bluuebunny/crossref_metadata_2025 huggingface dataset:
Peyer's Patches Are Required for Intestinal Immunoglobulin A Responses toSalmonellaspp
Authors: Hashizume Tomomi , Togawa Atsushi , Nochi Tomonori , Igarashi Osamu , Kweon Mi-Na , Kiyono Hiroshi , Yamamoto Masafumi
Published: December 2007

Previous studies have shown that Peyer's patches (PP) are not required for intestinal immunoglobulin A (IgA) responses to orally administered soluble protein. However, the roles of PP in regulation of mucosal immune responses against bacterial antigen remain to be clarified. In the present study, we generated several gut-associated lymphoreticular tissue-null mice by treatment with anti-interleukin-7 receptor antibody, the fusion protein of lymphotoxin β receptor and IgG Fc, and/or tumor necrosis factor receptor p55 and IgG Fc. These mice were then immunized with recombinantSalmonellaexpressing the C fragment of the tetanus toxin (rSalmonella-Tox C). Orally immunized PP-null mice as well as isolated lymphoid follicle (ILF)-null, PP/ILF-null, and PP/ILF/mesenteric lymph node-null mice induced identical levels of tetanus toxoid (TT)-specific systemic IgG responses to those of control mice. However, PP-null mice, but not ILF-null mice, failed to induce TT-specific intestinal IgA antibodies. Analysis of TT-specific CD4+T-cell responses showed a reduction of gamma interferon (IFN-γ) synthesis in the intestinal lamina propriae of PP-null mice given oral rSalmonella-Tox C. In contrast, TT-specific IFN-γ responses in the spleen and delayed-type hypersensitivity responses were intact in those immunized mice. Interestingly,Salmonellalipopolysaccharide (LPS)-specific fecal IgA responses were not elicited in PP-null mice, while serum IgG anti-LPS antibodies were identical to those of control mice. These results suggest that while none of the gut-associated lymphoreticular tissues are required for the induction of systemic immune responses, PP are an essential lymphoid tissue for induction and regulation of intestinal IgA immunity against orally administered rSalmonella.
Physical Linkage of Naturally Complexed Bacterial Outer Membrane Proteins Enhances Immunogenicity
Authors: Macmillan Henriette , Norimine Junzo , Brayton Kelly A. , Palmer Guy H. , Brown Wendy C.
Published: December 2007

The outer membrane proteins (OMPs) of bacterial pathogens are essential for their growth and survival and especially for attachment and invasion of host cells. Since the outer membrane is the interface between the bacterium and the host cell, outer membranes and individual OMPs are targeted for development of vaccines against many bacterial diseases. Whole outer membrane fractions often protect against disease, and this protection cannot be fully reproduced by using individual OMPs. Exactly how the interactions among individual OMPs influence immunity is not well understood. We hypothesized that one OMP rich in T-cell epitopes can act as a carrier for an associated OMP which is poor in T-cell epitopes to generate T-dependent antibody responses, similar to the hapten-carrier effect. Major surface protein 1a (MSP1a) and MSP1b1 occur as naturally complexed OMPs in theAnaplasma marginaleouter membrane. Previous studies demonstrated that immunization with the native MSP1 heteromer induced strong immunoglobulin G (IgG) responses to both proteins, but only MSP1a stimulated strong CD4+T-cell responses. Therefore, to test our hypothesis, constructs of CD4+T-cell epitopes from MSP1a linked to MSP1b1 were compared with individually administered MSP1a and MSP1b1 for induction of MSP1b-specific IgG. By linking the T-cell epitopes from MSP1a to MSP1b1, significantly higher IgG titers against MSP1b1 were induced. Understanding how the naturally occurring intermolecular interactions between OMPs influence the immune response may lead to more effective vaccine design.
MINIMAL SEMIGROUPS GENERATING VARIETIES WITH COMPLEX SUBVARIETY LATTICES
Authors: LEE EDMOND W. H.
Published: December 2007

A semigroup is complex if it generates a variety with the property that every finite lattice is embeddable in its subvariety lattice. In this paper, subvariety lattices of varieties generated by small semigroups will be investigated. Specifically, all complex semigroups of minimal order will be identified.
FRACTALITY IN LITERARY NARRATIVE
Authors: RAMÍREZ-MALO J. B. , DOMÍNGUEZ M. , BELLIDO F.
Published: December 2007

In the context of current Narratology, a novel can be regarded as an information generator system. This information can be symbolically and numerically codified and, subsequently, studied by nonlinear characteristic geometrical methods. Using this approach, geometric structures underlying the narrative discourse become evident. In this work, using a particular novel as our experimental data source, a formal expression for a discrete dynamical system is deduced, which generates a representative orbit of the narrative discourse evolution. The fractal dimension of this orbit is calculated from the correlation dimension and its deterministic character is unambiguously proved by solving the associated embedding problem. Finally, we describe the general features that a novel must satisfy in order to apply the proposed procedure.
Desk studies
Authors: Charman J. H.
Published: December 2007

