bluuebunny/crossref_metadata_2025 huggingface dataset:
The influence of layering and pre-existing joints on the development of internal structure in normal fault zones: the Lodève basin, France
Authors: van der Zee Wouter , Wibberley Christopher A. J. , Urai Janos L.
Published: July 2008

This paper examines the role of mechanical stratigraphy on the evolution of normal fault geometry and fault zone internal structure, using a well-exposed normal fault system from the Permian Lodève Basin, southern France. Faults formed early during the syn-deformation tilting history of the basin tend to have steeper segments in the competent sandstone layers due to refraction, assisted by pre-existing early bedding-perpendicular joints, where displacement remained on the order of bed thickness. Faults which continued to slip during tilting have a more complex structure of splays due both to the space incompatability problem of slip at fault bends of this irregular geometry, and because tilting favours the generation of new splays at a different angle to the earlier faults experiencing rotation. Continued deformation between faults and their splays often causes both distributed deformation in between the two, and reconnection of splays to the main fault forming isolated lenses. Thus, fault zone complexity increases greatly as slip exceeds competent bed thickness, owing both to the presence of the mechanical layering, and the fact that this layering is being tilted.
Displacement-length scaling for single-event fault ruptures: insights from Newberry Springs Fault Zone and implications for fault zone structure
Authors: Ferrill David A. , Smart Kevin J. , Necsoiu Marius
Published: July 2008

The Newberry Springs Fault Zone experienced slip associated with the 1992 Landers earthquake in the Mojave Desert of California, USA. Detailed analysis of scaling relationships from single-event ground ruptures in the Newberry Springs Fault Zone mapped in the field shows an average maximum displacement to length (
D
max
/
L
) relationship for fault segments (rupture lengths in the range of 100–1000 m) of 8×10
−5
–consistent with previously published
D
max
/
L
ratios for normal fault earthquake ground ruptures (rupture lengths in the range of 1–100 km) of 7×10
−5
. To explore the ability of remote sensing (interferometric synthetic aperture radar or InSAR) to map small-displacement single-event fault ruptures and add constraints on segment displacements, we applied established interferometry methods with phase unwrapping to produce maps of line-of-sight displacement and displacement gradient. These maps highlight fault traces that experienced displacement during the time between collection of the synthetic aperture radar images. Comparison of published 1992 single-event ground rupture maps with mapping based on photogeologic interpretation of 1950s vintage aerial photographs indicates that most of the 1992 ruptures occurred as reactivation of pre-existing slip surfaces. In general,
D
max
/
L
for total fault displacement is approximately 100 times
D
max
/
L
for single-event ruptures. Evidence from the Newberry Springs Fault Zone indicates that, since the Pleistocene, at least 10–20 Landers-like slip events have occurred, reactivating the Newberry Springs Fault Zone. Evidence of wide damage zones and reactivation of individual segments developed in alluvial floodplain deposits, at relatively small (order of metres) fault displacements, supports a conceptual model of fault damage zone width being established early, during fault propagation. With continued displacement by accumulation of additional slip events, fault zone damage intensifies. The fault zone width may remain relatively stable, although the active portion of the fault zone will likely narrow as faulting continues and a throughgoing slip surface develops and accumulates the bulk of displacement.
Normal fault terminations in limestones from the SE-Basin (France): implications for fluid flow
Authors: Micarelli L. , Benedicto A.
Published: July 2008

The geometry and evolution of normal fault terminations were studied in Tithonian limestones exposed on a vertical cliff in the French SE-Basin. The rocks consist of mainly limestone layers alternated with thin clayey interlayers. All studied fault zones die out vertically into bed-perpendicular veins striking approximately parallel to the fault. Displacement decreasing to zero towards the fault tip is accommodated horizontally by bed-parallel opening of calcite veins, and vertically by bed-perpendicular localized compaction. The latter mechanism leads the clayey interlayers to be thinned and in places completely pushed out, and enhances pressure solution in bed-parallel seams. The respective thicknesses of the limestone layers and clayey interlayers, and the ratio between local displacement amount and bed thickness influence the geometries of the fault termination and of the steps between slip surfaces. Relatively thick clayey interlayers localize low-angle slip surfaces and may impede the vertical propagation of the slip surface. Vertical fault restriction is also related to thick limestone layers, which are deflected and affected by outer arc extensional fractures, localized pressure solution and dilational jogs connecting adjacent propagating slip surfaces. However, beds keep their continuity if thicker than the local displacement amount. Where the local displacement is larger than the layer thickness, limestone beds are disconnected and clayey interlayers are completely cut but the slip surfaces. Tip-point veins, as well as outer arc veins, do not cross the clayey interlayers and fluid flow is local and confined within one limestone layer. In contrast, dilational jogs in places cut through several layers, and the breaking of clayey interlayers causes an increase in fluid flow. Conduits can be opened along the fault zone and fluids are driven into the jog, so slip surfaces may communicate separate reservoirs, until dilational jogs are sealed by mineral precipitation.
On the structure and mechanical properties of large strike-slip faults
Authors: Faulkner D. R. , Mitchell T. M. , Rutter E. H. , Cembrano J.
Published: July 2008

