bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiobjective Optimization for Reconfigurable Implementation of Medical Image Registration
Authors: Dandekar Omkar , Plishker William , Bhattacharyya Shuvra S. , Shekhar Raj
Published: February 2009

In real-time signal processing, a single application often has multiple computationally intensive kernels that can benefit from acceleration using custom or reconfigurable hardware platforms, such as field-programmable gate arrays (FPGAs). For adaptive utilization of resources at run time, FPGAs with capabilities for dynamic reconfiguration are emerging. In this context, it is useful for designers to derive sets of efficient configurations that trade off application performance with fabric resources. Such sets can be maintained at run time so that the best available design tradeoff is used. Finding a single, optimized configuration is difficult, and generating a family of optimized configurations suitable for different run-time scenarios is even more challenging. We present a novel multiobjective wordlength optimization strategy developed through FPGA-based implementation of a representative computationally intensive image processing application: medical image registration. Tradeoffs between FPGA resources and implementation accuracy are explored, and Pareto-optimized wordlength configurations are systematically identified. We also compare search methods for finding Pareto-optimized design configurations and demonstrate the applicability of search based on evolutionary techniques for identifying superior multiobjective tradeoff curves. We demonstrate feasibility of this approach in the context of FPGA-based medical image registration; however, it may be adapted to a wide range of signal processing applications.
Immunohistochemical Estimates of Angiogenesis, Proliferative Activity, p53 Expression, and Multiple Drug Resistance Have No Prognostic Impact in Osteosarcoma: A Comparative Clinicopathological Investigation
Authors: Sorensen Flemming Brandt , Jensen Kenneth , Vaeth Michael , Hager Henrik , Funder Anette Mariane Daa , Safwat Akmal , Keller Johnny , Christensen Mariann
Published: February 2009

Purpose. To investigate angiogenesis, multiple drug resistance (MDR) and proliferative activity as prognostic variables in patients suffering from osteosarcoma.Methods. Histologic biopsies from 117 patients treated in the period from 1972 through 1999 were immunohistologically investigated regarding angiogenesis (CD34), proliferative activity (MIB-1), and the expression of p53 and MDR (P-glycoprotein (Pgp); clones JSB-1, C494, and MRK16). Quantitative and semiquantitative scores of immunoreactive cells were analyzed statistically along with retrospectively obtained clinicopathologic variables.Results. Chemotherapy reduced the rate of amputations (P=.00002). The Pgp was overexpressed (score ≥2) in 48% of the primary, diagnostic biopsies, and high Pgp correlated with high Pgp in postsurgical specimens (P=.003). In contrast, no such associations were disclosed for estimates of angiogenesis (P=.64) and p53 (P>.32), whereas the MIB-1 index was reduced in the post-chemotherapy specimens (P=.02). The overall, disease-specific survival was 47%, increasing to 54% in patients receiving pre-operative chemotherapy. Statistical analyses showed prognostic impact exclusively by patient age and type of osteosarcoma.Discussion. The studied series of patients documented already prior to the chemotherapy era, a rather excellent survival and estimates of angiogenesis, proliferation, p53, and Pgp expressions, did not demonstrate sufficient power to serve as predictors of treatment response or survival.
Analytic Approximate Solutions for Unsteady Two‐Dimensional and Axisymmetric Squeezing Flows between Parallel Plates
Authors: Rashidi Mohammad Mehdi , Shahmohamadi Hamed , Dinarvand Saeed
Published: February 2009

The flow of a viscous incompressible fluid between two parallel plates due to the normal motion of the plates is investigated. The unsteady Navier‐Stokes equations are reduced to a nonlinear fourth‐order differential equation by using similarity solutions. Homotopy analysis method (HAM) is used to solve this nonlinear equation analytically. The convergence of the obtained series solution is carefully analyzed. The validity of our solutions is verified by the numerical results obtained by fourth‐order Runge‐Kutta.
Development of Predictive Techniques for Estimating Liquid Water‐Hydrate Equilibrium of Water‐Hydrocarbon System
Authors: Mohammadi Amir H. , Richon Dominique
Published: February 2009

In this communication, we review recent studies by these authors for modeling theLW‐Hequilibrium. With the aim of estimating the solubility of pure hydrocarbon hydrate former in pure water in equilibrium with gas hydrates, a thermodynamic model is introduced based on equality of water fugacity in the liquid water and hydrate phases. The solid solution theory of Van der Waals‐Platteeuw is employed for calculating the fugacity of water in the hydrate phase. The Henry′s law approach and the activity coefficient method are used to calculate the fugacities of the hydrocarbon hydrate former and water in the liquid water phase, respectively. The results of this model are successfully compared with some selected experimental data from the literature. A mathematical model based on feed‐forward artificial neural network algorithm is then introduced to estimate the solubility of pure hydrocarbon hydrate former in pure water being in equilibrium with gas hydrates. Independent experimental data (not employed in training and testing steps) are used to examine the reliability of this algorithm successfully.
Studies on Poly(propylene fumarate‐co‐caprolactone diol) Thermoset Composites towards the Development of Biodegradable Bone Fixation Devices
Authors: Jayabalan M.
Published: February 2009

