bluuebunny/crossref_metadata_2025 huggingface dataset:
T-trees
Authors: Yuh Ping-Hung , Yang Chia-Lin , Chang Yao-Wen
Published: August 2009

Improving logic capacity by time-sharing, dynamically reconfigurable FPGAs are employed to handle designs of high complexity and functionality. In this article, we model each task as a 3D-box and deal with the temporal floorplanning/placement problem for dynamically reconfigurable FPGA architectures. We present a tree-based data structure, called
T-trees
, to represent the spatial and temporal relations among tasks. Each node in a T-tree has at most three children which represent the dimensional relationship among tasks. For the T-tree, we develop an efficient packing method and derive the condition to ensure the satisfaction of precedence constraints which model the temporal ordering among tasks induced by the execution of dynamically reconfigurable FPGAs. Experimental results show that our tree-based formulation can obtain significantly better solution quality with less execution time than the most recent state-of-the-art work.
Power-delay optimization in VLSI microprocessors by wire spacing
Authors: Moiseev Konstantin , Kolodny Avinoam , Wimer Shmuel
Published: August 2009

The problem of optimal space allocation among interconnect wires in a VLSI layout, in order to minimize the switching power consumption and the average signal delay, is addressed in this article. We define a Weighted Power-Delay Sum (WPDS) objective function and derive necessary and sufficient conditions for the existence of optimal interwire space allocation, based on the notion of capacitance density. At the optimum, every wire must be in equilibrium of its line-to-line weighted capacitance density on its two opposite sides, and the WPDS of the whole circuit is minimal if and only if capacitance density is uniformly distributed across the entire layout. This condition is shown to be equivalent to all paths of the layout cross-capacitance graph having the same length and all cuts having the same flow. An implementation which has been used in the design of a recent commercial high-end microprocessor and yielded 17% power reduction and 9% delay reduction in top-level interconnects is presented.
SUPERB
Authors: Engelke Piet , Becker Bernd , Renovell Michel , Schloeffel Juergen , Braitling Bettina , Polian Ilia
Published: August 2009

A high-performance resistive bridging fault simulator SUPERB (Simulator Utilizing Parallel Evaluation of Resistive Bridges) is proposed. It is based on fault sectioning in combination with parallel-pattern or parallel-fault multiple-stuck-at simulation. It outperforms a conventional interval-based resistive bridging fault simulator by three orders of magnitude while delivering identical results. Further competing tools are outperformed by several orders of magnitude. Industrial-size circuits, including a multi-million-gates design, could be simulated with runtimes within an order of magnitude of the runtimes for pattern-parallel stuck-at fault simulation.
Comparison between surrogate indexes of insulin sensitivity/resistance and hyperinsulinemic euglycemic clamp estimates in rats
Authors: Muniyappa Ranganath , Chen Hui , Muzumdar Radhika H. , Einstein Francine H. , Yan Xu , Yue Lilly Q. , Barzilai Nir , Quon Michael J.
Published: August 2009

Assessing insulin resistance in rodent models gives insight into mechanisms that cause type 2 diabetes and the metabolic syndrome. The hyperinsulinemic euglycemic glucose clamp, the reference standard for measuring insulin sensitivity in humans and animals, is labor intensive and technically demanding. A number of simple surrogate indexes of insulin sensitivity/resistance have been developed and validated primarily for use in large human studies. These same surrogates are also frequently used in rodent studies. However, in general, these indexes have not been rigorously evaluated in animals. In a recent validation study in mice, we demonstrated that surrogates have a weaker correlation with glucose clamp estimates of insulin sensitivity/resistance than in humans. This may be due to increased technical difficulties in mice and/or intrinsic differences between human and rodent physiology. To help distinguish among these possibilities, in the present study, using data from rats substantially larger than mice, we compared the clamp glucose infusion rate (GIR) with surrogate indexes, including QUICKI, HOMA, 1/HOMA, log (HOMA), and 1/fasting insulin. All surrogates were modestly correlated with GIR ( r = 0.34–0.40). Calibration analyses of surrogates adjusted for body weight demonstrated similar predictive accuracy for GIR among all surrogates. We conclude that linear correlations of surrogate indexes with clamp estimates and predictive accuracy of surrogate indexes in rats are similar to those in mice (but not as substantial as in humans). This additional rat study (taken with the previous mouse study) suggests that application of surrogate insulin sensitivity indexes developed for humans may not be appropriate for determining primary outcomes in rodent studies due to intrinsic differences in metabolic physiology. However, use of surrogates may be appropriate in rodents, where feasibility of clamps is an obstacle and measurement of insulin sensitivity is a secondary outcome.
Type of Featural Attention Differentially Modulates hMT+ Responses to Illusory Motion Aftereffects
Authors: Castelo-Branco Miguel , Kozak Lajos R. , Formisano Elia , Teixeira João , Xavier João , Goebel Rainer
Published: August 2009

Activity in the human motion complex (hMT+/V5) is related to the perception of motion, be it either real surface motion or an illusion of motion such as apparent motion (AM) or motion aftereffect (MAE). It is a long-lasting debate whether illusory motion-related activations in hMT+ represent the motion itself or attention to it. We have asked whether hMT+ responses to MAEs are present when shifts in arousal are suppressed and attention is focused on concurrent motion versus nonmotion features. Significant enhancement of hMT+ activity was observed during MAEs when attention was focused either on concurrent spatial angle or color features. This observation was confirmed by direct comparison of adapting (MAE inducing) versus nonadapting conditions. In contrast, this effect was diminished when subjects had to report on concomitant speed changes of superimposed AM. The same finding was observed for concomitant orthogonal real motion (RM), suggesting that selective attention to concurrent illusory or real motion was interfering with the saliency of MAE signals in hMT+. We conclude that MAE-related changes in the global activity of hMT+ are present provided selective attention is not focused on an interfering feature such as concurrent motion. Accordingly, there is a genuine MAE-related motion signal in hMT+ that is neither explained by shifts in arousal nor by selective attention.
Rietveld quantification of amorphous portions with an internal standard—Mathematical consequences of the experimental approach
Authors: Westphal Torsten , Füllmann Thomas , Pöllmann Herbert
Published: August 2009

