bluuebunny/crossref_metadata_2025 huggingface dataset:
Basal and IGF-I-dependent regulation of potassium channels by MAP kinases and PI3-kinase during eccentric cardiac hypertrophy
Authors: Teos Leyla Y. , Zhao Aiqiu , Alvin Zikiar , Laurence Graham G. , Li Chuanfu , Haddad Georges E.
Published: August 2008

The potassium channels IK and IK1, responsible for the action potential repolarization and resting potential respectively, are altered during cardiac hypertrophy. The activation of insulin-like growth factor-I (IGF-I) during hypertrophy may affect channel activity. The aim was to examine the modulatory effects of IGF-I on IK and IK1 through mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways during hypertrophy. With the use of specific inhibitors for ERK1/2 (PD98059), p38 MAPK (SB203580) and PI3K/Akt (LY294002), Western blot and whole cell patch-clamp were conducted on sham and aorto-caval shunt-induced hypertrophy adult rat myocytes. Basal activation levels of MAPKs and Akt were increased during hypertrophy. Acute IGF-I (10−8 M) enhanced basal activation levels of these kinases in normal hearts but only those of Akt in hypertrophied ones. IK and IK1 activities were lowered by IGF-I. Inhibition of ERK1/2, p38 MAPK, or Akt reduced basal IK activity by 70, 32, or 50%, respectively, in normal cardiomyocytes vs. 53, 34, or 52% in hypertrophied ones. However, basal activity of IK1 was reduced by 45, 48, or 45% in the former vs. 63, 43, or 24% in the latter. The inhibition of either MAPKs or Akt alleviated IGF-I effects on IK and IK1. We conclude that basal IK and IK1 are positively maintained by steady-state Akt and ERK activities. K+ channels seem to be regulated in a dichotomic manner by acutely stimulated MAPKs and Akt. Eccentric cardiac hypertrophy may be associated with a change in the regulation of the steady-state basal activities of K+ channels towards MAPKs, while that of the acute IGF-I-stimulated ones toward Akt.
Aging increases upper airway collapsibility in Fischer 344 rats
Authors: Ray Andrew D. , Ogasa Toshiyuki , Magalang Ulysses J. , Krasney John A. , Farkas Gaspar A.
Published: August 2008

The upper airway muscles play an important role in maintaining upper airway collapsibility, and the incidence of sleep-disordered breathing increases with age. We hypothesize that the increase in airway collapsibility with increasing age can be linked to changes in upper airway muscle mechanics and structure. Eight young (Y: 6 mo) and eight old (O: 30 mo) Fischer 344 rats were anesthetized and mechanically ventilated, and the pharyngeal pressure associated with flow limitation (Pcrit) was measured 1) with the hypoglossal (cnXII) nerve intact, 2) following bilateral cnXII denervation, and 3) during cnXII stimulation. With the cnXII intact, the upper airways of older rats were more collapsible compared with their younger counterparts [Pcrit = −7.1 ± 0.6 (SE) vs. −9.5 ± 0.7 cmH2O, respectively; P = 0.033]. CnXII denervation resulted in an increase in Pcrit such that Pcrit became similar in both groups (O: −4.2 ± 0.5 cmH2O; Y: −5.4 ± 0.5 cmH2O). In all rats, cnXII stimulation decreased Pcrit (less collapsible) in both groups (O: −11.3 ± 1.0 cmH2O; Y: −10.2 ± 1.0 cmH2O). The myosin heavy chain composition of the genioglossus muscle demonstrated a decrease in the percentage of the IIb isoform (38.3 ± 2.5 vs. 21.7 ± 1.7%; P < 0.001); in contrast, the sternohyoid muscle demonstrated an increase in the percentage of the IIb isoform (72.2 ± 2.5 vs. 58.4 ± 2.3%; P = 0.001) with age. We conclude that the upper airway becomes more collapsible with age and that the increase in upper airway collapsibility with age is likely related to altered neural control rather than to primary alterations in upper airway muscle structure and function.
Cardiovascular dynamics in healthy subjects with differing heart rate responses to tilt
Authors: Ramirez-Marrero Farah A. , Charkoudian Nisha , Hart Emma C. , Schroeder Darrell , Zhong Liu , Eisenach John H. , Joyner Michael J.
Published: August 2008

Orthostatic stress such as head-up tilt (HUT) elicits a wide range of heart rate (HR) and arterial pressure (AP) responses among healthy individuals. In this study, we evaluated cardiovascular dynamics in healthy subjects with different HR responses to HUT, but without autonomic dysfunction. We measured AP (brachial artery) and HR (ECG) during 5 min of 60° HUT in 76 healthy normotensive individuals. We then chose individuals on the basis of the extremes of HR responses to HUT (high = ΔHR ≥ 20 beats/min, and low = ΔHR ≤ 10 beats/min; n = 15 per group). Peak HR during HUT was 87 ± 10 beats/min in the high and 69 ± 14 beats/min in the low group ( P < 0.05). High HR responders had lower systolic pressure at baseline (121 ± 9 vs. 129 ± 11 mmHg, P < 0.05) and during HUT (120 ± 10 vs. 131 ± 13 mmHg, P < 0.05), and higher plasma norepinephrine (NE) response to HUT (ΔNE: 156.9 ± 17.8 vs. 89.0 ± 17.2 pg/ml; P < 0.05). ΔNE during HUT was also significantly correlated with ΔHR when all 76 subjects were included in a regression analysis ( r = 0.39; P < 0.001). Pulse pressure was lower during HUT in high HR responders compared with low HR responders (45 ± 1 vs. 55 ± 2 mmHg, P < 0.05). High HR responders also had larger fluctuations in systolic and pulse pressure during HUT (coefficient of variation = 10.7 ± 0.7 vs. 5.7 ± 0.3%; 7.9 ± 0.5 vs. 4.1 ± 0.4%, respectively, P < 0.05). Sex distribution was different between groups (high: 5 women, 10 men; low: 10 women, 5 men). Higher HR with lower AP during HUT is consistent with normal baroreflex mechanisms of integration. Although interindividual variability appears to be a fundamental part of cardiovascular regulation, the mechanisms of these differences and the sex discrepancy requires further investigation.
X-ray powder diffraction and dielectric study of BaTi1−x(Zn1/3Nb2/3)xO3 (x=0.025 and 0.9)
Authors: Khemakhem L. , Kabadou A. , Ben Salah A. , Abdelmoula N.
Published: August 2008