The effect of reinforcement in the cross‐linked poly(propylene fumarate‐co‐caprolactone diol) thermoset composites based on Kevlar fibres and hydroxyapatite was studied. Cross‐linked poly(propylene fumarate‐co‐caprolactone diol) was also studied without any reinforcement for comparison. The reinforcing fibre acts as a barrier for the curing reaction leading to longer setting time and lesser cross‐link density. The fibre and HA reinforced composites have almost the same compressive strength. Nonreinforced material undergoes greater degree of swelling. Among the reinforced materials, the hydroxyapatite reinforced composite has a much higher swelling percentage than the fibre reinforced one. The studies on in vitro degradation of the cured materials reveal hydrolytic
degradation in Ringer′s solution and PBS medium during aging. All the three materials are found to swell initially in Ringer′s solution and PBS medium during aging and then undergo gradual degradation. Compression properties of these cross‐linked composites increase with aging; HA reinforced composite has the highest compressive strength and compressive modulus, whereas the aged fibre‐reinforced composite has
the least compressive strength and modulus.
Alternative Splicing of Cyr61 Is Regulated by Hypoxia and Significantly Changed in Breast Cancer
Authors: Hirschfeld Marc , zur Hausen Axel , Bettendorf Herta , Jäger Markus , Stickeler Elmar
Published: February 2009

Hypoxia is known to induce the transcriptional activation of pathways involved in angiogenesis, growth factor signaling, and tissue invasion and is therefore a potential key regulator of tumor growth. Cyr61 (cysteine rich 61) is a secreted, matricellular protein with proangiogenic capabilities and is transcriptionally induced under hypoxic conditions. High expression levels of Cyr61 were already detected in various cancer types and linked to tumor progression and advanced stages in breast cancer. Besides hypoxia, there is some evidence that posttranscriptional pre-mRNA processing could be involved in the regulation of Cyr61 expression, but was thus far not investigated. We studied the expression pattern of Cyr61 mRNA and protein in breast cancer cell lines as well as in matched pairs of noncancerous breast tissue, preinvasive lesions, and invasive breast cancers, respectively. In addition, we analyzed the potential regulatory capability of hypoxia on Cyr61 expression by functional tissue culture experiments. Our study revealed a stage-dependent induction of Cyr61 mRNA and protein in breast cancer tumorigenesis and for the first time alternative splicing of the Cyr61 gene due to intron retention. Breast carcinogenesis was accompanied by a shift from an intron 3 retaining toward an intron 3 skipping mRNA phenotype consecutively leading to processing of the biological active Cyr61 protein. The functional analyses strongly emphasize that hypoxia serves as a specific inducer of alternative Cyr61 splicing toward the intron skipping mRNA isoform with potential biological consequences in tumor cells. [Cancer Res 2009;69(5):2082–90]
l-Amino Acid Transporter-1 and Boronophenylalanine-Based Boron Neutron Capture Therapy of Human Brain Tumors
Authors: Detta Allah , Cruickshank Garth S.
Published: February 2009

The system l-amino acid transporter-1 (LAT-1) imports p-boronophenylalanine (BPA) into cells and may play a major role in the effectiveness of BPA-based boron neutron capture therapy. The functional status of LAT-1 and its relationship to cell proliferation were simultaneously examined in the same section of human tumor material using a dual-labeling technique. The uptake of BPA (boron inductively coupled plasma mass spectrometry) was profiled in the presence of agonists and antagonists in fresh tumor explants. The number of LAT-1–expressing cells (mean ± SD) was three times higher than that of proliferating cell nuclear antigen (PCNA)–expressing cells (71.5 ± 17.02% versus 23.8 ± 16.5%; P < 0.0001; n = 38 glioblastoma and metastatic tumors). There was no correlation between PCNA cells and the number of LAT-1/PCNA double-stained cells, and not all PCNA-expressing cells coexpressed LAT-1. Boron uptake reached 30 ± 15 μg/g of wet weight of tissue by 4 hours both in tumor and brain around tumor tissue containing tumor cells compared with time 0 (P < 0.005; n = 4 glioblastoma tumors). This uptake was inhibited by both phenylalanine and 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid. These LAT-1 data indicate that BPA-based boron neutron capture therapy might affect up to 70% of tumor cells, representing a three times higher proportion of tumor cells than their cell cycle status might suggest. Cells expressing PCNA, but not LAT-1, will require a different therapeutic strategy. [Cancer Res 2009;69(5):2126–32]
Characterization of a Novel Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor with a Unique Mechanism of Action for Cancer Therapy
Authors: Daouti Sherif , Wang Huisheng , Li Wen-hui , Higgins Brian , Kolinsky Kenneth , Packman Kathryn , Specian Anthony , Kong Norman , Huby Nicholas , Wen Yang , Xiang Qing , Podlaski Frank J. , He Yang , Fotouhi Nader , Heimbrook David , Niu Huifeng
Published: February 2009