Introduction

In many, if not most, instances of civil engineering or building projects that have suffered time or cost over-runs or have required premature remedial works, the reason can be attributed to geotechnical problems as a result of inadequate planning or poor interpretation of site investigation (Site Investigation Steering Group 1993). The difficulties experienced in civil engineering projects which can be related to the ground conditions occur either as a result of unawareness or as a result of failure to grasp the implications of a certain set of ground conditions on the proposed engineering design (Fookes 1991
a
). The site ground conditions pertaining at the present are the result of a long history of geological processes, from global tectonics, through climatic change to relatively recent landscape-forming processes. Major impact may also have been caused by man’s historical usage of the site. Much of this history of usage can be derived by the specialist from existing scientific records and published maps. The desk study is a fundamental first step in any site investigation programme. Its purpose is to access published information and other available records pertinent to the region, area and immediate environs of the project development site. This would include an investigation of geology, geomorphology, aerial photographs and other archival data.

The recently published updated British Standard
Code of Practice for Site Investigation
, BS5930:1999, is unequivocal in stating that Stage 1 of a site investigation comprises a desk study and site reconnaissance and it should be
Geographical information systems
Authors: Nathanail C. P. , Symonds A.
Published: December 2007

Definition of Geographical Information Systems (GIS)

GIS software can be used to manipulate and display spatial information. Burrough & McDonnell (1998, p. 11) provide a number of definitions of GIS, based upon the concepts of the toolbox, database and organizational systems. Examples of each include:

Toolbox definition: ‘...
a system for capturing, storing, checking, manipulating, analysing and displaying data which are spatially referenced to the earth
...’

Database definition: ‘...
any manual or computer based set of procedures used to store and manipulate geographically referenced data
...’

System definition: ‘
An organized collection of computer hardware, software, geographic data and personnel designed to efficiently capture, store, update, manipulate, analyse, and display all forms of geographically referenced information
’.

Organization based definition: ‘...
a decision support system involving the integration of spatially referenced data in a problem solving environment
...’

In the context of terrain evaluation the ‘organization based’ definition is considered to be the most appropriate. This is because the intended output of terrain evaluation is to support a decision making process. More specifically, GIS can help the terrain evaluation process answer questions such as those in Table 1.

GIS data models

Present day GIS store information in both raster and vector formats. Raster data comprise ‘pixels’ or tiles that fill space, thus something is stored about everywhere. The raster data structure has its origins in remote sensing and digital image processing software. Vector data are stored as points, lines or polygons, thus something is stored only where a change occurs.
Terrain systems mapping
Authors: Phipps P. J.
Published: December 2007

Description

The term ‘terrain systems mapping’ originated in the 1930s and early 1940s when the requirement was identified to classify large areas of terrain for the purposes of locating potential agricultural and economic resources, and identifying suitable sites for development in mainly undeveloped rural areas (Mitchell 1973). The view is adopted in this paper that ‘terrain’ and ‘land’ are synonymous, which follows both Christian & Stewart (1968) and Townshend (1981).

In many respects the methodology behind terrain systems mapping has not altered since one of its first significant applications came to prominence in Australia, with the publication of a series of reports summarizing terrain systems mapping of the Australian Territories (Christian & Stewart 1952). Areas up to hundreds of square kilometres were delineated in which characteristic assemblages of topography, soils and vegetation could be identified. This association is described in Cooke & Doornkamp (1990) after Stewart & Perry (1953). These authors established that the topography and soils are dependent on the nature of the underlying rocks (geology), the erosional and depositional processes that have produced the present topography (geomorphology) and the climate under which these processes have operated. Thus the land system is a scientific classification of country or landscape based on topography, soils and vegetation correlated with geology, geomorphology and climate.

The basic good practice for developing a suite of terrain systems maps has been succinctly covered in the 1982 Engineering Group Working Party Report. The three main landform units of terrain
Creation of functional ground models in an urban area
Authors: Edwards R. J. G.
Published: December 2007

Rationale

The ability to see the ground surface in an urban environment is limited by access and the amount of natural ground exposure. This is typically less than 10% by area. The assessment of the probable ground structure and the behaviour of critical ground elements can be achieved by comparison with non-urban environments exhibiting similar landforms. This model can be verified by a detailed study of historic maps and a review of existing local subsurface information.

The site

The City of Cardiff has largely been constructed in the last 150 years. The area studied relates to the whole city land area lying to the south of the A48T and between the west banks of the rivers Ely and Rhymney.

Area model

The area lies substantially on the Severn Levels, which comprise a recent tidal coastal margin zone of the Severn estuary. The area consists of a glaciated land surface comprising Mercia Mudstone and Dolomitic Conglomerate draped by a thin and partly discontinuous layer of glacial detritus that includes two identifiable layers of till and a consistent layer of fluvio-glacial sands and gravels which forms the dominant aquifer. These strata reflect Devensian and Flandrian glacial advance and recession.