Polycrystalline BaTi1−x(Zn1/3Nb2/3)xO3 (x=0.025 and 0.9) compounds were synthesized successfully and studied by XRD and dielectric measurements. The effects of the Ti/(Zn,Nb) ratio on the structure and dielectric properties of the compounds were investigated. XRD results indicated that the crystal structure of the x=0.09 compound is cubic perovskite with space group Pm3m and a=4.0095(4) Å. For the x=0.09 compound, a splitting of the (200) peak was observed near 40.2°, indicating that the crystal structure changed from cubic to tetragonal, with space group P4mm, a=4.026(4) Å, and c=4.0091(4) Å. Rietveld refinement of the crystal structures led to final confidence factors Rp=0.0353 and Rp=0.0349 for x=0.025 and 0.9, respectively. Dielectric measurements showed a relaxor behavior present in BaTi0.1(Zn1/3Nb2/3)0.9.
Effects of organic additives and temperature on the structures and morphologies of calcium carbonate crystals in the presence of cetyltrimethylammonium bromide
Authors: Du Yinxiao , Hou Haixing , Zeng Fanguang
Published: August 2008

Calcium carbonate crystals were prepared via a simple precipitation reaction of sodium carbonate with calcium chloride from mixed solutions of various amphiphilic organic solvents and water in the presence of cetyltrimethylammonium bromide at 25 and 60 °C. Our analysis shows that amphiphilic organic solvents and temperature have large influences on the structure and morphology of CaCO3. X-ray diffraction patterns show that single-phase hexahedral calcite was formed at 25 °C, and orthorhombic aragonite was obtained at 60 °C. Mixtures of major amounts of long aragonite crystals and minor amounts of calcite particles were also obtained at 60 °C in the methanol and the acetone solutions. Scanning electron microscopy images show that CaCO3 particles and aggregates with various morphologies, such as large solid and hollow hexahedral crystals and small round granules of calcite as well as glass-like and wheat-like aggregates of aragonite, were obtained depending on the experimental conditions. Based on the experimental results, a conclusion on the effects of temperature and amphiphilic organic solvents on the crystal structure and morphology are made.
An Extragradient Approximation Method for Equilibrium Problems and Fixed Point Problems of a Countable Family of Nonexpansive Mappings
Authors: Wangkeeree Rabian
Published: September 2008

We introduce a new iterative scheme for finding the common element of the set of common fixed points of nonexpansive mappings, the set of solutions of an equilibrium problem, and the set of solutions of the variational inequality. We show that the sequence converges strongly to a common element of the above three sets under some parameters controlling conditions. Moreover, we apply our result to the problem of finding a common fixed point of a countable family of nonexpansive mappings, and the problem of finding a zero of a monotone operator. This main theorem extends a recent result of Yao et al. (2007) and many others.
The Schwarz‐Christoffel Conformal Mapping for “Polygons” with Infinitely Many Sides
Authors: Riera Gonzalo , Carrasco Hernán , Preiss Rubén
Published: September 2008

The classical Schwarz‐Christoffel formula gives conformal mappings of the
upper half‐plane onto domains whose boundaries consist of a finite number
of line segments. In this paper, we explore extensions to boundary curves
which in one sense or another are made up of infinitely many line segments,
with specific attention to the “infinite staircase” and to the Koch snowflake,
for both of which we develop explicit formulas for the mapping function and
explain how one can use standard mathematical software to generate corresponding
graphics. We also discuss a number of open questions suggested
by these considerations, some of which are related to differentials on hyperelliptic
surfaces of infinite genus.
Diagnostic Approach to Reflux in 2007
Authors: Dave Sumit , Khoury Antoine E.
Published: September 2008

There is ongoing controversy regarding the association between vesicoureteric reflux (VUR), recurrent urinary tract infections (UTI), and renal damage. Despite this, routine work up for VUR is still recommended after febrile UTI in most children. The present article reviews the indications and imaging modalities available for VUR diagnosis. Alternative newer techniques like MR cystography and voiding urosonography are discussed. The increasing evidence of the role of DMSA scans in managing children with VUR is highlighted.
What Does the Anatomical Organization of the Entorhinal Cortex Tell Us?
Authors: Canto Cathrin B. , Wouterlood Floris G. , Witter Menno P.
Published: September 2008

The entorhinal cortex is commonly perceived as a major input and output structure of the hippocampal formation, entertaining the role of the nodal point of cortico-hippocampal circuits. Superficial layers receive convergent cortical information, which is relayed to structures in the hippocampus, and hippocampal output reaches deep layers of entorhinal cortex, that project back to the cortex. The finding of the grid cells in all layers and reports on interactions between deep and superficial layers indicate that this rather simplistic perception may be at fault. Therefore, an integrative approach on the entorhinal cortex, that takes into account recent additions to our knowledge database on entorhinal connectivity, is timely. We argue that layers in entorhinal cortex show different functional characteristics most likely not on the basis of strikingly different inputs or outputs, but much more likely on the basis of differences in intrinsic organization, combined with very specific sets of inputs. Here, we aim to summarize recent anatomical data supporting the notion that the traditional description of the entorhinal cortex as a layered input-output structure for the hippocampal formation does not give the deserved credit to what this structure might be contributing to the overall functions of cortico-hippocampal networks.
Detection of Variations of Local Irregularity of Traffic under DDOS Flood Attack
Authors: Li Ming , Zhao Wei
Published: September 2008