The mitogen-activated protein kinase (MAPK) signal transduction pathway plays a central role in regulating tumor cell growth, survival, differentiation, and angiogenesis. The key components of the Ras/Raf/MEK/ERK signal module are frequently altered in human cancers. Targeting this pathway represents a promising anticancer strategy. Small molecule inhibitors targeting MEK1/2 have shown promise in the clinic; however, ultimate clinical proof-of-concept remains elusive. Here, we report a potent and highly selective non–ATP-competitive MEK1/2 inhibitor, RO4927350, with a novel chemical structure and unique mechanism of action. It selectively blocks the MAPK pathway signaling both in vitro and in vivo, which results in significant antitumor efficacy in a broad spectrum of tumor models. Compared with previously reported MEK inhibitors, RO4927350 inhibits not only ERK1/2 but also MEK1/2 phosphorylation. In cancer cells, high basal levels of phospho-MEK1/2 rather than phospho-ERK1/2 seem to correlate with greater sensitivity to RO4927350. Furthermore, RO4927350 prevents a feedback increase in MEK phosphorylation, which has been observed with other MEK inhibitors. We show that B-Raf rather than C-Raf plays a critical role in the feedback regulation. The unique MAPK signaling blockade mediated by RO4927350 in cancer may reduce the risk of developing drug resistance. Thus, RO4927350 represents a novel therapeutic modality in cancers with aberrant MAPK pathway activation. [Cancer Res 2009;69(5):1924–32
Inactivation of the Nijmegen Breakage Syndrome Gene Leads to Excess Centrosome Duplication via the ATR/BRCA1 Pathway
Authors: Shimada Mikio , Sagae Ruri , Kobayashi Junya , Habu Toshiyuki , Komatsu Kenshi
Published: February 2009

Nijmegen breakage syndrome is characterized by genomic instability and a predisposition for lymphoma and solid tumors. Nijmegen breakage syndrome 1 (NBS1), the protein which is mutated in these patients, functions in association with BRCA1 and ATR as part of the cellular response to DNA double-strand breaks. We show here that NBS1 forms foci at the centrosomes via an interaction with γ-tubulin. Down-regulation of NBS1 by small interfering RNA induces supernumerary centrosomes, and this was confirmed with experiments using Nbs1 knockout mouse cells; the introduction of wild-type NBS1 (wt-NBS1) cDNA into these knockout mouse cells reduced the number of supernumerary centrosomes to normal levels. This phenotype in NBS1-deficient cells is caused by both centrosome duplication and impaired separation of centrioles, which have been observed in BRCA1-inhibited cells. In fact, supernumerary centrosomes were observed in Brca1 knockout mouse cells, and the frequency was not affected by NBS1 down-regulation, suggesting that NBS1 maintains centrosomes via a common pathway with BRCA1. This is consistent with findings that NBS1 physically interacts with BRCA1 at the centrosomes and is required for BRCA1-mediated ubiquitination of γ-tubulin. Moreover, the ubiquitination of γ-tubulin is compromised by either ATR depletion or an NBS1 mutation in the ATR interacting (FHA) domain, which is essential for ATR activation. These results suggest that, although centrosomes lack DNA, the NBS1/ATR/BRCA1 repair machinery affects centrosome behavior, and this might be a crucial role in the prevention of malignances. [Cancer Res 2009;69(5):1768–75]
Acquired Resistance to 17-Allylamino-17-Demethoxygeldanamycin (17-AAG, Tanespimycin) in Glioblastoma Cells
Authors: Gaspar Nathalie , Sharp Swee Y. , Pacey Simon , Jones Chris , Walton Michael , Vassal Gilles , Eccles Suzanne , Pearson Andrew , Workman Paul
Published: February 2009

Heat shock protein 90 (HSP90) inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), which is currently in phase II/phase III clinical trials, are promising new anticancer agents. Here, we explored acquired resistance to HSP90 inhibitors in glioblastoma (GB), a primary brain tumor with poor prognosis. GB cells were exposed continuously to increased 17-AAG concentrations. Four 17-AAG–resistant GB cell lines were generated. High-resistance levels with resistance indices (RI = resistant line IC50/parental line IC50) of 20 to 137 were obtained rapidly (2–8 weeks). After cessation of 17-AAG exposure, RI decreased and then stabilized. Cross-resistance was found with other ansamycin benzoquinones but not with the structurally unrelated HSP90 inhibitors, radicicol, the purine BIIB021, and the resorcinylic pyrazole/isoxazole amide compounds VER-49009, VER-50589, and NVP-AUY922. An inverse correlation between NAD(P)H/quinone oxidoreductase 1 (NQO1) expression/activity and 17-AAG IC50 was observed in the resistant lines. The NQO1 inhibitor ES936 abrogated the differential effects of 17-AAG sensitivity between the parental and resistant lines. NQO1 mRNA levels and NQO1 DNA polymorphism analysis indicated different underlying mechanisms: reduced expression and selection of the inactive NQO1*2 polymorphism. Decreased NQO1 expression was also observed in a melanoma line with acquired resistance to 17-AAG. No resistance was generated with VER-50589 and NVP-AUY922. In conclusion, low NQO1 activity is a likely mechanism of acquired resistance to 17-AAG in GB, melanoma, and, possibly, other tumor types. Such resistance can be overcome with novel HSP90 inhibitors. [Cancer Res 2009;69(5):1966–75]
Functional Significance of UDP-Glucuronosyltransferase Variants in the Metabolism of Active Tamoxifen Metabolites
Authors: Blevins-Primeau Andrea S. , Sun Dongxiao , Chen Gang , Sharma Arun K. , Gallagher Carla J. , Amin Shantu , Lazarus Philip
Published: February 2009

