) in human advanced plaques with IPH. These may be atheroprotective in view of raised heme oxygenase 1 (HO-1), CD163, and interleukin-10 expression and suppressed oxidative stress.

Methods and Results—

We have used a combination of small interfering RNA and pharmacological reagents, protein analysis, and oxidative stress measurements to dissect the pathway leading to the development of this phenotype. We found that erythrocytes, hemoglobin, or purified heme similarly induced CD163 and suppressed human leukocyte antigen and reactive oxygen species. HO-1 was required for the development of each of these features. Challenge of macrophages with purified heme provoked nuclear translocation of Nrf2, and Nrf2 small interfering RNA resulted in significant inhibition of the ability of heme to induce HO-1 protein. Furthermore,
tert
-butyl-hydroquinone, which activates Nrf2, upregulated CD163, suppressed human leukocyte antigen, and induced interleukin-10, further supporting a role for Nrf2-mediated signaling. However, an inducible protein transactivator is also probably necessary, as heme-induced HO-1 mRNA expression was fully inhibited by the protein synthesis inhibitor cycloheximide.

Conclusion—

Our experiments define an Nrf2-mediated pathway by which heme induces a homeostatic macrophage response following IPH.
Cathepsin L Activity Is Essential to Elastase Perfusion–Induced Abdominal Aortic Aneurysms in Mice
Authors: Sun Jiusong , Sukhova Galina K. , Zhang Jie , Chen Han , Sjöberg Sara , Libby Peter , Xiang Meixiang , Wang Jianan , Peters Christoph , Reinheckel Thomas , Shi Guo-Ping
Published: August 2011

Objective—

The development of abdominal aortic aneurysms (AAA) requires extensive aortic wall matrix degradation. Human AAA lesions express high levels of cathepsin L (CatL), one of the most potent mammalian elastases. Whether this protease participates directly in AAA pathogenesis, however, is unknown.

Methods and Results—

We generated experimental AAA with aortic elastase perfusion in mice and established an essential role of CatL in AAA formation. After 14 days postperfusion, most wild-type (Ctsl
+/+
) mice developed AAA, but none of the CatL-deficient (Ctsl
−/−
) mice did. AAA lesion macrophage contents, CD4
+
T cell numbers, CD31
+
and laminin-5 angiogenic fragment γ2
+
microvessel numbers, and elastin fragmentation were all significantly lower in Ctsl
−/−
mice than in Ctsl
+/+
mice. While lesions from Ctsl
−/−
mice contained fewer Ki67
+
proliferating cells than did Ctsl
+/+
mice, the absence of CatL did not affect lesion apoptotic cell contents or medial smooth-muscle cell loss significantly. Mechanistic studies indicated that the absence of CatL reduced lesion chemokine monocyte chemotactic protein-1 content, macrophage and T-cell in vitro transmigration, and angiogenesis, and altered the expression and activities of matrix metalloproteinases and other cysteinyl cathepsins in inflammatory cells, vascular cells, and AAA lesions.

Conclusion—

CatL contributes to AAA formation by promoting lesion inflammatory cell accumulation, angiogenesis, and protease expression.
Potentiation of Platelet-Derived Growth Factor Receptor-β Signaling Mediated by Integrin-Associated MFG-E8
Authors: Motegi Sei-ichiro , Garfield Susan , Feng Xu , Sárdy Miklós , Udey Mark C.
Published: August 2011

Objective—

Pericytes/pericyte precursors produce milk fat globule-associated protein with epidermal growth factor and factor VIII-like domains (MFG-E8) in vivo, and this α
v
integrin ligand enhances angiogenesis in tumors and in oxygen-induced retinopathy in mice. Inhibition of MFG-E8 production or function attenuates platelet-derived growth factor-BB (PDGF-BB)-induced migration of pericyte/pericyte precursor-like 10T1/2 cells in vitro. Herein, we describe mechanisms by which MFG-E8 modulates PDGF-BB:PDGF receptor β (PDGFRβ) signaling in 10T1/2 cells.

Methods and Results—

Small interfering RNA depletion of MFG-E8 from 10T1/2 cells or antibody inhibition of MFG-E8 action enhanced PDGF-BB-dependent degradation of PDGFRβ and attenuated signaling. Coimmunoprecipitation revealed transient association of MFG-E8 with PDGFRβ in PDGF-BB-treated 10T1/2 cells and reduced PDGFRβ-focal adhesion kinase association in MFG-E8-depleted cells. Confocal microscopy demonstrated that MFG-E8 binding to 10T1/2 cells was RGD motif and α
v
dependent but PDGF-BB treatment independent, whereas colocalization of MFG-E8 with PDGFRβ was enhanced by PDGF-BB. Ubiquitination of PDGFRβ was also increased in MFG-E8 small interfering RNA-transfected cells.