The aim of distributed denial‐of‐service (DDOS) flood attacks is to overwhelm the attacked site or to make its service performance deterioration considerably by sending flood packets to the target from the machines distributed all over the world. This is a kind of local behavior of traffic at the protected site because the attacked site can be recovered to its normal service state sooner or later even though it is in reality overwhelmed during attack. From a view of mathematics, it can be taken as a kind of short‐range phenomenon in computer networks. In this paper, we use the Hurst parameter (H) to measure the local irregularity or self‐similarity of traffic under DDOS flood attack provided that fractional Gaussian noise (fGn) is used as the traffic model. As flood attack packets of DDOS make theHvalue of arrival traffic vary significantly away from that of traffic normally arriving at the protected site, we discuss a method to statistically detect signs of DDOS flood attacks with predetermined detection probability and false alarm probability.
Hydatidosis of the Pelvic Cavity: A Big Masquerade
Authors: Varedi Peyman , Saadat Mostafavi Seyed Reza , Salouti Rambod , Saedi Daryoush , Nabavizadeh Seyed Ali , Samimi Kaveh , Larijani Tahereh , Darabi Mohsen , Mousavi Seyed Mehdi , Makhmalbaf Ahmad Ostadali
Published: September 2008

We report and discuss a case of primary hydatidosis of the pelvic cavity in a woman who presented with severe weight loss and abdominal pain. This unusual presentation was initially considered as a tumor process until surgical exploration and microscopic studies confirmed the diagnosis. The gynecologists should be aware of possibility of primary hydatid cyst of the pelvic cavity and should be considered in the differential diagnosis of cystic pelvic masses, especially in areas where the disease is endemic.
Direct Neighborhood Discriminant Analysis for Face Recognition
Authors: Cheng Miao , Fang Bin , Tang Yuan Yan , Wen Jing
Published: September 2008

Face recognition is a challenging problem in computer vision and pattern recognition. Recently, many local geometrical structure‐based techiniques are presented to obtain the low‐dimensional representation of face images with enhanced discriminatory power. However, these methods suffer from the small simple size (SSS) problem or the high computation complexity of high‐dimensional data. To overcome these problems, we propose a novel local manifold structure learning method for face recognition, named direct neighborhood discriminant analysis (DNDA), which separates the nearby samples of interclass and preserves the local within‐class geometry in two steps, respectively. In addition, the PCA preprocessing to reduce dimension to a large extent is not needed in DNDA avoiding loss of discriminative information. Experiments conducted on ORL, Yale, and UMIST face databases show the effectiveness of the proposed method.
Nonsteroidal Anti-inflammatory Drugs Suppress Glioma via 15-Hydroxyprostaglandin Dehydrogenase
Authors: Wakimoto Naoki , Wolf Ido , Yin Dong , O'Kelly James , Akagi Tadayuki , Abramovitz Lilach , Black Keith L. , Tai Hsin-Hsiung , Koeffler H. Phillip
Published: August 2008

Studies have conjectured that nonsteroidal anti-inflammatory drugs (NSAID) inhibit growth of various malignancies by inhibiting cyclooxygenase-2 (COX-2) enzyme activity. Yet, several lines of evidence indicate that a COX-2–independent mechanism may also be involved in their antitumor effects. Here, we report that NSAIDs may inhibit the growth of glioblastoma multiforme (GBM) cells through COX-2–independent mechanisms, including up-regulation of both 15-hydroxyprostaglandin dehydrogenase (15-PGDH, the key prostaglandin catabolic enzyme) and the cell cycle inhibitor p21. Using Western blot and real-time PCR analysis in various GBM cell lines, we observed up-regulation of 15-PGDH and p21 after NSAIDs treatment. To elucidate the role of 15-PGDH in GBM, transfection assays were conducted using the T98G GBM cell line. Overexpression of 15-PGDH suppressed cell growth and was associated with increased expression of p21. In an attempt to investigate the roles of COX-2, 15-PGDH, and p21 in the inhibition of growth of GBM, small interfering RNA (siRNA) against each of these proteins was transfected into T98G cells. Inhibition of growth mediated by NSAIDs was partially reversed after knockdown of either 15-PGDH or p21, but not after COX-2 knockdown. Moreover, expression level of p21 was not affected in COX-2 siRNA transfected cells. Our studies provide evidence that the up-regulation of 15-PGDH induced by NSAIDs has the potential to inhibit growth of GBM, in part, by up-regulation of p21 possibly independent from COX-2 enzymatic function. [Cancer Res 2008;68(17):6978–86]
Nitric Oxide Is a Key Component in Inflammation-Accelerated Tumorigenesis
Authors: Hussain S. Perwez , He Peijun , Subleski Jeffery , Hofseth Lorne J. , Trivers Glenwood E. , Mechanic Leah , Hofseth Anne B. , Bernard Mark , Schwank Jonathan , Nguyen Giang , Mathe Ewy , Djurickovic Draginja , Haines Diana , Weiss Jonathan , Back Timothy , Gruys Eilene , Laubach Victor E. , Wiltrout Robert H. , Harris Curtis C.
Published: August 2008

