bluuebunny/crossref_metadata_2025 huggingface dataset:
Androgen Receptor Requires JunD as a Coactivator to Switch on an Oxidative Stress Generation Pathway in Prostate Cancer Cells
Authors: Mehraein-Ghomi Farideh , Basu Hirak S. , Church Dawn R. , Hoffmann F. Michael , Wilding George
Published: May 2010

Relatively high oxidative stress levels in the prostate are postulated to be a major factor for prostate carcinogenesis and prostate cancer (CaP) progression. We focused on elucidating metabolic pathways of oxidative stress generation in CaP cells. Previously, we showed that the transcription factor JunD is essential for androgen-induced reactive oxygen species (ROS) production in androgen-dependent human CaP cells. We also recently showed that androgen induces the first and regulatory enzyme spermidine/spermine N1-acetyltransferase (SSAT) in a polyamine catabolic pathway that produces copious amounts of metabolic ROS. Here, we present coimmunoprecipitation and Gaussia luciferase reconstitution assay data that show that JunD forms a complex with androgen-activated androgen receptor (AR) in situ. Our chromatin immunoprecipitation assay data show that JunD binds directly to a specific SSAT promoter sequence only in androgen-treated LNCaP cells. Using a vector containing a luciferase reporter gene connected to the SSAT promoter and a JunD-silenced LNCaP cell line, we show that JunD is essential for androgen-induced SSAT gene expression. The elucidation of JunD-AR complex inducing SSAT expression leading to polyamine oxidation establishes the mechanistic basis of androgen-induced ROS production in CaP cells and opens up a new prostate-specific target for CaP chemopreventive/chemotherapeutic drug development. Cancer Res; 70(11); 4560–8. ©2010 AACR.
Phosphorescent Light–Emitting Iridium Complexes Serve as a Hypoxia-Sensing Probe for Tumor Imaging in Living Animals
Authors: Zhang Shaojuan , Hosaka Masahiro , Yoshihara Toshitada , Negishi Kazuya , Iida Yasuhiko , Tobita Seiji , Takeuchi Toshiyuki
Published: May 2010

Iridium complex is a promising organic light–emitting diode material for next generation video displays that emits phosphorescence quenched by oxygen. We used this oxygen-quenching feature for imaging tumor hypoxia. Red light–emitting Ir(btp)2(acac) (BTP) presented hypoxia-dependent light emission in culture cell lines, whose intensity was in parallel with hypoxia-inducible factor-1α images. BTP was further applied to imaging five nude mouse transplanted with tumors. All tumors presented a bright BTP-emitting image even 5 minutes after injection. The minimal image recognition size was ∼2 mm in diameter. By morphologic examination and phosphorescence lifetime measurement, BTP appeared to localize to the tumor cells. Because BTP is easily modifiable, we synthesized BTP analogues with a longer excitation/emission wavelength. One of them, BTPHSA, depicted clear imaging from tumors transplanted 6 to 7 mm deep from the skin surface. We suggest that iridium complex materials have a vast potential for imaging hypoxic lesions such as tumor tissues. Cancer Res; 70(11); 4490–8. ©2010 AACR.
Carcinomas Contain a Matrix Metalloproteinase–Resistant Isoform of Type I Collagen Exerting Selective Support to Invasion
Authors: Makareeva Elena , Han Sejin , Vera Juan Carlos , Sackett Dan L. , Holmbeck Kenn , Phillips Charlotte L. , Visse Robert , Nagase Hideaki , Leikin Sergey
Published: May 2010

Collagen fibers affect metastasis in two opposing ways, by supporting invasive cells but also by generating a barrier to invasion. We hypothesized that these functions might be performed by different isoforms of type I collagen. Carcinomas are reported to contain α1(I)3 homotrimers, a type I collagen isoform normally not present in healthy tissues, but the role of the homotrimers in cancer pathophysiology is unclear. In this study, we found that these homotrimers were resistant to all collagenolytic matrix metalloproteinases (MMP). MMPs are massively produced and used by cancer cells and cancer-associated fibroblasts for degrading stromal collagen at the leading edge of tumor invasion. The MMP-resistant homotrimers were produced by all invasive cancer cell lines tested, both in culture and in tumor xenografts, but they were not produced by cancer-associated fibroblasts, thereby comprising a specialized fraction of tumor collagen. We observed the homotrimer fibers to be resistant to pericellular degradation, even upon stimulation of the cells with proinflammatory cytokines. Furthermore, we confirmed an enhanced proliferation and migration of invasive cancer cells on the surface of homotrimeric versus normal (heterotrimeric) type I collagen fibers. In summary, our findings suggest that invasive cancer cells may use homotrimers for building MMP-resistant invasion paths, supporting local proliferation and directed migration of the cells whereas surrounding normal stromal collagens are cleaved. Because the homotrimers are universally secreted by cancer cells and deposited as insoluble, MMP-resistant fibers, they offer an appealing target for cancer diagnostics and therapy. Cancer Res; 70(11); 4366–74. ©2010 AACR.
The Skin Cancer Chemotherapeutic Agent Ingenol-3-Angelate (PEP005) Is a Substrate for the Epidermal Multidrug Transporter (ABCB1) and Targets Tumor Vasculature
Authors: Li Luowei , Shukla Suneet , Lee Andrew , Garfield Susan H. , Maloney David J. , Ambudkar Suresh V. , Yuspa Stuart H.
Published: May 2010