Tamoxifen (TAM) is a selective estrogen receptor modulator widely used in the prevention and treatment of breast cancer. A major mode of metabolism of the major active metabolites of TAM, 4-OH-TAM and endoxifen, is by glucuronidation via the UDP-glucuronosyltransferase (UGT) family of enzymes. To examine whether polymorphisms in the UGT enzymes responsible for the glucuronidation of active TAM metabolites play an important role in interindividual differences in TAM metabolism, cell lines overexpressing wild-type or variant UGTs were examined for their activities against TAM metabolites in vitro. For variants of active extrahepatic UGTs, the UGT1A8173Ala/277Tyr variant exhibited no detectable glucuronidation activity against the trans isomers of either 4-OH-TAM or endoxifen. Little or no difference in TAM glucuronidating activity was observed for the UGT1A8173Gly/277Cys or UGT1A10139Lys variants compared with their wild-type counterparts. For active hepatic UGTs, the UGT2B7268Tyr variant exhibited significant (P < 0.01) 2- and 5-fold decreases in activity against the trans isomers of 4-OH-TAM and endoxifen, respectively, compared with wild-type UGT2B7268His. In studies of 111 human liver microsomal specimens, the rate of O-glucuronidation against trans-4-OH-TAM and trans-endoxifen was 28% (P < 0.001) and 27% (P = 0.002) lower, respectively, in individuals homozygous for the UGT2B7 Tyr268Tyr genotype compared with subjects with the UGT2B7 His268His genotype, with a significant (P < 0.01) trend of decreasing activity against both substrates with increasing numbers of the UGT2B7268His allele. These results suggest that functional polymorphisms in TAM-metabolizing UGTs, including UGT2B7 and potentially UGT1A8, may be important in interindividual variability in TAM metabolism and response to TAM therapy. [Cancer Res 2009;69(5):1892–900]
A Novel Androgen Receptor Splice Variant Is Up-regulated during Prostate Cancer Progression and Promotes Androgen Depletion–Resistant Growth
Authors: Guo Zhiyong , Yang Xi , Sun Feng , Jiang Richeng , Linn Douglas E. , Chen Hege , Chen Hegang , Kong Xiangtian , Melamed Jonathan , Tepper Clifford G. , Kung Hsing-Jien , Brodie Angela M.H. , Edwards Joanne , Qiu Yun
Published: February 2009

The androgen receptor (AR) plays a key role in progression to incurable androgen ablation–resistant prostate cancer (PCA). We have identified three novel AR splice variants lacking the ligand-binding domain (designated as AR3, AR4, and AR5) in hormone-insensitive PCA cells. AR3, one of the major splice variants expressed in human prostate tissues, is constitutively active, and its transcriptional activity is not regulated by androgens or antiandrogens. Immunohistochemistry analysis on tissue microarrays containing 429 human prostate tissue samples shows that AR3 is significantly up-regulated during PCA progression and AR3 expression level is correlated with the risk of tumor recurrence after radical prostatectomy. Overexpression of AR3 confers ablation-independent growth of PCA cells, whereas specific knockdown of AR3 expression (without altering AR level) in hormone-resistant PCA cells attenuates their growth under androgen-depleted conditions in both cell culture and xenograft models, suggesting an indispensable role of AR3 in ablation-independent growth of PCA cells. Furthermore, AR3 may play a distinct, yet essential, role in ablation-independent growth through the regulation of a unique set of genes, including AKT1, which are not regulated by the prototype AR. Our data suggest that aberrant expression of AR splice variants may be a novel mechanism underlying ablation independence during PCA progression, and AR3 may serve as a prognostic marker to predict patient outcome in response to hormonal therapy. Given that these novel AR splice variants are not inhibited by currently available antiandrogen drugs, development of new drugs targeting these AR isoforms may potentially be effective for treatment of ablation-resistant PCA. [Cancer Res 2009;69(6):2305–13]
Sunitinib Inhibition of Stat3 Induces Renal Cell Carcinoma Tumor Cell Apoptosis and Reduces Immunosuppressive Cells
Authors: Xin Hong , Zhang Chunyan , Herrmann Andreas , Du Yan , Figlin Robert , Yu Hua
Published: February 2009

The novel multitargeted tyrosine kinase inhibitor sunitinib is used as an antiangiogenic agent for the treatment of several types of cancer, including metastatic renal cell carcinoma (RCC). Sunitinib was shown to positively change the immunosuppressive phenotype in RCC patients. To improve its antitumor efficacy, and offer strategies for its combination with other approaches, it is critical to fully elucidate its mechanisms of action. We show that sunitinib induces tumor cell apoptosis and growth arrest in RCC tumor cells, which correlates with signal transducer and activator of transcription 3 (Stat3) activity inhibition. Sunitinib-mediated direct effects on tumor cells occur regardless of von Hippel-Lindau tumor suppressor gene status and hypoxia-inducible transcription factor-2α levels. Reduction of Stat3 activity enhances the antitumor effects of sunitinib, whereas expression of a constitutively activated Stat3 mutant rescues tumor cell death. Intravital multiphoton microscopy data show that sunitinib induces mouse Renca tumor cell apoptosis in vivo before tumor vasculature collapse. Sunitinib also inhibits Stat3 in Renca tumor–associated myeloid-derived suppressor cells (MDSC), down-regulates angiogenic gene expression, and reduces MDSCs and tumor T regulatory cells. These results suggest that Stat3 activity is important for RCC response to sunitinib, and Stat3 inhibition permits the direct proapoptotic activity of sunitinib on tumor cells and positive effects on tumor immunologic microenvironment. [Cancer Res 2009;69(6):2506–13]
Cytosolic Phospholipase A2: Targeting Cancer through the Tumor Vasculature
Authors: Linkous Amanda , Geng Ling , Lyshchik Andrej , Hallahan Dennis E. , Yazlovitskaya Eugenia M.
Published: February 2009

Purpose: In vascular endothelial cells, low doses of ionizing radiation trigger the immediate activation of cytosolic phospholipase A2 (cPLA2). This event initiates prosurvival signaling that could be responsible for radioresistance of tumor vasculature. Thus, the development of radiosensitizers targeting these survival pathways may enhance tumor response to radiation therapy. Arachidonyltrifluoromethyl Ketone (AACOCF3), a specific cPLA2 inhibitor, was studied as a potential radiosensitizer.

