bluuebunny/crossref_metadata_2025 huggingface dataset:
Dermatan Sulfate Is Involved in the Tumorigenic Properties of Esophagus Squamous Cell Carcinoma
Authors: Thelin Martin A. , Svensson Katrin J. , Shi Xiaofeng , Bagher Mariam , Axelsson Jakob , Isinger-Ekstrand Anna , van Kuppevelt Toin H. , Johansson Jan , Nilbert Mef , Zaia Joseph , Belting Mattias , Maccarana Marco , Malmström Anders
Published: February 2012

Extracellular matrix, either produced by cancer cells or by cancer-associated fibroblasts, influences angiogenesis, invasion, and metastasis. Chondroitin/dermatan sulfate (CS/DS) proteoglycans, which occur both in the matrix and at the cell surface, play important roles in these processes. The unique feature that distinguishes DS from CS is the presence of iduronic acid (IdoA) in DS. Here, we report that CS/DS is increased five-fold in human biopsies of esophagus squamous cell carcinoma (ESCC), an aggressive tumor with poor prognosis, as compared with normal tissue. The main IdoA-producing enzyme, DS epimerase 1 (DS-epi1), together with the 6-O- and 4-O-sulfotransferases, were highly upregulated in ESCC biopsies. Importantly, CS/DS structure in patient tumors was significantly altered compared with normal tissue, as determined by sensitive mass spectrometry. To further understand the roles of IdoA in tumor development, DS-epi1 expression, and consequently IdoA content, was downregulated in ESCC cells. IdoA-deficient cells exhibited decreased migration and invasion capabilities in vitro, which was associated with reduced cellular binding of hepatocyte growth factor, inhibition of pERK-1/2 signaling, and deregulated actin cytoskeleton dynamics and focal adhesion formation. Our findings show that IdoA in DS influences tumorigenesis by affecting cancer cell behavior. Therefore, downregulation of IdoA by DS-epi1 inhibitors may represent a new anticancer therapy. Cancer Res; 72(8); 1943–52. ©2012 AACR.
miRNA Signatures Associate with Pathogenesis and Progression of Osteosarcoma
Authors: Jones Kevin B. , Salah Zaidoun , Del Mare Sara , Galasso Marco , Gaudio Eugenio , Nuovo Gerard J. , Lovat Francesca , LeBlanc Kimberly , Palatini Jeff , Randall R. Lor , Volinia Stefano , Stein Gary S. , Croce Carlo M. , Lian Jane B. , Aqeilan Rami I.
Published: February 2012

Osteosarcoma remains a leading cause of cancer death in adolescents. Treatment paradigms and survival rates have not improved in two decades. Driving the lack of therapeutic inroads, the molecular etiology of osteosarcoma remains elusive. MicroRNAs (miRNAs) have demonstrated far-reaching effects on the cellular biology of development and cancer. Their role in osteosarcomagenesis remains largely unexplored. Here we identify for the first time an miRNA signature reflecting the pathogenesis of osteosarcoma from surgically procured samples from human patients. The signature includes high expression of miR-181a,miR-181b, and miR-181c as well as reduced expression of miR-16, miR-29b, and miR-142-5p. We also demonstrate that miR-181b and miR-29b exhibit restricted expression to distinct cell populations in the tumor tissue. Further, higher expression of miR-27a and miR-181c* in pre-treatment biopsy samples characterized patients who developed clinical metastatic disease. In addition, higher expression of miR-451 and miR-15b in pre-treatment samples correlated with subsequent positive response to chemotherapy. In vitro and in vivo functional validation in osteosarcoma cell lines confirmed the tumor suppressive role of miR-16 and the pro-metastatic role of miR-27a. Furthermore, predicted target genes for miR-16 and miR-27a were confirmed as down-regulated by real-time PCR. Affymetrix array profiling of cDNAs from the osteosarcoma specimens and controls were interrogated according to predicted targets of miR-16, miR142-5p, miR-29b, miR-181a/b, and miR-27a. This analysis revealed positive and negative correlations highlighting pathways of known importance to osteosarcoma, as well as novel genes. Thus, our findings establish a miRNA signature associated with pathogenesis of osteosarcoma as well as critical pre-treatment biomarkers of metastasis and responsiveness to therapy. Cancer Res; 72(7); 1865–77. ©2012 AACR.
MiR-155 Is a Liposarcoma Oncogene That Targets Casein Kinase-1α and Enhances β-Catenin Signaling
Authors: Zhang Pingyu , Bill Katelynn , Liu Juehui , Young Eric , Peng Tingsheng , Bolshakov Svetlana , Hoffman Aviad , Song Yechun , Demicco Elizabeth G. , Terrada Dolores Lopez , Creighton Chad J. , Anderson Matthew L. , Lazar Alexander J. , Calin George G. , Pollock Raphael E. , Lev Dina
Published: February 2012