Ingenol-3-angelate (Ing3A), extracted from Euphorbia peplus, is currently in clinical trials for eradicating basal cell carcinoma, actinic keratosis, and squamous cell carcinoma (SCC) in situ by topical application. Although structurally related to phorbol esters and a protein kinase C activator, topical Ing3A, but not phorbol 12-myristate 13-acetate (PMA), inhibited the growth of subcutaneous tumors derived from PAM212 (mouse SCC) and B16 (mouse melanoma). Ing3A and PMA both induced acute neutrophilic inflammation on mouse skin, but only Ing3A caused subcutaneous hemorrhage and vascular damage. Both Ing3A and PMA activated extracellular signal-regulated kinase 1/2 (ERK1/2) in epidermis, but Ing3A also activated ERK1/2 in skin dermal fibroblasts and endothelial cells. Pretreatment with topical cyclosporin A (CsA), verapamil, or XR9576, modulators of P-glycoprotein (P-gp), prevented Ing3A-induced hemorrhage but not neutrophil infiltration. CsA also impaired the anticancer activity of Ing3A, whereas the anti-inflammatory dexamethasone did not. Ing3A, but not PMA, blocked photoaffinity labeling of human P-gp with [125I]iodoaryazidoprazosin and inhibited P-gp–mediated drug resistance to HCT-15 cells. The intracellular levels of Ing3A were significantly lower in P-gp–expressing cells, and treatment with XR9576 increased the levels to those of cells that do not express P-gp, showing that Ing3A binds to and is transported by P-gp. Taken together, our results suggest that P-gp–mediated absorptive transport, dermal penetration, and vascular damage contribute to the anticancer activity of Ing3A in vivo. Cancer Res; 70(11); 4509–19. ©2010 AACR.
Injectable Sustained Release Microparticles of Curcumin: A New Concept for Cancer Chemoprevention
Authors: Shahani Komal , Swaminathan Suresh Kumar , Freeman Diana , Blum Angela , Ma Linan , Panyam Jayanth
Published: May 2010

Poor oral bioavailability limits the use of curcumin and other dietary polyphenols in the prevention and treatment of cancer. Minimally invasive strategies that can provide effective and sustained tissue concentrations of these agents will be highly valuable tools in the fight against cancer. The objective of this study was to investigate the use of an injectable sustained release microparticle formulation of curcumin as a novel approach to breast cancer chemoprevention. A biodegradable and biocompatible polymer, poly(d,l-lactide-co-glycolide), was used to fabricate curcumin microparticles. When injected s.c. in mice, a single dose of microparticles sustained curcumin levels in the blood and other tissues for nearly a month. Curcumin levels in the lungs and brain, frequent sites of breast cancer metastases, were 10- to 30-fold higher than that in the blood. Further, curcumin microparticles showed marked anticancer efficacy in nude mice bearing MDA-MB-231 xenografts compared with other controls. Repeated systemic injections of curcumin were not effective in inhibiting tumor growth. Treatment with curcumin microparticles resulted in diminished vascular endothelial growth factor expression and poorly developed tumor microvessels, indicating a significant effect on tumor angiogenesis. These results suggest that sustained delivery of chemopreventives such as curcumin using polymeric microparticles is a promising new approach to cancer chemoprevention and therapy. Cancer Res; 70(11); 4443–52. ©2010 AACR.
Molecular Imaging of CXCR4 Receptor Expression in Human Cancer Xenografts with [64Cu]AMD3100 Positron Emission Tomography
Authors: Nimmagadda Sridhar , Pullambhatla Mrudula , Stone Kristie , Green Gilbert , Bhujwalla Zaver M. , Pomper Martin G.
Published: May 2010

The chemokine receptor CXCR4 and its cognate ligand CXCL12 are pivotal for establishing metastases from many tumor types. Thus, CXCR4 may offer a cell surface target for molecular imaging of metastases, assisting diagnosis, staging, and therapeutic monitoring. Furthermore, noninvasive detection of CXCR4 status of a primary tumor may provide an index of the metastatic potential of the lesion. Here, we report the development and evaluation of [64Cu]AMD3100, a positron-emitting analogue of the stem cell mobilizing agent plerixafor to image CXCR4 in human tumor xenografts preselected for graded expression of this receptor. This imaging method was evaluated in lung metastases derived from human MDA-MB-231 breast cancer cells. Ex vivo biodistribution studies, performed to validate the in vivo imaging data, confirmed the ability of [64Cu]AMD3100 to image CXCR4 expression. Our findings show the feasibility of imaging CXCR4 by positron emission tomography using a clinically approved agent as a molecular scaffold. Cancer Res; 70(10); 3935–44. ©2010 AACR.
Interaction of Integrin-Linked Kinase and Miniature Chromosome Maintenance 7–Mediating Integrin α7 Induced Cell Growth Suppression
Authors: Han Yu-Chen , Yu Yan P. , Nelson Joel , Wu Chuanyue , Wang Hui , Michalopoulos George K. , Luo Jian-Hua
Published: May 2010

