bluuebunny/crossref_metadata_2025 huggingface dataset:
Ground conditions and hazards: Suez City development, Egypt
Authors: Jones D. K. C.
Published: December 2007

Purpose

Rapid engineering geological/geomorphological surveys are sometimes required for extensive urban and industrial developments on tracts of land for which little or no background topographic or geotechnical information is available. In areas unobscured by vegetation, geomorphological mapping based on air-photo interpretation augmented by field checking and detailed ground survey, can quickly provide a robust framework of terrain units of value in:

planning cost-effective site investigations;

interpreting and extrapolating subsurface point data provided by trial pits/ boreholes;

the early identification of problematic locations requiring detailed investigation;

the preliminary identification and delimitation of surface material resources;

establishing a basis for preliminary assessments of ground hazard potential.

The classic example of such requirements arose in the proposal to redevelop and expand dramatically the size of Suez Town (El Suweis) in the aftermath of the October 1973 Yom Kippur War. The proposed new Suez City was to be developed on 85 km
2
of desert surface that had previously been little investigated and was presumed initially to be relatively uniform and non-problematic (Fig. 1). However, preliminary site investigations revealed unexpected lateral variations in near-surface materials, thereby necessitating a rapid geomorphological survey to establish terrain conditions and to identify the potential for aggressive soils and flash-flood hazard. This was achieved by a team of five specialists in three weeks; details are to be found in Doornkamp
et al
. (1979), Bush et al (1980) and Cooke
et al
. (1982).
Subsidence map development in an area of abandoned salt mines
Authors: Lee E. M. , Sakalas C. F.
Published: December 2007

Purpose of the study

Morphological mapping is not generally associated with mining and subsidence, having traditionally been used to define the nature and extent of surface features such as landslides and landforms. However, detailed morphological mapping, linked to subsurface investigation, can provide a preliminary indication of potential subsidence hazards in some areas of abandoned mine workings. This example describes how mapping was carried out in an undeveloped part of the Cheshire saltfleld, prior to any subsurface investigation, with the aim of establishing the likely extent to which a number of mines had collapsed.

The site

The site is in the Northwich area of Cheshire, England, and has had a long history of rock salt mining and brine pumping. The site is largely undeveloped, although locally important infrastructure routes cross the area, and it has potential for use as a community woodland and open space area.

At the site, rock salt (halite) occurs in two discrete horizons within the Triassic Mercia Mudstone sequence, separated by around 10 m of marls: the 20–30 m thick Top Bed (at
c
. 40 m b.g.l.) and the 23–28 m thick Bottom Bed (at
c
. 75 m b.g.l.). This sequence is overlain by glacial till. Salt was extensively mined at the site from around 1777 to 1933, with the one Top Bed and seven Bottom Bed mines opened over this period, varying in size from 0.8 to 13 ha.
Evaluation in urban and industrial environments: the Docklands Light Railway, Lewisham Extension, London
Authors: Shilston D. T. , Harrison N. E. , French D. J.
Published: December 2007

Objectives

This case history describes the use of information obtained from the initial desk-based engineering geological and geotechnical studies carried out as part of the design of civil engineering works for the Lewisham Extension of the Docklands Light Railway (DLR) which was constructed in a heavily developed urban environment. The desk study aimed to make best use of available information in order to evaluate the terrain, limit the need for further ground investigation and provide geological and geotechnical information to the design teams as quickly as possible.

A desk study is an integral part of terrain and site evaluation and, wherever possible, should be carried out in conjunction with a reconnaissance survey (or walk-over) of the site. Together they are likely to be of greatest value and most cost-effective when carried out early in the investigations for a proposed development. They can provide the project team with an early indication of the conditions at the site, such information being essential for master planning and concept design. As the project is advanced the desk study findings become the basis for the planning and interpretation of the subsequent more expensive and lengthy stage of physical investigation by (for example) boreholes and trial pits.

Conceptually, it should be self-evident that it is cheaper to obtain and evaluate information that already exists than to obtain new investigation data. But this is not the only reason for carrying out desk studies. Their ability to recover information that cannot be obtained by other means is also very
Structural geometry and timing of deformation in the Chainat duplex, Thailand
Authors: Smith M. , Chantraprasert S. , Morley C. K. , Cartwright I.
Published: December 2007

The Chainat duplex is about 100 km in a north–south direction, and was developed along the predominantly sinistral Mae Ping fault zone, which was active during the Cenozoic. The duplex is manifested as eroded, north–south- and NW–SE-striking outliers of Palaeozoic and Mesozoic rocks rising from the surrounding flat plains of the Central Basin (a Pliocene–Recent post-rift basin). Satellite images, geological maps and magnetic maps have been used to reconstruct the structural geometry of the duplex, which is composed of a series of north–south-striking ridges, bounded to the north and south by NW–SE-striking faults. Overall, the duplex has the geometry of analogue restraining-bend models with relatively low displacement. No well-developed duplex-traversing short-cut faults linking the principal displacement zones are apparent. The duplex shows evidence for widespread sinistral motion, as well as some dextral reactivation the latter of which is particularly marked in the eastern part of the duplex. The main sinistral activity ended at about 30 Ma: subsequently, minor, episodic reactivation of the duplex may have occurred. Detailed timing of events cannot be determined from structures within the duplex, but the evolution of adjacent rift basins suggests that stresses developed during episodes of inversion may have also caused reactivation of strike-slip faults (sinistral for NW–SE to north–south striking faults) during the Miocene. Minor episodic dextral motion may also have been of Late Oligocene–Miocene and/or Pliocene–Recent age.
Morphology, structure and evolution of California Continental Borderland restraining bends
Authors: Legg M.R. , Goldfinger C. , Kamerling M. J. , Chaytor J. D. , Einstein D. E.
Published: December 2007