Liposarcoma can be an aggressive, debilitating, and fatal malignancy. In this study, we identifed miRNAs associated with the differentiation status of liposarcoma to gain insight into the basis for its progression. miRNA expression profiles determined in human tumors and normal fat specimens identified a dedifferentiated tumor expression signature consisting of 35 miRNAs. Deregulated miRNA expression was confirmed in a second independent sample cohort. The miR-155 was the most overexpressed miRNA and functional investigations assigned an important role in the growth of dedifferentiated liposarcoma cell lines. Transient or stable knockdown of miR-155 retarded tumor cell growth, decreased colony formation, and induced G1-S cell-cycle arrest in vitro and blocked tumor growth in murine xenografts in vivo. We identified casein kinase 1α (CK1α) as a direct target of miR-155 control which enhanced β-catenin signaling and cyclin D1 expression, promoting tumor cell growth. In summary, our results point to important functions for miR-155 and β-catenin signaling in progression of liposarcoma, revealing mechanistic vulnerabilities that might be exploited for both prognostic and therapeutic purposes. Cancer Res; 72(7); 1751–62. ©2012 AACR.
RAF265 Inhibits the Growth of Advanced Human Melanoma Tumors
Authors: Su Yingjun , Vilgelm Anna E. , Kelley Mark C. , Hawkins Oriana E. , Liu Yan , Boyd Kelli L. , Kantrow Sara , Splittgerber Ryan C. , Short Sarah P. , Sobolik Tammy , Zaja-Milatovic Snjezana , Dahlman Kimberly Brown , Amiri Katayoun I. , Jiang Aixiang , Lu Pengcheng , Shyr Yu , Stuart Darrin D. , Levy Shawn , Sosman Jeffrey A. , Richmond Ann
Published: February 2012

Purpose: The purpose of this preclinical study was to determine the effectiveness of RAF265, a multikinase inhibitor, for treatment of human metastatic melanoma and to characterize traits associated with drug response.

Experimental Design: Advanced metastatic melanoma tumors from 34 patients were orthotopically implanted to nude mice. Tumors that grew in mice (17 of 34) were evaluated for response to RAF265 (40 mg/kg, every day) over 30 days. The relation between patient characteristics, gene mutation profile, global gene expression profile, and RAF265 effects on tumor growth, mitogen-activated protein/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation, proliferation, and apoptosis markers was evaluated.

Results: Nine of the 17 tumors that successfully implanted (53%) were mutant BRAF (BRAFV600E/K), whereas eight of 17 (47%) tumors were BRAF wild type (BRAFWT). Tumor implants from 7 of 17 patients (41%) responded to RAF265 treatment with more than 50% reduction in tumor growth. Five of the 7 (71%) responders were BRAFWT, of which 1 carried c-KITL576P and another N-RASQ61R mutation, while only 2 (29%) of the responding tumors were BRAFV600E/K. Gene expression microarray data from nonimplanted tumors revealed that responders exhibited enriched expression of genes involved in cell growth, proliferation, development, cell signaling, gene expression, and cancer pathways. Although response to RAF265 did not correlate with pERK1/2 reduction, RAF265 responders did exhibit reduced pMEK1, reduced proliferation based upon reduced Ki-67, cyclin D1 and polo-like kinase1 levels, and induction of the apoptosis mediator BCL2-like 11.

Conclusions: Orthotopic implants of patient tumors in mice may predict prognosis and treatment response for melanoma patients. A subpopulation of human melanoma tumors responds to RAF265 and can be characterized by gene mutation and gene expression profiles. Clin Cancer Res; 18(8); 2184–98. ©2012 AACR.
Tumor Epidermal Growth Factor Receptor and EGFR PY1068 Are Independent Prognostic Indicators for Head and Neck Squamous Cell Carcinoma
Authors: Wheeler Sarah , Siwak Doris R. , Chai Raymond , LaValle Courtney , Seethala Raja R. , Wang Lin , Cieply Kathleen , Sherer Carol , Joy Corwin , Mills Gordon B. , Argiris Athanassios , Siegfried Jill M. , Grandis Jennifer R. , Egloff Ann Marie
Published: February 2012

Purpose: To assess the prognostic value of epidermal growth factor receptor (EGFR) molecular characteristics of head and neck squamous cell carcinoma (HNSCC).

Patients and Methods: HNSCC tumors from patients prospectively enrolled in either an Early Detection Research Network (EDRN) study and treated with surgery without an EGFR-targeted agent (N = 154) or enrolled in a chemoradiation trial involving the EGFR-targeted antibody cetuximab (N = 39) were evaluated for EGFR gene amplification by FISH and EGFR protein by immunohistochemical staining. Fresh-frozen tumors (EDRN) were also evaluated for EGFR protein and site-specific phosphorylation at Y992 and Y1068 using reverse-phase protein array (n = 67). Tumor (n = 50) EGFR and EGFRvIII mRNA levels were quantified using real-time PCR.

Results: EGFR expression by immunohistochemistry (IHC) was significantly higher in the EDRN tumors with EGFR gene amplification (P < 0.001), and a similar trend was noted in the cetuximab-treated cohort. In the EDRN and cetuximab-treated cohorts elevated EGFR by IHC was associated with reduced survival (P = 0.019 and P = 0.06, respectively). Elevated expression of total EGFR and EGFR PY1068 were independently significantly associated with reduced progression-free survival in the EDRN cohort [HR = 2.75; 95% confidence interval (CI) = 1.26–6.00 and HR = 3.29; 95% CI = 1.34–8.14, respectively].

Conclusions: In two independent HNSCC cohorts treated with or without cetuximab, tumor EGFR levels were indicative of survival. Tumor EGFR PY1068 levels provided prognostic information independent of total EGFR. Clin Cancer Res; 18(8); 2278–89. ©2012 AACR.
ON 01910.Na Is Selectively Cytotoxic for Chronic Lymphocytic Leukemia Cells through a Dual Mechanism of Action Involving PI3K/AKT Inhibition and Induction of Oxidative Stress
Authors: Chapman Colby M. , Sun Xiameng , Roschewski Mark , Aue Georg , Farooqui Mohamed , Stennett Lawrence , Gibellini Federica , Arthur Diane , Pérez-Galán Patricia , Wiestner Adrian
Published: February 2012

Purpose: Chronic lymphocytic leukemia (CLL), a malignancy of mature B cells, is incurable with chemotherapy. Signals from the microenvironment support leukemic cell survival and proliferation and may confer chemotherapy resistance. ON 01910.Na (Rigosertib), a multikinase phosphoinositide 3-kinase (PI3K) inhibitor, is entering phase III trials for myelodysplastic syndrome. Our aim was to analyze the efficacy of ON 01910.Na against CLL cells in vitro and investigate the molecular effects of this drug on tumor biology.