The Rietveld method is increasingly used for amorphous portion determination. This article describes the quantification of amorphous portions using an internal standard in a formal mathematical way. From a set of basic assumptions and postulations, equations for the amorphous portion quantification, the optimum amount of internal standard, and the slope of the amorphous portion calculation formula were derived. With this tool set, the influence of the method principle on the analytical uncertainty is discussed. It is shown that the amount of internal standard has a strong influence on the precision of the amorphous portion determination. A poor choice can make the determination impossible, while a clever choice can enhance the precision compared to the precision of the Rietveld refinement.
Characterization of unidirectionally grown NaCl1−xBrxO3 crystals
Authors: Su Jingran , Song Youting , Zhang Daofan , Chang Xinan
Published: August 2009

NaCl1−xBrxO3 single crystals were prepared by unidirectional crystallization. The influences of the composition on structure, quality, and optical properties of NaCl1−xBrxO3 crystals were investigated. X-ray powder diffraction analysis revealed that the diffraction patterns for the NaCl1−xBrxO3 crystals have almost the same set of peaks as those of NaClO3 and NaBrO3, except that an extra very weak forbidden (100) diffraction peak was detected at about 13.3° 2θ for crystals grown from solutions of BrO3−∼15–70 at. % (i.e., x=0.15–0.70). These crystals can, therefore, be considered to have a distorted cubic structure closely related to the cubic structures of NaClO3 (x=0) and NaBrO3 (x=1). Our study also found that good-quality crystals can only be obtained in two doping ranges (x>0.75 or x<0.10). Outside these two ranges, the crystals tended to crack and even became opaque. Lattice distortions in the crystals were the probable cause as revealed by X-ray powder diffraction patterns. The optical activity of NaCl1−xBrxO3 crystals measured by a laser was found to decrease from 2.89 to 2.01°/mm with increasing value of x from 0 to 0.02. Stimulated Raman scattering of NaBr0.90Cl0.10O3 crystals was measured using a 0.532-μm ps laser as a pump source and four anti-Stokes lines plus six Stokes lines were observed. The fourth anti-Stokes emission was found to be at 454.5 nm and the sixth Stokes emission at 713.6 nm. Its Raman gain coefficient was determined to be 18.4 cm/Gw.
Arsenic in Water Resources of the Southern Pampa Plains, Argentina
Authors: Paoloni Juan D. , Sequeira Mario E. , Espósito Martín E. , Fiorentino Carmen E. , Blanco María del C.
Published: August 2009

Confronted with the need for accessible sources of good quality water and in view of the fact that the threat to public health posed by arsenic occurs mainly through the ingestion of contaminated drinking water, the presence and distribution of arsenic was evaluated in the southern Pampa Plains of Bahía Blanca district in Argentina. The findings show variable concentrations of arsenic in a complex distribution pattern. Complementary information is provided on the behavior of the groundwater resource and its salinity in terms of dissolved ions. Groundwater is the most severely affected, 97% of the samples exceeding the guideline value for arsenic in drinking water as recommended by the WHO (Guidelines for Drinking Water Quality, 2004). and showing maximum concentrations of up to 0.30 mg/L. Informing those responsible for preventive medicine and alerting the community at large will facilitate measures to mitigate exposure and ensure the safety of drinking water.
Evidence for a Potential Role of Metallothioneins in Inflammatory Bowel Diseases
Authors: Waeytens Anouk , De Vos Martine , Laukens Debby
Published: August 2009

Inflammatory bowel diseases (IBDs) are a group of chronic, relapsing, immune-mediated disorders of the intestine, including Crohn's disease and ulcerative colitis. Recent studies underscore the importance of the damaged epithelial barrier and the dysregulated innate immune system in their pathogenesis. Metallothioneins (MTs) are a family of small proteins with a high and conserved cysteine content that are rapidly upregulated in response to an inflammatory stimulus. Herein, we review the current knowledge regarding the expression and potential role of MTs in IBD. MTs exert a central position in zinc homeostasis, modulate the activation of the transcription factor nuclear factor (NF)-B, and serve as antioxidants. In addition, MTs could be involved in IBD through their antiapoptotic effects or through specific immunomodulating extracellular effects. Reports on MT expression in IBD are contradictory but clearly demonstrate a deviant MT expression supporting the idea that these aberrations in IBD require further clarification.
Production of Lipid Microparticles Magnetically Active by a Supercritical Fluid-Based Process
Authors: Vezzù Keti , Campolmi Chiara , Bertucco Alberto
Published: August 2009