Exceptional examples of restraining and releasing bend structures along major strike-slip fault zones are found in the California continental Borderland. Erosion in the deep sea is diminished, thereby preserving the morphology of active oblique fault deformation. Long-lived deposition of turbidites and other marine sediments preserve a high-resolution geological record of fault zone deformation and regional tectonic evolution. Two large restraining bends with varied structural styles are compared to derive a typical morphology of Borderland restraining bends. A 60-km-long, 15° left bend in the dextral San Clemente Fault creates two primary deformation zones. The southeastern uplift involves ‘soft’ turbidite sediments and is expressed as a broad asymmetrical ridge with right-stepping en echelon anticlines and local pull-apart basins at minor releasing stepovers along the fault. The northwest uplift involves more rigid sedimentary and possibly igneous or metamorphic basement rocks creating a steep-sided, narrow and more symmetrical pop-up. The restraining bend terminates in a releasing stepover basin at the NW end, but curves gently into a transtensional releasing bend to the SE. Seismic stratigraphy indicates that the uplift and transpression along this bend occurred within Quaternary times. The 80-km-long, 30–40° left bend in the San Diego Trough–Catalina fault zone creates a large pop-up structure that emerges to form Santa Catalina Island. This ridge of igneous and metamorphic basement rocks has steep flanks and a classic ‘rhomboid’ shape. For both major restraining bends, and most others in the Borderland, the uplift is asymmetrical, with the principal displacement zone lying along one flank of the pop-up. Faults within the pop-up structure are very steep dipping and subvertical for the principal displacement zone. In most cases, a Miocene basin has been structurally inverted by the transpression. Development of major restraining bends offshore of southern California appears to result from reactivation of major transform faults associated with Mid-Miocene oblique rifting during the evolution of the Pacific–North America plate boundary. Seismicity offshore of southern California demonstrates that deformation along these major strike-slip fault systems continues today.
Stepovers that migrate with respect to affected deposits: field characteristics and speculation on some details of their evolution
Authors: Wakabayashi J.
Published: December 2007

Traditionally, geologists have viewed strike-slip stepover regions as progressively increasing in structural relief with increasing slip along the principal displacement zones (PDZs). In contrast, some stepover regions may migrate along the strike of the PDZs with respect to deposits affected by them, leaving a ‘wake’ of formerly affected deposits trailing the active stepover region. Such stepovers generate comparatively little structural relief at any given location. For restraining bends of this type, little exhumation and erosion takes place at any given location. Another characteristic of migrating stepovers is local tectonic inversion that may migrate along the strike of the PDZs. This is most easily observed for migrating releasing bends where the wake is composed of former pull-apart basin deposits that have been subject to shortening and uplift. This type of basin inversion occurs along the San Andreas Fault, wherein the wake is affected by regional transpression. Some migrating stepovers may evolve by propagation of the PDZ on one side of the stepover, and shut-off of the PDZ on the other side. Possible examples of migrating stepovers are present along the northern San Andreas fault system at scales from metres (sag ponds and pressure ridges) to tens of kilometres (large basins and transpressional uplifts). Migrating stepovers and ‘traditional’ stepovers may be end members of stepover evolutionary types, and the ratio of wake length to the amount of slip along the PDZs during stepover development measures the ‘migrating stepover component’ of a given stepover. For a ‘pure’ migrating type, the wake length may be equal to or greater than the PDZ cumulative slip during the time of stepover evolution, whereas for a ‘pure’ traditional type, there would be no wake.
Structural and topographic characteristics of restraining bend mountain ranges of the Altai, Gobi Altai and easternmost Tien Shan
Authors: Cunningham D.
Published: December 2007

Restraining bend mountain ranges are fundamental orogenic elements in the Altai, Gobi Altai and eastern Tien Shan. In this paper, 12 separate restraining bends are reviewed to identify common structural and topographic characteristics. The 12 restraining bends occur in one of three different tectonic settings: (1) strike-slip fault termination zones; (2) at a major strike-slip fault bend where the individual strike-slip fault can be traced continuously from one end of the range to the other; and (3) where two separate strike-slip fault segments converge and overlap. Fault maps of the 12 separate bends reveal that they are all flower or half-flower structures in cross-section, but there is considerable architectural diversity and all have unique individual topographic, structural and dimensional characteristics. Many factors account for the architectural diversity of the restraining bend mountains, especially stepover width, total amounts of strike-slip displacement, reactivation of older structures, tectonic setting, and the angular relation between fault trace and maximum horizontal stress. The stepover sense for regionally important strike-slip faults is controlled by pre-existing basement heterogeneities and is dominantly contractional. Therefore, releasing bends and transtensional basins are largely absent. Throughout the region there is a continuum of mountain range types, from purely contractional ridges to isolated restraining bends along strike-slip-dominated zones. Nucleation, topographic uplift, along- and across-strike growth of the bend, and restraining bend coalescence with adjacent ranges appears to be an important mountain-building process in the Altai, Gobi Altai and eastern Tien Shan; similar processes are likely in other intracontinental transpressional orogens.
Toward a better understanding of the Late Neogene strike-slip restraining bend in Jamaica: geodetic, geological, and seismic constraints
Authors: Mann P. , Demets C. , Wiggins-Grandison M.
Published: December 2007