Elucidation of the internal structure of fault zones is paramount for understanding their mechanical, seismological and hydraulic properties. In order to observe representative brittle fault zone structures, it is preferable that the fault be passively exhumed from seismogenic depths and the exposure must be in arid or semi-arid environments where the fragile rocks are not subject to extensive weathering. Field observations of two such faults are used to constrain their likely mechanical properties. One fault is the Carboneras fault in southeastern Spain, where the predominant country rocks are phyllosilicate-rich lithologies, and the other is part of the Atacama fault system in northern Chile, where faults pass through crystalline rocks of acidic to intermediate composition. The Carboneras fault is a left lateral fault with several tens of kilometres offset exhumed from approximately 4 km depth, and displays multiple strands of clay-bearing fault gouge, each several metres wide, that contain variably fractured lenses of protolithic mica schists. The strain is evenly distributed across the gouge layers, in accordance with the measured laboratory mechanical behaviour which shows predominantly strain hardening characteristics. The overall width of the fault zone is several hundred metres. Additionally, there are blocks of dolomitic material that are contained within the fault zones that show extremely localized deformation in the form of faults several centimetres wide. These are typically arranged at an angle of
c
. 20° to the overall fault plane. These differing types of fault rock products allow for the possibility of ‘mixed mode’ seismicity, with fault creep occurring along the strands of velocity strengthening clay-rich gouge, punctuated by small seismic events that nucleate on the velocity weakening localized faults within the dolomite blocks. The Caleta Coloso fault in northern Chile has a left-lateral offset of at least 5 km and was exhumed from 5–10 km depth. The fault core is represented by a 200–300 m wide zone of hydrothermally altered protocataclasite and ultracataclasite. This is surrounded by a zone of micro and macro-fractures on the order of 150 m thick. The fault core shows a heterogeneous distribution of strain, with alternate layers of ultracataclasite and lower strain material. The strain-weakening behaviour of crystalline rocks might be expected to produce highly localized zones of deformation, and thus the wide core zone must be a result of additional process such as precipitation strengthening or geometric irregularities along the fault plane.
Evolution of Coloration Patterns
Authors: Protas Meredith E. , Patel Nipam H.
Published: July 2008

There is an amazing amount of diversity in coloration patterns in nature. The ease of observing this diversity and the recent application of genetic and molecular techniques to model and nonmodel animals are allowing us to investigate the genetic basis and evolution of coloration in an ever-increasing variety of animals. It is now possible to ask questions about how many genes are responsible for any given pattern, what types of genetic changes have occurred to generate the diversity, and if the same underlying genetic changes occur repeatedly when coloration phenotypes arise through convergent evolution or parallel evolution.
The Immunoglobulin-Like Cell Adhesion Molecule Nectin and Its Associated Protein Afadin
Authors: Takai Yoshimi , Ikeda Wataru , Ogita Hisakazu , Rikitake Yoshiyuki
Published: July 2008

Nectins are immunoglobulin-like cell adhesion molecules (CAMs) that compose a family of four members. Nectins homophilically and heterophilically interact in trans with each other to form cell-cell adhesions. In addition, they heterophilically interact in trans with other immunoglobulin-like CAMs. Nectins bind afadin, an actin filament (F-actin)-binding protein, at its cytoplasmic tail and associate with the actin cytoskeleton. Afadin additionally serves as an adaptor protein by further binding many scaffolding proteins and F-actin-binding proteins and contributes to the association of nectins with other cell-cell adhesion and intracellular signaling systems. Nectins and afadin play roles in the formation of a variety of cell-cell junctions cooperatively with, or independently of, cadherins. Cooperation between nectins and cadherins is required for the formation of cell-cell junctions; cadherins alone are not sufficient. Additionally, nectins regulate many other cellular activities (such as movement, proliferation, survival, differentiation, polarization, and the entry of viruses) in cooperation with other CAMs and cell surface membrane receptors.
Structural and Functional Aspects of Lipid Binding by CD1 Molecules
Authors: Silk Jonathan D. , Salio Mariolina , Brown James , Jones E. Yvonne , Cerundolo Vincenzo
Published: July 2008

Over the past ten years, investigators have shown that T lymphocytes can recognize not only peptides in the context of MHC class I and class II molecules but also foreign and self-lipids in association with the nonclassical MHC class I molecules the CD1 proteins. We describe the events that have led to the discovery of the role of CD1 molecules, their pattern of intracellular trafficking, and their ability to sample different intracellular compartments for self- and foreign lipids. Structural and functional aspects of lipid presentation by CD1 molecules are presented in the context of the function of CD1-restricted T cells in antimicrobial responses, antitumor immunity, and the regulation of the tolerance and autoimmunity immunoregulatory axis. Particular emphasis is on invariant NKT (iNKT) cells and their ability to modulate innate and adaptive immune responses.
Droughts
Authors: Kallis Giorgos
Published: July 2008

This chapter provides an interdisciplinary review of the drought literature. Droughts are widely perceived as hydroclimatic hazards. In reality droughts are socioenvironmental phenomena, produced by admixtures of climatic, hydrological, environmental, socioeconomic, and cultural forces. The complexity and context specificity of drought confound severity and impact assessments. Interdisciplinary analyses of drought events and collective assessments with the participation of scientists, policy makers, stakeholders, and the public provide promising new ways of producing information for understanding and managing droughts. Global warming is likely to exacerbate droughts in many semiarid, snow-fed, and coastal basins. Research on historical and paleoclimates warns about the prospect of decadal or centennial megadroughts. Enhancing adaptive capacity becomes essential in the face of such uncertain future extremes. But policies remain locked in supply-side food and water technologies. Policies for the support of impoverished, vulnerable groups, investments in water conservation and appropriate, low-scale technologies can reduce drought vulnerability but face political-economic barriers.
African Genetic Diversity: Implications for Human Demographic History, Modern Human Origins, and Complex Disease Mapping
Authors: Campbell Michael C. , Tishkoff Sarah A.
Published: July 2008