Mutation of integrin α7 (ITGA7) was previously identified in multiple human malignancies. Restoration of ITGA7 expression in prostate cancer and leiomyosarcoma cell lines suppressed tumor growth and cell motility both in vitro and in vivo. In this study, we showed that integrin-linked kinase (ILK) binds with miniature chromosome maintenance 7 (MCM7), a DNA replication licensing protein. A 58–amino acid ILK binding motif was identified in the NH2-terminus of MCM7. The expression of ITGA7 induced the phosphorylation of MCM7. Knocking down of ILK abrogated ITGA7-induced MCM7 phosphorylation. ANK, the dominant-negative mutant of ILK, also blocked the phosphorylation of MCM7 induced by ITGA7. The phosphorylation of MCM7 reduced MCM7 chromatin association and inhibited cell growth. A MCM7 mutant that does not bind with ILK did not respond to ITGA7 stimulation, and behaved similarly to a dominant MCM7-negative mutant and neutralized the effect of ITGA7. We conclude that ILK interaction with MCM7 and MCM7 phosphorylation may be a critical event in ITGA7 signaling pathway, leading to tumor suppression. Cancer Res; 70(11); 4375–84. ©2010 AACR.
Genome-Wide siRNA Screen for Modulators of Cell Death Induced by Proteasome Inhibitor Bortezomib
Authors: Chen Siquan , Blank Jonathan L. , Peters Theodore , Liu Xiaozhen J. , Rappoli David M. , Pickard Michael D. , Menon Saurabh , Yu Jie , Driscoll Denise L. , Lingaraj Trupti , Burkhardt Anne L. , Chen Wei , Garcia Khristofer , Sappal Darshan S. , Gray Jesse , Hales Paul , Leroy Patrick J. , Ringeling John , Rabino Claudia , Spelman James J. , Morgenstern Jay P. , Lightcap Eric S.
Published: May 2010

Multiple pathways have been proposed to explain how proteasome inhibition induces cell death, but mechanisms remain unclear. To approach this issue, we performed a genome-wide siRNA screen to evaluate the genetic determinants that confer sensitivity to bortezomib (Velcade (R); PS-341). This screen identified 100 genes whose knockdown affected lethality to bortezomib and to a structurally diverse set of other proteasome inhibitors. A comparison of three cell lines revealed that 39 of 100 genes were commonly linked to cell death. We causally linked bortezomib-induced cell death to the accumulation of ASF1B, Myc, ODC1, Noxa, BNIP3, Gadd45α, p-SMC1A, SREBF1, and p53. Our results suggest that proteasome inhibition promotes cell death primarily by dysregulating Myc and polyamines, interfering with protein translation, and disrupting essential DNA damage repair pathways, leading to programmed cell death. Cancer Res; 70(11); 4318–26. ©2010 AACR.
Pathway Analysis of Breast Cancer Genome-Wide Association Study Highlights Three Pathways and One Canonical Signaling Cascade
Authors: Menashe Idan , Maeder Dennis , Garcia-Closas Montserrat , Figueroa Jonine D. , Bhattacharjee Samsiddhi , Rotunno Melissa , Kraft Peter , Hunter David J. , Chanock Stephen J. , Rosenberg Philip S. , Chatterjee Nilanjan
Published: May 2010

Genome-wide association studies (GWAS) focus on relatively few highly significant loci, whereas less attention is given to other genotyped markers. Using pathway analysis to study existing GWAS data may shed light on relevant biological processes and illuminate new candidate genes. We applied a pathway-based approach to the breast cancer GWAS data of the National Cancer Institute (NCI) Cancer Genetic Markers of Susceptibility project that includes 1,145 cases and 1,142 controls. Pathways were retrieved from three databases: KEGG, BioCarta, and NCI Protein Interaction Database. Genes were represented by their most strongly associated SNP, and an enrichment score reflecting the overrepresentation of gene-based association signals in each pathway was calculated by using a weighted Kolmogorov-Smirnov procedure. Finally, hierarchical clustering was used to identify pathways with overlapping genes, and clusters with an excess of association signals were determined by the adaptive rank-truncated product (ARTP) method. A total of 421 pathways containing 3,962 genes was included in our study. Of these, three pathways (syndecan-1–mediated signaling, signaling of hepatocyte growth factor receptor, and growth hormone signaling) were highly enriched with association signals [PES < 0.001, false discovery rate (FDR) = 0.118]. Our clustering analysis revealed that pathways containing key components of the RAS/RAF/mitogen-activated protein kinase canonical signaling cascade were significantly more likely to have an excess of association signals than expected by chance (PARTP = 0.0051, FDR = 0.07). These results suggest that genetic alterations associated with these three pathways and one canonical signaling cascade may contribute to breast cancer susceptibility. Cancer Res; 70(11); 4453–9. ©2010 AACR.
C-Propeptides of Procollagens Iα1 and II that Differentially Accumulate in Enchondromas versus Chondrosarcomas Regulate Tumor Cell Survival and Migration
Authors: Vincourt Jean-Baptiste , Etienne Stéphanie , Cottet Justine , Delaunay Camille , Malanda Bantsimba , Lionneton Frédéric , Sirveaux François , Netter Patrick , Plénat François , Mainard Didier , Vignaud Jean-Michel , Magdalou Jacques
Published: May 2010

Chondrogenic tumors that exhibit benign or malignant behaviors synthesize variable amounts of cartilage-like extracellular matrix. To define the regulators of these phenotypes, we performed a proteomic comparison of multiple human chondrogenic tumors, which revealed differential accumulation of the C-propeptides of procollagens Iα1 and II (PC1CP and PC2CP) in malignant versus benign tumors, respectively. Expression patterns of PC1CP correlated with levels of tumor vascularization, whereas expression patterns of PC2CP suggested its susceptibility to immobilization within the extracellular matrix. Prompted by these observations, we investigated the functions of recombinant PC1CP and PC2CP in the extracellular matrix in soluble or immobilized states. Each induced β1 integrin–mediated chondrocyte adhesion by distinct domains and efficacies, suggesting that they initiated distinct signaling pathways. Indeed, immobilized PC2CP, but not PC1CP, induced apoptosis of primary chondrocytes and EAhy926 endothelial cells. In contrast, soluble PC1CP, but not PC2CP, induced the migration of EAhy926 cells and increased vascular endothelial growth factor (VEGF) and CXCR4 expression in chondrocytes. Soluble PC2CP also increased VEGF expression, but along with a more pronounced effect on CXCR4 and matrix metalloproteinase 13 expression. Our findings suggest that PC1CP favors angiogenesis and tumor progression, but that PC2CP acts in a more complex manner, exerting antitumor and antiangiogenic properties through apoptosis induction when immobilized, but progression and metastasis when soluble. In summary, the relative levels of PC1CP and PC2CP and their interactions within the extracellular matrix contribute to tumor progression, angiogenesis, and metastasis in chondrogenic tumors. Cancer Res; 70(11); 4739–48. ©2010 AACR.
Epigenetic Mechanisms of Promigratory Chemokine CXCL14 Regulation in Human Prostate Cancer Cells
Authors: Song Eun Young , Shurin Michael R. , Tourkova Irina L. , Gutkin Dmitriy W. , Shurin Galina V.
Published: May 2010

