bluuebunny/crossref_metadata_2025 huggingface dataset:
β-Lapachone Micellar Nanotherapeutics for Non–Small Cell Lung Cancer Therapy
Authors: Blanco Elvin , Bey Erik A. , Khemtong Chalermchai , Yang Su-Geun , Setti-Guthi Jagadeesh , Chen Huabing , Kessinger Chase W. , Carnevale Kevin A. , Bornmann William G. , Boothman David A. , Gao Jinming
Published: May 2010

Lung cancer is the leading cause of cancer-related deaths with current chemotherapies lacking adequate specificity and efficacy. β-Lapachone (β-lap) is a novel anticancer drug that is bioactivated by NAD(P)H:quinone oxidoreductase 1, an enzyme found specifically overexpressed in non–small cell lung cancer (NSCLC). Herein, we report a nanotherapeutic strategy that targets NSCLC tumors in two ways: (a) pharmacodynamically through the use of a bioactivatable agent, β-lap, and (b) pharmacokinetically by using a biocompatible nanocarrier, polymeric micelles, to achieve drug stability, bioavailability, and targeted delivery. β-Lap micelles produced by a film sonication technique were small (∼30 nm), displayed core-shell architecture, and possessed favorable release kinetics. Pharmacokinetic analyses in mice bearing subcutaneous A549 lung tumors showed prolonged blood circulation (t1/2, ∼28 h) and increased accumulation in tumors. Antitumor efficacy analyses in mice bearing subcutaneous A549 lung tumors and orthotopic Lewis lung carcinoma models showed significant tumor growth delay and increased survival. In summary, we have established a clinically viable β-lap nanomedicine platform with enhanced safety, pharmacokinetics, and antitumor efficacy for the specific treatment of NSCLC tumors. Cancer Res; 70(10); 3896–904. ©2010 AACR.
Wip1 Directly Dephosphorylates γ-H2AX and Attenuates the DNA Damage Response
Authors: Cha Hyukjin , Lowe Julie M. , Li Henghong , Lee Ji-Seon , Belova Galina I. , Bulavin Dmitry V. , Fornace Albert J.
Published: May 2010

The integrity of DNA is constantly challenged throughout the life of a cell by both endogenous and exogenous stresses. A well-organized rapid damage response and proficient DNA repair, therefore, become critically important for maintaining genomic stability and cell survival. When DNA is damaged, the DNA damage response (DDR) can be initiated by alterations in chromosomal structure and histone modifications, such as the phosphorylation of the histone H2AX (the phosphorylated form is referred to as γ-H2AX). γ-H2AX plays a crucial role in recruiting DDR factors to damage sites for accurate DNA repair. On repair completion, γ-H2AX must then be reverted to H2AX by dephosphorylation for attenuation of the DDR. Here, we report that the wild-type p53–induced phosphatase 1 (Wip1) phosphatase, which is often overexpressed in a variety of tumors, effectively dephosphorylates γ-H2AX in vitro and in vivo. Ectopic expression of Wip1 significantly reduces the level of γ-H2AX after ionizing as well as UV radiation. Forced premature dephosphorylation of γ-H2AX by Wip1 disrupts recruitment of important DNA repair factors to damaged sites and delays DNA damage repair. Additionally, deletion of Wip1 enhances γ-H2AX levels in cells undergoing constitutive oncogenic stress. Taken together, our studies show that Wip1 is an important mammalian phosphatase for γ-H2AX and shows an additional mechanism for Wip1 in the tumor surveillance network. Cancer Res; 70(10); 4112–22. ©2010 AACR.
Tyrosine Kinase Inhibitor Gefitinib Enhances Topotecan Penetration of Gliomas
Authors: Carcaboso Angel M. , Elmeliegy Mohamed A. , Shen Jun , Juel Stephen J. , Zhang Ziwei M. , Calabrese Christopher , Tracey Lorraine , Waters Christopher M. , Stewart Clinton F.
Published: May 2010

Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, increases brain parenchymal extracellular fluid (ECF) accumulation of topotecan, a substrate of the ATP-binding cassette (ABC) transporters P-glycoprotein (Pgp/MDR-1) and breast cancer resistance protein (BCRP/ABCG2). The effect of modulating these transporters on topotecan penetration in gliomas has not been thoroughly studied. Thus, we performed intracerebral microdialysis on mice bearing orthotopic human gliomas (U87 and MT330) and assessed topotecan tumor ECF (tECF) penetration and the effect of gefitinib on topotecan tECF penetration and intratumor topotecan distribution. We found that topotecan penetration (Ptumor) of U87 was 0.96 ± 0.25 (n = 7) compared with that of contralateral brain (Pcontralateral, 0.42 ± 0.11, n = 5; P = 0.001). In MT330 tumors, Ptumor (0.78 ± 0.26, n = 6) and Pcontralateral (0.42 ± 0.11, n = 5) also differed significantly (P = 0.013). Because both tumor models had disrupted blood-brain barriers and similar Ptumor values, we used U87 and a steady-state drug administration approach to characterize the effect of gefitinib on topotecan Ptumor. At equivalent plasma topotecan exposures, we found that Ptumor after gefitinib administration was lower. In a separate cohort of animals, we determined the volume of distribution of unbound topotecan in tumor (Vu,tumor) and found that it was significantly higher in groups receiving gefitinib, implying that gefitinib administration leads to a greater proportion of intracellular topotecan. Our results provide crucial insights into the role that transporters play in central nervous system drug penetration and provide a better understanding of the effect of coadministration of transporter modulators on anticancer drug distribution within a tumor. Cancer Res; 70(11); 4499–508. ©2010 AACR.
Intratumoral Therapy of Glioblastoma Multiforme Using Genetically Engineered Transferrin for Drug Delivery
Authors: Yoon Dennis J. , Kwan Byron H. , Chao Felix C. , Nicolaides Theodore P. , Phillips Joanna J. , Lam Gretchen Y. , Mason Anne B. , Weiss William A. , Kamei Daniel T.
Published: May 2010

Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor with median survival of only 12 to 15 months under the current standard of care. To both increase tumor specificity and decrease nonspecific side effects, recent experimental strategies in the treatment of GBM have focused on targeting cell surface receptors, including the transferrin (Tf) receptor, that are overexpressed in many cancers. A major limitation of Tf-based therapeutics is the short association of Tf within the cell to deliver its payload. We previously developed two mutant Tf molecules, K206E/R632A Tf and K206E/K534A Tf, in which iron is locked into each of the two homologous lobes. Relative to wild-type Tf, we showed enhanced delivery of diphtheria toxin (DT) from these mutants to a monolayer culture of HeLa cells. Here, we extend the application of our Tf mutants to the treatment of GBM. In vitro treatment of Tf mutants to a monolayer culture of glioma cells showed enhanced cellular association as well as enhanced delivery of conjugated DT. Treatment of GBM xenografts with mutant Tf-conjugated DT resulted in pronounced regression in vivo, indicating their potential use as drug carriers. Cancer Res; 70(11); 4520–7. ©2010 AACR.
MicroRNA-21 in Pancreatic Cancer: Correlation with Clinical Outcome and Pharmacologic Aspects Underlying Its Role in the Modulation of Gemcitabine Activity
Authors: Giovannetti Elisa , Funel Niccola , Peters Godefridus J. , Del Chiaro Marco , Erozenci Leyla A. , Vasile Enrico , Leon Leticia G. , Pollina Luca E. , Groen Annemieke , Falcone Alfredo , Danesi Romano , Campani Daniela , Verheul Henk M. , Boggi Ugo
Published: May 2010

MicroRNA-21 (miR-21) was reported to be overexpressed and contributes to invasion and gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to evaluate whether miR-21 expression was associated with the overall survival (OS) of PDAC patients treated with gemcitabine and to provide mechanistic insights for new therapeutic targets. miR-21 expression was evaluated in cells (including 7 PDAC cell lines, 7 primary cultures, fibroblasts, and a normal pancreatic ductal cell line) and tissues (neoplastic specimens from 81 PDAC patients and normal ductal samples) isolated by laser microdissection. The role of miR-21 on the pharmacologic effects of gemcitabine was studied with a specific miR-21 precursor (pre-miR-21). Patients with high miR-21 expression had a significantly shorter OS both in the metastatic and in the adjuvant setting. Multivariate analysis confirmed the prognostic significance of miR-21. miR-21 expression in primary cultures correlated with expression in their respective tissues and with gemcitabine resistance. Pre-miR-21 transfection significantly decreased antiproliferative effects and apoptosis induction by gemcitabine, whereas matrix metalloproteinase (MMP)-2/MMP-9 and vascular endothelial growth factor expression were upregulated. Addition of inhibitors of phosphoinositide 3-kinase and mammalian target of rapamycin resulted in decrease of phospho-Akt and prevented pre-miR-21–induced resistance to the proapoptotic effects of gemcitabine. miR-21 expression correlated with outcome in PDAC patients treated with gemcitabine. Modulation of apoptosis, Akt phosphorylation, and expression of genes involved in invasive behavior may contribute to the role of miR-21 in gemcitabine chemoresistance and to the rational development of new targeted combinations. Cancer Res; 70(11); 4528–38. ©2010 AACR.
Transforming Growth Factor-β Regulator SnoN Modulates Mammary Gland Branching Morphogenesis, Postlactational Involution, and Mammary Tumorigenesis
Authors: Jahchan Nadine S. , You Young-Hyun , Muller William J. , Luo Kunxin
Published: May 2010

SnoN is an important negative regulator of transforming growth factor-β (TGF-β) signaling that was originally identified as a transforming oncogene in chicken embryonic fibroblasts. Both pro-oncogenic and antioncogenic activities of SnoN have been reported, but its function in normal epithelial cells has not been defined. In the mouse mammary gland, SnoN is expressed at relatively low levels, but it is transiently upregulated at late gestation before being downregulated during lactation and early involution. To assess the effects of elevated levels of SnoN, we generated transgenic mice expressing a SnoN fragment under the control of the mouse mammary tumor virus promoter. In this model system, SnoN elevation increased side-branching and lobular-alveolar proliferation in virgin glands, while accelerating involution in postlactation glands. Increased proliferation stimulated by SnoN was insufficient to induce mammary tumorigenesis. In contrast, elevated levels of SnoN cooperated with polyoma middle T antigen to accelerate the formation of aggressive multifocal adenocarcinomas and to increase the formation of pulmonary metastases. Our studies define functions of SnoN in mammary epithelial cell proliferation and involution, and provide the first in vivo evidence of a pro-oncogenic role for SnoN in mammalian tumorigenesis. Cancer Res; 70(10); 4204–13. ©2010 AACR.
Antifungal Therapy with Itraconazole Impairs the Anti-Lymphoma Effects of Rituximab by Inhibiting Recruitment of CD20 to Cell Surface Lipid Rafts
Authors: Ringshausen Ingo , Feuerstacke Yvonne , Krainz Philipp , den Hollander Jürgen , Hermann Ken , Buck Andreas , Peschel Christian , Meyer zum Bueschenfelde Christian
Published: May 2010