Comparative studies of ethnically diverse human populations, particularly in Africa, are important for reconstructing human evolutionary history and for understanding the genetic basis of phenotypic adaptation and complex disease. African populations are characterized by greater levels of genetic diversity, extensive population substructure, and less linkage disequilibrium (LD) among loci compared to non-African populations. Africans also possess a number of genetic adaptations that have evolved in response to diverse climates and diets, as well as exposure to infectious disease. This review summarizes patterns and the evolutionary origins of genetic diversity present in African populations, as well as their implications for the mapping of complex traits, including disease susceptibility.
Ubiquitous Computing for Remote Cardiac Patient Monitoring: A Survey
Authors: Kumar Sunil , Kambhatla Kashyap , Hu Fei , Lifson Mark , Xiao Yang
Published: July 2008

New wireless technologies, such as wireless LAN and sensor networks, for telecardiology purposes give new possibilities for monitoring vital parameters with wearable biomedical sensors, and give patients the freedom to be mobile and still be under continuous monitoring and thereby better quality of patient care. This paper will detail the architecture and quality-of-service (QoS) characteristics in integrated wireless telecardiology platforms. It will also discuss the current promising hardware/software platforms for wireless cardiac monitoring. The design methodology and challenges are provided for realistic implementation.
Differential Induction of Long-Term Potentiation in the Horizontal versus Columnar Superficial Connections to Layer II Cells of the Entorhinal Cortex
Authors: Ma Li , Alonso Angel , Dickson Clayton T.
Published: July 2008

The entorhinal cortex (EC) is a nodal and independent mnemonic element of the medial temporal lobe memory circuit as it forms a bidirectional interface between the neocortex and hippocampus. Within the EC, intra- and inter-lamellar associational connections occur via horizontal and columnar projections, respectively. We undertook a comparative study of these two inputs as they converge upon EC layer II cells using whole-cell patch techniques in an adult rat EC horizontal slice preparation in which the deepest layers (V-VI) had been dissected out. Electrical stimulation of layers I and III during GABA blockade allowed us to study excitatory synaptic properties and plasticity in the horizontal and columnar fibre systems, respectively. Both pathways exhibited AMPA- and NMDA-receptor mediated transmission and both exhibited long-term potentiation (LTP) after high-frequency (tetanic) stimulation. LTP in the horizontal, but not in the columnar pathway, was blocked by NMDA receptor antagonism. Intriguingly, LTP in both appeared to be mediated by post synaptic increases inCa2+that may be coupled to differing second messenger pathways. Thus, the superficial excitatory horizontal and columnar associative pathways to layer II have divergent mechanisms for LTP which may endow the EC with even more complex and dynamic processing characteristics than previously thought.
Inhibition of Fibroblast Growth Factor 19 Reduces Tumor Growth by Modulating β-Catenin Signaling
Authors: Pai Rama , Dunlap Debra , Qing Jing , Mohtashemi Iman , Hotzel Kathy , French Dorothy M.
Published: July 2008

Fibroblast growth factors (FGF) play important roles in development, angiogenesis, and cancer. FGF19 uniquely binds to FGF receptor 4 (FGFR4). Our previous study has shown that FGF19 transgenic tumors have an activated Wnt-pathway phenotype. Wnt signaling is implicated in initiating or promoting FGF signaling in various cell types and organs. In this study, we examined whether FGF19 or inhibition of FGF19 affects the β-catenin signaling pathway using human colon cancer cell lines (HCT116, Colo201). Our results show that FGF19 increases tyrosine phosphorylation of β-catenin and causes loss of β-catenin–E-cadherin binding. FGF19 increases p-GSK3β and active β-catenin levels and anti-FGF19 antibody (1A6) treatment abrogates this effect of FGF19. Anti-FGF19 antibody treatment increases S33/S37/T41 phosphorylation and ubiquitination of β-catenin. Ion-trap mass spectrometric analysis confirmed that 1A6 increases phosphorylation of β-catenin in the NH2 terminus. Using HCT116-paired β-catenin knockout cells, we show that FGF19 induces TCF/LEF reporter activity in parental (WT/Δ45) and in WT/− but not in mutant (−/Δ45) cells, and that inhibition of endogenous FGF19 reduces this reporter activity, indicating that wild-type β-catenin is accessible for modulation. FGFR4 knockdown using inducible short hairpin RNA significantly reduces the colony-forming ability in vitro and tumor growth in vivo. Although cleaved caspase-3 immunoreactivity remains unchanged, the number of ki67-positive nuclei is reduced in FGFR4 knockdown tumor xenograft tissues. Consistent with the reduced β-catenin activation, Taqman analyses show that FGF19/FGFR4 inhibition reduced β-catenin target gene (cyclin D1, CD44, c-jun, Cox-2, UPAR) expression. These findings highlight that FGF19/FGFR4 cross-talk with β-catenin and that pathway intervention reduces tumor growth. [Cancer Res 2008;68(13):5086–95]
The Humoral Immune System Has a Key Prognostic Impact in Node-Negative Breast Cancer
Authors: Schmidt Marcus , Böhm Daniel , von Törne Christian , Steiner Eric , Puhl Alexander , Pilch Henryk , Lehr Hans-Anton , Hengstler Jan G. , Kölbl Heinz , Gehrmann Mathias
Published: July 2008