To the south of the historic natural shoreline a series of post-glacial foreshore alluvia are superimposed on the late-glacial surface and form a confining layer to the underlying fluvio-glacial sand and gravel aquifer. These alluvia represent a series of more recent marine transgressions modified by sea defence construction works of Bronze Age to late mediaeval antiquity.
Pipeline route selection and ground characterization, Algeria
Authors: Fookes P. G. , Lee E. M. , Sweeney M.
Published: December 2007

Purpose of the study

A terrain evaluation of a remote area of hyperarid desert in central Algeria was undertaken as part of the frontend engineering design (FEED) studies for a gas field development. The work was part of the identification of suitable route options for a large buried pipeline between the gas fields and the existing pipeline network, some 500 km to the north. The results of the study provided information to support construction costings and preliminary engineering design and construction evaluation of potential geohazards and geotechnical issues, notably trench excavatability and dune mobility, and to help subsequent selection of a specific alignment within the corridor.

Techniques used

The stages involved in the study are summarized in Figure 1, the work formed part of a broader programme of geological studies to characterize ground conditions along a preferred pipeline route. The basis for the preliminary terrain evaluation was a combination of a desk study review and interpretation of a 1:100 000 scale composite (SPOT and Landsat TM) satellite image of the route corridor (approximately 100 km either side of the proposed route). This evaluation was carried out in the UK and was used to identify locations for a limited number of boreholes and trenches. The results from the boreholes and trenches were used, along with a limited ‘ground truthing’ programme in Algeria, to refine the terrain evaluation and provide typical engineering geological and geomorphological characteristics for each terrain unit.

The terrain evaluation involved the identification of generic
terrain models
(i.e. landscape types) each with a characteristic assemblage of
terrain units
.
Terrain hazard around the Ok Tedi copper mine, Papua New Guinea
Authors: Hearn G. J. , Blong R. , Humphreys G.
Published: December 2007

Rationale

Located in the remote Star Mountains of Western Province, Papua New Guinea, the Ok Tedi open-cut copper mine operates under conditions of particular topographical and geotechnical adversity. Slopes are frequently steep, rocks are highly fractured and weakened due to tectonics and weathering, and rainfall is world record-breaking, with annual totals exceeding 10 m in the vicinity of the mine (Jones & Maconochie 1990). The mine is planned to occupy an area of 2 km diameter with a depth of 500 m at an altitude of 1800 m a.s.l. The mine supply corridor, along which power, food and other essential materials are brought in and copper concentrate is piped out, is 160 km long, and is itself at risk from slope, flooding and erosional hazards.

The threat posed by these hazards to the operation of the mine and the viability of its supply corridor has been recognized and evaluated by the geotechnical department of Ok Tedi Mining Ltd (OTML) since the project‘s inception. However, the severity and proximity of this risk were perhaps not fully realized until 1989 when a rock avalanche involving perhaps as much as 70 x 10
6
m
3
of material occurred within a very short distance of the mine office. The collapse of the mountainside was dramatic and was considered to have been responsible for the seismic event recorded at the time of failure in Port Moresby, approximately 800 km away. Although the infrastructure of the mine was not directly affected by this failure, it served as a
Blowing sand and dust hazard, Tabuk, Saudi Arabia
Authors: Jones D. K. C.
Published: December 2007

Rationale

Blowing sand and dust are increasingly common hazards associated with dryland economic development, largely because of disruption of desert soils by human activity (Cooke
et al.
1982; Cooke & Doornkamp 1990). Blowing sand has long been recognized as a problem; it has clearly identifiable sources (blowouts, scour zones) and sinks (drifts, dunes) and is amenable to a range of management techniques once the problem has been assessed objectively (Cooke
et al
. 1982, 1993). The ‘dustification’ problem, by contrast, has come to prominence morev recently. It is a more complex process involving greater transport distances, and results in a very wide range of adverse impacts including abrasion to paintwork, damage to machinery, contamination of houses, food and water, electrical short-circuits, disruption to radio signals, killing of plants, suffocation of livestock, the spreading of disease, disruption to transport, and general reduction in environmental quality and amenity. The different modes of transport - saltation for sand and suspension for dust - means that while defensive measures may be employed against sand, they are less effective in the case of dust where the emphasis must be placed on curbing the production of fine-grained sediment from identified source areas.
Land use planning in unstable areas: Ventnor, Isle of Wight
Authors: Lee E. M. , Moore R.
Published: December 2007

Purpose of the study

Recent UK Government guidance has emphasized the need to take account of landslide problems in the land use planning process (DoE 1990, 1996). To assist the implementation of this policy, the then Department of the Environment (DoE) commissioned a number of demonstration projects to develop approaches to assess the potential for landsliding and to identify the best ways of incorporating this information in the planning process.