Immunotherapy with rituximab alone or in conjunction with chemotherapy has significantly improved the treatment outcome of B-cell lymphoma patients. Nevertheless, a subpopulation of patients does not respond to rituximab. The reason for treatment failure as well as the exact mechanism of action is still uncertain. The function of rituximab has long been associated with the partitioning of CD20 molecules to membrane microdomains. Here, we show that concomitant antifungal treatment with itraconazole impairs the rituximab anti-lymphoma effect both in vitro and in vivo. At the molecular level, recruitment of CD20 to lipid rafts is inhibited in the presence of itraconazole. Furthermore, calcium influx, which is crucial for rituximab-mediated cell death, was nearly completely abolished by itraconazole treatment. In contrast, the antifungal drug caspofungin did not inhibit CD20 recruitment to lipid rafts, nor did it affect calcium influx or the cytotoxic effect of rituximab. The finding that itraconazole also abolished the cytotoxic effects of other therapeutic antibodies directed against lipid raft–associated molecules (i.e., CD20 and CD52) but not those against the non–raft-associated molecule CD33 further supported our proposed mechanism of action. Our results argue that concomitant medications must be adjusted carefully to achieve optimal antitumor effects with monoclonal antibodies. Cancer Res; 70(11); 4292–6. ©2010 AACR.
Princess Takamatsu Symposium on DNA Repair and Human Cancers
Authors: Loeb Lawrence A. , Nishimura Susumu
Published: May 2010

The 40th International Symposium of the Princess Takamatsu Cancer Research Fund, entitled “DNA Repair and Human Cancers,” was held on November 10–12, 2009 at Hotel Grand Palace, Tokyo, Japan. The meeting focused on the role of DNA repair in preventing mutations by endogenous and exogenous DNA damage and increasing the efficacy of chemotherapeutic agents by interfering with DNA repair. The 14 presentations by the speakers from the United States, four from the United Kingdom, one each from Italy, The Netherlands, and France, and 13 from Japan, covered most aspects of DNA repair, spanning DNA damage, molecular structures of repair enzymes, and clinical studies on inhibition of DNA repair processes. Extensive time was reserved for discussions with the active participation of the 150 invited Japanese scientists. The choice of a symposium on DNA repair in human cancers resulted in part from the excellent basic and clinical studies that have been carried out for many years in Japan, and the general lack of recognition versus the importance of DNA repair in understanding carcinogenesis. Cancer Res; 70(11); 4269–73. ©2010 AACR.
FTY720 Shows Promising In vitro and In vivo Preclinical Activity by Downmodulating Cyclin D1 and Phospho-Akt in Mantle Cell Lymphoma
Authors: Liu Qing , Alinari Lapo , Chen Ching-Shih , Yan Fengting , Dalton James T. , Lapalombella Rosa , Zhang Xiaoli , Mani Rajeswaran , Lin Teresa , Byrd John C. , Baiocchi Robert A. , Muthusamy Natarajan
Published: May 2010

Purpose: Despite the progress that has been made in the treatment of mantle cell lymphoma (MCL), all patients invariably relapse with the currently available therapies. Because of the absence of curative therapy for MCL, we explored FTY720 as a novel agent against MCL.

Experimental Design: The cytotoxic effect of FTY720 in primary MCL tumor cells and cell lines were evaluated in vitro. The effects of FTY720 on caspase activation, generation of reactive oxygen species, and modulation of Cyclin D1 and Akt, which are implied in the pathogenesis of MCL, were investigated. The in vivo efficacy of FTY720 was evaluated in a Jeko-severe combined immunodeficient xenograft model of human MCL.

Results: FTY720 mediated time- and dose-dependent cytotoxicity in primary MCL tumor cells and MCL cell lines in vitro. FTY720-induced cytotoxicity occured independent of caspase activation but dependent on the generation of ROS in MCL. In addition, FTY720 treatment resulted in the time-dependent downmodulation of Cyclin D1 and accumulation of cells in G0-G1 and G2-M phases of the cell cycle with concomitant decrease in S-phase entry. Furthermore, concentrations of FTY720 that induced cytotoxicity led to decreased phospho-Akt in primary MCL cells and cell lines. Most importantly, the in vivo therapeutic activity of FTY720 was shown in severe combined immunodeficient mice engrafted with the Jeko MCL cell line.

Conclusions: These results provide the first evidence for a potential use of FTY720 in targeting key pathways that are operable in the pathogenesis of MCL and warrant further investigation of FTY720 in clinical trials to treat patients with MCL. Clin Cancer Res; 16(12); 3182–92. ©2010 AACR.
Functional Proteomic Analysis of Advanced Serous Ovarian Cancer Using Reverse Phase Protein Array: TGF-β Pathway Signaling Indicates Response to Primary Chemotherapy
Authors: Carey Mark S. , Agarwal Roshan , Gilks Blake , Swenerton Kenneth , Kalloger Steve , Santos Jennifer , Ju Zhenlin , Lu Yiling , Zhang Fan , Coombes Kevin R. , Miller Dianne , Huntsman David , Mills Gordon B. , Hennessy Bryan T.
Published: May 2010

Purpose: Using reverse phase protein array, we measured protein expression associated with response to primary chemotherapy in patients with advanced-stage, high-grade serous ovarian cancer.