Nitric oxide (NO•), an important signaling molecule and a component of inflammatory response, is involved in tumorigenesis. However, the quantity of NO• and the cellular microenvironment influences the role of NO• in tumor development. We used a genetic strategy to test the hypothesis that an inflammatory microenvironment with an enhanced level of NO• accelerates spontaneous tumor development. C. parvum–induced inflammation and increased NO• synthase-2 (NOS2) expression coincided with accelerated spontaneous tumor development, mostly lymphomas, in p53−/−NOS2+/+ C57BL6 mice when compared with the controls (P = 0.001). However, p53−/−NOS2−/− mice did not show any difference in tumor latency between C. parvum–treated and control groups. In C. parvum–treated p53−/−NOS2+/+ mice, tumor development was preceded by a higher expression of NOS2 and phosphorylated Akt-Ser473 (pAkt-Ser473) in spleen, increased cell proliferation measured by Ki-67 IHC in spleen and thymus, and a lower apoptotic index and CD95-L expression in spleen and thymus. C. parvum–treated p53−/−NOS2+/+ mice showed an increase in the number of Foxp3(+) T-reg cells, dendritic cells (DC), as well as increased CD80+, CD86+, CD40+, and CD83+ on DC in the spleen. Regulatory T-cells (T-reg) and the maturation of DC may modulate tumorigenesis. An increase in the FoxP3(+)T-reg cells in C. parvum–treated p53−/−NOS2+/+ mice indicates a role of NO• in the regulation of T-reg cells that may contribute to a protumor shift of the immune environment favoring an accelerated tumor development. These data provide genetic and mechanistic evidence that an inflammatory microenvironment and an increased level of NO• can accelerate tumor development. [Cancer Res 2008;68(17):7130–6]
ATM Acts Downstream of ATR in the DNA Damage Response Signaling of Bystander Cells
Authors: Burdak-Rothkamm Susanne , Rothkamm Kai , Prise Kevin M.
Published: August 2008

This study identifies ataxia-telangiectasia mutated (ATM) as a further component of the complex signaling network of radiation-induced DNA damage in nontargeted bystander cells downstream of ataxia-telangiectasia and Rad3-related (ATR) and provides a rationale for molecular targeted modulation of these effects. In directly irradiated cells, ATR, ATM, and DNA-dependent protein kinase (DNA-PK) deficiency resulted in reduced cell survival as predicted by the known important role of these proteins in sensing DNA damage. A decrease in clonogenic survival was also observed in ATR/ATM/DNA-PK–proficient, nonirradiated bystander cells, but this effect was completely abrogated in ATR and ATM but not DNA-PK–deficient bystander cells. ATM activation in bystander cells was found to be dependent on ATR function. Furthermore, the induction and colocalization of ATR, 53BP1, ATM-S1981P, p21, and BRCA1 foci in nontargeted cells was shown, suggesting their involvement in bystander DNA damage signaling and providing additional potential targets for its modulation. 53BP1 bystander foci were induced in an ATR-dependent manner predominantly in S-phase cells, similar to γH2AX foci induction. In conclusion, these results provide a rationale for the differential modulation of targeted and nontargeted effects of radiation. [Cancer Res 2008;68(17):7059–65]
Functional Genetic Variations in Cytotoxic T-Lymphocyte Antigen 4 and Susceptibility to Multiple Types of Cancer
Authors: Sun Tong , Zhou Yifeng , Yang Ming , Hu Zhibin , Tan Wen , Han Xiaohong , Shi Yuankai , Yao Jiarui , Guo Yongli , Yu Dianke , Tian Tian , Zhou Xiaoyi , Shen Hongbing , Lin Dongxin
Published: August 2008

Antitumor T lymphocytes play a pivotal role in immunosurveillance of malignancy. The CTL antigen 4 (CTLA-4) is a vital negative regulator of T-cell activation and proliferation. This study examined whether genetic polymorphisms in CTLA-4 are associated with cancer susceptibility. A two-stage investigation using haplotype-tagging single nucleotide polymorphism approach and multiple independent case-control analyses was performed to assess the association between CTLA-4 genotypes and cancer risk. Functional relevance of the polymorphisms was examined by biochemical assays. We found that the 49G>A polymorphism in the CTLA-4 leading sequence causing 17Ala to 17Thr amino acid substitution is associated with increased susceptibility to multiple cancers, including lung, breast, esophagus, and gastric cardia cancers. Genotyping in 5,832 individuals with cancer and 5,831 control subjects in northern and southern Chinese populations showed that the CTLA-4 49AA genotype had an odds ratio of 1.72 (95% confidence interval, 1.50−2.10; P = 3.4 × 10−7) for developing cancer compared with the 49GG genotype. Biochemical analyses showed that CTLA-4−17Thr had higher capability to bind B7.1 and stronger inhibitory effect on T-cell activation compared with CTLA-4−17Ala. T cells carrying the 49AA genotype had significantly lower activation and proliferation rates compared with T cells carrying the 49GG genotype upon stimulation. These results are consistent with our hypothesis and indicate that genetic polymorphisms influencing T-cell activation modify cancer susceptibility. [Cancer Res 2008;68(17):7025–34]
PTEN Acetylation Modulates Its Interaction with PDZ Domain
Authors: Ikenoue Tsuneo , Inoki Ken , Zhao Bin , Guan Kun-Liang
Published: August 2008

The PTEN tumor suppressor gene is frequently inactivated in human cancer. As a major tumor suppressor, PTEN function must be tightly regulated. Both phosphorylation and membrane association have been reported to regulate PTEN activity. In addition, the COOH terminus of PTEN has a typical PDZ domain-binding motif that interacts with several PDZ domain-containing proteins. In this report, we show that PTEN is acetylated on Lys402, which is in the COOH-terminal PDZ domain-binding motif. We show that CBP plays a major role in PTEN acetylation, whereas the SIRT1 deacetylase is mainly responsible for PTEN deacetylation. Interestingly, Lys402 acetylation modulates PTEN interaction with PDZ domain-containing proteins, indicating a potential role of acetylation in regulating PTEN function. [Cancer Res 2008;68(17):6908–12]
Whole Chromosome Alterations Predict Survival in High-Risk Neuroblastoma without MYCN Amplification
Authors: Bilke Sven , Chen Qing-Rong , Wei Jun S. , Khan Javed
Published: September 2008

Purpose: Patients with stage IV neuroblastoma over the age of 500 days without MYCN amplification have a survival rate of <30% and there are currently no reliable means of predicting which of these patients will survive or succumb to the disease. The goal of this study is to develop a DNA copy number–based prognostic profile for these patients.