We describe the regional fault pattern, geological setting and active fault kinematics of Jamaica, from published geological maps, earthquakes and GPS-based geodesy, to support a simple tectonic model for both the initial stage of restraining-bend formation and the subsequent stage of bend bypassing. Restraining-bend formation and widespread uplift in Jamaica began in the Late Miocene, and were probably controlled by the interaction of roughly east–west-trending strike-slip faults with two NNW-trending rifts oriented obliquely to the direction of ENE-trending, Late Neogene interplate shear. The interaction of the interplate strike-slip fault system (Enriquillo- Plantain Garden fault zone) and the oblique rifts has shifted the strike-slip fault trace
c
. 50 km to the north and created the 150-km-long by 80-km-wide restraining bend that is now morphologically expressed as the island of Jamaica. Recorded earthquakes and recent GPS results from Jamaica illustrate continued bend evolution during the most recent phase of strike-slip displacement, at a minimum GPS-measured rate of 8±1 mm/a. GPS results show a gradient in left-lateral interplate strain from north to south, probably extending south of the island, and a likely gradient along a ENE–WSW cross-island profile. The observed GPS velocity field suggests that left-lateral shear continues to be transmitted across the Jamaican restraining bend by a series of intervening bend structures, including the Blue Mountain uplift of eastern Jamaica.
BCL-2 and Mutant NRAS Interact Physically and Functionally in a Mouse Model of Progressive Myelodysplasia
Authors: Omidvar Nader , Kogan Scott , Beurlet Stephanie , le Pogam Carole , Janin Anne , West Robert , Noguera Maria-Elena , Reboul Murielle , Soulie Annie , Leboeuf Christophe , Setterblad Niclas , Felsher Dean , Lagasse Eric , Mohamedali Azim , Thomas N. Shaun B. , Fenaux Pierre , Fontenay Michaela , Pla Marika , Mufti Ghulam J. , Weissman Irving , Chomienne Christine , Padua Rose Ann
Published: December 2007

Myelodysplastic syndromes (MDS) are clonal stem cell hematologic disorders that evolve to acute myeloid leukemia (AML) and thus model multistep leukemogenesis. Activating RAS mutations and overexpression of BCL-2 are prognostic features of MDS/AML transformation. Using NRASD12 and BCL-2, we created two distinct models of MDS and AML, where human (h)BCL-2 is conditionally or constitutively expressed. Our novel transplantable in vivo models show that expression of hBCL-2 in a primitive compartment by mouse mammary tumor virus–long terminal repeat results in a disease resembling human MDS, whereas the myeloid MRP8 promoter induces a disease with characteristics of human AML. Expanded leukemic stem cell (Lin−/Sca-1+/c-Kit+) populations and hBCL-2 in the increased RAS-GTP complex within the expanded Sca-1+ compartment are described in both MDS/AML–like diseases. Furthermore, the oncogenic compartmentalizations provide the proapoptotic versus antiapoptotic mechanisms, by activating extracellular signal-regulated kinase and AKT signaling, in determination of the neoplastic phenotype. When hBCL-2 is switched off with doxycycline in the MDS mice, partial reversal of the phenotype was observed with persistence of bone marrow blasts and tissue infiltration as RAS recruits endogenous mouse (m)BCL-2 to remain active, thus demonstrating the role of the complex in the disease. This represents the first in vivo progression model of MDS/AML dependent on the formation of a BCL-2:RAS-GTP complex. The colocalization of BCL-2 and RAS in the bone marrow of MDS/AML patients offers targeting either oncogene as a therapeutic strategy. [Cancer Res 2007;67(24):11657–67]
Concordant Epigenetic Silencing of Transforming Growth Factor-β Signaling Pathway Genes Occurs Early in Breast Carcinogenesis
Authors: Hinshelwood Rebecca A. , Huschtscha Lily I. , Melki John , Stirzaker Clare , Abdipranoto Andrea , Vissel Bryce , Ravasi Timothy , Wells Christine A. , Hume David A. , Reddel Roger R. , Clark Susan J.
Published: December 2007

Human mammary epithelial cells (HMEC) grown under standard cell culture conditions enter a growth phase referred to as selection, but a subpopulation is able to escape from arrest and continue to proliferate. These cells, called post-selection or variant HMECs, may be derived from progenitor cells found in normal mammary epithelium that subsequently acquire premalignant lesions, including p16INK4A promoter hypermethylation. Epigenetic silencing of tumor suppressor genes through DNA methylation and histone modification is an early event in tumorigenesis. A major challenge is to find genes or gene pathways that are commonly silenced to provide early epigenetic diagnostic and therapeutic cancer targets. To identify very early epigenetic events that occur in breast cancer, we used microarrays to screen for gene pathways that were suppressed in post-selection HMECs but reactivated after treatment with the demethylation agent 5-aza-2′-deoxycytidine. We found that several members of the transforming growth factor β (TGF-β) signaling pathway were consistently down-regulated in the post-selection HMEC populations, and this was associated with a marked decrease in Smad4 nuclear staining. Gene suppression was not associated with DNA methylation but with chromatin remodeling, involving a decrease in histone H3 lysine 27 trimethylation and an increase in histone H3 lysine 9 dimethylation and deacetylation. These results show for the first time that TGF-β2, its receptors TGF-βR1 and TGF-βR2, and activator thrombospondin-1 are concordantly suppressed early in breast carcinogenesis by histone modifications and indicate that the TGF-β signaling pathway is a novel target for gene activation by epigenetic therapy. [Cancer Res 2007;67(24):11517–27]
A Novel Bioluminescent Mouse Model and Effective Therapy for Adult T-Cell Leukemia/Lymphoma
Authors: Shu Sherry T. , Nadella Murali V.P. , Dirksen Wessel P. , Fernandez Soledad A. , Thudi Nanda K. , Werbeck Jillian L. , Lairmore Michael D. , Rosol Thomas J.
Published: December 2007