Experimental Design: Tumor samples were obtained from 45 patients with advanced high-grade serous cancers from the Gynecology Tumor Bank at the British Columbia Cancer Agency. Treatment consisted of platinum-based chemotherapy following debulking surgery. Protein lysates were prepared from fresh frozen tumor samples, and 80 validated proteins from signaling pathways implicated in ovarian carcinogenesis were measured by reverse phase protein array. Normalization of Ca-125 by the 3rd cycle of chemotherapy was chosen as the primary outcome measure of chemotherapy response. Logistic regression was used for multivariate analysis to identify protein predictors of Ca-125 normalization and Cox regression to test for the association between protein expression and progression-free survival. A significance level of P ≤ 0.05 was used.

Results: The mean age at diagnosis was 56.8 years. epidermal growth factor receptor, YKL-40, and several transforming growth factor β (TGF-β) pathway proteins [c-jun–NH2–kinase (JNK), JNK phosphorylated at residues 183 and 185, plasminogen activator inhibitor 1, Smad3, TAZ] showed significant associations with Ca-125 normalization on univariate testing. On multivariate analysis, epidermal growth factor receptor (P < 0.02), JNK (P < 0.01), and Smad3 (P < 0.04) were significantly associated with normalization of Ca-125. Contingency table analysis of pathway-classified proteins revealed that the selection of TGF-β pathway proteins was unlikely because of false discovery (P < 0.007; Bonferroni adjusted).

Conclusion: TGF-β pathway signaling likely plays an important role as a marker or mediator of chemoresistance in advanced serous ovarian cancer. On this basis, future studies to develop and validate a useful predictor of treatment failure are warranted. Clin Cancer Res; 16(10); 2852–60. ©2010 AACR.
Identification of a Quantitative MINT Locus Methylation Profile Predicting Local Regional Recurrence of Rectal Cancer
Authors: de Maat Michiel F.G. , van de Velde Cornelis J.H. , Benard Anne , Putter Hein , Morreau Hans , van Krieken J. Han J.M. , Meershoek Klein-Kranenbarg Elma , de Graaf Eelco J. , Tollenaar Rob A.E.M. , Hoon Dave S.B.
Published: May 2010

Purpose: Risk assessment for locoregional disease recurrence would be highly valuable in preoperative treatment planning for patients undergoing primary rectal tumor resection. Epigenetic aberrations such as DNA methylation have been shown to be significant prognostic biomarkers of disease outcome. In this study, we evaluated the significance of a quantitative epigenetic multimarker panel analysis of primary tumors to predict local recurrence in rectal cancer patients from a retrospective multicenter clinical trial.

Experimental Design: Primary tumors were studied from patients enrolled in the trial who underwent total mesorectal excision for rectal cancer (n = 325). Methylation levels of seven methylated-in-tumor (MINT) loci were assessed by absolute quantitative assessment of methylated alleles. Unsupervised random forest clustering of quantitative MINT methylation data was used to show subclassification into groups with matching methylation profiles.

Results: Variable importance parameters [Gini-Index (GI)] of the clustering algorithm indicated MINT3 and MINT17 (GI, 20.2 and 20.7, respectively) to be informative for patient grouping compared with the other MINT loci (highest GI, 12.2). When using this two-biomarker panel, four different patient clusters were identified. One cluster containing 73% (184 of 251) of the patients was at significantly increased risk of local recurrence (hazard ratio, 10.23; 95% confidence interval, 1.38-75.91) in multivariate analysis, corrected for standard prognostic factors of rectal cancer. This group showed a significantly higher local recurrence probability than patients receiving preoperative radiation (P < 0.0001).

Conclusion: Quantitative epigenetic subclassification of rectal cancers has clinical utility in distinguishing tumors with increased risk for local recurrence and may help tailor treatment regimens for locoregional control. Clin Cancer Res; 16(10); 2811–8. ©2010 AACR.
Efficacy, Biodistribution, and Pharmacokinetics of CD22-Targeted Pegylated Liposomal Doxorubicin in a B-cell Non–Hodgkin's Lymphoma Xenograft Mouse Model
Authors: Tuscano Joseph M. , Martin Shiloh M. , Ma Yunpeng , Zamboni William , O'Donnell Robert T.
Published: May 2010

Purpose: Non–Hodgkin's lymphoma (NHL) is the sixth most common cause of cancer death in the U.S. Pegylated liposomal doxorubicin (PLD) is a liposomal form of doxorubicin (DXR) that causes less toxicity than does free DXR. To further enhance efficacy and decrease toxicity, we conjugated HB22.7, an anti-CD22 monoclonal antibody to PLD, thus creating CD22-targeted immunoliposomal PLD (IL-PLD).

Experimental Design: In vitro cytotoxicity of IL-PLD and PLD was assessed in CD22-positive and CD22-negative cell lines. Biodistribution, myelotoxicity, and plasma pharmacokinetics were measured in NHL xenograft–bearing mice treated with IL-PLD or PLD. Survival, tumor volume, and toxicity (WBC counts, body weights) were assessed in mice receiving a single dose (8, 12, or 16 mg DXR/kg) or three doses (8 mg DXR/kg/dose) of IL-PLD; controls were PLD, free DXR, PLD plus unconjugated HB22.7, IL-null (HB22.7-conjugated empty liposome), and nontreated mice.