In the UK there are many situations where historic development has resulted in the concentration of urban development and infrastructure on unstable ground. This is often on a scale such that total avoidance or abandonment are out of the question, as is recourse to large-scale and inordinately expensive engineering solutions (e.g. the Bath area, Lyme Regis, the South Wales valleys, etc. (Jones & Lee 1994)). Under these circumstances, detailed knowledge of slope instability is required so that pragmatic policies can be developed to assist communities to reduce risk. This approach has been pioneered by the detailed study of the Undercliffat Ventnor, on the south coast of the Isle of Wight, England (Lee & Moore 1991; Lee
et al
. 1991
a,b,c
; Moore
et al
. 1991).
Terrain evaluation for military purposes: examples from the Balkans
Authors: Nathanail C. P.
Published: December 2007

Aim/purpose

Terrain has influenced military commanders and the outcome of military operations since ancient times (Rose & Nathanail 2000). The aim of terrain evaluation in support of military operations revolves around gaining maximum operational advantage from the ground. In war this includes maximizing the mobility of your own forces and ensuring the survival of your troops and in turn denying both of these to the enemy’s forces. Armed forces are also increasingly being used in peace keeping or peace enforcing roles. In such cases the aim of terrain evaluation is to support the humanitarian efforts of the military.

The United Nations Protection Force (UNPROFOR) was tasked with delivering humanitarian relief in Bosnia Herzegovina (Fig. 1). British troops were based in four main compounds at Vitez (School and Garage), Tuzla, Gornji Vakuf and Tomislavgrad. Terrain evaluation principles were used to advise on the feasibility of constructing water supply boreholes within the perimeter wire of each compound to ensure a secure supply of water independent of any of the warring factions.

Later, the NATO Implementation Force (IFOR) was tasked with ensuring that the provisions of the Dayton Peace Agreement were fully implemented (Haynes
et al.
1997). One of the concerns was to ensure that the boundary between warring factions, which had been agreed on maps, was securely and accurately delineated on the ground. Terrain evaluation principles were applied to advise on the ease of installation and, malicious, extraction of border marker posts.
Slope instability within a residential area in Cleveland, UK
Authors: Phipps P. J.
Published: December 2007

Purpose of survey

An integrated geomorphological survey involving detailed geomorphological field mapping and associated desk studies is a powerful tool in identifying the locations and nature of slope instability within built-up areas. When supplemented with existing or specifically designed ground investigation, initial instability processes and mechanism models can be re-evaluated and refined. This paper provides an example of a geomorphological survey at Yarm, County Cleveland, which aimed to delineate unstable areas and address the potential causes of ground movements within a residential area.

The site

Valley Drive and Denevale are situated at the far eastern end of Yarm, on the south side of the River Tees, near its confluence with the River Leven. The natural valley side slopes are about 10–15° in this area and rise up towards a plateau surface at 30 m A.O.D., some 20–25 m above the Tees Valley. In order to facilitate development on the valley side slopes, extensive cut and fill operations have been carried out. Artificial slopes steepened up to 37° and vertical walls to 3 m high were also evident.

The published 1:10 560 scale British Geological Survey map (1976) and the 1:50 000 scale British Geological Survey map (1987) indicate Triassic Sherwood Standstone formation (formerly ‘Bunter– Sandstone) as outcropping within the river channel. The valley side slopes have been developed in thick superficial deposits which comprise Upper and Lower Glacial Till units, separated by Glacial Sands and Gravels overlying Laminated Clay. These materials are believed to have been deposited during the
Slope stability hazard assessment: Coalport Railway Bridge, Shropshire
Authors: Shilston D. T.
Published: December 2007

Objectives

Escalating costs, disputes and delays can arise during construction as a result of inadequate research at the early stages of project development. The assessment of slope stability hazard described in this case history illustrates the relative ease, and therefore low cost, of rapidly accessing and evaluating a wide range of desk study and walkover survey data pertinent to a construction project.

The project

Coalport is a village on the north bank of the River Severn in the Ironbridge Gorge, near the new town of Telford, Shropshire. Coalport Railway Bridge (BC 17) is at the site of the former Coalport Railway Station. It is immediately adjacent to the much older Coalport (river) Bridge and carries the road from the river bridge across the former railway line (see Figs 1 and 2).

As part of a programme of bridge inspection and strengthening, the Commission for New Towns engaged WS Atkins to assess the condition of Railway Bridge BC 17 and make recommendations for remedial measures.