Experimental Design: Vascular endothelial cells (3B11 and MPMEC) and lung tumor cells (LLC and H460) were treated with 1 μmol/L AACOCF3 for 30 minutes prior to irradiation. Treatment response was evaluated by clonogenic survival, activation of extracellular signal-regulated kinase 1/2 (ERK1/2), tubule formation, and migration assays. For in vivo experiments, mice with LLC or H460 tumors in the hind limbs were treated for 5 consecutive days with 10 mg/kg AACOCF3 administered daily 30 minutes prior to irradiation. Treatment response was assessed by tumor growth delay, Power Doppler Sonography, and immunohistochemistry.

Results: In cell culture experiments, inhibition of cPLA2 with AACOCF3 prevented radiation-induced activation of ERK1/2 and decreased clonogenic survival of irradiated vascular endothelial cells but not the lung tumor cells. Treatment with AACOCF3 also attenuated tubule formation and migration in irradiated vascular endothelial cells. In both tumor mouse models, treatment with AACOCF3 prior to irradiation significantly suppressed tumor growth and decreased overall tumor blood flow and vascularity. Increased apoptosis in both tumor cells and tumor vascular endothelium was determined as a possible mechanism of the observed effect.

Conclusion: These findings identify cPLA2 as a novel molecular target for tumor sensitization to radiation therapy through the tumor vasculature.
Evidence of Systemic Th2-Driven Chronic Inflammation in Patients with Metastatic Melanoma
Authors: Nevala Wendy K. , Vachon Celine M. , Leontovich Alexey A. , Scott Christopher G. , Thompson Michael A. , Markovic Svetomir N. ,   for the Melanoma Study Group of the Mayo Clinic Cancer Center
Published: February 2009

Purpose: Immunotherapeutic modalities are commonly used for treatment of patients with melanoma. The therapeutic success in preclinical models has not yielded the expected clinical results. To understand this discrepancy, we attempted to define immune homeostasis of 209 patients with melanoma across stages of disease relative to normal controls.

Experimental Design: Peripheral blood mononuclear cells (PBMC) and plasma were collected from patients and healthy donors. PBMC were analyzed for frequencies of natural killer, dendritic, and T cells and their functional status. Matched plasma samples were analyzed for the concentrations of 27 cytokines, chemokines, and growth factors. RNA was isolated from 24 metastatic melanoma tumor biopsies and profiled by microarray analysis.

Results: The frequency of natural killer, T, and dendritic cells in patients does not significantly change across stages of melanoma. However, plasma concentrations of Th2 cytokines [interleukin (IL)-4, IL-5, IL-10, and IL-13] in tumor-bearing patients were significantly higher than those with resected melanoma. Expression array analysis of metastatic melanoma revealed that the malignant melanocytes were not the source of the Th2 cytokines but did highly up-regulate vascular endothelial growth factor (VEGF) transcripts, consistent with plasma VEGF concentrations. In vitro VEGF exposure of normal PBMC lead to repolarization from Th1 to Th2 emulating the state of metastatic melanoma.

Conclusions: Patients with metastatic melanoma exist in a state of Th2-mediated “chronic inflammation” as a result of at least VEGF overproduction by malignant tumors. These data support prior observations regarding the effect of VEGF on immune cell function and suggests consideration of VEGF inhibitors in future cancer immunotherapy clinical studies in metastatic melanoma.
Pilot Study on Light Dosimetry Variables for Photodynamic Therapy of Barrett's Esophagus with High-Grade Dysplasia
Authors: Gill Kanwar R.S. , Wolfsen Herbert C. , Preyer Norris W. , Scott Marquitta V. , Gross Seth A. , Wallace Michael B. , Jones Linda R.
Published: February 2009

Purpose: Photodynamic therapy (PDT) is used to treat Barrett's esophagus with high-grade dysplasia and mucosal carcinoma. Outcomes are variable with some patients having persistent disease, whereas others develop strictures. The aims of this study were (a) to compare porfimer sodium tissue uptake, light dose, and esophageal thickness with clinical outcomes and (b) to determine the selectivity of porfimer sodium uptake in diseased and normal epithelium.

Experimental Design: Forty-eight hours after porfimer sodium infusion, patients underwent mucosal biopsy for quantification of the porfimer sodium. Laser light was delivered at 48 hours and again 24 or 48 hours later. Porfimer sodium was extracted from the biopsy samples and quantified using fluorescence spectroscopy. The enhanced photodynamic dose was determined as [porfimer sodium content * light dose/esophageal thickness]. PDT efficacy was determined 6 to 8 weeks later based on persistence or complete ablation of dysplasia or carcinoma.

Results: Mean porfimer sodium content of 6.2 mg/kg (range, 2.6-11.2 mg/kg) and mean total light dose of 278 J/cm (range, 225-360 J/cm) resulted in a complete treatment. Mean porfimer sodium tissue content of 3.9 mg/kg (range, 2.1-8.1 mg/kg) and mean total light dose of 268 J/cm (range, 250-350 J/cm) resulted in an incomplete treatment. The total esophageal thickness (range, 1.7-6.0 mm) and enhanced photodynamic dose were correlated with treatment outcome.