Conclusion—

Integrin α
v
-bound MFG-E8 associates with PDGFRβ and focal adhesion kinase after PDGF-BB treatment, results in cell surface retention of PDGFRβ, delays receptor degradation, potentiates downstream signaling, and enhances migration of 10T1/2 cells. MFG-E8 may promote angiogenesis, in part, via cell autonomous actions on pericytes or pericyte precursors that result in enhanced PDGF-BB:PDGFRβ signaling mediated via integrin-growth factor receptor cross-talk.
Association of Health Professional Shortage Areas and Cardiovascular Risk Factor Prevalence, Awareness, and Control in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Allen Norrina B. , Diez-Roux Ana , Liu Kiang , Bertoni Alain G. , Szklo Moyses , Daviglus Martha
Published: August 2011

Background—

Individuals living in primary care health professional shortage areas (PC-HPSA), often have difficulty obtaining medical care; however, no previous studies have examined association of PC-HPSA residence with prevalence of cardiovascular disease risk factors.

Methods and Results—

To examine this question, the authors used data from the Multi-Ethnic Study of Atherosclerosis baseline examination (2000–2002). Outcomes included the prevalence of diabetes, hypertension, hyperlipidemia, smoking, and obesity as well as the awareness and control of diabetes, hypertension, and hyperlipidemia. Multivariable Poisson models were used to examine the independent association of PC-HPSA residence with each outcome. Models were sequentially adjusted for demographics, acculturation, socioeconomic status, access to health care, and neighborhood socioeconomic status. Similar to the national average, 16.7% of Multi-Ethnic Study of Atherosclerosis participants lived in a PC-HPSA. In unadjusted analyses, prevalence rates of diabetes (14.8% versus 11.0%), hypertension (48.2% versus 43.1%), obesity (35.7% versus 31.1%), and smoking (15.5% versus 12.1%) were significantly higher among residents of PC-HPSAs. There were no significant differences in the awareness or control of diabetes, hypertension, or hyperlipidemia. After adjustment, residence in a PC-HPSA was not independently associated with cardiovascular disease risk factor prevalence, awareness, or control.

Conclusions—

This study suggests that increased prevalence of cardiovascular disease risk factors in PC-HPSAs are explained by the demographic and socioeconomic characteristics of their residents. Future interventions aimed at increasing the number of primary care physicians may not improve cardiovascular risk without first addressing other factors underlying health care disparities.
Two-Hour Improvement of Patients in the National Institute of Neurological Disorders and Stroke Trials and Prediction of Final Outcome
Authors: Hemmen Thomas M. , Ernstrom Karin , Raman Rema
Published: August 2011

Background and Purpose—

Ongoing clinical trials are using early response to intravenous tissue-type plasminogen activator (tPA) to stratify patients into endovascular therapies. Little is known about the likelihood of early recovery and its correlation with final stroke outcome.

Methods—

We analyzed the National Institute of Neurological Disorders and Stroke tPA dataset for patients with early improvement (EI), a change of ≥4, or score 0 on the 2-hour National Institutes of Health Stroke Scale (NIHSS) to predict good 90-day outcome. We adjusted for multiple confounders and divided the patients by baseline NIHSS score 0 to 10, 11 to 20, >20, and stroke type to analyze if EI predicted good outcome across stroke severities and types. We analyzed different EI thresholds to identify the best level of NIHSS change to predict good 90-day outcome using a receiver-operator characteristic curve.

Results—

In total, 183 of 624 (29.3%) patients had EI, 112 of 312 (35.9%) in the tPA group had EI, and 71 of 312 (22.7%) in the placebo group had EI (
P
<0.0001). Smokers (
P
=0.012) and patients treated in <90 minutes (
P
=0.008) were more likely to have EI; diabetic patients (
P
=0.023) were less likely to show EI. The baseline NIHSS (mean±SD) of patients with EI was 16.1±6.5 versus 14.3±7.4 (
P
=0.001). A 90-day modified Rankin Scale score of 0 to 1 was achieved in 68 of 112 (60.7%) tPA-treated patient with EI and 65 of 200 (32.5%) without (placebo groups 30 of 71 [42.3%] versus 53/241 [22.0%]). The adjusted odds ratio for good outcome was 1.71 (95% confidence interval [CI], 1.1–2.6;
P
=0.011) for tPA treatment and 7.69 (95% CI, 4.63–12.76;
P
<0.0001) for early improvement. EI predicted good outcome in patients with cardioembolic (13.6; 95% CI, 3.6–51.5) and small vessel (6.98; 95% CI, 2.86–17.03), but not large vessel stroke (1.82; 95% CI, 0.38–8.59). The receiver-operator characteristic curve showed that a threshold of 4 on the NIHSS for prediction of good outcome had a sensitivity of 84% and 36% specificity.