An initial inspection of the Railway Bridge concluded that it was in a poor state of repair and that it may be at risk from ground movements caused by landslipping, being in an area that is well known for the presence of landslips (Carson & Fisher 1991). A more detailed desk study, including a walk-over survey, was therefore carried out specifically to assess the landslide hazard at the railway bridge and to help design the ground investigation that was planned as part of the design of remedial works to the bridge’s abutments.
Evolution of deformation styles at a major restraining bend, constraints from cooling histories, Mae Ping fault zone, western Thailand
Authors: Morley C. K. , Smith M. , Carter A. , Charusiri P. , Chantraprasert S.
Published: December 2007

The
c.
500-km-long Mae Ping fault zone trends NW–SE across Thailand into eastern Myanmar and has probably undergone in excess of 150 km sinistral motion during the Cenozoic. A large,
c.
150-km-long, restraining bend in this fault zone lies on the western margin of the Chainat duplex. The duplex is a low-lying region dominated by north–south-trending ridges of Mesozoic and Palaeozoic sedimentary, metamorphic and igneous rocks, flanked by flat, post-rift basins of Pliocene–Recent age to the north and south. A review of published cooling-age data, plus new apatite and zircon fission-track results indicates that significant changes in patterns of exhumation occurred along the fault zone with time. Oldest uplift and erosion (Eocene) occurred in the Umphang Gneiss region, west of an inferred thrust-dominated restraining-bend setting. From 36 Ma to 30 Ma, exhumation was strongest north of the duplex, along the NW–SE-trending segment of the fault zone at the (northern) exiting bend of the Chainat duplex. This region of the fault zone is characterized by a mid-crustal level shear zone 5–6 km wide (Lan Sang Gneisses), that passes to the NW into an apparent strike-slip duplex geometry. The deformation is interpreted to have occurred during passage around the northern restraining bend, which resulted in vertical thickening, uplift, erosion and extensional collapse of the northern side of the shear zone. This concentration of deformation at the bends at the ends of the restraining bend is thought to be a characteristic of strike-slip-dominated restraining bends. Following Late Oligocene–Early Miocene extension, there is apatite fission-track evidence for 22–18 Ma exhumation in the Chainat duplex, that coincides with a phase of inversion in the Phitsanulok Basin to the north. The Miocene–Recent history of the Chainat duplex is one of minor sinistral and dextral displacements, related to a rapidly evolving stress field, influenced by the numerous tectonic reorganizations that affected SE Asia during that time.
Evolution of a poly-deformed relay zone between fault segments in the eastern Southern Alps, Italy
Authors: Zampieri D. , Massironi M.
Published: December 2007

In the eastern Southern Alps (NE Italy), Liassic north–south extensional structures are prominent. The southern Trento Platform also experienced extension during the Palaeogene, when reactivation of some pre-existing faults occurred, coupled with nucleation of new faults. During Neogene shortening, these structures were reactivated once again, but with strike-slip kinematics. In this framework, the Gamonda–Tormeno restraining stepover represents the final result of an overlap zone which evolved through time. In the first stage (Lias to Early Cretaceous) a prominent splay developed at the tip of the Gamonda Fault by lateral propagation and breaching of independent segments. At the same time, there was kinematic interaction between the antithetic Gamonda and Tormeno faults, followed by diachronous motion on crossing faults and the development of a narrow graben. During the second stage of extensional tectonics (Palaeocene to Early Oligocene), the reactivation and propagation of the overlapping faults along with the generation of new faults led to deepening of the graben. In the third stage (Miocene to present), the final structure of a strike-slip restraining stepover was accomplished. Due to the mechanical stratigraphy and complex inherited architecture of the relay zone where stratigraphic sequences with different rheological properties are juxtaposed, the style of shortening is different in the western and eastern sides of the stepover. The Gamonda–Tormeno structure represents a unique example of how a relay zone may change through time.
Transpressional structures on a Late Palaeozoic intracontinental transform fault, Canadian Appalachians
Authors: Waldron J. W. F. , Roselli C. , Johnston S. K.
Published: December 2007

The east–west Minas fault zone, separating the Early Palaeozoic Meguma and Avalon terranes of the Appalachians, experienced dextral strike-slip motion during the Carboniferous. Abundant oblique contractional structures indicate localized dextral transpression, immediately south of the zone, probably associated with a restraining bend. Subsurface data indicate that the deformed Horton Group clastic rocks are thrust above younger Windsor Group evaporites.

Excellent exposures on wave-cut platforms of the Bay of Fundy show structures developed in transpression, including NE-trending upright and inclined folds; south-verging thrust and reverse faults; and NW-striking normal faults. Northwest-trending boudins, which are perpendicular and slightly rotated in a clockwise sense relative to fold hinges, provide a field indicator for dextral transpression. The earliest folds (F
1
) are curvilinear and may have formed by deformation of wet sediment. F
2
tectonic folds show weak axial-planar cleavage. Locally, these have been rotated into reclined orientations; spectacular downward-facing folds are probably due to refolding by more east–west F
3
folds. The structures observed are consistent with pure-shear-dominated transpression, with the local angle of convergence α increasing over time. This strain history is compatible with progressive strain partitioning, probably associated with the spreading of topography developed at the restraining bend.
Relatively simple through-going fault planes at large-earthquake depth may be concealed by the surface complexity of strike-slip faults
Authors: Graymer R. W. , Langenheim V. E. , Simpson R. W. , Jachens R. C. , Ponce D. A.
Published: December 2007