Experimental Design: Cytotoxicity of ON 01910.Na against CLL cells from 34 patients was determined in vitro with flow cytometry of cells stained with Annexin V and CD19. Global gene expression profiling on Affymetrix microarrays, flow cytometry, Western blotting, and cocultures with stroma cells were used to delineate ON 01910.Na mechanism of action.

Results: ON 01910.Na induced apoptosis in CLL B cells without significant toxicity against T cells or normal B cells. ON 01910.Na was equally active against leukemic cells associated with a more aggressive disease course [immunoglobulin heavy-chain variable region unmutated, adverse cytogenetics] than against cells without these features. Gene expression profiling revealed two main mechanisms of action: PI3K/AKT inhibition and induction of ROS that resulted in an oxidative stress response through activating protein 1 (AP-1), c-jun-NH2-terminal kinase, and ATF3 culminating in the upregulation of NOXA. ROS scavengers and shRNA mediated knockdown of ATF3- and NOXA-protected cells from drug-induced apoptosis. ON 01910.Na also abrogated the prosurvival effect of follicular dendritic cells on CLL cells and reduced SDF-1–induced migration of leukemic cells.

Conclusions: These data support the clinical development of ON 01910.Na in CLL. Clin Cancer Res; 18(7); 1979–91. ©2012 AACR.
A Comprehensive Analysis of Human Gene Expression Profiles Identifies Stromal Immunoglobulin κ C as a Compatible Prognostic Marker in Human Solid Tumors
Authors: Schmidt Marcus , Hellwig Birte , Hammad Seddik , Othman Amnah , Lohr Miriam , Chen Zonglin , Boehm Daniel , Gebhard Susanne , Petry Ilka , Lebrecht Antje , Cadenas Cristina , Marchan Rosemarie , Stewart Joanna D. , Solbach Christine , Holmberg Lars , Edlund Karolina , Kultima Hanna Göransson , Rody Achim , Berglund Anders , Lambe Mats , Isaksson Anders , Botling Johan , Karn Thomas , Müller Volkmar , Gerhold-Ay Aslihan , Cotarelo Christina , Sebastian Martin , Kronenwett Ralf , Bojar Hans , Lehr Hans-Anton , Sahin Ugur , Koelbl Heinz , Gehrmann Mathias , Micke Patrick , Rahnenführer Jörg , Hengstler Jan G.
Published: February 2012

Purpose: Although the central role of the immune system for tumor prognosis is generally accepted, a single robust marker is not yet available.

Experimental Design: On the basis of receiver operating characteristic analyses, robust markers were identified from a 60-gene B cell–derived metagene and analyzed in gene expression profiles of 1,810 breast cancer; 1,056 non–small cell lung carcinoma (NSCLC); 513 colorectal; and 426 ovarian cancer patients. Protein and RNA levels were examined in paraffin-embedded tissue of 330 breast cancer patients. The cell types were identified with immunohistochemical costaining and confocal fluorescence microscopy.

Results: We identified immunoglobulin κ C (IGKC) which as a single marker is similarly predictive and prognostic as the entire B-cell metagene. IGKC was consistently associated with metastasis-free survival across different molecular subtypes in node-negative breast cancer (n = 965) and predicted response to anthracycline-based neoadjuvant chemotherapy (n = 845; P < 0.001). In addition, IGKC gene expression was prognostic in NSCLC and colorectal cancer. No association was observed in ovarian cancer. IGKC protein expression was significantly associated with survival in paraffin-embedded tissues of 330 breast cancer patients. Tumor-infiltrating plasma cells were identified as the source of IGKC expression.

Conclusion: Our findings provide IGKC as a novel diagnostic marker for risk stratification in human cancer and support concepts to exploit the humoral immune response for anticancer therapy. It could be validated in several independent cohorts and carried out similarly well in RNA from fresh frozen as well as from paraffin tissue and on protein level by immunostaining. Clin Cancer Res; 18(9); 2695–703. ©2012 AACR.
First Evidence That γ-Tocotrienol Inhibits the Growth of Human Gastric Cancer and Chemosensitizes It to Capecitabine in a Xenograft Mouse Model through the Modulation of NF-κB Pathway
Authors: Manu Kanjoormana A. , Shanmugam Muthu K. , Ramachandran Lalitha , Li Feng , Fong Chee Wai , Kumar Alan Prem , Tan Patrick , Sethi Gautam
Published: February 2012

Purpose: Because of poor prognosis and development of resistance against chemotherapeutic drugs, the existing treatment modalities for gastric cancer are ineffective. Hence, novel agents that are safe and effective are urgently needed. Whether γ-tocotrienol can sensitize gastric cancer to capecitabine in vitro and in a xenograft mouse model was investigated.

Experimental Design: The effect of γ-tocotrienol on proliferation of gastric cancer cell lines was examined by mitochondrial dye uptake assay, apoptosis by esterase staining, NF-κB activation by DNA-binding assay, and gene expression by Western blotting. The effect of γ-tocotrienol on the growth and chemosensitization was also examined in subcutaneously implanted tumors in nude mice.