Conclusions: Esophageal thickness is the strongest predictor of treatment outcome. The porfimer sodium content of Barrett's and normal tissue is not significantly different. “Photodynamic dose” for esophageal PDT should incorporate the esophageal thickness.
Palettes of Vaccines and Immunostimulatory Monoclonal Antibodies for Combination
Authors: Melero Ignacio , Martinez-Forero Ivan , Dubrot Juan , Suarez Natalia , Palazón Asis , Chen Lieping
Published: February 2009

Various monoclonal antibodies (mAb) target immune system molecules to enhance immunity by costimulating T cells (i.e., CD137, OX40, CD40, GITR) or interfering in coinhibitory signals (i.e., CTLA-4, PD-1). These powerful agents can be guided by cancer vaccines to enhance immunity against tumor but not self tissues. Clinically powerful therapeutic synergies are at hand.
Identification of novel small-molecule compounds that inhibit the proproliferative Krüppel-like factor 5 in colorectal cancer cells by high-throughput screening
Authors: Bialkowska Agnieszka B. , Du Yuhong , Fu Haian , Yang Vincent W.
Published: February 2009

Colorectal cancer is one of the leading causes of cancer mortality and morbidity worldwide. Previous studies indicate that the zinc finger-containing transcription factor Krüppel-like factor 5 (KLF5) positively regulates proliferation of intestinal epithelial cells and colorectal cancer cells. Importantly, inhibition of KLF5 expression in intestinal epithelial cells and colorectal cancer cells by pharmacologic or genetic means reduces their rate of proliferation. To identify additional and novel small molecules that inhibit KLF5 expression and thus colorectal cancer proliferation, we developed a reporter assay using colorectal cancer cell line (DLD-1) that stably expressed a luciferase reporter gene directed by 1,959 bp of the human KLF5 promoter upstream of the ATG start codon and performed a cell-based high-throughput screen with the Library of Pharmacologically Active Compounds that contains 1,280 biologically active compounds. The screen identified 8 potential inhibitors and 6 potential activators of the KLF5 promoter. Three potential inhibitors, wortmannin, AG17, and AG879, were further evaluated by secondary analyses. All three significantly reduced both KLF5 promoter-luciferase activity and protein level in DLD-1 cells in a dose- and time-dependent manner when compared with controls. They also significantly reduced the rate of proliferation of DLD-1 and two other colorectal cancer cell lines, HCT116 and HT29. Our results show the principle of using high-throughput screening to identify small-molecule compounds that modulate KLF5 activity and consequently inhibit colorectal cancer proliferation. [Mol Cancer Ther 2009;8(3):563–70]
Interleukin-6 increases prostate cancer cells resistance to bicalutamide via TIF2
Authors: Feng Siting , Tang Qizhu , Sun Meng , Chun Jae Yeon , Evans Christopher P. , Gao Allen C.
Published: February 2009

The standard treatment for advanced, androgen-responsive prostate cancer is androgen deprivation therapy with or without a nonsteroidal antiandrogen, such as bicalutamide. Although maximal androgen blockade exhibits favorable responses in the majority of patients, prostate cancer eventually progresses to an androgen-refractory stage. The mechanism underlying bicalutamide resistance in the course of prostate cancer progression is incompletely understood. However, interleukin-6 (IL-6) plays a critical role in the development and progression of CRPC. Herein, we explored an association between IL-6 and bicalutamide resistance. To study this, series of lower and higher passages of LNCaP cell sublines generated by long-term exposure to IL-6 were used. The cells from higher passages of LNCaP treated with IL-6 developed resistance to bicalutamide treatment compared with parental LNCaP cells. The levels of transcriptional intermediary factor 2 (TIF2) in IL-6-treated LNCaP cells were found to be significantly higher than parental LNCaP cells. Down-regulation of TIF2 expression via short hairpin RNA in IL-6-treated LNCaP cells sensitized these cells to bicalutamide treatment, whereas overexpression of TIF2 in the parental LNCaP cells increased resistance to bicalutamide. Furthermore, overexpression of IL-6 attenuated bicalutamide-mediated blockage of androgen-induced androgen receptor nuclear translocation and recruitment. These results show that overexpression of IL-6 increases the resistance of prostate cancer cells to bicalutamide via TIF2. Overexpression of IL-6 not only plays an important role in prostate cancer progression but also contributes to bicalutamide resistance. Our studies suggest that bicalutamide-IL-6-targeted adjunctive therapy may lead to a more effective intervention than bicalutamide alone. [Mol Cancer Ther 2009;8(3):665–71]
Performing Resistance in Burma
Authors: Colman Xan , Searle Tamara
Published: February 2009

Art—or at least the kind we most like to write about—is almost always political, whether it is inter/national or personal; and though TDR has already taken this up in its “War and Other Bad Shit” issue, the topic remains center stage. In his review of Dutch theatre troupe Dood Paard's medEia, Jacob Gallagher-Ross notes the emergence of “a new age of the chorus” in which spectatorship becomes inseparable from paralyzed witnessing and Medea's tragedy is reconceived as a metaphor for the West's tragic relations with the East. Laurietz Seda explores Guillermo Gómez-Peña's recent performance/installation Mapa/Corpo 2: Interactive Rituals for the New Millennium, a fluid piece that, like much of the artist's recent work, addresses the xenophobia and “war on difference” that underlies the US's ongoing War on Terror. The Burmese stand-up trio the Moustache Brothers is the subject of Xan Colman and Tamara Searle's personal account of how performance can be both art and resistance in a contradictory and charged political regime.
Rehearsing the “Warrior Ethos”: “Theatre Immersion” and the Simulation of Theatres of War
Authors: Magelssen Scott
Published: February 2009