Results: IL-PLD improved cytotoxicity over PLD only in CD22-positive cells. IL-PLD displayed similar pharmacokinetics and toxicities as PLD. Tumor DXR accumulation was greater and tumor/normal tissue ratios were similar (spleen) or greater (kidney, lung, and liver) in mice treated with IL-PLD versus PLD. IL-PLD reduced tumor volume more effectively than PLD at all doses; the three-dose regimen was superior. The three-dose regimen was used in confirmatory studies, which showed that IL-PLD produced significantly greater tumor volume reduction and enhanced survival versus PLD.

Conclusion: IL-PLD has increased efficacy without increased toxicity compared with PLD. This suggests that IL-PLD may be an improved form of DXR-based therapy of NHL. Clin Cancer Res; 16(10); 2760–8. ©2010 AACR.
Graft-versus-Leukemia Antigen CML66 Elicits Coordinated B-Cell and T-Cell Immunity after Donor Lymphocyte Infusion
Authors: Zhang Wandi , Choi Jaewon , Zeng Wanyong , Rogers Shelby A. , Alyea Edwin P. , Rheinwald James G. , Canning Christine M. , Brusic Vladimir , Sasada Tetsuro , Reinherz Ellis L. , Ritz Jerome , Soiffer Robert J. , Wu Catherine J.
Published: May 2010

Purpose: The target antigens of graft-versus-leukemia that are tumor associated are incompletely characterized.

Experimental Design: We examined responses developing against CML66, an immunogenic antigen preferentially expressed in myeloid progenitor cells identified from a patient with chronic myelogenous leukemia who attained long-lived remission following CD4+ donor lymphocyte infusion (DLI).

Results: From this patient, CML66-reactive CD8+ T-cell clones were detected against an endogenously presented HLA-B*4403–restricted epitope (HDVDALLW). Neither CML66-specific antibody nor T-cell responses were detectable in peripheral blood before DLI. However, by 1 month after DLI, CD8+ T cells were present in peripheral blood and at 10-fold higher frequency in marrow. Subsequently, plasma antibody to CML66 developed in association with disease remission. Donor-derived CML66-reactive T cells were detected at low levels in vivo in marrow before DLI by ELISpot and by a nested PCR-based assay to detect clonotypic T-cell receptor sequences but not in blood of the patient pre-DLI nor of the graft donor.

Conclusions: CD4+ DLI results in rapid expansion of preexisting marrow-resident leukemia-specific donor CD8+ T cells, followed by a cascade of antigen-specific immune responses detectable in blood. Our single-antigen analysis thus shows that durable posttransplant tumor immunity is directed in part against nonpolymorphic overexpressed leukemia antigens that elicit coordinated cellular and humoral immunity. Clin Cancer Res; 16(10); 2729–39. ©2010 AACR.
Overexpression of miR-21 Promotes an In vitro Metastatic Phenotype by Targeting the Tumor Suppressor RHOB
Authors: Connolly Erin C. , Van Doorslaer Koenraad , Rogler Leslie E. , Rogler Charles E.
Published: May 2010

Metastasis is a multistep process that involves the deregulation of oncogenes and tumor suppressors beyond changes required for primary tumor formation. RHOB is known to have tumor suppressor activity, and its knockdown is associated with more aggressive tumors as well as changes in cell shape, migration, and adhesion. This study shows that oncogenic microRNA, miR-21, represses RHOB expression by directly targeting the 3′ untranslated region. Loss of miR-21 is associated with an elevation of RHOB in hepatocellular carcinoma cell lines Huh-7 and HepG2 and in the metastatic breast cancer cell line MDA-MB-231. Using in vitro models of distinct stages of metastasis, we showed that loss of miR-21 also causes a reduction in migration, invasion, and cell elongation. The reduction in migration and cell elongation can be mimicked by overexpression of RHOB. Furthermore, changes in miR-21 expression lead to alterations in matrix metalloproteinase-9 activity. Therefore, we conclude that miR-21 promotes multiple components of the metastatic phenotype in vitro by regulating several important tumor suppressors, including RHOB. Mol Cancer Res; 8(5); 691–700. ©2010 AACR.
Development of Aggressive Squamous Cell Carcinoma in Epidermodysplasia Verruciformis Associated with Human Papillomavirus Type 22b
Authors: Kim Taegyun , Park Jae Chan , Roh Mi Ryung , Park Jin Mo , Kim Se Heon , Cho Nam Hoon , Lee Min-Geol
Published: May 2010

Epidermodysplasia verruciformis (EV) is a rare genetic disease characterized by abnormal susceptibility to infection with EV-related human papillomavirus (HPV), now known as the β-papillomavirus (β-PV). Clinically specific β-PV-type-associated EV, especially HPV-5 and -8, shows a high rate of progression to squamous cell carcinoma (SCC). In this report, we describe a 39-year-old Korean man with HPV-22b-associated EV who developed a rapidly progressing SCC. The patient presented with a huge destructive mass on the nose. Histopathological evaluation of the mass was compatible with well-differentiated SCC. HPV typing results from both EV and SCC specimens demonstrated HPV-22b which has not been considered to be associated with SCC in EV patients so far. The patient underwent surgical excision and postoperative radiotherapy for locoregional control. This is the first report presenting the association of an SCC arising from previous EV with HPV-22b infection only.
Patient-Specific Model-Based Investigation of Speech Intelligibility and Movement during Deep Brain Stimulation
Authors: Åström Mattias , Tripoliti Elina , Hariz Marwan I. , Zrinzo Ludvic U. , Martinez-Torres Irene , Limousin Patricia , Wårdell Karin
Published: May 2010