Chemokines play the key role in initiating immune responses by regulating the attraction and homing of immune cells to the lymphoid and nonlymphoid tissues. CXCL14 is a chemokine that in tumors may act as chemoattractant for monocytes and dendritic cells (DC), which may modulate antitumor immune responses in certain cancers. In this study, we investigated the mechanisms of loss of CXCL14 in prostate cancer cells. Cell treatment with the demethylating agent 5-aza-2-deoxycytidine resulted in the recovery of CXCL14 mRNA and protein expression. Hypermethylated CpG island sequences encompassing the CXCL14 gene promoter were identified. The restoration of CXCL14 by 5-aza-2-deoxycytidine treatment had functional impact, based on the DC chemoattractant activity of conditioned medium from drug-treated cells. Conversely, CXCL14 removal from conditioned media by affinity chromatography abolished its chemotactic properties, confirming that functionally active CXCL14 was generated in prostate cancer cells by relieving its transcriptional silencing with 5-aza-2-deoxycytidine. Our findings offer the first direct evidence for epigenetic regulation of chemokine expression in tumor cells. Cancer Res; 70(11); 4394–401. ©2010 AACR.
New Strategies for Treatment of KRAS Mutant Metastatic Colorectal Cancer
Authors: Prenen Hans , Tejpar Sabine , Cutsem Eric Van
Published: May 2010

The introduction of new cytotoxic agents and new targeted therapies has significantly broadened the therapeutic options for and the outcomes of patients with metastatic colorectal cancer (CRC). The introduction of the anti-epidermal growth factor receptor (EGFR) antibodies, cetuximab and panitumumab, has clearly contributed to this development. The concept of KRAS as a marker for resistance to anti-EGFR antibodies has been validated. However, new challenges have emerged: the complete understanding of the crucial and central role of KRAS in processes of tumor growth and the development of new treatment strategies for KRAS mutant tumors. KRAS seems to be so crucial that a further classification and description in KRAS wild-type and mutant may be warranted. Testing for KRAS mutations marks, therefore, a paradigm shift in the management of metastatic CRC. This testing also highlights the unmet need for new treatment options in KRAS mutant metastatic CRC. In this review we will focus on possible new treatment options for these patients. Clin Cancer Res; 16(11); 2921–6. ©2010 AACR.
Gene Expression Profiling–Based Identification of Molecular Subtypes in Stage IV Melanomas with Different Clinical Outcome
Authors: Jönsson Göran , Busch Christian , Knappskog Stian , Geisler Jürgen , Miletic Hrvoje , Ringnér Markus , Lillehaug Johan R. , Borg Åke , Lønning Per Eystein
Published: May 2010

Purpose: The incidence of malignant melanoma is increasing worldwide in fair-skinned populations. Melanomas respond poorly to systemic therapy, and metastatic melanomas inevitably become fatal. Although spontaneous regression, likely due to immune defense activation, rarely occurs, we lack a biological rationale and predictive markers in selecting patients for immune therapy.

Experimental Design: We performed unsupervised hierarchical clustering of global gene expression data from stage IV melanomas in 57 patients. For further characterization, we used immunohistochemistry of selected markers, genome-wide DNA copy number analysis, genetic and epigenetic analysis of the CDKN2A locus, and NRAS/BRAF mutation screening.

Results: The analysis revealed four distinct subtypes with gene signatures characterized by expression of immune response, pigmentation differentiation, proliferation, or stromal composition genes. Although all subtypes harbored NRAS and BRAF mutations, there was a significant difference between subtypes (P < 0.01), with no BRAF/NRAS wild-type samples in the proliferative subtype. Additionally, the proliferative subtype was characterized by a high frequency of CDKN2A homozygous deletions (P < 0.01). We observed a different prognosis between the subtypes (P = 0.01), with a particularly poor survival for patients harboring tumors of the proliferative subtype compared with the others (P = 0.003). Importantly, the clinical relevance of the subtypes was validated in an independent cohort of 44 stage III and IV melanomas. Moreover, low expression of an a priori defined gene set associated with immune response signaling was significantly associated with poor outcome (P = 0.001).

Conclusions: Our data reveal a biologically based taxonomy of malignant melanomas with prognostic effect and support an influence of the antitumoral immune response on outcome. Clin Cancer Res; 16(13); 3356–67. ©2010 AACR.
Phase II Study on the Addition of ASA404 (Vadimezan; 5,6-Dimethylxanthenone-4-Acetic Acid) to Docetaxel in CRMPC
Authors: Pili Roberto , Rosenthal Mark A. , Mainwaring Paul N. , Van Hazel Guy , Srinivas Sandy , Dreicer Robert , Goel Sanjay , Leach Joseph , Wong Shirley , Clingan Peter
Published: May 2010

Purpose: This randomized phase II study evaluated ASA404 (vadimezan; 5,6-dimethylxanthenone-4-acetic acid) in combination with docetaxel in castration-refractory metastatic prostate cancer (CRMPC).