An original technique, based on supercriticalCO2and on the particles from gas saturated solution (PGSS) micronization method, was developed to obtain magnetically active lipid microparticles. Magnetite nanoparticles (MNPs) were encapsulated into triestearin and phosphatidylcholine mixtures to increase their biocompatibility for future applications in the fields of biomedical diagnostics and therapeutic medications. The lipid particles produced were characterized to determine size and size distribution, and to confirm the encapsulation of MNP. The mean size was in the range of 200–800 nm. The possibility to drive these magnetically active particles by an external magnet was demonstrated in a simple apparatus simulating a vessel of the circulatory system. The results obtained indicate that the modified PGSS technique is suitable to produce lipid microparticles with magnetic activity for possible use in medical applications.
Identification of Novel Gene Amplifications in Breast Cancer and Coexistence of Gene Amplification with an Activating Mutation of PIK3CA
Authors: Kadota Mitsutaka , Sato Misako , Duncan Beverly , Ooshima Akira , Yang Howard H. , Diaz-Meyer Natacha , Gere Sheryl , Kageyama Shun-Ichiro , Fukuoka Junya , Nagata Takuya , Tsukada Kazuhiro , Dunn Barbara K. , Wakefield Lalage M. , Lee Maxwell P.
Published: August 2009

To identify genetic events that characterize cancer progression, we conducted a comprehensive genetic evaluation of 161 primary breast tumors. Similar to the “mountain-and-hill” view of mutations, gene amplification also shows high- and low-frequency alterations in breast cancers. The frequently amplified genes include the well-known oncogenes ERBB2, FGFR1, MYC, CCND1, and PIK3CA, whereas other known oncogenes that are amplified, although less frequently, include CCND2, EGFR, FGFR2, and NOTCH3. More importantly, by honing in on minimally amplified regions containing three or fewer genes, we identified six new amplified genes: POLD3, IRAK4, IRX2, TBL1XR1, ASPH, and BRD4. We found that both the IRX2 and TBL1XR1 proteins showed higher expression in the malignant cell lines MCF10CA1h and MCF10CA1a than in their precursor, MCF10A, a normal immortalized mammary epithelial cell line. To study oncogenic roles of TBL1XR1, we performed knockdown experiments using a short hairpin RNA approach and found that depletion of TBL1XR1 in MCF10CA1h cells resulted in reduction of cell migration and invasion as well as suppression of tumorigenesis in mouse xenografts. Intriguingly, our mutation analysis showed the presence of activation mutations in the PIK3CA gene in a subset of tumors that also had DNA copy number increases in the PIK3CA locus, suggesting an additive effect of coexisting activating amino acid substitution and dosage increase from amplification. Our gene amplification and somatic mutation analysis of breast primary tumors provides a coherent picture of genetic events, both corroborating and novel, offering insight into the genetic underpinnings of breast cancer progression. [Cancer Res 2009;69(18):7357–65]
Dietary Feeding of Dibenzoylmethane Inhibits Prostate Cancer in Transgenic Adenocarcinoma of the Mouse Prostate Model
Authors: Oo Khor Tin , Yu Siwang , Barve Avanthika , Hao Xingpei , Hong Jin-Liern , Lin Wen , Foster Barbara , Huang Mou-Tuan , Newmark Harold L. , Kong Ah-Ng
Published: August 2009

Dibenzoylmethane (DBM), a minor β-diketone constituent of licorice, has been shown to exhibit antineoplastic effects in prostate cancer cell lines by induction of cell cycle arrest and regulation of androgen receptor expression. In the present study, we investigated the in vitro and in vivo efficacy of DBM using TRAMP-C1 cell lines and TRAMP mice. DBM was found to arrest TRAMP-C1 cells at G2-M phase of cell cycle and suppressed phosphorylated retinoblastoma, cyclin D1, and cyclin A. Importantly, DBM was found to be equally effective in suppression of prostate tumor progression in TRAMP mice. At 8 or 12 weeks of age, mice were fed control or 1% DBM-supplemented diets until 24 weeks of age. Our results show that DBM-fed groups had a lower incidence of palpable tumor and high-grade prostatic intraepithelial neoplasia. Subsequent mechanistic studies show that the expression of phosphorylated retinoblastoma, c-myc, cyclin D1, cyclin A, phosphorylated Akt, phosphorylated PDK-1, and phosphorylated S6 was significantly reduced by DBM. Our findings suggest that DBM blocks the growth and progression of prostate cancer in TRAMP mice via modulation of tumor cell cycle regulation and therefore merits its consideration for future clinical intervention of human prostate cancer. [Cancer Res 2009;69(17):7096–102]
The CHRNA5-CHRNA3-CHRNB4 Nicotinic Receptor Subunit Gene Cluster Affects Risk for Nicotine Dependence in African-Americans and in European-Americans
Authors: Saccone Nancy L. , Wang Jen C. , Breslau Naomi , Johnson Eric O. , Hatsukami Dorothy , Saccone Scott F. , Grucza Richard A. , Sun Lingwei , Duan Weimin , Budde John , Culverhouse Robert C. , Fox Louis , Hinrichs Anthony L. , Steinbach Joseph Henry , Wu Meng , Rice John P. , Goate Alison M. , Bierut Laura J.
Published: August 2009