Background/Aims: Deep brain stimulation (DBS) is widely used to treat motor symptoms in patients with advanced Parkinson’s disease. The aim of this study was to investigate the anatomical aspects of the electric field in relation to effects on speech and movement during DBS in the subthalamic nucleus. Methods: Patient-specific finite element models of DBS were developed for simulation of the electric field in 10 patients. In each patient, speech intelligibility and movement were assessed during 2 electrical settings, i.e. 4 V (high) and 2 V (low). The electric field was simulated for each electrical setting. Results: Movement was improved in all patients for both high and low electrical settings. In general, high-amplitude stimulation was more consistent in improving the motor scores than low-amplitude stimulation. In 6 cases, speech intelligibility was impaired during high-amplitude electrical settings. Stimulation of part of the fasciculus cerebellothalamicus from electrodes positioned medial and/or posterior to the center of the subthalamic nucleus was recognized as a possible cause of the stimulation-induced dysarthria. Conclusion: Special attention to stimulation-induced speech impairments should be taken in cases when active electrodes are positioned medial and/or posterior to the center of the subthalamic nucleus.
Treatment of Primary Systemic Vasculitis with the Inosine Monophosphate Dehydrogenase Inhibitor Mycophenolic Acid
Authors: Hiemstra Thomas F. , Jones Rachel B. , Jayne David R.W.
Published: May 2010

Despite advances in the treatment of vasculitis, modern therapies fail to induce or maintain remission in a significant proportion of patients. Mycophenolic acid is increasingly used to treat vasculitis syndromes. Here, we consider relevant pharmacokinetic and pharmacodynamic properties of mycophenolate, with emphasis on the impact of renal impairment, and we review the existing evidence for and current trials of mycophenolate in the treatment of primary systemic vasculitides.
Inflammation in Peritoneal Dialysis
Authors: Lai Kar Neng , Leung Joseph C.K.
Published: May 2010

During peritoneal dialysis, peritoneal cells are repeatedly exposed to a non-physiological hypertonic environment with high glucose content and low pH. Current sterile dialysis solutions cause inflammation in the submesothelial compact zone that leads to fibrosis, neoangiogenesis, progressive increases in solute transfer and even ultrafiltration failure. The peritoneal dysfunction will further be amplified with the development of an epithelial-to-mesenchymal transition of mesothelial cells and the dissipation of the osmotic driving force through increased area and solute transport that accompanied neoangiogenesis of the submesothelial microvasculature. The alteration in the peritoneal membrane will further be aggravated by peritonitis, advanced glycation end-products and glucose degradation products. Finally, there are emerging new data supporting a pro-inflammatory role of peritoneal adipocytes.
Association between Depression Symptoms with Inflammation and Cardiovascular Risk Factors in Patients Undergoing Peritoneal Dialysis
Authors: Ko Gang Jee , Kim Myung Gyu , Yu Young Mi , Jo Sang-Kyung , Cho Won Yong , Kim Hyoung Kyu
Published: May 2010

Despite medical progress, high morbidity and mortality rates, due primarily to cardiovascular diseases, have persisted in patients with end-stage renal disease (ESRD). Recently, nontraditional risk factors, such as inflammation and malnutrition, have been emphasized in the development or progression of atherosclerosis in ESRD patients. Depression, the most common psychological problem in the ESRD population, is also known to be associated with inflammation and malnutrition, suggesting a possible link between depression with inflammation and cardiovascular diseases. The purpose of this study was to investigate the relationship between depression with cardiovascular risk factors and inflammation in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Eighty-one stable CAPD patients were enrolled. Depressive symptoms were assessed with the Beck Depression Inventory. Various cardiovascular risk factors and inflammatory markers were measured. Forty-three patients had depressive symptoms (53.8%). Patients with depressive symptoms showed significantly lower levels of albumin and IL-10, but higher levels of inflammatory markers than patients without depressive symptoms. Left ventricular hypertrophy was also found more frequently and pulse wave velocity and asymmetric dimethylarginine were all significantly increased in patients with depressive symptoms. Depression in CAPD patients was associated with inflammation and cardiovascular risk factors, and might be used as a predictor of cardiovascular diseases.
Measuring Labor Market Discrimination: An Overview of Methods and Their Characteristics
Authors: Veenman Justus
Published: May 2010

The labor market is a distribution mechanism that assigns individuals to differently rated positions. Labor market processes therefore lead to social inequality. The question of whether social descent, age, gender, ethnic origin, religion, or sexual orientation plays a role in these processes is thus as important as it is delicate. This article describes four main methods to empirically investigate discrimination. These methods are systematically compared on methodological and substantial criteria. Dutch labor market research on the effects of ethnic origin is used to clarify the methods. Particular attention is paid to access to jobs, whereas wage discrimination is briefly discussed. The general conclusion is that no one method is superior. For this reason, it is advisable to use triangulation, that is, a combination of methods to reveal discrimination.
Commitment to an Emerging Organizational Field
Authors: Marcus Alfred A. , Anderson Marc H.
Published: May 2010