Experimental Design: We have used comparative genomic hybridization to identify genome copy number changes that can predict outcome in patients with stage IV neuroblastoma without MYCN amplification.

Results: A strong correlation of patient survival with the presence of whole chromosome changes (WCC ≥2) was observed, even in the group of patients older than 500 days at time of diagnosis. This novel prognostic marker showed a significant dependence on the date of diagnosis; patients with WCC ≥2 diagnosed after 1998 had a significantly higher probability of survival compared with those diagnosed earlier. At the same time, no such time dependence was found among the samples with WCC <2, suggesting that medical progress patients in recent years has particularly benefited those patients with a stage IV non–MYCN-amplified disease if WCC ≥2 were present.

Conclusions: In this pilot study, we present a novel prognostic marker for survival of high-risk neuroblastoma patients over the age of 500 days without MYCN amplification and diagnosed after 1998. Further validation study is required to establish this risk stratification for these patients.
A Phase I Study of Bexarotene, a Retinoic X Receptor Agonist, in Non-M3 Acute Myeloid Leukemia
Authors: Tsai Donald E. , Luger Selina M. , Andreadis Charalambos , Vogl Dan T. , Kemner Allison , Potuzak Melissa , Goradia Ami , Loren Alison W. , Perl Alexander E. , Schuster Stephen J. , Porter David L. , Stadtmauer Edward A. , Goldstein Steven C. , Thompson James E. , Swider Cezary , Bagg Adam , Mato Anthony R. , Carroll Martin
Published: September 2008

Purpose: Bexarotene is a retinoic X receptor agonist that has been shown in vitro to inhibit growth and induce differentiation of myeloid leukemic cell lines. We therefore conducted a phase I dose escalation study to assess the maximum tolerated dose, toxicities, and activity of bexarotene in patients with non-M3 acute myeloid leukemia (AML).

Experimental Design: We enrolled patients with active non-M3 AML who had either relapsed or refractory disease or were not eligible for standard cytotoxic chemotherapy. Cohorts of three to six patients received escalating doses of daily oral bexarotene ranging from 100 to 400 mg/m2 until evidence of disease progression or unacceptable adverse events occurred.

Results: Twenty-seven patients, with median age of 69 years (range, 51-82 years), were treated. Twenty-four (89%) patients had undergone prior chemotherapy. At the highest dose level tested (400 mg/m2), three of six patients had to reduce their dose of bexarotene due to grade 3 adverse events. The maximum tolerable dose of bexarotene was determined to be 300 mg/m2. Clinical activity was manifested by 4 (15%) patients with reduction in bone marrow blasts to ≤5%, 11 (41%) patients with improved platelet counts, and 7 (26%) patients with improved neutrophil counts. Three patients with relapsed AML survived >1 year while taking bexarotene. Leukemic blast differentiation was suggested by the presence of the leukemic cytogenetic abnormality in mature circulating granulocytes and the occurrence of differentiation syndrome.

Conclusions: The recommended dose of bexarotene for future studies is 300 mg/m2/d. Bexarotene is well tolerated in patients with non-M3 AML and has evidence of antileukemic activity.
Thymidine Selectively Enhances Growth Suppressive Effects of Camptothecin/Irinotecan in MSI+ Cells and Tumors Containing a Mutation of MRE11
Authors: Rodriguez Rene , Hansen Lasse Tengbjerg , Phear Geraldine , Scorah Jennifer , Spang-Thomsen Mogens , Cox Angela , Helleday Thomas , Meuth Mark
Published: September 2008

Purpose: DNA synthesis inhibitors and damaging agents are widely used in cancer therapy; however, sensitivity of tumors to such agents is highly variable. The response of tumor cells in culture to these agents is strongly influenced by the status of DNA damage response pathways. Here, we attempt to exploit the altered response of mismatch repair (MMR)-deficient colon cancer cells and tumors to camptothecin or irinotecan and thymidine by combining them to improve therapeutic response.

Experimental Design: A panel of colon cancer cell lines was assayed for response to camptothecin-thymidine combinations by measuring colony formation, cell cycle distribution, and senescence. Cell strains defective in p53, p21, or Mre11 were used in these assays to investigate the role of these cell cycle regulators. The in vivo antitumor response of xenografts to irinotecan and thymidine combinations was assessed in nude mice.

Results: Camptothecin-thymidine combinations suppress colony formation of MMR-deficient tumor cells 10- to 3,000-fold relative to that obtained with camptothecin alone and significantly reduce the concentrations of the agents required to induce late S/G2 arrest and senescence. Sensitivity is not a direct result of MMR, p53, or p21 status. However MMR-deficient cell lines containing an intronic frameshift mutation of MRE11 show greatest sensitivity to these agents. Increased sensitivity to this combination is also evident in vivo as thymidine enhances irinotecan-induced growth suppression of MMR-deficient tumors carrying the MRE11 mutation in mouse xenografts.