At the surface, strike-slip fault stepovers, including abrupt fault bends, are typically regions of complex, often disconnected faults. This complexity has traditionally led geologists studying the hazard of active faults to consider such stepovers as important fault segment boundaries, and to give lower weight to earthquake scenarios that involve rupture through the stepover zone. However, recent geological and geophysical studies of several stepover zones along the San Andreas fault system in California have revealed that the complex nature of the fault zone at the surface masks a much simpler and direct connection at depths associated with large earthquakes (greater than 5 km). In turn, the simplicity of the connection suggests that a stepover zone would provide less of an impediment to through-going rupture in a large earthquake, so that the role of stepovers as segment boundaries has probably been overemphasized. However, counter-examples of fault complexity at depth associated with surface stepovers are known, so the role of stepovers in fault rupture behaviour must be carefully established in each case.
Kinematics of the Amanos Fault, southern Turkey, from Ar/Ar dating of offset Pleistocene basalt flows: transpression between the African and Arabian plates
Authors: Seyrek A. , Demi̇r T. , Pringle M. S. , Yurtmen S. , Westaway R. W. C. , Beck A. , Rowbotham G.
Published: December 2007

We report four new Ar/Ar dates and 18 new geochemical analyses of Pleistocene basalts from the Karasu Valley of southern Turkey. These rocks have become offset left-laterally by slip on the N20°E-striking Amanos Fault. The geochemical analyses help to correlate some of the less-obvious offset fragments of basalt flows, and thus to measure amounts of slip; the dates enable slip rates to be calculated. On the basis of four individual slip-rate determinations, obtained in this manner, we estimate a weighted mean slip rate for this fault of 2.89±0.05mm/a (±2σ). We have also obtained a slip rate of 2.68±0.54mm/a (±2σ) for the subparallel East Hatay Fault farther east. Summing these values gives 5.57±0.54mm/a (±2σ) as the overall left-lateral slip rate across the Dead Sea fault zone (DSFZ) in the Karasu Valley. These slip-rate estimates and other evidence from farther south on the DSFZ are consistent with a preferred Euler vector for the relative rotation of the Arabian and African plates of 0.434±0.012° Ma
−1
about 31.1°N, 26.7°E. The Amanos Fault is misaligned to the tangential direction to this pole by 52° in the transpressive sense. Its geometry thus requires significant fault-normal distributed crustal shortening, taken up by crustal thickening and folding, in the adjacent Amanos Mountains. The vertical component of slip on the Amanos Fault is estimated as
c.
0.15mm/a. This minor component contributes to the uplift of the Amanos Mountains, which reaches rates of
c.
0.2–0.4mm/a. These slip rate estimates are considered representative of time since. 3.73±0.05Ma, when the modern geometry of strike-slip faulting developed in this region; an estimated 11km of slip on the Amanos Fault and
c.
10km of slip on the East Hatay Fault have occurred since then. It is inferred that both these faults came into being, and the associated deformation in the Amanos Mountains began, at that time. Prior to that, the northern part of the Africa–Arabia plate boundary was located further east.
Targeting the Nuclear Factor-κB Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy
Authors: Sourbier Carole , Danilin Sabrina , Lindner Véronique , Steger Jacques , Rothhut Sylvie , Meyer Nicolas , Jacqmin Didier , Helwig Jean-Jacques , Lang Hervé , Massfelder Thierry
Published: December 2007

Metastatic renal cell carcinoma (RCC) remains refractory to therapies. The nuclear factor-κB (NF-κB) transcription factor is involved in cell growth, cell motility, and vascularization. We evaluated whether targeting NF-κB could be of therapeutic and prognostic values in human RCC. The activation of the NF-κB pathway in human RCC cells and tumors was investigated by Western blot. In vitro, the effects of BAY 11-7085 and sulfasalazine, two NF-κB inhibitors, on tumor cell growth were investigated by cell counting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling, and fluorescence-activated cell sorting. Their specificity toward NF-κB was analyzed by Western blot, confocal microscopy, NF-κB small interfering RNA, and NF-κB transcription assay. In vivo, the effects of BAY 11-7085 on the growth of human RCC tumors were investigated in nude mice. A tissue microarray (TMA) containing 241 cases of human RCC with 12 to 22 years of clinical follow-up and corresponding normal tissues was built up to assess prognostic significance of activated NF-κB. NF-κB is constitutively activated in cultured cells expressing or not the von Hippel-Lindau (VHL) tumor suppressor gene as a consequence of Akt kinase activation and in tumors. In vitro and in vivo NF-κB inhibition blocked tumor cell growth by inducing cell apoptosis. On the TMA, NF-κB activation was correlated with tumor dimension but was not found to be an independent prognostic factor for patient survival. This report provides strong evidence that the mechanisms responsible for the intrinsic resistance of RCC cells to apoptosis converge on NF-κB independently of VHL expression and that targeting this pathway has great anticancer potential. [Cancer Res 2007;67(24):11668–76]
Role of Tumor Necrosis Factor-α and TRAIL in High-Dose Radiation–Induced Bystander Signaling in Lung Adenocarcinoma
Authors: Shareef Mohammed M. , Cui Nuan , Burikhanov Ravshan , Gupta Seema , Satishkumar Sabapathi , Shajahan Shahin , Mohiuddin Mohammed , Rangnekar Vivek M. , Ahmed Mansoor M.
Published: December 2007