Results: γ-Tocotrienol inhibited the proliferation of various gastric cancer cell lines, potentiated the apoptotic effects of capecitabine, inhibited the constitutive activation of NF-κB, and suppressed the NF-κB–regulated expression of COX-2, cyclin D1, Bcl-2, CXCR4, VEGF, and matrix metalloproteinase-9 (MMP-9). In a xenograft model of human gastric cancer in nude mice, we found that administration of γ-tocotrienol alone (1 mg/kg body weight, intraperitoneally 3 times/wk) significantly suppressed the growth of the tumor and this effect was further enhanced by capecitabine. Both the markers of proliferation index Ki-67 and for microvessel density CD31 were downregulated in tumor tissue by the combination of capecitabine and γ-tocotrienol. As compared with vehicle control, γ-tocotrienol also suppressed the NF-κB activation and the expression of cyclin D1, COX-2, intercellular adhesion molecule-1 (ICAM-1), MMP-9, survivin, Bcl-xL, and XIAP.

Conclusions: Overall our results show that γ-tocotrienol can potentiate the effects of capecitabine through suppression of NF-κB–regulated markers of proliferation, invasion, angiogenesis, and metastasis. Clin Cancer Res; 18(8); 2220–9. ©2012 AACR.
The HSP90 Inhibitor XL888 Overcomes BRAF Inhibitor Resistance Mediated through Diverse Mechanisms
Authors: Paraiso Kim H.T. , Haarberg H. Eirik , Wood Elizabeth , Rebecca Vito W. , Chen Y. Ann , Xiang Yun , Ribas Antoni , Lo Roger S. , Weber Jeffrey S. , Sondak Vernon K. , John Jobin K. , Sarnaik Amod A. , Koomen John M. , Smalley Keiran S.M.
Published: February 2012

Purpose: The clinical use of BRAF inhibitors is being hampered by the acquisition of drug resistance. This study shows the potential therapeutic use of the HSP90 inhibitor (XL888) in six different models of vemurafenib resistance.

Experimental Design: The ability of XL888 to inhibit growth and to induce apoptosis and tumor regression of vemurafenib-resistant melanoma cell lines was shown in vitro and in vivo. A novel mass spectrometry–based pharmacodynamic assay was developed to measure intratumoral HSP70 levels following HSP90 inhibition in melanoma cell lines, xenografts, and melanoma biopsies. Mechanistic studies were carried out to determine the mechanism of XL888-induced apoptosis.

Results: XL888 potently inhibited cell growth, induced apoptosis, and prevented the growth of vemurafenib-resistant melanoma cell lines in 3-dimensional cell culture, long-term colony formation assays, and human melanoma mouse xenografts. The reversal of the resistance phenotype was associated with the degradation of PDGFRβ, COT, IGFR1, CRAF, ARAF, S6, cyclin D1, and AKT, which in turn led to the nuclear accumulation of FOXO3a, an increase in BIM (Bcl-2 interacting mediator of cell death) expression, and the downregulation of Mcl-1. In most resistance models, XL888 treatment increased BIM expression, decreased Mcl-1 expression, and induced apoptosis more effectively than dual mitogen-activated protein–extracellular signal–regulated kinase/phosphoinositide 3-kinase (MEK/PI3K) inhibition.

Conclusions: HSP90 inhibition may be a highly effective strategy at managing the diverse array of resistance mechanisms being reported to BRAF inhibitors and appears to be more effective at restoring BIM expression and downregulating Mcl-1 expression than combined MEK/PI3K inhibitor therapy. Clin Cancer Res; 18(9); 2502–14. ©2012 AACR.
Implications of Plasma Protein Binding for Pharmacokinetics and Pharmacodynamics of the γ-Secretase Inhibitor RO4929097
Authors: Wu Jianmei , LoRusso Patricia M. , Matherly Larry H. , Li Jing
Published: February 2012

Purpose: Understanding of plasma protein binding will provide mechanistic insights into drug interactions or unusual pharmacokinetic properties. This study investigated RO4929097 binding in plasma and its implications for the pharmacokinetics and pharmacodynamics of this compound.

Experimental Design: RO4929097 binding to plasma proteins was determined using a validated equilibrium dialysis method. Pharmacokinetics of total and unbound RO4929097 was evaluated in eight patients with breast cancer receiving RO4929097 alone and in combination with the Hedgehog inhibitor GDC-0449. The impact of protein binding on RO4929097 pharmacodynamics was assessed using an in vitro Notch cellular assay.

Results: RO4929097 was extensively bound in human plasma, with the total binding constant of 1.0 × 106 and 1.8 × 104 L/mol for α1-acid glycoprotein (AAG) and albumin, respectively. GDC-0449 competitively inhibited RO4929097 binding to AAG. In patients, RO4929097 fraction unbound (Fu) exhibited large intra- and interindividual variability; GDC-0449 increased RO4929097 Fu by an average of 3.7-fold. Concomitant GDC-0449 significantly decreased total (but not unbound) RO4929097 exposure. RO4929097 Fu was strongly correlated with the total drug exposure. Binding to AAG abrogated RO4929097 in vitro Notch-inhibitory activity.