Experimental Design: Seventy-four patients with histopathologically confirmed CRMPC previously untreated with chemotherapy were randomized to receive either ≤10 cycles of docetaxel 75 mg/m2 alone (D; n = 39) or docetaxel plus ASA404 1,200 mg/m2 (A-D; n = 35). Study endpoints included prostate-specific antigen response, tumor response, median time to tumor progression, median survival, and toxicity.

Results: The overall pattern of adverse events was similar in the two groups; however, there was a higher incidence of cardiac adverse events and neutropenia in the A-D group. Coadministration of ASA404 with docetaxel did not affect total systemic exposure of either drug. A higher prostate-specific antigen response rate was reported with A-D versus D (59.4% versus 36.8%), together with a larger median percentage reduction in prostate-specific antigen (84.0% versus 61.9%) and a shorter median time to prostate-specific antigen nadir (105 versus 119 d). Tumor response rate was 23.1% with A-D and 9.1% with D. Time to tumor progression and median survival were similar in the groups (time to tumor progression, 8.7 mo for A-D and 8.4 mo for D; survival, 17.0 mo for A-D and 17.2 mo for D). Hazard ratios for time to tumor progression and survival were 0.81 and 0.80, respectively, favoring A-D; 2-year survival was 33.3% with A-D and 22.8% with D.

Conclusion: The study met some endpoints (prostate-specific antigen response, tumor response) but not others (i.e., time to tumor progression). The results indicate that the combination of ASA404 with docetaxel has acceptable toxicity, lacks adverse pharmacokinetic interaction, and, overall, has activity in CRMPC. Clin Cancer Res; 16(10); 2906–14. ©2010 AACR.
Two Distinct Mechanisms of Augmented Antitumor Activity by Modulation of Immunostimulatory/Inhibitory Signals
Authors: Mitsui Jun , Nishikawa Hiroyoshi , Muraoka Daisuke , Wang Linan , Noguchi Takuro , Sato Eiichi , Kondo Satoshi , Allison James P. , Sakaguchi Shimon , Old Lloyd J. , Kato Takuma , Shiku Hiroshi
Published: May 2010

Purpose: Blockade of CTL-associated antigen-4 (CTLA-4), an inhibitory immunomodulatory molecule on T cells, has been shown to enhance T-cell responses and induce tumor rejection, and a number of clinical trials with anti-CTLA-4 blocking monoclonal antibody (mAb) are under way. However, accumulating evidence indicates that anti-CTLA-4 mAb increases the number of CD4+CD25+Foxp3+ regulatory T cells (Treg) and that anti-CTLA4 mAb alone is often insufficient to reject established tumors in mice and humans. Thus, finding maneuvers to control Tregs and other immunosuppressive mechanisms remains a critical challenge.

Experimental Design: The potential to enhance antitumor immune responses by combining anti-CTLA-4 mAb with anti–glucocorticoid-induced tumor necrosis factor receptor family related gene (GITR) mAb, a costimulatory molecule that abrogates directly/indirectly Treg-mediated immune suppression or anti-CD25 mAb that depletes Tregs was analyzed with two tumor models, CT26 (a murine colon carcinoma cell line) and CMS5a (a murine fibrosarcoma cell line).

Results: Anti-CTLA-4/anti-GITR mAb combination treatment exhibited far stronger antitumor effects compared with either antibody alone. This strong antitumor effect was attributed to (a) increased numbers of CD8+ T cells infiltrating tumor sites in anti-CTLA-4 mAb–treated mice and (b) increased cytokine secretion and Treg resistance of tumor-specific CD8+ T cells with strongly upregulated CD25 expression in anti-GITR mAb–treated mice, indicating distinct quantitative/qualitative changes induced by modulating CTLA-4 and GITR signaling.

Conclusions: This study shows that combined treatment with different immune modulators can augment antitumor immune responses and provides justification for exploring anti-CTLA-4/anti-GITR mAb combination treatment in the clinic. Clin Cancer Res; 16(10); 2781–91. ©2010 AACR.
Susceptibility Loci Associated with Prostate Cancer Progression and Mortality
Authors: Gallagher David J. , Vijai Joseph , Cronin Angel M. , Bhatia Jasmine , Vickers Andrew J. , Gaudet Mia M. , Fine Samson , Reuter Victor , Scher Howard I. , Halldén Christer , Dutra-Clarke Ana , Klein Robert J. , Scardino Peter T. , Eastham James A. , Lilja Hans , Kirchhoff Tomas , Offit Kenneth
Published: May 2010

Purpose: Prostate cancer is a heterogenous disease with a variable natural history that is not accurately predicted by currently used prognostic tools.

Experimental Design: We genotyped 798 prostate cancer cases of Ashkenazi Jewish ancestry treated for localized prostate cancer between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to clinical data. The survival analysis was adjusted for Gleason score and prostate-specific antigen. We investigated associations between 29 single nucleotide polymorphisms (SNP) and biochemical recurrence, castration-resistant metastasis, and prostate cancer–specific survival. Subsequently, we did an independent analysis using a high-resolution panel of 13 SNPs.

Results: On univariate analysis, two SNPs were associated (P < 0.05) with biochemical recurrence, three SNPs were associated with clinical metastases, and one SNP was associated with prostate cancer–specific mortality. Applying a Bonferroni correction (P < 0.0017), one association with biochemical recurrence (P = 0.0007) was significant. Three SNPs showed associations on multivariable analysis, although not after correcting for multiple testing. The secondary analysis identified an additional association with prostate cancer–specific mortality in KLK3 (P < 0.0005 by both univariate and multivariable analysis).