To pre-expose deployment-bound troops to combatants' unconventional tactics, the Army has constructed vast simulations of wartime Iraq and Afghanistan. Termed “Theatre Immersion,” these sites feature entire towns bustling with costumed villagers. The largest facility is at Fort Irwin in the Mojave Desert. It is part of a long tradition of performance and war games, but never before has a military simulation worked to produce an environment with this kind of scale and attention to fidelity.
Effects of Pressure on Collision, Coalescence, and Breakup of Raindrops. Part II: Parameterization and Spectra Evolution at 50 and 100 kPa
Authors: List Roland , Nissen R. , Fung C.
Published: February 2009

Fragment size distributions, experimentally obtained for six drop pairs colliding at 50 kPa, are parameterized similarly to the 100-kPa drop pair experiments by Low and List. This information is then introduced into a box model to allow assessment of the spectra evolution and a comparison of the two datasets taken at the two pressures. The differences in breakup patterns include the following: The contributions to mass transfer by breakup and coalescence are very similar at the two pressures, with larger values at lower pressure; the overall mass evolution is not particularly sensitive to pressure; and disk breakup plays an “erratic” role. The situation for the number concentration, however, is totally different and develops gradually. At 50 kPa there is also no three-peak equilibrium developing as for 100 kPa. The times to reach equilibrium are ∼12 h. Note that the box model does not include accretion of cloud droplets—which may well be more important than growth by accretion of fragments.

Application of the new parameterization is not beneficial for low rain rates, but it is strongly recommended for large rain rates (>50 mm h−1).
Soil Moisture Impacts on Convective Margins
Authors: Lintner Benjamin R. , Neelin J. David
Published: February 2009

An idealized prototype for the location of the margins of tropical land region convection zones is extended to incorporate the effects of soil moisture and associated evaporation. The effect of evaporation, integrated over the inflow trajectory into the convection zone, is realized nonlocally where the atmosphere becomes favorable to deep convection. This integrated effect produces “hot spots” of land surface–atmosphere coupling downstream of soil moisture conditions. Overall, soil moisture increases the variability of the convective margin, although how it does so is nontrivial. In particular, there is an asymmetry in displacements of the convective margin between anomalous inflow and outflow conditions that is absent when soil moisture is not included. Furthermore, the simple cases presented here illustrate how margin sensitivity depends strongly on the interplay of factors, including net top-of-the-atmosphere radiative heating, the statistics of inflow wind, and the convective parameterization.
Two-Way Particle-Tracking Model for Specifying Sources of Drifting Objects: Application to the East China Sea Shelf
Authors: Isobe Atsuhiko , Kako Shin’ichiro , Chang Pil-Hun , Matsuno Takeshi
Published: February 2009

The two-way Lagrangian particle-tracking model (PTM) is proposed for specifying sources of objects drifting with random-walk processes on the sea surface. First, to determine object source candidates, modeled particles are released from the point (hereafter, “receptor”) where an observer finds the objects using a backward-in-time PTM with modeled ocean currents of which directions are reversed in sign. Second, the modeled particles are released from these source candidates in a forward-in-time PTM using ocean currents originally computed in hydrographic models. Third, the source candidates are considered to be reliable at a 5% significance level if the observed receptor is located inside the ellipse whose center is the mean position of the modeled particles at the time when the observer found the objects and whose axis length is twice the standard deviation computed using all modeled particle positions. The two-way PTM experiments are carried out in a realistic hydrographic model over the East China Sea shelf for the period from June through August 2004. Statistically significant sources are well specified close to the true source because 58%–90% of source candidates are rejected in the experiments.
Convective Contribution to the Genesis of Hurricane Ophelia (2005)
Authors: Houze Robert A. , Lee Wen-Chau , Bell Michael M.
Published: February 2009

The convection occurring in the tropical depression that became Hurricane Ophelia (2005) was investigated just prior to tropical storm formation. Doppler radar showed a deep, wide, intense convective cell of a type that has been previously thought to occur in intensifying tropical depressions but has not heretofore been documented in detail. The updraft of the cell was 10 km wide, 17 km deep, had updrafts of 10–20 m s−1 throughout its mid- to upper levels, and contained a cyclonic vorticity maximum. The massive convective updraft was maintained by strong positive buoyancy, which was maximum at about the 10-km level, probably aided by latent heat of freezing. Evaporative cooling and precipitation drag occurred in the rain shower of the cell but were insufficient to produce a strong downdraft or gust front outflow to force the updraft. The convective updraft was fed by a layer of strong inflow that was several kilometers deep. Wind-induced turbulence, just above the ocean surface, enriched the equivalent potential temperature of the boundary layer of the inflow air, thus creating an unstable layer with little convective inhibition. This air was raised to its level of free convection when it encountered the denser air in the rainy core of the convection. The updraft motion and latent heat release in the intense cell generated potential vorticity throughout the low to midlevels, and contained a cyclonic vortex at the midlevels. Vorticity generated throughout the depth of the low to midtroposphere within convective updraft cells was subsequently incorporated into a stratiform region attached to the region of active convective cells. The vorticity perturbations at the low to midlevels in convective cells and their attached stratiform regions were available to be axisymmetrized into the larger-scale intensifying depression vortex.
High-density Lipoprotein Cholesterol: Current Perspective for Clinicians
Authors: Whayne Thomas F.
Published: February 2009