Genetic association studies have shown the importance of variants in the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit gene cluster on chromosome 15q24-25.1 for the risk of nicotine dependence, smoking, and lung cancer in populations of European descent. We have carried out a detailed study of this region using dense genotyping in both European-Americans and African-Americans. We genotyped 75 known single nucleotide polymorphisms (SNPs) and one sequencing-discovered SNP in an African-American sample (N = 710) and in a European-American sample (N = 2,062). Cases were nicotine-dependent and controls were nondependent smokers. The nonsynonymous CHRNA5 SNP rs16969968 is the most significant SNP associated with nicotine dependence in the full sample of 2,772 subjects [P = 4.49 × 10−8; odds ratio (OR), 1.42; 95% confidence interval (CI), 1.25–1.61] as well as in African-Americans only (P = 0.015; OR, 2.04; 1.15–3.62) and in European-Americans only (P = 4.14 × 10−7; OR, 1.40; 1.23–1.59). Other SNPs that have been shown to affect the mRNA levels of CHRNA5 in European-Americans are associated with nicotine dependence in African-Americans but not in European-Americans. The CHRNA3 SNP rs578776, which has a low correlation with rs16969968, is associated with nicotine dependence in European-Americans but not in African-Americans. Less common SNPs (frequency ≤ 5%) are also associated with nicotine dependence. In summary, multiple variants in this gene cluster contribute to nicotine dependence risk, and some are also associated with functional effects on CHRNA5. The nonsynonymous SNP rs16969968, a known risk variant in populations of European-descent, is also significantly associated with risk in African-Americans. Additional SNPs contribute to risk in distinct ways in these two populations. [Cancer Res 2009;69(17):6848–56]
Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer
Authors: Stern Mariana C. , Lin Jie , Figueroa Jonine D. , Kelsey Karl T. , Kiltie Anne E. , Yuan Jian-Min , Matullo Giuseppe , Fletcher Tony , Benhamou Simone , Taylor Jack A. , Placidi Donatella , Zhang Zuo-Feng , Steineck Gunnar , Rothman Nathaniel , Kogevinas Manolis , Silverman Debra , Malats Nuria , Chanock Stephen , Wu Xifeng , Karagas Margaret R. , Andrew Angeline S. , Nelson Heather H. , Bishop D. Timothy , Sak Sei Chung , Choudhury Ananya , Barrett Jennifer H. , Elliot Faye , Corral Román , Joshi Amit D. , Gago-Dominguez Manuela , Cortessis Victoria K. , Xiang Yong-Bing , Gao Yu-Tang , Vineis Paolo , Sacerdote Carlotta , Guarrera Simonetta , Polidoro Silvia , Allione Alessandra , Gurzau Eugen , Koppova Kvetoslava , Kumar Rajiv , Rudnai Peter , Porru Stefano , Carta Angela , Campagna Marcello , Arici Cecilia , Park Sung Shim Lani , Garcia-Closas Montserrat ,   for the International Consortium of Bladder Cancer
Published: August 2009

Tobacco smoking is the most important and well-established bladder cancer risk factor and a rich source of chemical carcinogens and reactive oxygen species that can induce damage to DNA in urothelial cells. Therefore, common variation in DNA repair genes might modify bladder cancer risk. In this study, we present results from meta-analyses and pooled analyses conducted as part of the International Consortium of Bladder Cancer. We included data on 10 single nucleotide polymorphisms corresponding to seven DNA repair genes from 13 studies. Pooled analyses and meta-analyses included 5,282 cases and 5,954 controls of non-Latino white origin. We found evidence for weak but consistent associations with ERCC2 D312N [rs1799793; per-allele odds ratio (OR), 1.10; 95% confidence interval (95% CI), 1.01–1.19; P = 0.021], NBN E185Q (rs1805794; per-allele OR, 1.09; 95% CI, 1.01–1.18; P = 0.028), and XPC A499V (rs2228000; per-allele OR, 1.10; 95% CI, 1.00–1.21; P = 0.044). The association with NBN E185Q was limited to ever smokers (interaction P = 0.002) and was strongest for the highest levels of smoking dose and smoking duration. Overall, our study provides the strongest evidence to date for a role of common variants in DNA repair genes in bladder carcinogenesis. [Cancer Res 2009;69(17):6857–64]
c-Jun NH2-Terminal Kinase Activation Is Essential for DRAM-Dependent Induction of Autophagy and Apoptosis in 2-Methoxyestradiol–Treated Ewing Sarcoma Cells
Authors: Lorin Séverine , Borges Amélie , Ribeiro Dos Santos Lisandra , Souquère Sylvie , Pierron Gérard , Ryan Kevin M. , Codogno Patrice , Djavaheri-Mergny Mojgan
Published: August 2009

Ewing sarcoma and osteosarcoma are two aggressive cancers that affect bones and soft tissues in children and adolescents. Despite multimodal therapy, patients with metastatic sarcoma have a poor prognosis, emphasizing a need for more effective treatment. We have shown previously that 2-methoxyestradiol (2-ME), an antitumoral compound, induces apoptosis in Ewing sarcoma cells through c-Jun NH2-terminal kinase (JNK) activation. In the present study, we provide evidence that 2-ME elicits macroautophagy, a process that participates in apoptotic responses, in a JNK-dependent manner, in Ewing sarcoma and osteosarcoma cells. We also found that the enhanced activation of JNK by 2-ME is partially regulated by p53, highlighting the relationship of JNK and autophagy to p53 signaling pathway. Furthermore, we showed that 2-ME up-regulates damage-regulated autophagy modulator (DRAM), a p53 target gene, in Ewing sarcoma cells through a mechanism that involves JNK activation. The silencing of DRAM expression reduced both apoptosis and autophagy triggered by 2-ME in Ewing sarcoma and osteosarcoma cells. Our results therefore identify JNK as a novel mediator of DRAM regulation. These findings suggest that 2-ME or other anticancer therapies that increase DRAM expression or function could be used to effectively treat sarcoma patients. [Cancer Res 2009;69(17):6924–31]
The Double-Edged Sword of Autophagy Modulation in Cancer
Authors: White Eileen , DiPaola Robert S.
Published: August 2009