Adult T-cell /lymphomaleukemia (ATLL) is caused by human T-cell lymphotropic virus type 1 (HTLV-1). Approximately 80% of ATLL patients develop humoral hypercalcemia of malignancy (HHM), a life-threatening complication leading to a poor prognosis. Parathyroid hormone–related protein (PTHrP) and macrophage inflammatory protein-1α (MIP-1α) are important factors in the pathogenesis of HHM in ATLL and the expression of PTHrP can be activated by nuclear factor κB (NF-κB). NF-κB is constitutively activated in ATLL cells and is essential for leukemogenesis including transformation of lymphocytes infected by HTLV-1. Our goal was to evaluate the effects of NF-κB disruption by a proteasomal inhibitor (PS-341) and osteoclastic inhibition by zoledronic acid (Zol) on the development of ATLL and HHM using a novel bioluminescent mouse model. We found that PS-341 decreased cell viability, increased apoptosis, and down-regulated PTHrP expression in ATLL cells in vitro. To investigate the in vivo efficacy, nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice were xenografted with ATLL cells and treated with vehicle control, PS-341, Zol, or a combination of PS-341 and Zol. Bioluminescent imaging and tumor cell count showed a significant reduction in tumor burden in mice from all treatment groups. All treatments also significantly reduced the plasma calcium concentrations. Zol treatment increased trabecular bone volume and decreased osteoclast parameters. PS-341 reduced PTHrP and MIP-1α expression in tumor cells in vivo. Our results indicate that both PS-341 and Zol are effective treatments for ATLL and HHM, which are refractory to conventional therapy. [Cancer Res 2007;67(24):11859–66]
Novel Noncatalytic Role for Caspase-8 in Promoting Src-Mediated Adhesion and Erk Signaling in Neuroblastoma Cells
Authors: Finlay Darren , Vuori Kristiina
Published: December 2007

Neuroblastomas are extremely aggressive, although heterogeneous, cancers with a poor prognosis upon metastasis. Some evidence has suggested a correlative silencing of caspase-8 with MYCN amplification in neuroblastoma. A prognostic effect of this silencing, however, has been disputed. We report here hitherto undescribed roles for caspase-8 in the modulation of cell adhesion and subsequent activation of the Erk signaling pathway. Re-expression of caspase-8 in neuroblastoma cells lacking endogenous caspase-8 expression was found to promote cell adhesion to extracellular matrix and to activate adhesion-dependent signaling pathways, such as the Erk kinase cascade. This function of caspase-8 occurred irrespective of its proteolytic activity. Additionally, a pool of caspase-8 was shown to co-localize with the Src tyrosine kinase at the cellular periphery. Furthermore, our studies showed that caspase-8 forms a physical protein complex with Src via its death effector domains (DED) and maintains the complex in a detergent-soluble fraction. We also show that the DEDs of caspase-8 alone are necessary and sufficient to recreate the adhesive and biochemical phenotypes observed with the full-length protein, suggesting that caspase-8 may exert these effects via its association with Src. This protein complex association of caspase-8 and Src, and concomitant downstream signaling events, may help reconcile why a potential tumor suppressor such as caspase-8 is rarely absent in cancers. [Cancer Res 2007;67(24):11704–11]
Differential Sensitivity of Malignant Glioma Cells to Methylating and Chloroethylating Anticancer Drugs: p53 Determines the Switch by Regulating xpc, ddb2, and DNA Double-Strand Breaks
Authors: Batista Luís F.Z. , Roos Wynand P. , Christmann Markus , Menck Carlos F.M. , Kaina Bernd
Published: December 2007

Glioblastoma multiforme is the most severe form of brain cancer. First line therapy includes the methylating agent temozolomide and/or the chloroethylating nitrosoureas [1-(2-chloroethyl)-1-nitrosourea; CNU] nimustine [1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea; ACNU], carmustine [1,3-bis(2-chloroethyl)-1-nitrosourea; BCNU], or lomustine [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; CCNU]. The mechanism of cell death after CNU treatment is largely unknown. Here we show that ACNU and BCNU induce apoptosis in U87MG [p53 wild-type (p53wt)] and U138MG [p53 mutant (p53mt)] glioma cells. However, contrary to what we observed previously for temozolomide, chloroethylating drugs are more toxic for p53-mutated glioma cells and induce both apoptosis and necrosis. Inactivation of p53 by pifithrin-α or siRNA down-regulation sensitized p53wt but not p53mt glioma cells to ACNU and BCNU. ACNU and BCNU provoke the formation of DNA double-strand breaks (DSB) in glioma cells that precede the onset of apoptosis and necrosis. Although these DSBs are repaired in p53wt cells, they accumulate in p53mt cells. Therefore, functional p53 seems to stimulate the repair of CNU-induced cross-links and/or DSBs generated from CNU-induced lesions. Expression analysis revealed an up-regulation of xpc and ddb2 mRNA in response to ACNU in U87MG but not U138MG cells, indicating p53 regulates a pathway that involves these DNA repair proteins. ACNU-induced apoptosis in p53wt glioma cells is executed via both the extrinsic and intrinsic apoptotic pathway, whereas in p53mt glioma cells, the mitochondrial pathway becomes activated. The data suggest that p53 has opposing effects in gliomas treated with methylating or chloroethylating agents and, therefore, the p53 status should be taken into account when deciding which therapeutic drug to use. [Cancer Res 2007;67(24):11886–95]
Flat Colorectal Cancers Are Genetically Determined and Progress to Invasion without Going through a Polypoid Stage
Authors: Uronis Joshua M. , Herfarth Hans H. , Rubinas Tara C. , Bissahoyo Anika C. , Hanlon Kathleen , Threadgill David W.
Published: December 2007