High-density lipoproteins are regarded as “good guys” but not always. Situations involving high-density lipoproteins are discussed and medication results are considered. Clinicians usually consider high-density lipoprotein cholesterol. Nicotinic acid is the best available medication to elevate high-density lipoprotein cholesterol and this appears beneficial for cardiovascular risk. The major problem with nicotinic acid is that many patients do not tolerate the associated flushing. Laropiprant decreases this flushing and has an approval in Europe but not in the United States. The most potent medications for increasing high-density lipoprotein cholesterol are cholesteryl ester transfer protein inhibitors. The initial drug in this class, torcetrapib, was eliminated by excess cardiovascular problems. Two newer cholesteryl ester transfer protein inhibitors, R1658 and anacetrapib, initially appear promising. High-density lipoprotein cholesterol may play an important role in improving cardiovascular risk in the 60% of patients who do not receive cardiovascular mortality/morbidity benefit from low-density lipoproteins reduction by statins.
Endothelial Function Impairment in Chronic Venous Insufficiency: Effect of Some Cardiovascular Protectant Agents
Authors: Carrasco Omar F. , Ranero Alejandra , Hong Enrique , Vidrio Horacio
Published: February 2009

In segments of human varicose veins, endothelial function was assessed by measuring relaxation induced by acetylcholine in noradrenaline-precontracted preparations. In addition, concentration-response curves to acetylcholine were obtained before and after incubation with the arterial endothelium protectant agents captopril, losartan, troglitazone, pravastatin, or simvastatin. The antivaricose agent escin was also tested. Mean acetylcholine-induced relaxation of varicose venous rings was about 13%, approximately one third of that reported for control saphenous veins. Concentration-response curves to acetylcholine were ‘‘u’’ shaped, the result of endothelium-mediated relaxation at low concentrations, superseded by subsequent smooth muscle contractile responses. Relaxation was enhanced by the endothelium-protecting agents and by escin, troglitazone being the least, and simvastatin the most effective. It was concluded that endothelial dysfunction is present in varicose veins, that this anomaly can be reverted by cardiovascular protecting agents, and that it can play a role in the pathogenesis and treatment of chronic venous insufficiency.
The Politicized Participant
Authors: van der Meer Tom W. G. , van Deth Jan W. , Scheepers Peer L. H.
Published: February 2009

Modern liberal democracies demand high and equal levels of political action. Unequal levels of political action between ideological groups may ultimately lead to biased policy. But to what extent do citizens’ ideological preferences affect their likelihood to participate politically? And does the institutional environment moderate this relationship? From rivaling theories, the authors construct hypotheses regarding the relationship between ideological preferences and participation and those regarding the moderating effect of state institutions. They test them for six modes of political action—voting, contacting, campaigning, cooperating, persuading, and protesting—through multilevel analyses of 27 elections in 20 Western democracies. First, they find that citizens’ ideological preferences are an important determinant political action. Second, they find that majoritarianism outperforms consensualism: In majoritarian systems, political action is more widespread and not less equal across the crucial factor of ideological preferences. The field should therefore reconsider Lijphart’s conclusions about the superiority of consensualism.
Mechanical Properties of Basalt Fiber Reinforced Composites Prepared by Partial Pyrolysis of a Polymer Precursor
Authors: Černý M. , Glogar P. , Sucharda Z.
Published: February 2009

Heat resistant composites reinforced with continuous basalt fibers were made by incomplete pyrolysis (to 650—750°C in nitrogen) of their precursors — composites with a polysiloxane matrix. The flexural strength of the unidirectional composites ranges from 620 to 820 MPa or from 405 to 510 MPa for composites pyrolyzed to 650 or 750°C, respectively. The Young's and tensile modulus from the resonant frequencies range from 50 to 80 GPa, shear modulus from 10 to 22 GPa. The shear modulus values increase after pyrolysis to 750°C, which expresses the increasing integrity and stiffness of the material. After exposition to hot air (at 650 or 750°C) the strength fell further and the failure mode became brittle.
Structural Integrity of Composite Columns Subject to Fire
Authors: Kardomateas George A. , Simitses George J. , Birman Victor
Published: February 2009

This article investigates the thermal response of an axially restrained composite column, which is exposed to a heat flux due to fire. The heat damage, the charred layer formation and nonuniform transient temperature distribution in the column exposed to fire from one side are calculated by the thermal model developed by Gibson et al. [1]. For the thermal response analysis, the mechanical properties of the fire-damaged (charred) region are considered negligible, while the degradation of the elastic properties with temperature in the undamaged layer (especially near the glass transition temperature of the matrix) is accounted for using experimental data for the elastic moduli. Due to the nonuniform stiffness distribution through the thickness and the effect of the ensuing thermal moment, the structure behaves like an imperfect column, and responds by bending rather than buckling in the classical Euler (bifurcation) sense. Another important effect of the non-uniform temperature is that the neutral axis moves away from the centroid of the cross-section, resulting in an additional moment due to eccentric mechanical loading, which tends to bend the structure. The compressive behavior of a column subjected to simultaneous high intensity surface heating and axial compressive loading was investigated experimentally to verify the anticipated theoretical response. All specimens exhibited bending and subsequent catastrophic failure, even at compressive stresses well below these corresponding to the Euler load.