Macroautophagy (autophagy) is a lysosomal degradation pathway for the breakdown of intracellular proteins and organelles. Although constitutive autophagy is a homeostatic mechanism for intracellular recycling and metabolic regulation, autophagy is also stress responsive, in which it is important for the removal of damaged proteins and organelles. Autophagy thereby confers stress tolerance, limits damage, and sustains viability under adverse conditions. Autophagy is a tumor-suppression mechanism, yet it enables tumor cell survival in stress. Reconciling how loss of a prosurvival function can promote tumorigenesis, emerging evidence suggests that preservation of cellular fitness by autophagy may be key to tumor suppression. As autophagy is such a fundamental process, establishing how the functional status of autophagy influences tumorigenesis and treatment response is important. This is especially critical as many current cancer therapeutics activate autophagy. Therefore, efforts to understand and modulate the autophagy pathway will provide new approaches to cancer therapy and prevention. (Clin Cancer Res 2009;15(17):5308–16)
Targeted Radiotherapy for Prostate Cancer with an Oncolytic Adenovirus Coding for Human Sodium Iodide Symporter
Authors: Hakkarainen Tanja , Rajecki Maria , Sarparanta Mirkka , Tenhunen Mikko , Airaksinen Anu J. , Desmond Renée A. , Kairemo Kalevi , Hemminki Akseli
Published: August 2009

Purpose: Oncolytic adenoviruses are promising tools for cancer therapy. Although several clinical reports have indicated both safety and promising antitumor capabilities for these viruses, there are only a few examples of complete tumor eradication. Thus, the antitumor efficacy of oncolytic adenoviruses needs to be improved. One potentially useful approach is combination with radiotherapy.

Experimental Design: To target systemically administered radioiodide to tumors, we created Ad5/3-Δ24-human sodium iodide symporter (hNIS), a Rb-p16 pathway selective infectivity enhanced oncolytic adenovirus encoding hNIS.

Results: Ad5/3-Δ24-hNIS replication effectively killed prostate cancer cells in vitro and in vivo. Also, the virus-mediated radioiodide uptake into prostate cancer cells in vitro and into tumors in vivo. Furthermore, Ad5/3-Δ24-hNIS with radioiodide was significantly more effective than virus alone in mice with prostate cancer xenografts.

Conclusions: These results suggest that oncolytic adenovirus-mediated targeted radiotherapy might be a potentially useful option for enhancing the efficacy or adenoviral virotherapy. (Clin Cancer Res 2009;15(17):5396–403)
Inflammatory Biomarkers and Fatigue during Radiation Therapy for Breast and Prostate Cancer
Authors: Bower Julienne E. , Ganz Patricia A. , Tao May Lin , Hu Wenhua , Belin Thomas R. , Sepah Saviz , Cole Steve , Aziz Najib
Published: August 2009

Purpose: Biomarkers of radiation-induced behavioral symptoms, such as fatigue, have not been identified. Studies linking inflammatory processes to fatigue in cancer survivors led us to test the hypothesis that activation of the proinflammatory cytokine network is associated with fatigue symptoms during radiation therapy for breast and prostate cancer.

Experimental Design: Individuals with early-stage breast (n = 28) and prostate cancer (n= 20) completed questionnaires and provided blood samples for determination of serum levels of interleukin 1β (IL-1β) and IL-6 at assessments conducted before, during, and after a course of radiation therapy. Serum markers of proinflammatory cytokine activity, including IL-1 receptor antagonist and C-reactive protein, were examined in a subset of participants. Random coefficient models were used to evaluate the association between changes in cytokine levels and fatigue.

Results: As expected, there was a significant increase in fatigue during radiation treatment. Changes in serum levels of inflammatory markers C-reactive protein and IL-1 receptor antagonist were positively associated with increases in fatigue symptoms (Ps < 0.05), although serum levels of IL-1β and IL-6 were not associated with fatigue. These effects remained significant (Ps < 0.05) in analyses controlling for potential biobehavioral confounding factors, including age, body mass index, hormone therapy, depression, and sleep disturbance.

Conclusions: Results suggest that activation of the proinflammatory cytokine network and associated increases in downstream biomarkers of proinflammatory cytokine activity are associated with fatigue during radiation therapy for breast and prostate cancer.(Clin Cancer Res 2009;15(17):5534–40)
The Importance of Protein Kinase A in Prostate Cancer: Relationship to Patient Outcome in Radiation Therapy Oncology Group Trial 92-02
Authors: Pollack Alan , Bae Kyounghwa , Khor Li-Yan , Al-Saleem Tahseen , Hammond M. Elizabeth , Venkatesan Varagur , Byhardt Roger W. , Asbell Sucha O. , Shipley William U. , Sandler Howard M.
Published: August 2009

Purpose: We previously reported that protein kinase A type I (PKARIα) overexpression was predictive of outcome in prostate cancer patients treated with radiotherapy (RT) ± short-term androgen deprivation (STAD) on Radiation Therapy Oncology Group (RTOG) protocol 86-10. Here, we attempt to verify our prior findings and test the hypothesis that the relationship of the length of AD to patient outcome is affected by PKARIα overexpression.

Experimental Design: There were 313 cases in the RTOG 92-02 study cohort with available tissue and suitable staining by immunohistochemistry. Median follow-up was 10.1 years. The intensity of PKARIα staining intensity was quantified manually and by image analysis. Multivariate analyses were done for overall mortality using Cox proportional hazards models and for local failure, biochemical failure, distant metastasis, and cause-specific mortality using Fine and Gray's regression models.

Results: The expression levels of PKARIα, determined by manual and image analysis, were strongly correlated (P < 0.0001). In the multivariate analyses, manual-quantified and image analysis–quantified PKARIα staining intensities were independent predictors of distant metastasis (P < 0.01), local failure (P < 0.05), and biochemical failure (P ≤ 0.01). Furthermore, the benefit of long-term AD over STAD was much less when PKARIα expression was high.