Growing evidence suggests that flat colorectal cancers (CRC) account for 10% to 20% of all CRCs and that these are frequently associated with more advanced pathologies. However, controversy exists as to the origin and progression of flat CRCs compared with the more common polypoid-type morphology. We report using the azoxymethane mouse model for human CRC that KK/HIJ and I/LNJ mice develop different frequencies of flat and polypoid tumors; 83% of colon tumors in I/LNJ mice are flat compared with only 19% in KK/HIJ mice, indicating a strong genetic predisposition to the development of specific CRC morphologies. Like polypoid tumors, all flat tumors show a significant increase in the level of nuclear β-catenin (CATNNB1), supported by similar frequencies of mutations in the phosphorylation domain–coding region (codons 32–41) of Catnnb1. However, in contrast to previous reports, tumors bearing higher “oncogenic potential” do not cluster in codon 41 of Catnnb1. There are no differences between flat and polypoid tumors in the frequency of mutations in codons 12 and 13 of Kras or codon 624 of Braf. Similarly, there are no differences between tumor morphologies in their location along the proximal-to-distal colonic axis or in the relative quantity of intratumor stromal myofibrobasts as marked by the expression of α-smooth muscle actin. Using a combination of serial colonoscopic and histologic analyses, we definitively show that flat CRCs do not develop de novo but progress through a flat adenomatous stage to invasive carcinoma without transit through an intermediary polypoid stage. [Cancer Res 2007;67(24):11594–600]
Altered MicroRNA Expression Confined to Specific Epithelial Cell Subpopulations in Breast Cancer
Authors: Sempere Lorenzo F. , Christensen Mette , Silahtaroglu Asli , Bak Mads , Heath Catherine V. , Schwartz Gary , Wells Wendy , Kauppinen Sakari , Cole Charles N.
Published: December 2007

MicroRNAs (miRNAs) are a new class of short noncoding regulatory RNAs (18–25 nucleotides) that are involved in diverse developmental and pathologic processes. Altered miRNA expression has been associated with several types of human cancer. However, most studies did not establish whether miRNA expression changes occurred within cells undergoing malignant transformation. To obtain insight into miRNA deregulation in breast cancer, we implemented an in situ hybridization (ISH) method to reveal the spatial distribution of miRNA expression in archived formalin-fixed, paraffin-embedded specimens representing normal and tumor tissue from >100 patient cases. Here, we report that expression of miR-145 and miR-205 was restricted to the myoepithelial/basal cell compartment of normal mammary ducts and lobules, whereas their accumulation was reduced or completely eliminated in matching tumor specimens. Conversely, expression of other miRNAs was detected at varying levels predominantly within luminal epithelial cells in normal tissue; expression of miR-21 was frequently increased, whereas that of let-7a was decreased in malignant cells. We also analyzed the association of miRNA expression with that of epithelial markers; prognostic indicators such as estrogen receptor, progesterone receptor, and HER2; as well as clinical outcome data. This ISH approach provides a more direct and informative assessment of how altered miRNA expression contributes to breast carcinogenesis compared with miRNA expression profiling in gross tissue biopsies. Most significantly, early manifestation of altered miR-145 expression in atypical hyperplasia and carcinoma in situ lesions suggests that this miRNA may have a potential clinical application as a novel biomarker for early detection. [Cancer Res 2007;67(24):11612–20]
Adenovirus-Based Strategies Overcome Temozolomide Resistance by Silencing the O6-Methylguanine-DNA Methyltransferase Promoter
Authors: Alonso Marta M. , Gomez-Manzano Candelaria , Bekele B. Nebiyou , Yung W.K. Alfred , Fueyo Juan
Published: December 2007

Currently, the most efficacious treatment for malignant gliomas is temozolomide; however, gliomas expressing the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) are resistant to this drug. Strong clinical evidence shows that gliomas with methylation and subsequent silencing of the MGMT promoter are sensitive to temozolomide. Based on the fact that adenoviral proteins directly target and inactivate key DNA repair genes, we hypothesized that the oncolytic adenovirus Δ-24-RGD could be successfully combined with temozolomide to overcome the reported MGMT-mediated resistance. Our studies showed that the combination of Δ-24-RGD and temozolomide induces a profound therapeutic synergy in glioma cells. We observed that Δ-24-RGD treatment overrides the temozolomide-mediated G2-M arrest. Furthermore, Δ-24-RGD infection was followed by down-modulation of the RNA levels of MGMT. Chromatin immunoprecipitation assays showed that Δ-24-RGD prevented the recruitment of p300 to the MGMT promoter. Importantly, using mutant adenoviruses and wild-type and dominant-negative forms of the p300 protein, we showed that Δ-24-RGD interaction with p300 was required to induce silencing of the MGMT gene. Of further clinical relevance, the combination of Δ-24-RGD and temozolomide significantly improved the survival of glioma-bearing mice. Collectively, our data provide a strong mechanistic rationale for the combination of oncolytic adenoviruses and temozolomide, and should propel the clinical testing of this therapy approach in patients with malignant gliomas. [Cancer Res 2007;67(24):11499–504]
Zoledronic acid affects over-angiogenic phenotype of endothelial cells in patients with multiple myeloma
Authors: Scavelli Claudio , Di Pietro Giulia , Cirulli Teresa , Coluccia Mauro , Boccarelli Angela , Giannini Teresa , Mangialardi Giuseppe , Bertieri Raffaello , Coluccia Addolorata Maria Luce , Ribatti Domenico , Dammacco Franco , Vacca Angelo
Published: December 2007