Conclusions: RO4929097 is highly bound in human plasma with high affinity to AAG. Changes in plasma protein binding caused by concomitant drug (e.g., GDC-0449) or disease states (e.g., ↑AAG level in cancer) can alter total (but not unbound) RO4929097 exposure. Unbound RO4929097 is pharmacologically active. Monitoring of unbound RO4929097 plasma concentration is recommended to avoid misleading conclusions on the basis of the total drug levels. Clin Cancer Res; 18(7); 2066–79. ©2012 AACR.
Responsiveness of Intrinsic Subtypes to Adjuvant Anthracycline Substitution in the NCIC.CTG MA.5 Randomized Trial
Authors: Cheang Maggie C.U. , Voduc K. David , Tu Dongsheng , Jiang Shan , Leung Samuel , Chia Stephen K. , Shepherd Lois E. , Levine Mark N. , Pritchard Kathleen I. , Davies Sherri , Stijleman Inge J. , Davis Carole , Ebbert Mark T.W. , Parker Joel S. , Ellis Matthew J. , Bernard Philip S. , Perou Charles M. , Nielsen Torsten O.
Published: February 2012

Purpose: Recent studies suggest that intrinsic breast cancer subtypes may differ in their responsiveness to specific chemotherapy regimens. We examined this hypothesis on NCIC.CTG MA.5, a clinical trial randomizing premenopausal women with node-positive breast cancer to adjuvant CMF (cyclophosphamide-methotrexate-fluorouracil) versus CEF (cyclophosphamide-epirubicin-fluorouracil) chemotherapy.

Experimental Design: Intrinsic subtype was determined for 476 tumors using the quantitative reverse transcriptase PCR PAM50 gene expression test. Luminal A, luminal B, HER2-enriched (HER2-E), and basal-like subtypes were correlated with relapse-free survival (RFS) and overall survival (OS), estimated using Kaplan–Meier plots and log-rank testing. Multivariable Cox regression analyses determined significance of interaction between treatment and intrinsic subtypes.

Results: Intrinsic subtypes were associated with RFS (P = 0.0005) and OS (P < 0.0001) on the combined cohort. The HER2-E showed the greatest benefit from CEF versus CMF, with absolute 5-year RFS and OS differences exceeding 20%, whereas there was a less than 2% difference for non–HER2-E tumors (interaction test P = 0.03 for RFS and 0.03 for OS). Within clinically defined Her2+ tumors, 79% (72 of 91) were classified as the HER2-E subtype by gene expression and this subset was strongly associated with better response to CEF versus CMF (62% vs. 22%, P = 0.0006). There was no significant difference in benefit between CEF and CMF in basal-like tumors [n = 94; HR, 1.1; 95% confidence interval (CI), 0.6–2.1 for RFS and HR, 1.3; 95% CI, 0.7–2.5 for OS].

Conclusion: HER2-E strongly predicted anthracycline sensitivity. The chemotherapy-sensitive basal-like tumors showed no added benefit for CEF over CMF, suggesting that nonanthracycline regimens may be adequate in this subtype although further investigation is required. Clin Cancer Res; 18(8); 2402–12. ©2012 AACR.
Targeting the Epigenome with Bioactive Food Components for Cancer Prevention
Authors: Ong Thomas Prates , Moreno Fernando Salvador , Ross Sharon Ann
Published: February 2012

Epigenetic processes participate in cancer development and likely influence cancer prevention. Global DNA hypomethylation, gene promoter hypermethylation and aberrant histone post-translational modifications are hallmarks of neoplastic cells which have been associated with genomic instability and altered gene expression. Because epigenetic deregulation occurs early in carcinogenesis and is potentially reversible, intervention strategies targeting the epigenome have been proposed for cancer prevention. Bioactive food components (BFCs) with anticancer potential, including folate, polyphenols, selenium, retinoids, fatty acids, isothiocyanates and allyl compounds, influence DNA methylation and histone modification processes. Such activities have been shown to affect the expression of genes involved in cell proliferation, death and differentiation that are frequently altered in cancer. Although the epigenome represents a promising target for cancer prevention with BFCs, few studies have addressed the influence of dietary components on these mechanisms in vivo, particularly on the phenotype of humans, and thus the exact mechanisms whereby diet mediates an effect on cancer prevention remains unclear. Primary factors that should be elucidated include the effective doses and dose timing of BFCs to attain epigenetic effects. Because diet-epigenome interactions are likely to occur in utero, the impact of early-life nutrition on cancer risk programming should be further investigated.
The Effect of Nutrition during Early Life on the Epigenetic Regulation of Transcription and Implications for Human Diseases
Authors: Lillycrop Karen A. , Burdge Graham C.
Published: February 2012

Epigenetic processes which include DNA methylation, histone modification and miRNAs are integral in determining when and where specific genes are expressed. There is now increasing evidence that the epigenome is susceptible to a variety of environmental cues, such as nutrition, during specific periods of development. The changes induced by early-life nutrition may reflect an adaptive response of the foetus to environmental cues acting through the process of developmental plasticity. This may allow an organism to adjust its developmental programme resulting in long-term changes in its metabolism and physiology in order to be better matched to the future environment. However, when the future environment lies outside the anticipated range, metabolic and homoeostatic capacity will be mismatched with the environment and that individual will be at increased risk of developing a range of non-communicable diseases. Thus the environmental regulation of epigenetic processes is a central component in the developmental origins of non-communicable diseases and our understanding of these processes is, therefore, critical both for the identification of individuals at risk and for the development of new intervention strategies.
Temporal Bone High-Resolution Computed Tomography in Non-Syndromic Unilateral Hearing Loss in Children
Authors: Cama Elona , Inches Ingrid , Muzzi Enrico , Sadushi Orjona , Santarelli Rosamaria , De Colle Wladimiro , Rossi Roberta , di Paola Francesco , Arslan Edoardo
Published: February 2012