Conclusions—

Early improvement was more common in tPA-treated patients and was associated with good 90-day outcome. Whereas 32.5% of nonresponders after tPA had a good 90-day outcome, the use of EI to predict stroke outcome shows value.
Safety and Tolerability of Deferoxamine Mesylate in Patients With Acute Intracerebral Hemorrhage
Authors: Selim Magdy , Yeatts Sharon , Goldstein Joshua N. , Gomes Joao , Greenberg Steven , Morgenstern Lewis B. , Schlaug Gottfried , Torbey Michel , Waldman Bonnie , Xi Guohua , Palesch Yuko ,   The Deferoxamine Mesylate in Intracerebral Hemorrhage Investigators
Published: August 2011

Background and Purpose—

Treatment with the iron chelator, deferoxamine mesylate (DFO), improves neurological recovery in animal models of intracerebral hemorrhage (ICH). We aimed to evaluate the feasibility, safety, and tolerability of varying dose-tiers of DFO in patients with spontaneous ICH, and to determine the maximum tolerated dose to be adopted in future efficacy studies.

Methods—

This was a multicenter, phase-I, dose-finding study using the Continual Reassessment Method. DFO was administered by intravenous infusion for 3 consecutive days, starting within 18 hours of ICH onset. Subjects underwent repeated clinical assessments through 90 days, and computed tomography neuroimaging pre- and post-drug-administration.

Results—

Twenty subjects were enrolled onto 5 dose tiers, starting with 7 mg/kg per day and ending with 62 mg/kg per day as the maximum tolerated dose. Median age was 68 years (range, 50–90); 60% were men; and median Glasgow Coma Scale and National Institutes of Health Stroke Scale scores on admission were 15 (5–15) and 9 (0–39), respectively. ICH location was lobar in 40%, deep in 50%, and brain stem in 10%; intraventricular hemorrhage was present in 15%. DFO was discontinued because of adverse events in 2 subjects (10%). Six subjects (30%) experienced 12 serious adverse events, none of which were drug-related. DFO infusions were associated with mild blood-pressure-lowering effects. Fifty percent of patients had modified Rankin scale scores ≤2, and 39% had modified Rankin scale scores of 4 to 6 on day 90; 15% died.

Conclusions—

Consecutive daily infusions of DFO after ICH are feasible, well-tolerated, and not associated with excessive serious adverse events or mortality. Our findings lay the groundwork for future studies to evaluate the efficacy of DFO in ICH.
Higher Incidence of In-Hospital Complications in Patients With Clipped Versus Coiled Ruptured Intracranial Aneurysms
Authors: Vergouwen Mervyn D.I. , Fang Jiming , Casaubon Leanne K. , Stamplecoski Melissa , Robertson Annette , Kapral Moira K. , Silver Frank L.
Published: August 2011

Background and Purpose—

After aneurysmal subarachnoid hemorrhage (SAH), patients with clipped aneurysms have a higher incidence of neurocognitive deficits and seizures compared with patients with coiled aneurysms. It remains unknown if patients with clipped aneurysms also have a higher incidence of other in-hospital complications.

Methods—

We used data from the Registry of the Canadian Stroke Network on consecutive patients admitted to hospital with aneurysmal SAH. Patients who died within 2 days after admission were excluded. Baseline characteristics, incidence of various in-hospital complications within 30 days after admission, length of stay, poor functional outcome (modified Rankin Scale score at discharge of ≥3), and mortality were compared between patients with clipped versus coiled aneurysms.

Results—

Of the 931 patients, 548 (59%) were clipped and 383 (41%) coiled. Baseline characteristics were similar. Compared with patients with coiled aneurysms, patients with clipped aneurysms had a higher incidence of in-hospital complications (37.2% versus 24.5% of patients;
P
<0.0001), poor functional outcome at discharge (69.4% versus 51.4%;
P
<0.0001), mortality (at discharge: 14.6% versus 9.1%;
P
=0.01), and a longer length of stay (17 [interquartile range, 11 to 29] versus 13 [interquartile range, 7 to 22] days;
P
<0.0001). Higher incidences were observed for urinary tract infection (
P
=0.02), pneumonia (
P
=0.01), cardiac/respiratory arrest (
P
=0.007), seizure (
P
=0.01), and decubitus ulcer (
P
=0.02). Urinary tract infection, pneumonia, cardiac/respiratory arrest, and seizure were independent predictors of poor functional outcome.