Estrogen receptor (ER) expression and proliferative activity are established prognostic factors in breast cancer. In a search for additional prognostic motifs, we analyzed the gene expression patterns of 200 tumors of patients who were not treated by systemic therapy after surgery using a discovery approach. After performing hierarchical cluster analysis, we identified coregulated genes related to the biological process of proliferation, steroid hormone receptor expression, as well as B-cell and T-cell infiltration. We calculated metagenes as a surrogate for all genes contained within a particular cluster and visualized the relative expression in relation to time to metastasis with principal component analysis. Distinct patterns led to the hypothesis of a prognostic role of the immune system in tumors with high expression of proliferation-associated genes. In multivariate Cox regression analysis, the proliferation metagene showed a significant association with metastasis-free survival of the whole discovery cohort [hazard ratio (HR), 2.20; 95% confidence interval (95% CI), 1.40–3.46]. The B-cell metagene showed additional independent prognostic information in carcinomas with high proliferative activity (HR, 0.66; 95% CI, 0.46–0.97). A prognostic influence of the B-cell metagene was independently confirmed by multivariate analysis in a first validation cohort enriched for high-grade tumors (n = 286; HR, 0.78; 95% CI, 0.62–0.98) and a second validation cohort enriched for younger patients (n = 302; HR, 0.83; 95% CI, 0.7–0.97). Thus, we could show in three cohorts of untreated, node-negative breast cancer patients that the humoral immune system plays a pivotal role in metastasis-free survival of carcinomas of the breast. [Cancer Res 2008;68(13):5405–13]
GM1 Expression of Non-Hodgkin's Lymphoma Determines Susceptibility to Rituximab Treatment
Authors: Meyer zum Büschenfelde Christian , Feuerstacke Yvonne , Götze Katharina S. , Scholze Katrin , Peschel Christian
Published: July 2008

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 lipid microdomains. We now show that the extent of CD20 recruitment to lipid rafts correlates with response to rituximab. In addition, expression of the raft-associated sphingolipid GM1 on lymphoma cells is associated with the susceptibility of lymphoma cells to rituximab. Furthermore, we show substantially different GM1 expression in various primary non-Hodgkin's lymphomas. Whereas chronic lymphocytic leukemia (CLL) cells have a low GM1 expression, marginal zone lymphoma cells exhibit much higher levels. Differences were not only detected among various lymphoma subgroups but also within one lymphoma subtype. Interestingly, whereas CLL cells from patients with high GM1 expression responded to rituximab, patients with low GM1 expressing CLL cells did not. These data show the importance of membrane microdomains in the effect of rituximab and may offer a predictive factor for the responsiveness of lymphoma cells to rituximab. [Cancer Res 2008;68(13):5414–22]
Rb Depletion Results in Deregulation of E-Cadherin and Induction of Cellular Phenotypic Changes that Are Characteristic of the Epithelial-to-Mesenchymal Transition
Authors: Arima Yoshimi , Inoue Yasumichi , Shibata Tatsuhiro , Hayashi Hidemi , Nagano Osamu , Saya Hideyuki , Taya Yoichi
Published: July 2008

The retinoblastoma tumor suppressor protein (Rb) is mutated or expressed at very low levels in several tumor types, including retinoblastoma and osteosarcoma, as well as small cell lung, colon, prostate, bladder, and breast carcinomas. Loss or reduction of Rb expression is seen most commonly in high-grade breast adenocarcinomas, suggesting that a relationship may exist between loss of Rb function and a less-differentiated state, increased proliferation, and high metastatic potential. In this study, we found that knockdown of Rb by small interfering RNA in MCF7 breast cancer cells disrupts cell-cell adhesion and induces a mesenchymal-like phenotype. The epithelial-to-mesenchymal transition (EMT), a key event in embryonic morphogenesis, is implicated in the metastasis of primary tumors. Additionally, Rb is decreased during growth factor– and cytokine-induced EMT and overexpression of Rb inhibits the EMT in MCF10A human mammary epithelial cells. Ectopic expression and knockdown of Rb resulted in increased or reduced expression of E-cadherin, which is specifically involved in epithelial cell-cell adhesion. Other EMT-related transcriptional factors, including Slug and Zeb-1, are also induced by Rb depletion. Furthermore, we confirmed that Rb binds to an E-cadherin promoter sequence in association with the transcription factor activator protein-2α. Finally, in breast cancer specimens, we observed a concurrent down-regulation of Rb and E-cadherin expression in mesenchymal-like invasive cancers. These findings suggest that Rb inactivation contributes to tumor progression due to not only loss of cell proliferation control but also conversion to an invasive phenotype and that the inhibition of EMT is a novel tumor suppressor function of Rb. [Cancer Res 2008;68(13):5104–12]
Aplidin, a Marine Organism–Derived Compound with Potent Antimyeloma Activity In vitro and In vivo
Authors: Mitsiades Constantine S. , Ocio Enrique M. , Pandiella Atanasio , Maiso Patricia , Gajate Consuelo , Garayoa Mercedes , Vilanova David , Montero Juan Carlos , Mitsiades Nicholas , McMullan Ciaran J. , Munshi Nikhil C. , Hideshima Teru , Chauhan Dharminder , Aviles Pablo , Otero Gabriel , Faircloth Glynn , Mateos M. Victoria , Richardson Paul G. , Mollinedo Faustino , San-Miguel Jesus F. , Anderson Kenneth C.
Published: July 2008