Conclusion: Irinotecan-thymidine combinations may be particularly effective when targeted to MSI+ tumors containing this readily detectable MRE11 mutation.
Tasigna for Chronic and Accelerated Phase Philadelphia Chromosome–Positive Chronic Myelogenous Leukemia Resistant to or Intolerant of Imatinib
Authors: Hazarika Maitreyee , Jiang Xiaoping , Liu Qi , Lee Shwu-Luan , Ramchandani Roshni , Garnett Christine , Orr Micheal S. , Sridhara Rajeshwari , Booth Brian , Leighton John K. , Timmer William , Harapanhalli Ravi , Dagher Ramzi , Justice Robert , Pazdur Richard
Published: September 2008

Purpose: This Food and Drug Administration (FDA) approval report describes the data and analyses leading to the approval by the FDA of nilotinib (Tasigna, AMN-107; Novartis Pharmaceuticals Corporation), an inhibitor of Bcr-Abl tyrosine kinase, for the treatment of chronic-phase (CP) and accelerated-phase (AP) chronic myelogenous leukemia (CML) resistant to or intolerant of imatinib.

Experimental Design: The FDA approval of the efficacy and safety of nilotinib was based on the results of an ongoing single-arm, open-label, phase 2 clinical trial. The primary end point for CML-CP was unconfirmed major cytogenetic response. The efficacy end point for CML-AP was confirmed hematologic response.

Results: The major cytogenetic response rate in 232 evaluable CP patients was 40% (95% confidence interval, 33%, 46%). The hematologic response rate in 105 evaluable AP patients was 26% (95% confidence interval, 18%, 35%). The median duration of response has not been reached for both CML-CP and CML-AP responding patients. In CML-CP patients, the common serious drug-related adverse reactions were thrombocytopenia and neutropenia. In CML-AP patients, the common serious drug-related adverse reactions were thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase, and pyrexia. Nilotinib prolongs the QT interval and sudden deaths have been reported; these risks and appropriate risk minimization strategies are described in a boxed warning on the labeling.

Conclusions: On October 29, 2007, the U.S. FDA granted accelerated approval to nilotinib (Tasigna) for use in the treatment of CP and AP Philadelphia chromosome positive CML in adult patients resistant to or intolerant of prior therapy that included imatinib.
Molecular Diagnosis of Sentinel Lymph Node Metastases in Cervical Cancer Using Squamous Cell Carcinoma Antigen
Authors: Yuan Song-Hua , Liang Xue-Fang , Jia Wei-Hua , Huang Jian-Ling , Wei Mei , Deng Ling , Liang Li-Zhi , Wang Xiao-Yun , Zeng Yi-Xin
Published: September 2008

Purpose: To clarify the prognostic value of molecular diagnosis of SLN metastases in cervical cancer using SCCA.

Experimental Design: All SLNs and primary tumors, part of non-SLNs, were harvested from 36 patients with cervical cancer. Expression levels of SCCA, cytokeratin 19 (CK19), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA in 178 samples (29 primary tumors, 5 histologic positive nodes, 60 histologic negative SLNs, 69 non-SLNs, and 15 normal nodes) were assessed by quantitative reverse transcription-PCR assay. The quantitative value of SCCA or CK19 mRNA was described as each value relative to GAPDH mRNA. The cutoff value was set at the upper limit of the quantitative value of nodes from noncancer patients, and those above this value constituted the molecular metastasis group.

Results: The SCCA mRNA expression values were more than 1 × 103 in 28 primary tumors and all histologic positive nodes, and its expression levels in SLNs were higher than in non-SLNs. SLNs from patients with adverse prognostic features had higher SCCA mRNA expression levels. Four histologic negative SLNs were diagnosed molecular metastases based on SCCA mRNA. Two cases with histologically uninvolved pelvic nodes recurred. Survival analysis indicates that molecular lymphatic metastasis based on elevated SCCA mRNA level is the best predictor of recurrence. However, CK19 is not a suitable marker due to its low specificity and relative higher baseline expression in normal nodes.

Conclusions: SCCA mRNA levels for molecular diagnosis of SLN metastases in cervical cancer more accurately identifies patients at risk for recurrence than the routine histology does.
A Phase I Study of EKB-569 in Combination with Capecitabine in Patients with Advanced Colorectal Cancer
Authors: Laheru Dan , Croghan Gary , Bukowski Ronald , Rudek Michelle , Messersmith Wells , Erlichman Charles , Pelley Robert , Jimeno Antonio , Donehower Ross , Boni Joseph , Abbas Richat , Martins Patricia , Zacharchuk Charles , Hidalgo Manuel
Published: September 2008

Purpose: To determine the maximum tolerated dose (MTD), characterize the principal toxicities, and assess the pharmacokinetics of EKB-569, an oral selective irreversible inhibitor of the epidermal growth factor receptor tyrosine kinase, in combination with capecitabine in patients with advanced colorectal cancer.

Experimental Design: Patients were treated with EKB-569 daily for 21 days and capecitabine twice daily for 14 days of a 21-day cycle. The dose levels of EKB-569 (mg/day) and capecitabine (mg/m2 twice daily) assessed were 25/750, 50/750, 50/1,000 and 75/1,000. An expanded cohort was enrolled at the MTD to better study toxicity and efficacy. Samples of plasma were collected to characterize the pharmacokinetics of the agents. Treatment efficacy was assessed every other cycle.

Results: A total of 37 patients, the majority of whom had prior chemotherapy, received a total of 163 cycles of treatment. Twenty patients were treated at the MTD, 50 mg EKB-569, daily and 1,000 mg/m2 capecitabine twice daily. Dose-limiting toxicities were diarrhea and rash. No patients had complete or partial responses but 48% had stable disease. The conversion of capecitabine to 5-fluorouracil was higher for the combination of EKB-569 and capecitabine (321 ± 151 ng*h/mL) than for capecitabine alone (176 ± 62 ng*hours/mL; P = 0.0037).