Conclusions: PKARIα overexpression has been shown in two RTOG trials to be associated with an increased risk of failure after AD + RT. In this series of contemporary high-risk patients, PKARIα overexpression was associated with diminished response to LTAD + RT relative to STAD + RT, suggesting that such patients would be ideal for a PKARIα knockdown strategy. (Clin Cancer Res 2009;15(17):5478–84)
Expression of EBV Latent Antigens, Mammalian Target of Rapamycin, and Tumor Suppression Genes in EBV-Positive Smooth Muscle Tumors: Clinical and Therapeutic Implications
Authors: Ong Kong Wee , Teo Marissa , Lee Victor , Ong Danny , Lee Ann , Tan Chieh Suai , Vathsala A. , Toh Han Chong
Published: August 2009

Purpose: EBV-positive smooth muscle tumor (EBV+SMT) is a rare disease with no established therapy. We describe the largest single institution analysis in renal transplant recipients. It aims to define its clinical features and determine the expression of EBV latent genes as well as key molecular pathways.

Experimental Design: Patients with EBV+SMT were identified from the Singapore General Hospital Renal Transplant Registry database. These tumors were investigated for expression of EBV latent genes with Southern blots, EBV latent antigens, mammalian target of rapamycin (mTOR), Akt, p70 S6 kinase, and vascular endothelial growth factor using immunohistochemistry, as well as methylation status of cancer-related genes using methylation-specific PCR.

Results: Eight were found to be EBV+SMT in 1,123 transplant patients. All displayed indolent clinical courses and were unresponsive to immunosuppression reduction. Complete tumor regression was seen in one patient following administration of sirolimus. These tumors display the full range of known EBV latent genes. Immunohistochemistry with total and phosphorylated mTOR and Akt were positive for all patients, and vascular endothelial growth factor was positive in 25% of patients, suggesting activation of the mTOR/Akt pathway. Methylation of RASSF1A was found in all tissue samples, whereas promoter hypermethylation of RARβ, GSTP1, DAPK, and p14 was observed in some samples.

Conclusions: Our results suggest that these tumors display a EBV type III latency pattern. The mTOR pathway is also activated. EBV may play a role in silencing RASSF1A. EBV-specific immunotherapy, mTOR inhibitors, and demethylating agents are possible therapeutic options in this disease. (Clin Cancer Res 2009;15(17):5350–8)
Erythropoietin Receptor Expression and Correlation to Tamoxifen Response and Prognosis in Breast Cancer
Authors: Larsson Anna-Maria , Jirström Karin , Fredlund Erik , Nilsson Sofie , Rydén Lisa , Landberg Göran , Påhlman Sven
Published: August 2009

Purpose: The main function of erythropoietin (EPO) is to stimulate erythropoiesis. EPO receptors (EPOR) are expressed in other cell types, including tumor cells, suggesting that the EPO/EPOR pathway governs additional cellular processes besides erythropoiesis. Recombinant EPO (rhEPO) is frequently given to anemic cancer patients, although data on clinical outcome are conflicting. In an attempt to understand these clinical data, we analyzed EPO and EPOR expression in breast cancer and evaluated EPOR as a putative prognostic and predictive marker in breast cancer patients treated with tamoxifen.

Experimental Design: EPO mRNA/protein and EPOR mRNA were quantified by PCR and ELISA, respectively. Tissue microarrays containing 500 breast tumors from premenopausal women randomized to tamoxifen or no adjuvant treatment were evaluated for EPOR expression by immunohistochemistry. Predictive and prognostic information was evaluated using Kaplan-Meier curves and log-rank tests to estimate recurrence-free survival (RFS).

Results: EPO and EPOR were expressed in cultured cells, and breast tumor specimens expressed EPOR at varying levels. Tamoxifen treatment significantly increased RFS in patients with estrogen receptor–positive/progesterone receptor–positive (ER+/PR+) tumors with low EPOR expression (P = 0.001) but had no effect on RFS in patients with tumors with high EPOR expression (P = 0.98). In the untreated cohort, RFS was significantly improved for patients with ER+ tumors with high EPOR expression.

Conclusion: EPOR is abundantly expressed in breast cancer specimens. The fact that high expression of EPOR is related to an impaired tamoxifen response in ER+/PR+ tumors and to improved survival in untreated patients suggests that EPOR expression in breast cancer affects tumor behavior. (Clin Cancer Res 2009;15(17):5552–9)
A New Immunostain Algorithm Classifies Diffuse Large B-Cell Lymphoma into Molecular Subtypes with High Accuracy
Authors: Choi William W.L. , Weisenburger Dennis D. , Greiner Timothy C. , Piris Miguel A. , Banham Alison H. , Delabie Jan , Braziel Rita M. , Geng Huimin , Iqbal Javeed , Lenz Georg , Vose Julie M. , Hans Christine P. , Fu Kai , Smith Lynette M. , Li Min , Liu Zhongfeng , Gascoyne Randy D. , Rosenwald Andreas , Ott German , Rimsza Lisa M. , Campo Elias , Jaffe Elaine S. , Jaye David L. , Staudt Louis M. , Chan Wing C.
Published: August 2009

Purpose: Hans and coworkers previously developed an immunohistochemical algorithm with ∼80% concordance with the gene expression profiling (GEP) classification of diffuse large B-cell lymphoma (DLBCL) into the germinal center B-cell–like (GCB) and activated B-cell–like (ABC) subtypes. Since then, new antibodies specific to germinal center B-cells have been developed, which might improve the performance of an immunostain algorithm.