Objective: The aim of this study was to disclose possible inner ear abnormalities/pathologies by means of high-resolution computed tomography (HRCT) of the temporal bone (TBHRCT) in children with unilateral hearing loss (UHL). Methods: Retrospective review of audiological evaluation and TBHRCT in 22 children with UHL. Results: Two thirds of the children showed profound hearing loss. Review of HRCT scans identified inner ear malformations/pathologies in 9 (41%) cases and a high jugular bulb (HJB), always dehiscent with the vestibular aqueduct, in another 5 (22%). Inner ear malformations included enlarged vestibular aqueduct, common cavity and cochleovestibular hypoplasia, while labyrinthine ossification was the detected pathology. In 1 child, the common cavity of the right ear was associated with congenital melanocytic naevus of the left eyelid and lipomeningocele. To the best of our knowledge, this condition has never been described. Conclusions: The aetiology of UHL may be revealed in more than half of patients by means of TBHRCT. Besides common inner ear abnormalities, TBHRCT should be evaluated carefully to rule out HJB, dehiscences, diverticulum or erosion of inner ear structures.
Effect of Aerosol on Circulations and Precipitation in Deep Convective Clouds
Authors: Lee Seoung Soo
Published: February 2012

This study examines the effect of a mesoscale perturbation of aerosol on a larger-scale cloud system driven by deep convective clouds. An aerosol-perturbed domain of size 120 km is prescribed in the middle of the larger-scale domain of size 1100 km. Aerosol perturbations in the mesoscale domain result in an intensification of convection in a mesoscale convective system (MCS). This leads to an intensification of the larger-scale circulations, which in turn leads to an intensification of the larger-scale subsidence. While the invigorated convection enhances precipitation in the MCS, the intensified larger-scale subsidence acts to increase the larger-scale stability and thus to suppress convection and precipitation in the larger-scale domain. The suppression of precipitation in the larger-scale domain outweighs the enhancement of precipitation in the mesoscale domain, leading to suppressed precipitation over the entire domain. The ramifications of aerosol perturbations therefore need to be considered on scales much larger than the scale of the perturbation.
Precipitation Climatology in an Ensemble of CORDEX-Africa Regional Climate Simulations
Authors: Nikulin Grigory , Jones Colin , Giorgi Filippo , Asrar Ghassem , Büchner Matthias , Cerezo-Mota Ruth , Christensen Ole Bøssing , Déqué Michel , Fernandez Jesus , Hänsler Andreas , van Meijgaard Erik , Samuelsson Patrick , Sylla Mouhamadou Bamba , Sushama Laxmi
Published: February 2012

An ensemble of regional climate simulations is analyzed to evaluate the ability of 10 regional climate models (RCMs) and their ensemble average to simulate precipitation over Africa. All RCMs use a similar domain and spatial resolution of ~50 km and are driven by the ECMWF Interim Re-Analysis (ERA-Interim) (1989–2008). They constitute the first set of simulations in the Coordinated Regional Downscaling Experiment in Africa (CORDEX-Africa) project. Simulated precipitation is evaluated at a range of time scales, including seasonal means, and annual and diurnal cycles, against a number of detailed observational datasets. All RCMs simulate the seasonal mean and annual cycle quite accurately, although individual models can exhibit significant biases in some subregions and seasons. The multimodel average generally outperforms any individual simulation, showing biases of similar magnitude to differences across a number of observational datasets. Moreover, many of the RCMs significantly improve the precipitation climate compared to that from their boundary condition dataset, that is, ERA-Interim. A common problem in the majority of the RCMs is that precipitation is triggered too early during the diurnal cycle, although a small subset of models does have a reasonable representation of the phase of the diurnal cycle. The systematic bias in the diurnal cycle is not improved when the ensemble mean is considered. Based on this performance analysis, it is assessed that the present set of RCMs can be used to provide useful information on climate projections over Africa.
A Global Intercomparison of Modeled and Observed Land–Atmosphere Coupling*
Authors: Ferguson Craig R. , Wood Eric F. , Vinukollu Raghuveer K.
Published: February 2012

Land–atmosphere coupling strength or the degree to which land surface anomalies influence boundary layer development—and in extreme cases, rainfall—is arguably the single most fundamental criterion for evaluating hydrological model performance. The Global Land–Atmosphere Coupling Experiment (GLACE) showed that strength of coupling and its representation can affect a model’s ability to simulate climate predictability at the seasonal time scale. And yet, the lack of sufficient observations of coupling at appropriate temporal and spatial scales has made achieving “true” coupling in models an elusive goal. This study uses Advanced Microwave Scanning Radiometer for Earth Observing System (AMSR-E) soil moisture (SM), multisensor remote sensing (RS) evaporative fraction (EF), and Atmospheric Infrared Sounder (AIRS) lifting condensation level (LCL) to evaluate the realism of coupling in the Global Land Data Assimilation System (GLDAS) suite of land surface models (LSMs), Princeton Global Forcing Variable Infiltration Capacity model (PGF–VIC), seven global reanalyses, and the North American Regional Reanalysis (NARR) over a 5-yr period (2003–07). First, RS and modeled estimates of SM, EF, and LCL are intercompared. Then, emphasis is placed on quantifying RS and modeled differences in convective-season daily correlations between SM–LCL, SM–EF, and EF–LCL for global, regional, and conditional samples. RS is found to yield a substantially weaker state of coupling than model products. However, the rank order of basins by coupling strength calculated from RS and models do roughly agree. Using a mixture of satellite and modeled variables, a map of hybrid coupling strength was produced, which supports the findings of GLACE that transitional zones tend to have the strongest coupling.
Uncertainties in North American Land Data Assimilation Systems over the Contiguous United States
Authors: Mo Kingtse C. , Chen Li-Chuan , Shukla Shraddhanand , Bohn Theodore J. , Lettenmaier Dennis P.
Published: February 2012