Conclusions: We identified associations between prostate cancer susceptibility SNPs and clinical end points. The rs61752561 in KLK3 and rs2735839 in the KLK2-KLK3 intergenic region were strongly associated with prostate cancer–specific survival, and rs10486567 in the 7JAZF1 gene were associated with biochemical recurrence. A larger study will be required to independently validate these findings and determine the role of these SNPs in prognostic models. Clin Cancer Res; 16(10); 2819–32. ©2010 AACR.
Epigenetic Markers in Rectal Cancer
Authors: Xu Lei , Czito Brian G. , Willett Christopher G.
Published: May 2010

DNA methylation changes in rectal cancer may serve as a new screening marker and a tool for monitoring recurrence. Importantly, these changes may also function as a predictive marker to allow appropriate exclusion of (neo)adjuvant therapies in patients at low risk for disease recurrence, sparing them from potential treatment-related morbidities. Clin Cancer Res; 16(10); 2699–701. ©2010 AACR.
Preoperative CTLA-4 Blockade: Tolerability and Immune Monitoring in the Setting of a Presurgical Clinical Trial
Authors: Carthon Bradley C. , Wolchok Jedd D. , Yuan Jianda , Kamat Ashish , Ng Tang Derek S. , Sun Jingjing , Ku Geoffrey , Troncoso Patricia , Logothetis Christopher J. , Allison James P. , Sharma Padmanee
Published: May 2010

Purpose: Cytotoxic T lymphocyte associated antigen (CTLA-4) blockade is being explored in numerous clinical trials as an immune-based therapy for different malignancies. Our group conducted the first preoperative clinical trial with the anti–CTLA-4 antibody ipilimumab in 12 patients with localized urothelial carcinoma of the bladder.

Experimental Design: Six patients were treated with 3 mg/kg/dose of anti–CTLA-4 and six patients were treated with 10 mg/kg/dose of antibody. Primary end points of the study were safety and immune monitoring.

Results: Most drug-related adverse events consisted of grade 1/2 toxicities. All patients had measurable immunologic pharmacodynamic effects, consisting of an increased frequency of CD4+ICOShi T cells in tumor tissues and the systemic circulation. To determine if CD4+ICOShi T cells could be a correlative marker for clinical outcome after treatment with anti–CTLA-4, a cohort of metastatic melanoma patients was studied retrospectively for frequency of CD4+ICOShi T cells and survival. Data from this small cohort of patients indicated that an increased frequency of CD4+ICOShi T cells, sustained over a period of 12 weeks of therapy, correlates with increased likelihood of clinical benefit consisting of overall survival.

Conclusions: Our trial shows that anti–CTLA-4 therapy has a tolerable safety profile in the presurgical setting and that a preoperative model can be used to obtain biological data on human immune responses, which can efficiently guide the monitoring of patients treated in the metastatic disease setting. Clin Cancer Res; 16(10); 2861–71. ©2010 AACR.
Microenvironmental Regulation of Chemokine (C-X-C-Motif) Receptor 4 in Ovarian Carcinoma
Authors: Barbolina Maria V. , Kim Mijung , Liu Yueying , Shepard Jaclyn , Belmadani Abdelhak , Miller Richard J. , Shea Lonnie D. , Stack M. Sharon
Published: May 2010

The majority of women diagnosed with epithelial ovarian carcinoma (EOC) succumb due to complications of metastatic disease, suggesting that antimetastatic therapies may improve patient survival. EOC metastasis involves intraperitoneal shedding of cells from the primary tumor, followed by adhesion and localized penetration of the submesothelial matrix to anchor metastatic implants. Accumulation of malignant ascites is also common. Thus, a unique microenvironmental niche is established, which includes malignant cells and a plethora of soluble factors secreted by—or in response to—tumor cells. As cells penetrating the submesothelial surface encounter an interstitial collagen-rich extracellular matrix, we have used three-dimensional type I collagen gels to model early events resulting from intraperitoneal anchoring. In this study, we show a novel pathway of CXCR4 upregulation through β1 integrin – and NFκB-dependent signaling pathways in response to three-dimensional type I collagen. We also show the involvement of CXCR4-SDF1 axis in collagen invasion and proliferation, relevant to the metastatic EOC. Our data show that CXCR4 expression in human EOCs, as well as SDF1 presence in the ascites, is correlated with disease progression and metastasis. These data emphasize the importance of the CXCR4-SDF1 axis in EOC metastasis and suggest that this mechanism should be accounted for when targeting EOC metastasis. Mol Cancer Res; 8(5); 653–64. ©2010 AACR.
Mechanisms of Motility in Metastasizing Cells
Authors: Yilmaz Mahmut , Christofori Gerhard
Published: May 2010

Cell migration and invasion are critical parameters in the metastatic dissemination of cancer cells and the formation of metastasis, the major cause of death in cancer patients. Migratory cancer cells undergo dramatic molecular and cellular changes by remodeling their cell-cell and cell-matrix adhesion and their actin cytoskeleton, molecular processes that involve the activity of various signaling networks. Although in the past years, we have substantially expanded our knowledge on the cellular and molecular processes underlying cell migration and invasion in experimental systems, we still lack a clear understanding of how cancer cells disseminate in metastatic cancer patients. Different types of cancer cell migration seem to exist, including single-cell mesenchymal or amoeboid migration and collective cell migration. In most epithelial cancers, loss of the cell-cell adhesion molecule E-cadherin and gain of mesenchymal markers and promigratory signals underlie the conversion of epithelial, differentiated cells to mesenchymal, migratory, and invasive cells, a process referred to as the epithelial-to-mesenchymal transition. Although solitary migrating epithelial cancer cells have mostly undergone epithelial-to-mesenchymal transition (mesenchymal migration), and sometimes even lose their cell-matrix adhesion (amoeboid migration), collective migration of cancer cells in cell sheets, clusters, or streams is also frequently observed. The molecular mechanisms defining the different modes of cancer cell migration remain in most parts to be delineated. Mol Cancer Res; 8(5); 629–42. ©2010 AACR.
Plasticity in the Human Motor System
Authors: Rothwell John C.
Published: May 2010