Experimental Design: We studied 84 cases of cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP)–treated DLBCL (47 GCB, 37 ABC) with GCET1, CD10, BCL6, MUM1, FOXP1, BCL2, MTA3, and cyclin D2 immunostains, and compared different combinations of the immunostaining results with the GEP classification. A perturbation analysis was also applied to eliminate the possible effects of interobserver or intraobserver variations. A separate set of 63 DLBCL cases treated with rituximab plus CHOP (37 GCB, 26 ABC) was used to validate the new algorithm.

Results: A new algorithm using GCET1, CD10, BCL6, MUM1, and FOXP1 was derived that closely approximated the GEP classification with 93% concordance. Perturbation analysis indicated that the algorithm was robust within the range of observer variance. The new algorithm predicted 3-year overall survival of the validation set [GCB (87%) versus ABC (44%); P < 0.001], simulating the predictive power of the GEP classification. For a group of seven primary mediastinal large B-cell lymphoma, the new algorithm is a better prognostic classifier (all “GCB”) than the Hans' algorithm (two GCB, five non-GCB).

Conclusion: Our new algorithm is significantly more accurate than the Hans' algorithm and will facilitate risk stratification of DLBCL patients and future DLBCL research using archival materials. (Clin Cancer Res 2009;15(17):5494–502)
CD24 Is a Novel Predictor for Poor Prognosis of Hepatocellular Carcinoma after Surgery
Authors: Yang Xin-Rong , Xu Yang , Yu Bin , Zhou Jian , Li Jia-Chu , Qiu Shuang-Jian , Shi Ying-Hong , Wang Xiao-Ying , Dai Zhi , Shi Guo-Ming , Wu Bin , Wu Li-Ming , Yang Guo-Huan , Zhang Bo-Heng , Qin Wen-Xin , Fan Jia
Published: August 2009

Purpose: To investigate the role of CD24 in tumor invasion and prognostic significance in hepatocellular carcinoma (HCC).

Experimental Design: CD24 expression was measured in stepwise metastatic HCC cell lines, tumor, peritumoral tissues, and normal liver tissues by quantitative real-time PCR and Western blot. The role of CD24 in HCC was investigated by CD24 depletion using small interfering RNA. Tumor tissue microarrays of 314 HCC patients who underwent resection between 1997 and 2000 were used to detect expression of CD24, β-catenin, and proliferating cell nuclear antigen. Prognostic significance was assessed using Kaplan-Meier survival estimates and log-rank tests.

Results: CD24 was overexpressed in the highly metastatic HCC cell line and in tumor tissues of patients with recurrent HCC. Depletion of CD24 caused a notable decrease in cell proliferation, migration, and invasiveness in vitro. Univariate and multivariate analyses revealed that CD24 was a significant predictor for overall survival and relapse-free survival. CD24 expression was correlated with poor prognosis independent of α-fetoprotein, tumor-node-metastasis stage, and Edmondson stage. High CD24 expression was significantly associated with cytoplasmic and nuclear accumulation of β-catenin (P = 0.023), high tumor proliferative status (P = 0.018), and diffused intrahepatic recurrence and distant metastasis (P = 0.026). Adjuvant transcatheter arterial chemoembolization after surgery reduced the rate of early recurrence (≤1 year) in CD24+ HCC patients (P = 0.024) but had no significant effect in CD24− patients (P = 0.284).

Conclusions: Overexpression of CD24 in HCC was associated with high invasiveness and metastatic potential, high tumor proliferation status, and activation of the Wnt/β-catenin pathway. CD24 may be a novel predictor for poor prognosis of HCC patients after surgery. (Clin Cancer Res 2009;15(17):5518–27)
Salivary microRNA: Discovery, Characterization, and Clinical Utility for Oral Cancer Detection
Authors: Park Noh Jin , Zhou Hui , Elashoff David , Henson Bradley S. , Kastratovic Dragana A. , Abemayor Elliot , Wong David T.
Published: August 2009

Purpose: We have previously shown that a transcriptome is found in saliva and subpanels of these mRNAs can be used as oral cancer biomarkers. In this study, we measured the presence of microRNAs (miRNA) in saliva and determined their potential as an additional set of oral cancer biomarkers.

Experimental Design: A total of 314 miRNAs were measured using reverse transcriptase-preamplification-quantitative PCR in 12 healthy controls. Degradation pattern of endogenous and exogenous saliva miRNAs were measured at room temperature over time. Selected miRNAs were validated in saliva of 50 oral squamous cell carcinoma patients and 50 healthy matched control subjects.

Results: We detected ∼50 miRNAs in both the whole and supernatant saliva. Endogenous saliva miRNA degraded much slower compared with exogenous miRNA. Two miRNAs, miR-125a and miR-200a, were present in significantly lower levels (P < 0.05) in the saliva of oral squamous cell carcinoma patients than in control subjects.