Despite recent progress in its treatment, multiple myeloma (MM) remains incurable, thus necessitating identification of novel anti-MM agents. We report that the marine-derived cyclodepsipeptide Aplidin exhibits, at clinically achievable concentrations, potent in vitro activity against primary MM tumor cells and a broad spectrum of human MM cell lines, including cells resistant to conventional (e.g., dexamethasone, alkylating agents, and anthracyclines) or novel (e.g., thalidomide and bortezomib) anti-MM agents. Aplidin is active against MM cells in the presence of proliferative/antiapoptotic cytokines or bone marrow stromal cells and has additive or synergistic effects with some of the established anti-MM agents. Mechanistically, a short in vitro exposure to Aplidin induces MM cell death, which involves activation of p38 and c-jun NH2-terminal kinase signaling, Fas/CD95 translocation to lipid rafts, and caspase activation. The anti-MM effect of Aplidin is associated with suppression of a constellation of proliferative/antiapoptotic genes (e.g., MYC, MYBL2, BUB1, MCM2, MCM4, MCM5, and survivin) and up-regulation of several potential regulators of apoptosis (including c-JUN, TRAIL, CASP9, and Smac). Aplidin exhibited in vivo anti-MM activity in a mouse xenograft model. The profile of the anti-MM activity of Aplidin in our preclinical models provided the framework for its clinical testing in MM, which has already provided favorable preliminary results. [Cancer Res 2008;68(13):5216–25]
γ-Irradiation–Induced DNA Damage Checkpoint Activation Involves Feedback Regulation between Extracellular Signal-Regulated Kinase 1/2 and BRCA1
Authors: Yan Ying , Black Claudine P. , Cao Phu T. , Haferbier Jamie L. , Kolb Ryan H. , Spieker Rebecca S. , Ristow Alexandra M. , Cowan Kenneth H.
Published: July 2008

Previous studies from our laboratory have shown that the activation of G2-M checkpoint after exposure of MCF-7 breast cancer cells to γ-irradiation (IR) is dependent on the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. Studies presented in this report indicate that IR exposure of MCF-7 cells is associated with a marked increase in expression of breast cancer 1 (BRCA1) tumor suppressor, an effect that requires ERK1/2 activation and involves posttranscriptional control mechanisms. Furthermore, reciprocal coimmunoprecipitation, as well as colocalization studies, indicate an interaction between BRCA1 and ERK1/2 in both nonirradiated and irradiated cells. Studies using short hairpin RNA targeting BRCA1 show that BRCA1 expression is necessary for IR-induced G2-M cell cycle arrest, as well as ERK1/2 activation in MCF-7 cells. Although BRCA1 expression is not required for IR-induced phosphorylation of ataxia telangiectasia mutated (ATM)–Ser1981, it is required for ATM-mediated downstream signaling events, including IR-induced phosphorylation of Chk2-Thr68 and p53-Ser20. Moreover, BRCA1 expression is also required for IR-induced ATM and rad3 related activation and Chk1 phosphorylation in MCF-7 cells. These results implicate an important interaction between BRCA1 and ERK1/2 in the regulation of cellular response after IR-induced DNA damage in MCF-7 cells. [Cancer Res 2008;68(13):5113–21]
c-Myc and eIF4F Are Components of a Feedforward Loop that Links Transcription and Translation
Authors: Lin Chen-Ju , Cencic Regina , Mills John R. , Robert Francis , Pelletier Jerry
Published: July 2008

The Myc/Max/Mad family of transcription factors and the eukaryotic initiation factor 4F (eIF4F) complex play fundamental roles in regulating cell growth, proliferation, differentiation, and oncogenic transformation. eIF4F is involved in the recruitment of ribosomes to mRNAs and is thought to generally be the rate-limiting phase of translation. Here, we show that c-Myc directly activates transcription of the three subunits of eIF4F (eIF4E, eIF4AI, and eIF4GI). These transcriptional effects are mediated through canonical E-boxes (5′CACGTG3′) present in the promoters of these genes. In addition, the c-Myc antagonist Mad1 down-regulates the expression of eIF4F subunits. We also show that MycER activation stimulates protein synthesis at the level of translation initiation. Increased eIF4F levels result in stimulation of c-Myc mRNA translation specifically, as assessed by quantitative reverse transcription–PCR. We use a murine model of lymphomagenesis to show the expression of eIF4F subunits is also up-regulated by c-Myc in vivo. Our results suggest the presence of a feedforward loop involving c-Myc and eIF4F that serves to link transcription and translation and that could contribute to the effects of c-Myc on cell proliferation and neoplastic growth. [Cancer Res 2008;68(13):5326–34]
In vivo Colocalization of Antigen and CpG within Dendritic Cells Is Associated with the Efficacy of Cancer Immunotherapy
Authors: Nierkens Stefan , den Brok Martijn H. , Sutmuller Roger P.M. , Grauer Oliver M. , Bennink Erik , Morgan Mary E. , Figdor Carl G. , Ruers Theo J.M. , Adema Gosse J.
Published: July 2008

Immunostimulatory cytidyl guanosyl (CpG) motifs are of great interest as cancer vaccine adjuvants. They act as potent inducers of Th1 responses, including the activation of cytotoxic CD8+ T lymphocytes (CTL). Whereas animal models have provided clear evidence that CpG enhances antitumor immunity, clinical trials in humans have thus far been less successful. Applying cryosurgery as an instant in situ tumor destruction technique, we now show that timing of CpG administration crucially affects colocalization of antigen and CpG within EEA-1+ and LAMP-1+ compartments within dendritic cells in vivo. Moreover, antigen/CpG colocalization is directly correlated with antigen cross-presentation, the presence of CTL, and protective antitumor immunity. Thus, failure or success of CpG as a vaccine adjuvant may depend on colocalization of antigen/CpG inside DCs and hence on the timing of CpG administration. These data might aid in the design of future immunotherapeutic strategies for cancer patients. [Cancer Res 2008;68(13):5390–6]
The p53 Homologue ΔNp63α Interacts with the Nuclear Factor-κB Pathway to Modulate Epithelial Cell Growth
Authors: King Kathryn E. , Ponnamperuma Roshini M. , Allen Clint , Lu Hai , Duggal Praveen , Chen Zhong , Van Waes Carter , Weinberg Wendy C.
Published: July 2008