It is well recognized that the number and effectiveness of synapses in the adult brain change in response to learning and that similar processes contribute to the restoration of function after central nervous system damage. It is possible to use non-invasive methods of brain stimulation in humans (transcranial magnetic stimulation or transcranial direct current stimulation) to study and even manipulate these processes. Initial studies are now underway to test whether modification of synaptic plasticity by neurostimulation can improve the recovery of motor function in patients after stroke.
Chronic Kidney Disease in Older People: Physiology, Pathology or Both?
Authors: Abdelhafiz Ahmed H. , Brown Siobhan H.M. , Bello Aminu , El Nahas Meguid
Published: May 2010

The global population is aging due to a reduction in youthful deaths and an extension of the later stages of life. With aging comes a decline in the physiologic functions of various organs and systems. Vascular aging is associated with structural and functional changes of the arterial wall leading to loss of elasticity and compliance. Renal vasculature is not spared as aging is associated with arterial, arteriolar and capillary, glomerular changes (glomerulosclerosis). It is likely that age-related vascular changes are linked to the decline in renal function observed with aging. These changes occur at varying stages of aging depending on predisposing genetic factors and associated life course exposure to cardiovascular risk factors including hypertension and diabetes. The decline in renal function with ‘normal’ aging in the absence of associated progressive cardiovascular disease is slow and does not seem to be of major clinical significance. The current definition of chronic kidney disease (CKD), including microalbuminuria, and the method of estimation of glomerular filtration rate have inadvertently resulted in an exaggerated prevalence of CKD in the elderly. This is combined with the fact that most of the studies showing decline in renal function with aging are limited by the absence of a correction for associated comorbid confounding factors, resulting in difficulty separating the effect of physiological aging on kidney function from pathological aging due to comorbidities. Such a correction is difficult, if not impossible, to objectively construct. We suggest that only those fractions of older patients with underlying progressive vascular pathology likely to involve the kidneys will, in the future, warrant attention to reduce vascular risk and the associated kidney damage.
CD70-Driven Chronic Immune Activation Is Protective against Atherosclerosis
Authors: van Olffen Ronald W. , de Bruin Alex M. , Vos Mariska , Staniszewska Anna D. , Hamann Jörg , van Lier René A.W. , de Vries Carlie J.M. , Nolte Martijn A.
Published: May 2010

Chronic infection and inflammation are strongly associated with the development of atherosclerosis. To investigate whether chronic inflammation in the absence of an infectious cause also predisposes to the development of atherosclerosis, we used a mouse model in which sterile inflammation is driven by enhanced costimulation. Constitutive triggering of CD27 on T cells through overexpression of CD70 on B cells increases the numbers of IFNγ-producing effector T cells, which reduces the numbers of B cells. However, despite these pro-atherogenic features, we found that CD70-transgenic (CD70TG) mice on an ApoE*3-Leiden background were strongly protected against the induction of atherosclerotic lesions, with a normal increase in serum cholesterol level and the absence of atheroprotective antibodies. We found that circulating monocytes in CD70TG mice were activated and increased in numbers, in particular the pool of inflammatory (Ly6C+) monocytes. Importantly, monocytes from CD70TG mice had no defects in phagocytosis nor in TNFα production, but they were more prone to apoptosis, which was IFNγ-dependent. These data indicate that sterile pro-inflammatory conditions can be protective against atherosclerosis development, possibly due to a reduced viability of circulating monocytes. This unexpected outcome provides a new insight into the consequences of costimulatory signals and their impact on innate immunity.
Roles of Heparin-Binding Protein in Bacterial Infections
Authors: Linder Adam , Soehnlein Oliver , Åkesson Per
Published: May 2010

Infectious diseases remain a major health problem, where sepsis and other severe infectious diseases are common causes of morbidity and mortality. The importance of early and appropriate treatment of sepsis and severe bacterial infections has been underlined by the successes of measures like the Surviving Sepsis Campaign, among others. Thus, there is a need for clinical and laboratory tools to identify a patient with severe infection early and to distinguish between bacterial and non-bacterial conditions. Heparin-binding protein (HBP) is also called azurocidin, or cationic antimicrobial protein of 37 kDa (CAP37). It is a multifunctional granule-associated protein that is rapidly mobilized from migrating polymorphonuclear leukocytes. HBP acts as a chemoattractant, an activator of monocytes and macrophages, and induces vascular leakage and edema formation. The release of HBP is triggered by ligation of neutrophilic β2-integrins, a process that may be initiated by bacterial structures. The overall outcome is powerful vascular leakage. It has been shown that patients with severe sepsis express high levels of HBP in plasma before they develop hypotension. HBP is also involved in the pathophysiology of soft tissue infection. In conclusion, this protein is strongly involved in the pathophysiology of severe bacterial infections, and thus represents a potential diagnostic marker and a target for treatment.
Incremental Prognostic Value of Coronary CT Angiography in Patients With Suspected Coronary Artery Disease
Authors: Russo Vincenzo , Zavalloni Andrea , Bacchi Reggiani Maria Letizia , Buttazzi Katia , Gostoli Valentina , Bartolini Simone , Fattori Rossella
Published: May 2010

Background—

Multidetector CT coronary angiography (MDCTCA) is capable of detecting coronary artery disease (CAD) with a high diagnostic accuracy. In particular, this technique is credited with having a negative predictive value close to 100%. However, data about the prognostic value of MDCTCA are currently lacking. We sought to determine the prognostic value of MDCTCA in patients with suspected but undocumented CAD and, in particular, the incremental prognostic value as compared with clinical risk and calcium scoring.