Therapeutic doses of zoledronic acid markedly inhibit in vitro proliferation, chemotaxis, and capillarogenesis of bone marrow endothelial cells of patients with multiple myeloma. Zoledronic acid also induces a sizeable reduction of angiogenesis in the in vivo chorioallantoic membrane assay. These effects are partly sustained by gene and protein inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in an autocrine loop. Mevastatin, a specific inhibitor of the mevalonate pathway, reverts the zoledronic acid antiangiogenic effect, indicating that the drug halts this pathway. Our results provide evidence of a direct antiangiogenic activity of zoledronic acid on multiple myeloma patient-derived endothelial cells due to at least four different mechanisms identified either in vitro or in vivo. Tentatively, we suggest that the zoledronic acid antitumoral activity in multiple myeloma is also sustained by antiangiogenesis, which would partly account for its therapeutic efficacy in multiple myeloma. [Mol Cancer Ther 2007;6(12):3256–62]
New inhibitors of ABCG2 identified by high-throughput screening
Authors: Henrich Curtis J. , Robey Robert W. , Bokesch Heidi R. , Bates Susan E. , Shukla Suneet , Ambudkar Suresh V. , Dean Michael , McMahon James B.
Published: December 2007

In order to identify novel inhibitors of the ATP-binding cassette transporter, ABCG2, a high-throughput assay measuring the accumulation of the ABCG2 substrate pheophorbide a in ABCG2-overexpressing NCI-H460 MX20 cells was used to screen libraries of compounds. Out of a library of 7,325 natural products and synthetic compounds from the National Cancer Institute/Developmental Therapeutics Program collection, 18 were found to inhibit ABCG2 at 10 μmol/L. After eliminating flavonoids and compounds of limited availability from the 18 original compounds, 10 of the 11 remaining compounds reversed mitoxantrone resistance in NCI-H460/MX20 cells and prevented ABCG2-mediated BODIPY-prazosin transport in ABCG2-transfected HEK293 cells, confirming an interaction with ABCG2. Based on the activity profiles and the availability of materials, five inhibitors were examined for their ability to compete with [125I]iodoarylazidoprazosin labeling of ABCG2, increase binding of the anti-ABCG2 antibody 5D3, and prevent P-glycoprotein or multidrug resistance protein 1–mediated transport. At a concentration of 20 μmol/L, all of the compounds reduced iodoarylazidoprazosin labeling by 50% to 80% compared with controls. All five compounds also increased 5D3 labeling of ABCG2, indicating that these compounds are inhibitors but not substrates of ABCG2. None of the compounds affected P-glycoprotein–mediated rhodamine 123 transport, whereas three affected multidrug resistance protein-1–mediated calcein transport at 25 μmol/L, suggesting that the compounds are relatively specific for ABCG2. These five novel inhibitors of ABCG2 activity may provide a basis for further investigation of ABCG2 function and its relevance in multidrug resistance. [Mol Cancer Ther 2007;6(12):3271–8]
Antineoplastic agents target the 25-hydroxyvitamin D3 24-hydroxylase messenger RNA for degradation: implications in anticancer activity
Authors: Tan Joseph , Dwivedi Prem P. , Anderson Paul , Nutchey Barbara K. , O'Loughlin Peter , Morris Howard A. , May Brian K. , Ferrante Antonio , Hii Charles S.
Published: December 2007

Calcitriol or 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] has antitumor activity and hence its levels in patients may play an important role in disease outcome. Here, we report that the antineoplastic agents, daunorubicin hydrochloride, etoposide, and vincristine sulfate inhibited the ability of 1,25(OH)2D3 to cause the accumulation of mRNA for kidney 25-hydroxyvitamin D3 24-hydroxylase (CYP24), an enzyme which catabolizes this hormone. This was not due to a drug-induced cytotoxic effect, reduction in the expression of the vitamin D receptor or inhibition of the vitamin D receptor–mediated activation of the mitogen-activated protein kinases or CYP24 promoter activity. Interestingly, there was selective degradation of CYP24 mRNA in the presence of the drugs. This was accompanied by an enhancement in the levels of 1,25(OH)2D3 in cells incubated with 25-hydroxy vitamin D3. These data identify a novel mechanism of action of some commonly used antineoplastic agents which by decreasing the stability of CYP24 mRNA would prolong the bioavailability of 1,25(OH)2D3 for anticancer actions. [Mol Cancer Ther 2007;6(12):3131–8]
Chemopreventive effects of silymarin and silibinin on N-butyl-N-(4-hydroxybutyl) nitrosamine–induced urinary bladder carcinogenesis in male ICR mice
Authors: Tyagi Alpna , Raina Komal , Singh Rana P. , Gu Mallikarjuna , Agarwal Chapla , Harrison Gail , Glode L. Michael , Agarwal Rajesh
Published: December 2007