The p53 homologue ΔNp63α is overexpressed and inhibits apoptosis in a subset of human squamous cell carcinomas (SCC). Here, we report that in normal keratinocytes overexpressing ΔNp63α and in human squamous carcinoma cells, ΔNp63α physically associates with phosphorylated, transcriptionally active nuclear c-Rel, a nuclear factor-κB family member, resulting in increased c-Rel nuclear accumulation. This accumulation and the associated enhanced proliferation driven by elevated ΔNp63α are attenuated by c-Rel small interfering RNA or overexpression of mutant IκBαM, indicating that c-Rel–containing complex formation is critical to the ability of elevated ΔNp63α to maintain proliferation in the presence of growth arresting signals. Consistent with a role in growth regulation, ΔNp63α-c-Rel complexes bind a promoter motif and repress the cyclin-dependent kinase inhibitor p21WAF1 in both human squamous carcinoma cells and normal keratinocytes overexpressing ΔNp63α. The relationship between ΔNp63α and activated c-Rel is reflected in their strong nuclear staining in the proliferating compartment of primary head and neck SCC. This is the first report indicating that high levels of ΔNp63α interact with activated c-Rel in keratinocytes and SCC, thereby promoting uncontrolled proliferation, a key alteration in the pathogenesis of cancers. [Cancer Res 2008;68(13):5122–31]
The Cullin 4B–Based UV-Damaged DNA-Binding Protein Ligase Binds to UV-Damaged Chromatin and Ubiquitinates Histone H2A
Authors: Guerrero-Santoro Jennifer , Kapetanaki Maria G. , Hsieh Ching L. , Gorbachinsky Ilya , Levine Arthur S. , Rapić-Otrin Vesna
Published: July 2008

By removing UV-induced lesions from DNA, the nucleotide excision repair (NER) pathway preserves the integrity of the genome. The UV-damaged DNA-binding (UV-DDB) protein complex is involved in the recognition of chromatin-embedded UV-damaged DNA, which is the least understood step of NER. UV-DDB consists of DDB1 and DDB2, and it is a component of the cullin 4A (CUL4A)–based ubiquitin ligase, DDB1-CUL4ADDB2. We previously showed that DDB1-CUL4ADDB2 ubiquitinates histone H2A at the sites of UV lesions in a DDB2-dependent manner. Mutations in DDB2 cause a cancer prone syndrome, xeroderma pigmentosum group E (XP-E). CUL4A and its paralog, cullin 4B (CUL4B), copurify with the UV-DDB complex, but it is unclear whether CUL4B has a role in NER as a separate E3 ubiquitin ligase. Here, we present evidence that CUL4A and CUL4B form two individual E3 ligases, DDB1-CUL4ADDB2 and DDB1-CUL4BDDB2. To investigate CUL4B's possible role in NER, we examined its subcellular localization in unirradiated and irradiated cells. CUL4B colocalizes with DDB2 at UV-damaged DNA sites. Furthermore, CUL4B binds to UV-damaged chromatin as a part of the DDB1-CUL4BDDB2 E3 ligase in the presence of functional DDB2. In contrast to CUL4A, CUL4B is localized in the nucleus and facilitates the transfer of DDB1 into the nucleus independently of DDB2. Importantly, DDB1-CUL4BDDB2 is more efficient than DDB1-CUL4ADDB2 in monoubiquitinating histone H2A in vitro. Overall, this study suggests that DDB1-CUL4BDDB2 E3 ligase may have a distinctive function in modifying the chromatin structure at the site of UV lesions to promote efficient NER. [Cancer Res 2008;68(13):5014–22]
Serotonin Receptors, Novel Targets of Sulforaphane Identified by Proteomic Analysis in Caco-2 Cells
Authors: Mastrangelo Lina , Cassidy Aedin , Mulholland Francis , Wang Wei , Bao Yongping
Published: July 2008

Cancer chemopreventive activity of sulforaphane has been predominantly associated with its ability to induce phase II detoxification enzymes. In the present study, novel targets of sulforaphane were identified and characterized using a proteomics approach. Two-dimensional gel electrophoresis and mass spectrometry were used to produce protein profiles of human colon adenocarcinoma Caco-2 cells treated with 5 μmol/L sulforaphane for 48 h and control cells (0.05% DMSO). Gel comparisons showed the down-regulation to undetectable level of the serotonin receptor 5-HT3 after sulforaphane treatment. In addition, Aldo-keto reductase and d-dopachrome decarboxylase were also differentially expressed in control and treated cell extracts. To elucidate two-dimensional gel findings, the neurotransmitter receptors 5-HT3A, 5-HT1A, 5-HT2C, and the serotonin reuptake transporter were analyzed using Western blotting. Results showed a decrease of neurotransmitter receptors in a dose-dependent manner after sulforaphane treatment. Moreover, after exposure of Caco-2 cells to sulforaphane, nicotinic acetylcholine receptor protein level was increased. These findings suggested a potential effect of sulforaphane on serotonin release. Activation of neurotransmitter receptors followed by initiation of cyclic AMP signaling might be crucial events in colon carcinoma progression. Thus, the effect of sulforaphane may help to elucidate signaling pathways serotonin-mediated in colon cancer and lead to development of potential novel therapeutic agents. [Cancer Res 2008;68(13):5487–91]
Genomic and Proteomic Analysis Reveals a Threshold Level of MYC Required for Tumor Maintenance
Authors: Shachaf Catherine M. , Gentles Andrew J. , Elchuri Sailaja , Sahoo Debashis , Soen Yoav , Sharpe Orr , Perez Omar D. , Chang Maria , Mitchel Dennis , Robinson William H. , Dill David , Nolan Garry P. , Plevritis Sylvia K. , Felsher Dean W.
Published: July 2008