In the present study, ionizing radiation (IR)–induced bystander effects were investigated in two lung cancer cell lines. A549 cells were found to be more resistant to radiation-conditioned medium (RCM) obtained from A549 cells when compared with the H460 exposed to RCM procured from H460 cells. Significant release of tumor necrosis factor-α (TNF-α) was observed in A549 cells after IR/RCM exposure, and the survival was reversed with neutralizing antibody against TNF-α. In H460 cells, significant release of TNF-related apoptosis-inducing ligand (TRAIL), but not TNF-α, was observed in response to IR, RCM exposure, or RCM + 2Gy, and neutralizing antibody against TRAIL diminished clonogenic inhibition. Mechanistically, TNF-α present in RCM of A549 was found to mediate nuclear factor-κB (NF-κB) translocation to nucleus, whereas the soluble TRAIL present in RCM of H460 cells mobilized the nuclear translocation of PAR-4 (a proapoptotic protein). Analysis of IR-inducible early growth response-1 (EGR-1) function showed that EGR-1 was functional in A549 cells but not in H460 cells. A significant decrease in RCM-mediated apoptosis was observed in both A549 cells stably expressing small interfering RNA EGR-1 and EGR-1−/− mouse embryonic fibroblast cells. Thus, the high-dose IR-induced bystander responses in A549 may be dependent on the EGR-1 function and its target gene TNF-α. These findings show that the reduced bystander response in A549 cells is due to activation of NF-κB signaling by TNF-α, whereas enhanced response to IR-induced bystander signaling in H460 cells was due to release of TRAIL associated with nuclear translocation of PAR-4. [Cancer Res 2007;67(24):11811–20]
Biological Role and Potential Therapeutic Targeting of the Chemokine Receptor CXCR4 in Undifferentiated Thyroid Cancer
Authors: De Falco Valentina , Guarino Valentina , Avilla Elvira , Castellone Maria Domenica , Salerno Paolo , Salvatore Giuliana , Faviana Pinuccia , Basolo Fulvio , Santoro Massimo , Melillo Rosa Marina
Published: December 2007

Anaplastic thyroid carcinoma (ATC) is a rare thyroid cancer type with an extremely poor prognosis. Despite appropriate treatment, which includes surgery, radiotherapy, and chemotherapy, this cancer is invariably fatal. CXCR4 is the receptor for the stromal cell–derived factor-1 (SDF-1)/CXCL12 chemokine and it is expressed in a variety of solid tumors, including papillary thyroid carcinoma. Here, we show that ATC cell lines overexpress CXCR4, both at the level of mRNA and protein. Furthermore, we found that CXCR4 was overexpressed in ATC clinical samples, with respect to normal thyroid tissues by real-time PCR and immunohistochemistry. Treatment of ATC cells with SDF-1 induced proliferation and increase in phosphorylation of extracellular signal–regulated kinases and protein kinase B/AKT. These effects were blocked by the specific CXCR4 antagonist AMD3100 and by CXCR4 RNA interference. Moreover, AMD3100 effectively reduced tumor growth in nude mice inoculated with different ATC cells. Thus, we suggest that CXCR4 targeting is a novel potential strategy in the treatment of human ATC. [Cancer Res 2007;67(24):11821–9]
Tumor Irradiation Increases the Recruitment of Circulating Mesenchymal Stem Cells into the Tumor Microenvironment
Authors: Klopp Ann H. , Spaeth Erika L. , Dembinski Jennifer L. , Woodward Wendy A. , Munshi Anupama , Meyn Raymond E. , Cox James D. , Andreeff Michael , Marini Frank C.
Published: December 2007

Mesenchymal stem cells (MSC) migrate to and proliferate within sites of inflammation and tumors as part of the tissue remodeling process. Radiation increases the expression of inflammatory mediators that could enhance the recruitment of MSC into the tumor microenvironment. To investigate this, bilateral murine 4T1 breast carcinomas (expressing renilla luciferase) were irradiated unilaterally (1 or 2 Gy). Twenty-four hours later, 2 × 105 MSC-expressing firefly luciferase were injected i.v. Mice were then monitored with bioluminescent imaging for expression of both renilla (tumor) and firefly (MSC) luciferase. Forty-eight hours postirradiation, levels of MSC engraftment were 34% higher in tumors receiving 2 Gy (P = 0.004) than in the contralateral unirradiated limb. Immunohistochemical staining of tumor sections from mice treated unilaterally with 2 Gy revealed higher levels of MSC in the parenchyma of radiated tumors, whereas a higher proportion of MSC remained vasculature-associated in unirradiated tumors. To discern the potential mediators involved in MSC attraction, in vitro migration assays showed a 50% to 80% increase in MSC migration towards conditioned media from 1 to 5 Gy–irradiated 4T1 cells compared with unirradiated 4T1 cells. Irradiated 4T1 cells had increased expression of the cytokines, transforming growth factor-β1, vascular endothelial growth factor, and platelet-derived growth factor-BB, and this up-regulation was confirmed by immunohistochemistry in tumors irradiated in vivo. Interestingly, the chemokine receptor CCR2 was found to be up-regulated in MSC exposed to irradiated tumor cells and inhibition of CCR2 led to a marked decrease of MSC migration in vitro. In conclusion, clinically relevant low doses of irradiation increase the tropism for and engraftment of MSC in the tumor microenvironment. [Cancer Res 2007;67(24):11687–95]
Endostatin Overexpression Inhibits Lymphangiogenesis and Lymph Node Metastasis in Mice
Authors: Brideau Gaëlle , Mäkinen Markus J. , Elamaa Harri , Tu Hongmin , Nilsson Gunnar , Alitalo Kari , Pihlajaniemi Taina , Heljasvaara Ritva
Published: December 2007