Effective strategies are lacking for the management of urinary bladder cancer for which smoking is a potential risk factor. Herein, we evaluated chemoprevention of urinary bladder cancer by natural chemopreventive agents, silymarin and silibinin, in a preclinical animal (ICR mouse) model of bladder cancer induced by tobacco smoke carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (OH-BBN). Mice were fed p.o. with saline or OH-BBN (0.05%, w/v) in drinking water for 6 weeks or with silymarin or silibinin (200 mg/kg body weight for both) starting 1 week before OH-BBN exposure for 51 weeks. Silymarin and silibinin strongly arrested OH-BBN–induced tumor progression at the stage of mucosal dysplasia with a striking reduction in papillary nodular dysplasia as well as invasive carcinoma. Some silymarin- or silibinin-treated mice developed no urothelial lesions in spite of OH-BBN exposure. Immunohistochemical analyses at study conclusion revealed that silymarin and silibinin decreased cell proliferation by 42% (P < 0.001) and 44% (P < 0.001) and increased apoptosis by 4-fold (P < 0.05) and 6-fold (P < 0.05) in OH-BBN–induced urothelium, respectively. Antiproliferative and apoptotic effects of silymarin and silibinin were associated with decreases in (a) cyclin D1 protein level and extracellular signal–regulated kinase-1/2 phosphorylation and in (b) protein levels of survivin and nuclear phospho-p65 (Ser276 and Ser536), respectively. Together, these results suggest that silymarin and silibinin inhibit chemically induced urinary bladder tumor growth and progression possibly by inhibiting cell proliferation and enhancing apoptosis. [Mol Cancer Ther 2007;6(12):3248–55]
Learning Curve of Conventional Transbronchial Needle Aspiration in Pulmonologists Experienced in Bronchoscopy
Authors: Hermens Frank H.W. , Limonard Gijs J.M. , Termeer René , van den Berg Willem , Visser Frank J. , Hol Bernard E.A. , Janssen Julius P.
Published: December 2007

Background: Despite its proven efficacy, transbronchial needle aspiration (TBNA) remains an underutilized technique for sampling enlarged mediastinal lymph nodes in the staging of lung cancer. Previous investigators have reported on TBNA experience, but without mentioning individual learning curves related to lymph node size in pulmonologists experienced in bronchoscopy. Objectives: The aim of this study was to evaluate the TBNA learning curve in a group of pulmonologists already experienced in bronchoscopy, and to relate their yields to lymph node size and location. Methods: Data on TBNA yield and related lymph node size were collected retrospectively for five individual pulmonologists. Results: The diagnostic yield of five pulmonologists who started to perform TBNA was evaluated over the first 32 months. TBNA was performed on 138 lymph nodes in 119 patients. The overall diagnostic yield was 77% (range 67–91%). The average diagnostic yield increased from 77% at the start of the learning curve to 82% after 32 months of experience. It was related to lymph node size, but not to lymph node location. The average lymph node size was 22 mm. Conclusions: Satisfactory results were obtained immediately after introduction of TBNA in the bronchoscopy workup. There is no significant TBNA learning curve. The diagnostic yield was related to lymph node size but not to lymph node location.
Radiofrequency Ablation of Atrial Fibrillation
Authors: Pratola Claudio , Baldo Elisa , Notarstefano Pasquale , Toselli Tiziano , Ferrari Roberto
Published: December 2007

Background—

Several approaches have been developed for radiofrequency catheter ablation of atrial fibrillation, but the correct intraprocedural end point is still under debate, and few data exist about the destiny of ablation lesions over time. The aim of the present study was to evaluate the long-term maintenance of intraprocedural end points of ablation procedures.

Methods and Results—

Inclusion criteria were (1) a previous ablation procedure of pulmonary vein (PV) encircling performed for drug-refractory persistent atrial fibrillation; (2) a “complete” intraprocedural end point, which consisted of voltage abatement inside the lesions, PV disconnection, and exit-block pacing from inside the lesions, attained in all PVs; and (3) stable sinus rhythm documented during a minimum follow-up of 2.5 years after the procedure. Twenty volunteers were selected (12 males, mean age 59±7 years) and underwent a repeat electrophysiological study. After a follow-up of 36.4±4.7 months, complete voltage abatement was maintained around 32 PVs (40.0%), PV disconnection persisted in 12 (37.5%) of the previously isolated PVs, and exit block was present in 39 PVs (48.7%). Ten patients who underwent a redo ablation procedure because of recurrences of atrial fibrillation were used as the control group. Differences in intraprocedural end-point maintenance between the 2 groups were not statistically significant.

Conclusions—

Common intraprocedural end points such as voltage abatement, PV disconnection, and exit block persist only in a limited number of patients, even when the outcome is favorable during follow-up. Further investigation will be required to determine whether such data will have implications for ablation strategies.
The Interaction Between Coronary Endothelial Dysfunction, Local Oxidative Stress, and Endogenous Nitric Oxide in Humans
Authors: Lavi Shahar , Yang Eric H. , Prasad Abhiram , Mathew Verghese , Barsness Gregory W. , Rihal Charanjit S. , Lerman Lilach O. , Lerman Amir
Published: December 2007