Methods and Results—

A total of 441 patients (age, 59.7±11.6 years) with suspected CAD underwent MDCTCA to evaluate the presence and severity of the disease. Patients were followed up as to the occurrence of hard cardiac events (cardiac death, nonfatal myocardial infarction, and unstable angina requiring hospitalization). Coronary lesions were detected in 297 (67.3%) patients. During a mean follow-up of 31.9±14.8 months, 44 hard cardiac events occurred in 40 patients. CT calcium scoring showed a statistically significant incremental prognostic value as compared to a baseline clinical risk model (
P
=0.018), whereas MDCTCA provided an additional incremental prognostic value as compared with a baseline clinical risk model plus calcium scoring if considering both nonobstructive versus obstructive CAD (
P
=0.016) or, better, plaque composition (calcified versus noncalcified and/or mixed plaques,
P
=0.0001). During follow-up, an excellent prognosis was noted in patients with normal coronary arteries, with an annualized incidence rate of 0.88% if compared with those with mild CAD (3.89%) and with patients with significant coronary disease (8.09%). The presence of noncalcified or mixed plaques, regardless of lesion severity, was found to be the strongest predictor of events (
P
<0.0001) as a potential marker of plaque vulnerability.

Conclusions—

MDCTCA provides independent and incremental prognostic information as compared to baseline clinical risk factors and calcium scoring in patients with suspected CAD.
Unreliable Assessment of Necrotic Core by Virtual Histology Intravascular Ultrasound in Porcine Coronary Artery Disease
Authors: Thim Troels , Hagensen Mette Kallestrup , Wallace-Bradley David , Granada Juan F. , Kaluza Greg L. , Drouet Ludovic , Paaske William P. , Bøtker Hans Erik , Falk Erling
Published: May 2010

Background—

Intravascular ultrasound–derived virtual histology (VH IVUS) is used increasingly in clinical research to assess composition and vulnerability of coronary atherosclerotic lesions. However, the ability of VH IVUS to quantify individual plaque components, in particular the size of the destabilizing necrotic core, has never been validated. We tested for correlation between VH IVUS necrotic core size and necrotic core size by histology in porcine coronary arteries with human-like coronary disease.

Methods and Results—

In adult atherosclerosis-prone minipigs, 18 advanced coronary lesions were assessed by VH IVUS in vivo followed by postmortem microscopic examination (histology). We found no correlation between the size of the necrotic core determined by VH IVUS and histology. VH IVUS displayed necrotic cores in lesions lacking cores by histology.

Conclusions—

We found no correlation between necrotic core size determined by VH IVUS and real histology, questioning the ability of VH IVUS to detect rupture-prone plaques, so-called thin-cap fibroatheromas.
NGOs Moving Business: An Analysis of Contrasting Strategies
Authors: van Huijstee Mariëtte , Glasbergen Pieter
Published: May 2010

In this article, we seek to advance understanding of nongovernmental organization (NGO) strategies with regard to influencing corporations. We study two contrasting NGO strategies (symbolic gain and symbolic damage), which simultaneously target the same corporation on the same issue. In so doing, we highlight three previously neglected dimensions of NGO influence strategies: (a) the influence effected by contrasting strategies; (b) the interplay between contrasting strategies; and (c) the dynamic relation between firm— stakeholder resource dependence relationship and NGO influence strategy.
Beyond Adaptation: Resilience for Business in Light of Climate Change and Weather Extremes
Authors: Linnenluecke Martina , Griffiths Andrew
Published: May 2010

Scientific findings forecast that one of the major consequences of human-induced climate change and global warming is a greater occurrence of extreme weather events with potentially catastrophic effects for organizations, industries, and society. Current management and adaptation approaches typically focus on economic factors of competition, such as technology and innovation. Although offering useful insights, these approaches are potentially ill equipped to deal with any increases in drastic changes in the natural environment. This article argues that discussions on organizational adaptation need to be broadened and that new conceptual and practical approaches are needed to incorporate the effects of climate change and a greater occurrence of weather extremes into corporate strategy and decision making. The authors advance the notion that a resilience framework might provide insights into dealing with new types of environmental change. They contend that by developing resilience, organizations can develop resources and capabilities to avoid or minimize organizational collapse and to reorganize in light of discontinuities associated with climate change and weather extremes. Implications for organizational practice and research are discussed.
Conceptions of the Business-Society-Nature Interface: Implications for Management Scholarship
Authors: Marcus Joel , Kurucz Elizabeth C. , Colbert Barry A.
Published: May 2010

This article explores the implicit and explicit conceptions of the relationship between business, society, and nature that are evident in the management literature. The authors derive three conceptions, termed the disparate, intertwined, and embedded views, and consider how they relate to the economic, social, and environmental challenges of our time. It is argued that an embedded view is best able to help us address these challenges, as it infers a holarchical (or holistically hierarchical) perspective of the business— society—nature interface: the notion that the business, societal, and biospheric systems are not only interrelated but that they are most realistically (and therefore most usefully) viewed as nested systems. The embedded view highlights systemic limits and the dependency of society and economy on nature, and it thus provides a logical value ordering to these domains. The authors conclude by discussing the research implications of an embedded view.