Conclusions—

Patients with clipped aneurysms have a higher incidence of in-hospital complications than patients with coiled aneurysms, which attributes to a higher risk of poor functional outcome and death and an increased length of stay.
High Levels of Apolipoprotein B/AI Ratio Are Associated With Intracranial Atherosclerotic Stenosis
Authors: Park Jong-Ho , Hong Keun-Sik , Lee Eun-Ja , Lee Juneyoung , Kim Dong-Eog
Published: August 2011

Background and Purpose—

The apolipoprotein B (apoB)/apoAI ratio is recognized as a better indicator of cardiovascular disease than other cholesterol measures. Whether intracranial or extracranial atherosclerosis is more closely associated with an increased apoB/apoAI ratio has not been investigated.

Methods—

A total of 464 statin or fibrate naïve Korean patients with acute ischemic stroke was categorized into 3 groups: intracranial (ICAS, n=236), extracranial (n=44), and no cerebral atherosclerotic stenosis (n=184). The apoB/apoAI ratio and demographics, including the presence of metabolic syndrome, were compared among the groups.

Results—

The ICAS group showed a higher apoB/apoAI ratio (0.81±0.02) than both the extracranial atherosclerotic stenosis (0.74±0.03) and no cerebral atherosclerotic stenosis (0.72±0.02) groups (
P
=0.002). The ratio was substantially increased (0.93±0.03) in patients with advanced ICAS (≥3 intracranial stenoses). With a multivariable analysis, the highest apoB/apoAI ratio quartile was an independent predictor of ICAS (OR, 2.13; 95% CI, 1.05 to 4.33). A dose–response relationship was observed between the presence of advanced ICAS and the apoB/apoAI ratio quartiles (OR, 4.03; 95% CI, 1.26 to 12.88 for the second quartile; OR, 4.88; 95% CI, 1.54 to 15.49 for the third quartile; and OR, 7.79; 95% CI, 2.41 to 25.16 for the fourth quartile when referenced to the first quartile). Patients having more metabolic syndrome components were more likely to have ICAS, advanced ICAS, and a higher apoB/apoAI ratio (
P
<0.001 for all).

Conclusions—

A higher apoB/apoAI ratio is a predictor of ICAS rather than of extracranial atherosclerotic stenosis or no cerebral atherosclerotic stenosis. The apoB/apoAI ratio might be a biomarker for ICAS in Asian patients with stroke.
Nicotine Replacement Therapy After Subarachnoid Hemorrhage Is Not Associated With Increased Vasospasm
Authors: Carandang Raphael A. , Barton Bruce , Rordorf Guy A. , Ogilvy Christopher S. , Sims John R.
Published: August 2011

Background and Purpose—

A significant number of patients with aneurysmal subarachnoid hemorrhage are active smokers and at risk for acute nicotine withdrawal. There is conflicting literature regarding the vascular effects of nicotine and theoretical concern that it may worsen vasospasm. The literature on the safety of nicotine replacement therapy and its effects on vasospasm is limited.

Methods—

A retrospective analysis was conducted of a prospectively collected database of aneurysmal subarachnoid hemorrhage patients admitted to the neurointensive care unit from 1994 to 2008. Paired control subjects matched for age, sex, Fisher score, aneurysm size and number, hypertension, and current medication were analyzed. The primary outcome was clinical and angiographic vasospasm and the secondary outcome was Glasgow Outcome Score on discharge. Conditional logistic models were used to investigate univariate and multivariate relationships between predictors and outcome.

Results—

Two hundred fifty-eight active smoking patients were included of which 87 were treated with transdermal nicotine replacement therapy. Patients were well matched for age, sex, gender, Fisher score, aneurysm size and number, hypertension, and current medications, but patients who received nicotine replacement therapy had less severe Hunt-Hess scores and Glasgow coma scores. There was no difference in angiographic vasospasm, but patients who received nicotine replacement therapy were less likely to have clinical vasospasm (19.5 versus 32.8%;
P
=0.026) and a Glasgow Outcome Score <4 on discharge (62.6% versus 81.6%;
P
=0.005) on multivariate analysis.

Conclusions—

Nicotine replacement therapy was not associated with increased angiographic vasospasm and was associated with less clinical vasospasm and better Glasgow Outcome Score scores on discharge.