In vitro and animal studies suggest that oxidative stress is associated with endothelial dysfunction. We tested whether local oxidative stress and nitric oxide (NO) bioavailability in the coronary circulation is associated with coronary endothelial dysfunction in humans. Blood samples were obtained simultaneously from the left main coronary artery and the coronary sinus for measurement of F2-isoprostanes, myeloperoxidase, nitrotyrosine, and superoxide dismutase in 20 patients without significant coronary disease. Afterward, coronary blood flow and the vascular response to intracoronary acetylcholine and
N
G
-monomethyl-
L
-arginine (L-NMMA) were assessed. The gradient of isoprostanes between the arterial levels and coronary sinus correlated with the change in coronary artery diameter in response to acetylcholine (
r
=−0.79,
P
<0.0001). Isoprostanes net production across the left anterior descending artery territory correlated with a decrease in superoxide dismutase activity (
r
=0.66,
P
=0.002) and decrease in coronary artery diameter in response to L-NMMA
(r
s
=0.48,
P
<0.05). Myeloperoxidase and nitrotyrosine gradients were similar in patients with endothelial dysfunction and controls. The effect of L-NMMA was similar in both groups. We conclude that coronary endothelial dysfunction in humans is characterized by local enhancement of oxidative stress without a decrease in basal NO release. This study supports the hypothesis that local oxidative stress has a role in reduction of NO bioavailability in humans with coronary endothelial dysfunction.
Apocynin Is Not an Inhibitor of Vascular NADPH Oxidases but an Antioxidant
Authors: Heumüller Sabine , Wind Sven , Barbosa-Sicard Eduardo , Schmidt Harald H.H.W. , Busse Rudi , Schröder Katrin , Brandes Ralf P.
Published: December 2007

A large body of literature suggest that vascular reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases are important sources of reactive oxygen species. Many studies, however, relied on data obtained with the inhibitor apocynin (4′-hydroxy-3′methoxyacetophenone). Because the mode of action of apocynin, however, is elusive, we determined its mechanism of inhibition on vascular NADPH oxidases. In HEK293 cells overexpressing NADPH oxidase isoforms (Nox1, Nox2, or Nox4), apocynin failed to inhibit superoxide anion generation detected by lucigenin chemiluminescence. In contrast, apocynin interfered with the detection of reactive oxygen species in assay systems selective for hydrogen peroxide or hydroxyl radicals. Importantly, apocynin interfered directly with the detection of peroxides but not superoxide, if generated by xanthine/xanthine oxidase or nonenzymatic systems. In leukocytes, apocynin is a prodrug that is activated by myeloperoxidase, a process that results in the formation of apocynin dimers. Endothelial cells and smooth muscle cells failed to form these dimers and, therefore, are not able to activate apocynin. Dimer formation was, however, observed in Nox-overexpressing HEK293 cells when myeloperoxidase was supplemented. As a consequence, apocynin should only inhibit NADPH oxidase in leukocytes, whereas in vascular cells, the compound could act as an antioxidant. Indeed, in vascular smooth muscle cells, the activation of the redox-sensitive kinases p38-mitogen-activate protein kinase, Akt, and extracellular signal–regulated kinase 1/2 by hydrogen peroxide and by the intracellular radical generator menadione was prevented in the presence of apocynin. These observations indicate that apocynin predominantly acts as an antioxidant in endothelial cells and vascular smooth muscle cells and should not be used as an NADPH oxidase inhibitor in vascular systems.
Importance of Measuring the Time Course of Flow-Mediated Dilatation in Humans
Authors: Black Mark A. , Cable N. Timothy , Thijssen Dick H.J. , Green Daniel J.
Published: December 2007

Flow-mediated dialation (FMD) is widely used to describe conduit artery endothelial function. The traditional approaches to FMD calculation assess diameter change at arbitrary time points after occluding cuff deflation. The aim of this study was to examine the time course of brachial artery FMD after a 5-minute period of forearm ischemia in 12 young, 12 fitness matched older and 12 older untrained subjects. Edge-detection and wall tracking of high resolution B-mode arterial ultrasound images, combined with synchronized Doppler waveform envelope analysis, were used to calculate brachial artery diameter, blood flow, and shear rate continuously across the cardiac cycle after forearm ischemia. FMD was significantly higher in young healthy subjects (7.8±3.2%) compared with sedentary older subjects (5.2±2.8%,
P
<0.05) but not trained older subjects (6.4±2.3%). Time to peak diameter differed between young (50±11 seconds) and both older groups (trained; 80±21,
P
<0.001; sedentary: 83±36 seconds,
P
<0.001). A large proportion (>42%) of true peak diameters fell outside the time frames typically used to assess FMD in the literature. When calculated according to the commonly used approach, ie, 60 secs after cuff deflation, FMD was significantly lower compared with true peak FMD in all groups (
P
<0.001), and no differences were evident between the groups. The time course of FMD differs significantly between young and older subjects. Studies assuming that peak dilation occurs at an arbitrary time point, or within limited time windows, may draw misleading conclusions regarding differences between groups. More sophisticated approaches to measurement of FMD are required if it is to be considered a valid biomarker of vascular disease.
Compassion, Suffering and the Self
Authors: Williams Christopher R.
Published: December 2007

Concerns for social justice have figured prominently in much current sociological and criminological discourse. Often implicated by these critiques is the enduring presence of harm, suffering and injustice in contemporary western society — particularly as these are reinforced and perpetuated by organizational and institutional policies and practices. Less often considered are the moral-psychological foundations that give rise to these problems and pathologies. Opposing the struggle for social justice, it could be argued, is a generalized impoverishment of moral sensibilities that would forefront the good of the other, thereby giving rise to relationships, communities and institutional policies and practices conducive to widespread human flourishing. This article suggests that meaningful social transformation in pursuit of social justice requires significant alterations of our collective value framework. More specifically, what seems needed is an overcoming of habitual cognitive and affective obstacles to the embodiment of compassion. Two such impediments to compassion are explored: appraisals of desert and responsibility; and perceptions of likeness and difference. The underlying concern throughout is to affirm the importance of the virtue of compassion as a crucial component of the struggle for social justice and human flourishing.