The Environmental Modeling Center (EMC) at the National Centers for Environmental Prediction (NCEP) and the University of Washington (UW) run parallel drought monitoring systems over the continental United States based on the North American Land Data Assimilation System (NLDAS). The NCEP system uses four land surface models (LSMs): Variable Infiltration Capacity (VIC), Noah, Mosaic, and Sacramento (SAC). The UW system uses VIC, SAC, Noah, and the Community Land Model (CLM). An assessment of differences in drought characteristics using both systems for the period 1979–2008 was performed. For soil moisture (SM) percentiles and runoff indices, differences are relatively small among different LSMs in the same system. However, the ensemble mean differences between the two systems are large over the western United States—in some cases exceeding 20% for SM and runoff percentile differences. These differences are most apparent after 2002 when the NCEP system transitioned to use the real-time North American Regional Reanalysis (NARR) and its precipitation gauge station data. (The UW system went into real-time operation in 2005.) Experiments were performed to address the sources of uncertainties. Comparison of simulations using the two systems with different model forcings indicates that the precipitation forcing differences are the primary source of the SM and runoff differences. While temperature, shortwave and longwave radiation, and wind speed forcing differences are also large after 2002, their contributions to SM and runoff differences are much smaller than precipitation.
An Extended Kalman Filter Framework for Polarimetric X-Band Weather Radar Data Processing
Authors: Schneebeli Marc , Berne Alexis
Published: February 2012

The different quantities measured by dual-polarization radar systems are closely linked to each other. An extended Kalman filter framework is proposed in order to make use of constraints on individual radar observables that are induced by these relations. This new approach simultaneously estimates the specific differential phase on propagation Kdp, the attenuation-corrected reflectivity at horizontal polarization Zh, and the attenuation-corrected differential reflectivity Zdr, as well as the differential phase shift on backscatter δhυ. In a simulation experiment it is found that Kdp and δhυ can be retrieved with higher accuracy and spatial resolution than existing estimators that solely rely on a smoothed measurement of the differential phase shift Ψdp. Attenuation-corrected Zh was retrieved with an accuracy similar to standard algorithms, but improvements were found for attenuation-corrected Zdr. In addition, the algorithm can be used for radar calibration by comparing the directly retrieved differential phase shift on propagation Φdp with the accumulated Kdp estimates. The extended Kalman filter estimation scheme was applied to data collected with an X-band polarimetric radar in the Swiss Alps in 2010. Radome attenuation appears to be significant (up to 5 dB) in moderate to intense rain events and hence needs to be corrected in order to have reliable quantitative precipitation estimates. Measurements corrected for radome and propagation attenuation were converted into rain-rate R with a newly developed relation between R, Kdp, and Zdr. The good agreement between rain-rate values inferred from ground observations and from the radar measurements confirms the reliability of the proposed radar processing technique.
WHOI SDSL Data-Link Project—Ethernet Telemetry through Sea Cables
Authors: Swartz Marshall , Torres Daniel J. , Liberatore Steve , Millard Robert
Published: February 2012

A data telemetry technique for communicating over standard oceanographic sea cables that achieves a nearly 100-fold increase in bandwidth as compared to traditional systems has been recently developed and successfully used at sea on board two Research Vessel (R/V) Atlantis cruises with an 8.5-km, 0.322-in.-diameter three-conductor sea cable. The system uses commercially available modules to provide Ethernet connectivity through existing sea cables, linking serial and video underwater instrumentation to the shipboard user. The new method applies Synchronous Digital Subscriber Line (SDSL) communications technology to undersea applications, greatly increasing the opportunities to use scientific instrumentation from existing ships and sea cables at minimal cost and without modification.
Effect of hybrid phenolic hollow microsphere and silica-filled vinyl ester composites
Authors: Yusriah L , Mariatti M
Published: February 2012

Study on phenolic hollow microspheres (PHMS)-filled vinyl ester (VE) composites has been carried out. Effect of adding PHMS fillers at different filler loading on flexural, impact, and thermal properties were studied. The impact strength increased with the addition of PHMS fillers but at the expense of flexural strength, flexural modulus, and thermal stability of the composites. The second stage of this article aims to study the effect of adding silica as second filler in PHMS-filled VE composite system, and the influence of silane treatment on the mechanical properties of silica/PHMS/VE hybrid composites. PHMS/VE composites filled with silane-treated silica were found to show an increase in flexural modulus with increasing filler content. On contrary, the untreated silica fillers were observed to provide reinforcing effect in PHMS/VE composites at rather low filler concentration. The flexural strengths of silica/PHMS/VE hybrid composites were found to decrease with addition of silica content in the composites, and further decreased with increasing in silica content for both untreated and treated silica/PHMS-filled VE composites. Addition of silane-treated silica in the composites also provided an increase in the impact resistance of the PHMS/VE composites. Interestingly, the addition of silica and PHMS fillers in VE matrix has resulting in low density composites with improved flexural modulus and impact resistance.
Objective and subjective evaluation of the human thermal sensation of wet fabrics
Authors: Niedermann Reto , Rossi René Michel
Published: February 2012

The aim of the current study was to investigate if human subjects can distinguish five different drying states of three different fabrics. We defined five time-points (drying states) for each fabric with an in-house developed infrared test, as well as gravimetrically. This test records the surface temperature of wetted fabrics with an infrared camera during the drying process. In addition, the weight course during drying was recorded. The subjects evaluated fabrics with different wetting and wicking behaviours in a perception questionnaire. They answered questions about thermal sensation, thermal comfort, pain sensation and wetness perception. In conclusion, the human subjects could not differentiate the drying states of the fabrics as long as they contained water. Only the last drying state (100% dry, as measured with the infrared test) was distinguishable from the other four. However, the dry time-point of a fabric measured with the gravimetric method did not coincide with the drying time measured with the infrared test or perceived by human subjects.
Schooling, Child Labor, and Reserve Army Evidences from India
Authors: Mukherjee Dipa
Published: February 2012