Conclusion: In advanced colorectal cancer, 50 mg EKB-569 daily can be safely combined with 1,000 mg/m2 capecitabine twice a day. A statistically significant increase in plasma levels of 5-fluorouracil for the combination of EKB-569 and capecitabine may be due to the single-dose versus multiple-dose exposure difference, variability in exposure or a potential drug interaction.
Eradication of Ovarian Tumor Xenografts by Locoregional Administration of Targeted Immunotherapy
Authors: De Cesare Michelandrea , Calcaterra Claudia , Pratesi Graziella , Gatti Laura , Zunino Franco , Mènard Sylvie , Balsari Andrea
Published: September 2008

Purpose: Oligodeoxynucleotides containing unmethylated CpG motifs (CpG-ODN) are potent activators of innate and adaptive immunity. Recognition of CpG-ODN is mediated by Toll-like receptor 9 expressed by immune cells, endothelial and epithelial cells, and fibroblasts. We examined the antitumor effect of CpG-ODN and the role of administration route on human ovarian cancers growing in the peritoneal cavity of nude mice.

Experimental Design: Mice implanted i.p. with human ovarian carcinoma cells were treated i.p., s.c., or i.v. and assessed for survival and tumor-free incidence. Peritoneal washings were analyzed for keratinocyte chemokine production and for functional and phenotypic profiles as indicators of the cell types involved in mediating the antitumor effects.

Results: IGROV-1-bearing mice treated i.p. survived significantly longer than those treated i.v. or s.c. (P = 0.0005), and nearly half of them (8 of 17) were tumor-free by the end of the experiment, a rate never achieved using a variety of chemotherapeutic drugs. High rates of tumor-free mice were observed in three other ovarian tumor xenografts treated i.p. Compared with peritoneal washings of mice treated s.c. or i.v., those from mice treated i.p. showed the highest level of serum and tissue keratinocyte chemokine, the highest number of natural killer cells and neutrophils, and the highest antiproliferative activity in vitro.

Conclusions: The superior antitumor effect obtained by locoregional administration of CpG-ODN in i.p. tumor-bearing mice with a limited adaptive immune response points to the importance of innate effector cells amplification at the site of tumor growth and suggests the promise of i.p. CpG-ODN in clinical trials for ovarian cancer.
Vorinostat and Sorafenib Synergistically Kill Tumor Cells via FLIP Suppression and CD95 Activation
Authors: Zhang Guo , Park Margaret A. , Mitchell Clint , Hamed Hossein , Rahmani Mohamed , Martin Aditi Pandya , Curiel David T. , Yacoub Adly , Graf Martin , Lee Ray , Roberts John D. , Fisher Paul B. , Grant Steven , Dent Paul
Published: September 2008

Purpose and Design: Mechanism(s) by which the multikinase inhibitor sorafenib and the histone deacetylase inhibitor vorinostat interact to kill hepatic, renal, and pancreatic adenocarcinoma cells has been defined.

Results: Low doses of sorafenib and vorinostat interacted in vitro in a synergistic fashion to kill hepatic, renal, and pancreatic adenocarcinoma cells in multiple short-term viability (24-96 h) and in long-term colony formation assays. Cell killing was suppressed by inhibition of cathepsin proteases and caspase-8 and, to a lesser extent, by inhibition of caspase-9. Twenty-four hours after exposure, the activities of extracellular signal-regulated kinase 1/2, AKT, and nuclear factor-κB were only modestly modulated by sorafenib and vorinostat treatment. However, 24 h after exposure, sorafenib- and vorinostat-treated cells exhibited markedly diminished expression of c-FLIP-s, full-length BID, BCL-2, BCL-XL, MCL-1, XIAP, increased expression of BIM, and increased activation of BAX, BAK, and BAD. Expression of eIF2α S51A blocked sorafenib- and vorinostat-induced suppression of c-FLIP-s levels and overexpression of c-FLIP-s abolished lethality. Sorafenib and vorinostat treatment increased surface levels of CD95 and CD95 association with caspase-8. Knockdown of CD95 or FADD expression significantly reduced sorafenib/vorinostat-mediated lethality.

Conclusions: These data show that combined exposure of epithelial tumor cell types to sorafenib and vorinostat diminishes expression of multiple antiapoptotic proteins and promotes activation of the CD95 extrinsic apoptotic and the lysosomal protease pathways, and that suppression of c-FLIP-s expression represents a critical event in transduction of the proapoptotic signals from CD95 to promote mitochondrial dysfunction and death.
Postradiation Sensitization of the Histone Deacetylase Inhibitor Valproic Acid
Authors: Chinnaiyan Prakash , Cerna David , Burgan William E. , Beam Katie , Williams Eli S. , Camphausen Kevin , Tofilon Philip J.
Published: September 2008

Purpose: Preclinical studies evaluating histone deacetylase (HDAC) inhibitor-induced radiosensitization have largely focused on the preirradiation setting based on the assumption that enhanced radiosensitivity was mediated by changes in gene expression. Our previous investigations identified maximal radiosensitization when cells were exposed to HDAC inhibitors in both the preradiation and postradiation setting. We now expand on these studies to determine whether postirradiation exposure alone affects radiosensitivity.

Experimental Design: The effects of the HDAC inhibitor valproic acid (VA) on postirradiation sensitivity in human glioma cell lines were evaluated using a clonogenic assay, exposing cells to VA up to 24 h after irradiation. DNA damage repair was evaluated using γH2AX and 53BP1 foci and cell cycle phase distribution was analyzed by flow cytometry. Western blot of acetylated γH2AX was done following histone extraction on AUT gels.

Results: VA enhanced radiosensitivity when delivered up to 24 h after irradiation. Cells accumulated in G2-M following irradiation, although they returned to baseline at 24 h, mitigating the role of cell cycle redistribution in postirradiation sensitization by VA. At 12 h after irradiation, significant γH2AX and 53BP1 foci dispersal was shown in the control, although cells exposed to VA after irradiation maintained foci expression. VA alone had no effect on the acetylation or phosphorylation of H2AX, although it did acetylate radiation-induced γH2AX.