This article builds an enactment theory to explain the continuing commitment of entrepreneurs to an emerging organizational field like energy efficiency and renewable energy, which is widely seen as being in the interests of society. The authors propose that when such a field is constrained by such factors as low energy prices and a lack of government support, the actions that entrepreneurs take to educate stakeholders drives the entrepreneurs’ continuing commitment to the field. These actions are supported by the entrepreneurs’ perceptions of the field’s attractiveness, their beliefs that they produce superior products and services, and their beliefs regarding the likelihood of disruptive exogeneous change.
Review Essay: Disagreeing About the Climate
Authors: Nordberg Donald
Published: May 2010

This review article reflects on the current controversy concerning climate change. The article does so through a review of Hulme’s book Why We Disagree About Climate Change . The article also considers the implications of the Stern Report.
Why Get Technical? Corruption and the Politics of Public Service Reform in the Indian States
Authors: Bussell Jennifer L.
Published: May 2010

The emergence of new information and communication technologies in the 1990s offered governments opportunities to deliver public services more effectively to their citizens. Yet national and subnational authorities have employed such technologies in highly uneven ways. Drawing on a new data set of technology policy adoption by Indian states, the author argues that political calculations drive variation in the timing and scope of technology policies. Politicians weigh the expected electoral benefits from providing new goods to citizens against the expected electoral costs of reduced access to corrupt funds because of increased transparency. The author shows that the level of bureaucratic corruption in a state is the best predictor of both when states implement policies promoting computer-enabled services and the number of services made available.This finding contrasts with arguments that posit economic or developmental conditions, or alternative electoral and institutional characteristics, as the major drivers of technology investment.
Multisensory Integration With a Head-Mounted Display: Role of Mental and Manual Load
Authors: Thompson Matthew B. , Tear Morgan J. , Sanderson Penelope M.
Published: May 2010

Objective: The aim of this study was to replicate the finding that multisensory integration with a head-mounted display (HMD) is particularly difficult when a person is walking and hearing sound from a free-field speaker, and to extend the finding with a response method intended to reduce workload. Background: HMDs can support the information needs of workers whose work requires mobility, but some low-cost solutions for delivering auditory information may be less effective than others. Method: For the study, 24 participants detected whether shapes moving on the HMD screen made a sound appropriate to their forms when they collided with other shapes. Independent variables were self-motion (participants were mobile or seated), sound delivery (free-field speakers or an earpiece), and response method (noting mismatches via a mental count or via a manual clicker). Results: Unexpectedly, overall mismatch task accuracy was worse with the clicker ( p = .027) than without. Participants also reported that it was harder to time-share the mismatch task with clicker responses ( p = .033). In the clicker condition, self-motion and sound delivery interacted but in the opposite direction to the previous study. Conclusion: The best way of delivering auditory information to mobile workers performing a multisensory integration task with an HMD may depend on whether responding involves mental load or manual load. Broader theories are needed to capture factors influencing performance. Application: Until more powerful theory is developed, designers should perform careful formative and summative tests of whether the activities to be performed by mobile HMD wearers will make some sound delivery solutions less effective than others.
Using Monochromatic Design Views to Avoid a Premature Fixation on Design Solutions
Authors: Damle Amod
Published: May 2010

Objective: This study investigates whether the availability of a monochromatic design view can prevent an early fixation on details during the preliminary stages of a design task. Background: Design students are trained to tentatively sketch the overall form of a design concept before attending to its details. Literature suggests that using multiple colors for sketching a concept causes a gestalt-like grouping phenomenon and influences designers to adopt a contrasting strategy of adding details before sketching the overall form. An empirical study was conducted to assess the validity of these findings. Method: In the study, 20 participants, randomly assigned to two groups, were allowed to use multiple colors to sketch a design concept within a digital sketching environment. However, only the single-color group had the ability to view a sketch, as it would appear in monochrome. Results: Both groups parsed the design concepts into their basic components and used colors as a means of distinguishing one component from another. However, the single-color group added significantly more details than the first or the multicolor group after sketching the overall form. Conclusion: Verbal reports suggest that the single-color group was able to avoid an early fixation on details because the single-color view eliminated the discontinuities induced by the variation in color and allowed the participants to attend to the overall form instead of the individual components. Application: The current findings highlight the importance of providing a monochrome design view within a sketching environment to avoid an early fixation on a specific design solution.
Nineteen Days in April: Urban Protest and Democracy in Nepal
Authors: Routledge Paul
Published: May 2010

For 19 days in April 2006, Nepal witnessed a popular uprising against the royal-military coup staged by King Gyanendra in February 2005. The Jana Andolan II (People’s Movement II) demanded a return to democracy, the establishment of a lasting peace in Nepal and more political and economic inclusion for the various ethnic and caste groups historically marginalised in Nepali society. Through an analysis of the Jana Andolan (particularly within the urban space of Nepal’s capital, Kathmandu) and the subsequent peace process that has unfolded in Nepal, this paper will consider how and why the city was a key terrain for the prosecution of conflict by the people’s movement, and how such protest entailed the articulation of particular democratic rights discourses. The paper will also consider the role of civil society within urban protest in order to reflect upon debates concerning liberal and radical democracy, and the ‘politics of the governed’.
Timely Partnerships? Contrasting Geographies of Activism in New Zealand and Australia
Authors: Panelli Ruth , Larner Wendy
Published: May 2010