It is accepted that working from an early age causes physical, moral and psychological trauma for the children and loss of childhood. This article contends that apart from working children, those out of school but not working constitute a reserve army of child workers and policies must focus on them as well. Incidence of schooling, work and the reserve army in India has been examined and factors determining such decisions have been identified using a Multinomial Logit Model. Economic condition, Parental education, Social class, and Gender of the child emerge as important determinants. Focused and collaborative policies are necessary to reach goals of universal schooling.
Singapore’s Ethnic Relations’ Scorecard
Authors: Mutalib Hussin
Published: February 2012

This is an assessment and analysis about the Singapore government’s management of its multiethnic, plural society; particularly its ethnic minority, the Malays. It appears that, in spite of its relative success in pursuing the national integration quest, the State (read: Government) is still grappling with some pertinent socioeconomic and religious identity issues besetting its Malay citizens. Not only has the latter’s malaise lagged behind their Chinese and Indian counterparts but have also persisted since Independence. Arguably, the State, given its dominant and preponderant power, could mitigate the Malay dilemma if it acknowledges the reality that in Singapore’s globalizing culture, the Malay minority, if left without greater State intervention, has little chance to progress and keep pace with other citizens – thereby impeding, if not impairing the Republic’s hard-won stability and prosperity.
Demystifying the Rise of Hamas
Authors: Haboub Wael J.
Published: February 2012

Most scholarly and popular writings portray Hamas as either extremist or anti- systemic and as a threat to democracy. Expected utility theory assumes that voters will reward centrist parties because voters are risk-averse, while prospect theory expects extremist parties to be supported by voters since they tend to become risk-takers when in loss. After contrasting Hamas’s ideological distance from other Palestinian political parties, I argue that the secret of Hamas’s electoral success in 2006 lies not in its extremism but in its ideological centrist domestic message, consistent with expected utility theory. Palestinian voters supported what they saw as a centrist Hamas although it was viewed as extremist in the West. More importantly, the participation of Hamas in the democratic process has moderated its domestic and foreign policies, while its exclusion has destabilizing and radicalizing effects.
Gender, General Theory of Crime and Computer Crime
Authors: Moon Byongook , McCluskey John D. , McCluskey Cynthia P. , Lee Sangwon
Published: February 2012

Regarding the gender gap in computer crime, studies consistently indicate that boys are more likely than girls to engage in various types of computer crime; however, few studies have examined the extent to which traditional criminology theories account for gender differences in computer crime and the applicability of these theories in explaining computer crime across gender. Using a panel of 2,751 Korean youths, the current study tests the applicability of the general theory of crime in explaining the gender gap in computer crime and assesses the theory’s utility in explaining computer crime across gender. Analyses show that self-control theory performs well in predicting illegal use of others’ resident registration number (RRN) online for both boys and girls, as predicted by the theory. However, low self-control, a dominant criminogenic factor in the theory, fails to mediate the relationship between gender and computer crime and is inadequate in explaining illegal downloading of software in both boy and girl models. Theoretical implication of the findings and the directions for future research are discussed.
Boundary element analysis of riveted aircraft panels
Authors: Di Pisa C , Aliabadi MH
Published: February 2012

In this paper the boundary element method is applied to riveted aircraft structures. There are several ways of investigating the behaviour of rivets, such as two-dimensional elasticity (either for cross-sections or for in-plane analysis), plate theory and full three-dimensional analyses. Here a boundary element formulation for shear-deformable plate structures joined with rivets is proposed. Several test on lap joints are presented and compared with references to show the validity and the accuracy of the present formulation. Finally, applications to stiffened aircraft structures are also presented.
Climate change in Peruvian newspapers: The role of foreign voices in a context of vulnerability
Authors: Takahashi Bruno , Meisner Mark
Published: February 2012

Media coverage of climate change has been an area of continued research during the last years, mostly with a focus on developed countries. This study attempts to contribute to this body of work by analyzing the coverage in a developing country. The study presents a content analysis of newspaper coverage of climate change in Peru through the study of frames, geographical focus, and climate change strategies (mitigation/adaptation). Additionally, the role of foreign voices is assessed by comparing the coverage by Peruvian reporters with the coverage by wire services, and by determining the types of sources present in the articles. Results show a prevalence of an effects frame, followed by a politics frame. Also, the study found a significant amount of stories originating from wire services. In general, coverage prioritizes mitigation strategies and policies while providing limited attention to adaptation, which can be insufficient for a highly vulnerable country.
Determinants of Firms’ Liquidation and Acquisition in the Indian Electronics Industry
Authors: Irfan Mohd
Published: February 2012

This study examines the determinants of firms’ liquidation and acquisition in the Indian electronics industry during the period 1990–2006. It is argued that liquidation and acquisition are alternative modes of exit. Therefore, these modes of exit might have different determinants. To explore this possibility, a multinomial logistic (MNL) regression model is estimated using cross-sectional data of 540 firms. We find that the effects of age, size, leverage, innovative competence and profitability are significant for the likelihood of liquidation. In contrast, the effect of profitability was found insignificant for the likelihood of acquisition. Moreover, the effects of size and leverage are dissimilar across the exit modes, that is, large firms are more likely to be liquidated but less likely to be acquired, and high leverage firms are more likely to be liquidated but less likely to be acquired. The findings of this study show that the determinants of liquidation and acquisition modes of exit are different in the Indian electronics industry.

JEL Classification: C25, G33, G34, L63