Conclusions: Both whole and supernatant saliva of healthy controls contained dozens of miRNAs, and similar to saliva mRNAs, these miRNAs are stable. Saliva miRNAs can be used for oral cancer detection. (Clin Cancer Res 2009;15(17):5473–7)
Integration of Molecular Profiling into the Lung Cancer Clinic
Authors: Pao William , Kris Mark G. , Iafrate A. John , Ladanyi Marc , Jänne Pasi A. , Wistuba Ignacio I. , Miake-Lye Ryn , Herbst Roy S. , Carbone David P. , Johnson Bruce E. , Lynch Thomas J.
Published: August 2009

Individuals from five thoracic oncology centers in the United States recently met to discuss how to integrate molecular profiling into the care of all patients with carcinoma of the lung. Lung cancer is an area of medical oncology in which clinicians are beginning to use specific tumor-associated molecular aberrations to assign and/or prioritize targeted therapies for patients. At this early stage, multiple hurdles remain before molecular profiling becomes a routine part of thoracic oncology practice. Concrete collaborative next steps were discussed that could help lead to standardized methods across institutions. In particular, to develop specific targeted therapies for patients whose tumors harbor rare mutations, it will be important for multiple institutions to work together to identify appropriate candidates, design the appropriate trials, and execute the trials with adequate numbers to achieve the necessary end points. Implementation will facilitate realization of the promise of molecularly tailored therapy, which could lead to more effective treatments with fewer side effects. (Clin Cancer Res 2009;15(17):5317–22)
Blood Flow-Metabolism Mismatch: Good for the Tumor, Bad for the Patient
Authors: Mankoff David A. , Dunnwald Lisa K. , Partridge Savannah C. , Specht Jennifer M.
Published: August 2009

Although tightly coupled in most normal tissues, blood flow and metabolism are often not well matched in tumors. A flow-metabolism mismatch, specifically, high metabolism relative to blood flow, can be recognized in tumors by functional and molecular imaging and is associated with poor response to treatment and early relapse or disease progression. (Clin Cancer Res 2009;15(17):5294–6)
Indications and Common Surgical Approaches for Cochlear Implantation in China
Authors: Chen Zhengnong , Yu Dongzhen , Wu Yaqin , Zhou Huiqun , Shi Haibo , Yin Shankai
Published: August 2009

Cochlear implants have become widely used in the management of profound sensorineural hearing loss. With today’s technology and the demonstrated success of cochlear implantation, candidacy criteria have greatly widened. In this paper, we describe issues concerning the current indications and common surgical approaches to cochlear implantation in China.
High Prevalence of the Connexin 26 (GJB2) Mutation in Chinese Cochlear Implant Recipients
Authors: Chen Dongye , Chen Xiaowei , Cao Keli , Zuo Jin , Jin Xin , Wei Caogang , Fang Fude
Published: August 2009

Background: The GJB2 gene, mapping to chromosome 13q12, encodes a gap junction protein, connexin 26, and is responsible for certain forms of congenital deafness, such as DFNB1 and DFNA3. Mutations of this gene are responsible for about one half of severe autosomal recessive non-syndromic deafness. Methods: To determine whether GJB2 mutations are major causes of deafness in Chinese cochlear implant recipients, we enrolled 115 cochlear implant recipients for mutation screening. Results: The results showed that 36.5% (42/115) of all cochlear implant recipients and 41% (41/100) of non-syndromic deafness patients exhibit GJB2 mutations; only 1 inner ear malformation patient was detected with GJB2 mutations. The present study found 11 different variations in the GJB2 gene. Conclusion: The 235delC mutation was the most prevalent mutation, found in 18.3% (42/230 alleles) of all cochlear implant recipients and 21.0% (42/200 alleles) of the non-syndromic deafness group. Only 0.6% of GJB2 mutations were detected in the inner ear malformation group. The novel 187G→T mutations are likely to be pathological mutations.
Electrode Interaction in Cochlear Implant Recipients: Comparison of Straight and Contour Electrode Arrays
Authors: Xi Xin , Ji Fei , Han Dongyi , Hong Mengdi , Chen Aiting
Published: August 2009

The degree of overlap among cochlear nerve fibers stimulated by different electrodes results in electrode interaction, which has been shown to have a significantly deleterious effect on speech recognition performance in multi-electrode cochlear implant users. The Nucleus CI24R(CS) Contour array, which lies substantially closer to the modiolus than the CI24M straight array, is expected to exhibit narrower excitation patterns. The neural response telemetry (NRT) 3.0 software provides a method of measuring the spread of neural excitation by presenting the masker and probe pulses on different intra-cochlear electrode bands. Nine pairs of children, using Nucleus CI24M/CI24R(CS) cochlear implants with a similar etiology and duration of deafness, insertion depth, age of implantation and loudest acceptable presentation level (LAPL) in NRT sessions, participated in the study. Profiles of the spread of neural excitation stimulated at the LAPL at 3 probe locations were examined for each pair of the 2 types of electrode array. The spread of neural excitation with respect to array type and location revealed significant effects (p < 0.001; p = 0.002) and no interaction between array type and probe location (p = 0.559). The results demonstrated that the Contour array improved electrode discrimination, especially for the electrodes at the basal end of the cochlea. The findings have implications for future electrode array design and current implant mapping strategies.
Minimally Invasive Strabismus Surgery Technique in Horizontal Rectus Muscle Surgery for Esotropia
Authors: Pellanda Niccolò , Mojon Daniel S.
Published: August 2009

Purpose: To evaluate the minimally invasive strabismus surgery (MISS) technique in combined unilateral horizontal rectus muscle operations for esotropia. Methods: This study included 61 patients operated by one surgeon with MISS medial rectus muscle recession and lateral rectus muscle plication. Alignment, binocular vision, conjunctival injection and swelling as well as complications during the first 6 postoperative months were recorded prospectively. Conjunctival swelling and injection on postoperative day 1 were scored retrospectively and compared to a study, which included patients operated with a limbal approach. Results: Conjunctival swelling and injection were less pronounced than following surgery with limbal approach (comparison of swelling and injection: p < 0.001 for MISS vs. limbal opening plication and p < 0.001 for MISS vs. limbal opening resection). A conversion to a limbal opening was necessary in 2.4% of muscles. No scleral perforation or other serious complication was observed. Conclusions: This study indicates that MISS induces less conjunctival swelling and injection compared to the usual limbal approach.