MYC overexpression has been implicated in the pathogenesis of most types of human cancers. MYC is likely to contribute to tumorigenesis by its effects on global gene expression. Previously, we have shown that the loss of MYC overexpression is sufficient to reverse tumorigenesis. Here, we show that there is a precise threshold level of MYC expression required for maintaining the tumor phenotype, whereupon there is a switch from a gene expression program of proliferation to a state of proliferative arrest and apoptosis. Oligonucleotide microarray analysis and quantitative PCR were used to identify changes in expression in 3,921 genes, of which 2,348 were down-regulated and 1,573 were up-regulated. Critical changes in gene expression occurred at or near the MYC threshold, including genes implicated in the regulation of the G1-S and G2-M cell cycle checkpoints and death receptor/apoptosis signaling. Using two-dimensional protein analysis followed by mass spectrometry, phospho-flow fluorescence-activated cell sorting, and antibody arrays, we also identified changes at the protein level that contributed to MYC-dependent tumor regression. Proteins involved in mRNA translation decreased below threshold levels of MYC. Thus, at the MYC threshold, there is a loss of its ability to maintain tumorigenesis, with associated shifts in gene and protein expression that reestablish cell cycle checkpoints, halt protein translation, and promote apoptosis. [Cancer Res 2008;68(13):5132–42]
CAAT/Enhancer Binding Protein Homologous Protein–Dependent Death Receptor 5 Induction Is a Major Component of SHetA2-Induced Apoptosis in Lung Cancer Cells
Authors: Lin Yi-Dan , Chen Shuzhen , Yue Ping , Zou Wei , Benbrook Doris M. , Liu Shengquan , Le Thanh C. , Berlin K. Darrell , Khuri Fadlo R. , Sun Shi-Yong
Published: July 2008

The flexible heteroarotinoids (Flex-Het) represent a novel type of atypical retinoids lacking activity in binding to and transactivating retinoid receptors. Preclinical studies have shown that Flex-Hets induce apoptosis of cancer cells while sparing normal cells and exhibit anticancer activity in vivo with improved therapeutic ratios over conventional retinoid receptor agonists. Flex-Hets have been shown to induce apoptosis through activation of the intrinsic apoptotic pathway. The present study has revealed a novel mechanism underlying Flex-Het–induced apoptosis involving induction of death receptor 5 (DR5). The representative Flex-Het SHetA2 effectively inhibited the growth of human lung cancer cells in cell culture and in mice. SHetA2 induced apoptosis, which could be abrogated by silencing caspase-8 expression, indicating that ShetA2 triggers a caspase-8–dependent apoptosis. Accordingly, SHetA2 up-regulated DR5 expression, including cell surface levels of DR5, and augmented tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–induced apoptosis. Importantly, small interfering RNA (siRNA)–mediated blockade of DR5 induction conferred cell resistance to SHetA2-induced apoptosis, as well as SHetA2/TRAIL-induced apoptosis. These results show that DR5 induction is a key component of apoptosis induced by SHetA2 or by SHetA2 combined with TRAIL. SHetA2 exerted CAAT/enhancer-binding protein homologous protein (CHOP)–dependent transactivation of the DR5 promoter. Consistently, SHetA2 induced CHOP expression, which paralleled DR5 up-regulation, whereas siRNA-mediated blockage of CHOP induction prevented DR5 up-regulation, indicating CHOP-dependent DR5 up-regulation by SHetA2. Collectively, we conclude that CHOP-dependent DR5 up-regulation is a key event mediating SHetA2-induced apoptosis. [Cancer Res 2008;68(13):5335–44]
Complement-Dependent Tumor Cell Lysis Triggered by Combinations of Epidermal Growth Factor Receptor Antibodies
Authors: Dechant Michael , Weisner Wencke , Berger Sven , Peipp Matthias , Beyer Thomas , Schneider-Merck Tanja , Lammerts van Bueren Jeroen J. , Bleeker Wim K. , Parren Paul W.H.I. , van de Winkel Jan G.J. , Valerius Thomas
Published: July 2008

Therapeutic monoclonal antibodies against the epidermal growth factor receptor (EGFR) have advanced the treatment of colon and head and neck cancer, and show great promise for the development of treatments for other solid cancers. Antibodies against EGFR have been shown to act via inhibition of receptor signaling and induction of antibody-dependent cellular cytoxicity. However, complement-dependent cytotoxicity, which is considered one of the most powerful cell killing mechanisms of antibodies, seems inactive for such antibodies. Here, we show a remarkable synergy for EGFR antibodies. Combinations of antibodies against EGFR were identified, which resulted in potent complement activation via the classic pathway and effective lysis of tumor cells. Studies on a large panel of antibodies indicated that the observed synergy is a general mechanism, which can be activated by combining human IgG1 antibodies recognizing different, nonoverlapping epitopes. Our findings show an unexpected quality of therapeutic EGFR antibodies, which may be exploited to develop novel and more effective treatments for solid cancers. [Cancer Res 2008;68(13):4998–5003]
Hypoxia-Inducible Factor-1α Obstructs a Wnt Signaling Pathway by Inhibiting the hARD1-Mediated Activation of β-Catenin
Authors: Lim Ji-Hong , Chun Yang-Sook , Park Jong-Wan
Published: July 2008