Conclusions: These results indicate that VA enhances radiosensitivity at times up to 24 h after irradiation, which has direct clinical application.
Gemtuzumab Ozogamicin as Part of Reduced-Intensity Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients with Relapsed Acute Myeloid Leukemia
Authors: Bornhäuser Martin , Illmer Thomas , Oelschlaegel Uta , Schetelig Johannes , Ordemann Rainer , Schaich Markus , Hänel Mathias , Schuler Ulrich , Thiede Christian , Kiani Alexander , Platzbecker Uwe , Ehninger Gerhard
Published: September 2008

Purpose: Gemtuzumab ozogamicin (GO) has been associated with an increased risk of liver sinusoidal obstruction syndrome (SOS) when applied within 3 months of allogeneic hematopoietic cell transplantation (HCT). We hypothesized that GO might be safe and effective as part of a reduced-intensity conditioning regimen as salvage therapy of CD33+ acute myeloid leukemia.

Experimental Design: Thirty-one patients with acute myeloid leukemia which relapsed following conventional therapy (n = 15), autologous (n = 3), or allogeneic (n = 13) HCT were included in a prospective phase I/II trial. The preparative regimen contained 6 and 3 mg/m2 of GO on days −21 and −14 before transplantation, leading to a reduction of marrow blasts in 18 patients (58%). Eight patients received further cytoreductive chemotherapy before conditioning therapy was initiated. Fludarabine-based reduced-intensity (n = 11) or nonmyelablative (n = 16) conditioning and peripheral blood stem cell infusion from related (n = 6) or unrelated (n = 21) donors could be done in 27 patients during cytopenia.

Results: Primary engraftment occurred in all evaluable patients. Only one case of reversible hepatic sinusoidal obstruction syndrome was documented. Non–relapse mortality until day 100 was 22% (n = 6). The probabilities of overall and disease-free survival at 24 months were 39% and 35%, respectively. Relapse of leukemia occurring between 2 and 24 months after transplantation (median, 8 months) was the major reason for treatment failure and death.

Conclusion: These data suggest that GO can be combined with reduced-intensity conditioning even after previous autologous or allogeneic HCT.
Expanding the Roles for Pregnane X Receptor in Cancer: Proliferation and Drug Resistance in Ovarian Cancer
Authors: Gupta Divya , Venkatesh Madhukumar , Wang Hongwei , Kim Sean , Sinz Michael , Goldberg Gary L. , Whitney Kathleen , Longley Clifford , Mani Sridhar
Published: September 2008

Purpose: We examined the presence of the pregnane X receptor (PXR) and its effects on ovarian cancer cells after activation by its cognate ligand.

Experimental Design: SKOV-3 and OVCAR-8 ovarian carcinoma cells were analyzed for expression of PXR by quantitative reverse transcription-PCR and Western blot. Human ovarian cancer tissue was also analyzed for PXR expression by immunochemistry. Ligand (agonist)–induced PXR target genes were analyzed in SKOV-3 cells by quantitative reverse transcription-PCR. SKOV-3 cell proliferation was assessed by MTT assay. In vivo confirmation of in vitro effects of PXR ligands were done in NOD.SCID mice carrying SKOV-3 xenografts.

Results: PXR is expressed in ovarian cancer cells. In SKOV-3 cells, PXR is functional and its activation by cognate ligands induces PXR target genes (CYP2B6, CYP3A4, and UGT1A1) but not MDR1 and MRP2. PXR activation in SKOV-3 cells induces cell proliferation and drug resistance. In mice harboring SKOV-3 xenografts, rifampicin (PXR agonist) induces cell proliferation and tumor growth.

Conclusion: PXR activation, regardless of the type of ligand agonist present, promotes the “malignant” phenotype of cancer cells. These data serve as the basis for finding novel nontoxic inhibitors of PXR activation as a method to control cell growth and prevent induction of drug resistance.
Homocysteine and Its Relationship to Stroke Subtypes in a UK Black Population
Authors: Khan Usman , Crossley Carollyn , Kalra Lalit , Rudd Anthony , Wolfe Charles D.A. , Collinson Paul , Markus Hugh S.
Published: August 2008

Background and Purpose—

Homocysteine is an endothelial toxin and elevated levels have been associated with stroke risk. Stroke, particularly the small vessel disease (SVD) subtype, is increased in U.S. and UK black populations. In white populations elevated homocysteine has been associated with SVD, especially confluent leukoaraiosis, and may be acting through endothelial dysfunction. We determined the association between homocysteine and stroke subtypes, especially SVD, in a well-phenotyped UK cohort of black stroke patients compared to community controls.

Methods—

Homocysteine, vitamin B12, folate levels, and renal function were measured in 457 black stroke patients recruited consecutively through the prospective South London Ethnicity and Stroke Study and 179 black community controls. All patients were subtyped using modified TOAST criteria. Leukoaraiosis in SVD patients was graded according to severity, and patients were additionally categorized on the basis of presence or absence of confluent leukoaraiosis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated.

Results—

The highest homocysteine levels were seen in SVD patients compared to controls (16.2 [11.6] versus 11.8 [5.7] μmol/L,
P
<0.001) after adjusting for age, gender, vascular risk factors, vitamin levels, and renal function. Within SVD cases, highest homocysteine levels were found in lacunar infarction with confluent leukoaraiosis (19.6 [14.9] μmol/L) compared to lacunar infarction without leukoaraiosis (13.6 [7.1] μmol/L,
P
=0.001) and controls (
P
<0.001). Homocysteine correlated with leukoaraiosis severity (
r
=0.225,
P
<0.001).

Conclusions—

In this well characterized UK black stroke population homocysteine levels were elevated and highest levels were found in lacunar stroke with leukoaraiosis.