Analyses of activism have inspired geographers for many years, but most of this work has focused on relatively short time-frames, events and struggles. This paper suggests that there is much to be gained from a greater engagement with issues of time and time—spaces. It outlines and applies the contrasting conceptions of chrono/ chora and kairo/ topos notions of time—space as potentially useful ways to interrogate geographies of activism. The paper focuses on two specific forms of activism—an Australian women’s ‘Heritage Project’ and a New Zealand ‘Fishbowl’ evaluation of a community development programme— to show how politics is contingent on diverse temporal as well as spatial conditions. It reveals the complex navigations that are made as these politics are negotiated via both mutual learning processes and the forging of new activist—state relations. It is concluded that these ‘timely partnerships’ have involved moving beyond adversarial conceptions of ‘state’ and ‘activist’, but at the risk of reconstituting activism as ‘social capital’.
The Urban Geography of Red Power: The American Indian Movement in Minneapolis-Saint Paul, 1968-70
Authors: D'Arcus Bruce
Published: May 2010

Drawing on recent theories of citizenship that argue the city as the pre-eminent ‘difference machine’, this paper argues that it is also a crucial site for the production of resistance as a social identity and practice. This argument is presented through an analysis of an example from the ‘Red Power’ movement in the US in the 1960s and early 1970s. The paper examines how American Indian activism—while often dramatised in rural reservation locations and centred on rather grand abstractions quite far removed from typically urban concerns and politics—also has a profoundly urban historical geography.
Urban Social Movements in ‘Weak’ Civil Societies: The Right to the City and Cosmopolitan Activism in Southern Europe
Authors: Leontidou Lila
Published: May 2010

The transition from fast spontaneous urbanisation in southern Europe, with popular squatting as a form of civil disobedience, to ‘new social movements’ (NSMs) for democratic globalisation in cities, is taking place in the context of a broader transition. In the 20th century, there were unstable politics, civil wars and also still dictatorships in the south, which contributed in a north—south divide in Europe, engulfing civil societies, the welfare state, planning and grassroots mobilisations for a ‘right to the city’. This paper focuses on social transformation during the 21st century and points to three directions. First, it explores the nature of several NSMs as urban social movements (USMs) organised by loosely networked cosmopolitan collectivities, social centres and flâneur activists demanding a ‘right to the city’, and interprets this with reference to globalisation, democratisation and the Europeanisation of southern civil societies. Secondly, it unveils innovative forms of ‘urban’ mobilisations in the south, influencing the rest of the Europe: squatting in the past, social centres and the ESF (both starting in Italy) at present. Thirdly, it traces transformations of USMs between two centuries and argues about the deconstruction of the north—south divide in Europe with regard to movements and definitions of the ‘right to the city’. Mediterranean USMs have offered new insights and have broadened geographical imaginations in Europe.
Scriptedness and Televised Sports: Violent Consumption and Viewer Enjoyment
Authors: Westerman David , Tamborini Ron
Published: May 2010

Extending Raney and Depalma’s research, this study examined effects of sport production on sport consumption. An experimental design crossed scripted (vs. unscripted) sport with violence (vs. nonviolence) to investigate the effects of both variables on violent outcomes and enjoyment. After viewing one of four clips, participants responded to three incomplete story stems, and responses were coded to measure hostile expectancy bias as a form of violent outcome. Participants also responded to their enjoyment of the clip they consumed. Analyses showed a main effect that consuming sport violence increased participants’ hostile expectancy bias. However, a significant interaction showed that scriptedness moderated this effect, such that violence increased hostile expectancy bias only in the scripted condition. Enjoyment was also affected by scriptedness and violence, as violent nonscripted sports were enjoyed more than all other conditions. Results suggest that violence in sports may be interpreted differently based on the scriptedness of the sport and may be processed differently than violence in other forms of entertainment. Implications of these findings are discussed, as are limitations and future directions for study.
Amelanotic Melanoma in a New Zealand White Rabbit (Oryctolagus cuniculus)
Authors: Zerfas P. M. , Brinster L. R. , Starost M. F. , Burkholder T. H. , Raffeld M. , Eckhaus M. A.
Published: May 2010

A 3.5-year-old intact male double-transgenic New Zealand white rabbit ( Oryctolagus cuniculus), apoA-I and LCAT (apolipoprotein and lecithin:cholesterol acyltransferase), was presented with a discrete, raised facial mass (0.5 × 1.0 × 1.0 cm). The mass was surgically excised, with reoccurrence to the same site 88 days later. A second surgical excision was performed, and the rabbit died 3 weeks later from respiratory distress. At necropsy, multiple varying-sized masses were observed in the ventral mandibular region and throughout the lungs, pleura, and diaphragm. On histopathology, the masses were composed of moderately anisocytotic and anisokaryotic polygonal to spindloid cells with moderate finely granular, lightly eosinophilic cytoplasm, having round to oval nuclei with one to several nucleoli and finely stippled chromatin. Mitotic figures were frequent. Lymphatic and venous invasion were noted with neoplastic cells metastasized to the submandibular lymph nodes, lungs, liver, and adventitial surface of the aorta. Fontana-Masson stain was negative for melanin, thereby necessitating immunohistochemistry and transmission electron microscopy. Positive staining with MART-1 (a melanocyte protein marker) combined with transmission electron microscopy revealing type II melanosomes confirmed the diagnosis of an amelanotic melanoma.