Although a splice variant of mouse mARD1s was found to acetylate and destabilize hypoxia-inducible factor-1α (HIF-1α), human hARD1 has no such activities. Nonetheless, hARD1 has been reported to bind directly with HIF-1α. Here, we addressed the functional significance of the hARD1–HIF-1α interaction. Because hARD1 acetylates and activates β-catenin, we examined whether HIF-1α regulates the hARD1-mediated activation of Wnt signaling. It was found that HIF-1α binds hARD1 through the oxygen-dependent degradation domain and, in so doing, dissociates hARD1 from β-catenin, which prevents β-catenin acetylation. In LiCl-stimulated HEK293 or cancer cell lines with active Wnt signaling, β-catenin acetylation and activity were suppressed in hypoxia, and these suppressions were mediated by HIF-1α. Moreover, HIF-1α disruption of hARD1/β-catenin repressed TCF4 activity, resulting in c-Myc suppression and p21cip1 induction. In addition, we confirmed that the HIF-1α NH2 terminal inactivates TCF4 by directly binding β-catenin. In conclusion, HIF-1α was found to inactivate the Wnt signaling by binding to hARD1 or β-catenin, which may contribute to the hypoxia-induced growth arrest of tumor cells. [Cancer Res 2008;68(13):5177–84]
c-Jun NH2-Terminal Kinase 1 Is a Critical Regulator for the Development of Gastric Cancer in Mice
Authors: Shibata Wataru , Maeda Shin , Hikiba Yohko , Yanai Ayako , Sakamoto Kei , Nakagawa Hayato , Ogura Keiji , Karin Michael , Omata Masao
Published: July 2008

c-Jun NH2-terminal kinase (JNK) links several cellular processes, including proliferation and survival, and is believed to be involved in carcinogenesis. However, the role of JNK in gastric tumorigenesis is unknown. Immunohistochemical analysis reveals that JNK is frequently activated in human gastric cancer tissue. We investigated whether JNK1, a major JNK isozyme, is involved in chemically induced gastric cancer development. Mice lacking JNK1 exhibited a marked decrease in gastric carcinogenesis induced by N-methyl-N-nitrosourea, relative to their wild-type counterparts. Impaired tumor development correlated with decreased tumor initiation, which is associated with the production of reactive oxygen species. We also found that lower levels of tumorigenesis were correlated with the decreased expression of cyclin D and CDK as well as decreased cell proliferation. Taken together, JNK seems to be involved in both tumor initiation and promotion and may be an attractive target for the prevention of gastric carcinogenesis. [Cancer Res 2008;68(13):5031–9]
Phosphoinositide 3-kinase/AKT Signaling Can Promote AIB1 Stability Independently of GSK3 Phosphorylation
Authors: Ferrero Macarena , Avivar Álvaro , García-Macías María Carmen , de Mora Jaime Font
Published: July 2008

The transcriptional coactivator AIB1 is an oncogene overexpressed in different types of tumors, including breast cancer. Although the subcellular compartimentalization of AIB1 seems to be intimately linked to abnormal proliferation, the molecular mechanisms that regulate its subcellular distribution are not well defined. Here, we report that the nuclear accumulation and half-life of AIB1 vary between cancer cell lines. Using these differences as an experimental model, our results reveal that alterations to the Akt signaling pathway and nuclear export determine the stability of AIB1 and nuclear content of this coactivator. Moreover, our results show that AIB1 is degraded in the nucleus by the proteasome in an ubiquitin-dependent manner. However, this process does not require phosphorylation by GSK3, thereby revealing an alternative mechanism for regulating the turnover of AIB1. We define a new region at the carboxy terminus of AIB1 that is required for proteasome-dependent transcriptional activation and is preceded by a PEST domain that is required for adequate protein turnover. Based on differences in Akt signaling and the subcellular distribution of AIB1 between different cell lines, our results suggest that dysregulation of nuclear shuttling and proteasomal degradation may modulate the oncogenic potential of AIB1. [Cancer Res 2008;68(13):5450–9]
Implications of Aging and Self-Tolerance on the Generation of Immune and Antitumor Immune Responses
Authors: Dominguez Ana Lucia , Lustgarten Joseph
Published: July 2008

Cancer statistics show a disproportionately higher burden of tumors in the old. Most of the studies evaluating vaccination strategies have not taken into consideration the effect that aging has on the immune system. For the first time, we describe an animal tumor model in which self-tolerance and aging are present at the same time. FVB-Her-2/neu mice which are tolerant to neu antigens crossed with HLA-A2/Kb mice (A2xneu) develop spontaneous tumors when they are more than 22 months old. Analysis of CD8+ T-cell–specific responses in A2xneu mice indicated that the priming activity of old A2xneu mice to induce an immune response was diminished compared with young animals. Following intratumoral injections of CpG-ODN, ∼30% of young A2xneu mice rejected the tumor; however, no antitumor effect was observed in old A2xneu mice. Analysis of T regulatory cells (Treg) indicated that there are significantly more Tregs in old animals. After CpG-ODN vaccination plus Treg depletion, 70% of young A2xneu mice rejected the tumor. The same treatment prolonged survival in old A2xneu mice, but none of the animals rejected the tumor. Even though CpG-ODN injections plus Treg depletion could rescue the antitumor responses against self-tumor antigens in young tolerant mice, the same therapy is not as effective in old tolerant hosts. Relevant tumor models such as the A2xneu mice in which self-tolerance and aging are present at the same time are critical to allow the optimization of vaccination strategies to effectively stimulate immune responses against self-tumor antigens in the young and the old. [Cancer Res 2008;68(13):5423–31]