Endostatin, a proteolytic fragment of collagen XVIII, is a potent inhibitor of angiogenesis and tumor growth. We studied the development of carcinogen-induced skin tumors in transgenic J4 mice overexpressing endostatin in their keratinocytes. Unexpectedly, we did not observe any differences in tumor incidence and multiplicity between these and control mice, nor in the rate of conversion of benign papillomas to malignant squamous cell carcinomas (SCC). We did find, however, that endostatin regulates the terminal differentiation of keratinocytes because the SCCs in the J4 mice were less aggressive and more often well differentiated than those in the control mice. We observed an inhibition of tumor angiogenesis by endostatin at an early stage in skin tumor development, but more strikingly, there was a significant reduction in lymphatic vessels in the papillomas and SCCs in association with elevated endostatin levels and also a significant inhibition of lymph node metastasis in the J4 mice. We showed that tumor-infiltrating mast cells strongly expressed vascular endothelial growth factor-C (VEGF-C), and that the accumulation of these cells was markedly decreased in the tumors of the J4 mice. Moreover, endostatin inhibited the adhesion and migration of murine MC/9 mast cells on fibronectin in vitro. Our data suggest that endostatin can inhibit tumor lymphangiogenesis by decreasing the VEGF-C levels in the tumors, apparently via inhibition of mast cell migration and adhesion, and support the view that the biological effects of endostatin are not restricted to endothelial cells because endostatin also regulates tumor-associated inflammation and differentiation, and the phenotype of epithelial tumors. [Cancer Res 2007;67(24):11528–35]
Hepatocellular Carcinoma Associated with Liver-Gender Disruption in Male Mice
Authors: Rogers Arlin B. , Theve Elizabeth J. , Feng Yan , Fry Rebecca C. , Taghizadeh Koli , Clapp Kristen M. , Boussahmain Chakib , Cormier Kathleen S. , Fox James G.
Published: December 2007

Hepatocellular carcinoma (HCC) is a male-predominant cancer associated with chronic hepatitis. Like human viral hepatitis, murine Helicobacter hepaticus infection produces inflammation and HCC with a masculine bias. We used this model to identify potential mechanisms of male HCC predisposition. Male weanling A/JCr mice (n = 67) were gavaged with H. hepaticus or vehicle. At 1 year, mice were distributed into four groups: surgical castration, chemical castration, castration followed by dihydrotestosterone supplementation, or sexually intact controls. Responses to infection were compared with IFN-γ challenge alone. At 21 months, there was no significant difference in hepatitis between groups. Neither castration nor androgen receptor agonism altered tumor incidence. Infected mice with severe, but not mild, disease exhibited a mosaic of alterations to sexually dimorphic genes and microsomal long-chain fatty acids. By microarray, tumorigenic hepatitis was strongly associated with liver-gender disruption, defined as the loss of a gender-identifying hepatic molecular signature. IFN-γ alone produced similar changes, demonstrating a role for proinflammatory cytokines in this process. In conclusion, hepatocarcinogenesis in male mice with chronic hepatitis is maturationally imprinted and androgen-independent. Proinflammatory cytokines may promote HCC in a male-predominant fashion due to high sensitivity of the masculinized liver to loss of sex-specific transcriptional balance. Liver-gender disruption has pleiotropic implications for hepatic enzyme activity, lipid processing, nuclear receptor activation, apoptosis, and proliferation. We propose a multistep model linking chronic hepatitis to liver cancer through cytokine-mediated derangement of gender-specific cellular metabolism. This model introduces a novel mechanism of inflammation-associated carcinogenesis consistent with male-predominant HCC risk. [Cancer Res 2007;67(24):11536–46]
The Ataxia Telangiectasia–Mutated Target Site Ser18 Is Required for p53-Mediated Tumor Suppression
Authors: Armata Heather L. , Garlick David S. , Sluss Hayla K.
Published: December 2007

The p53 tumor suppressor is phosphorylated at multiple sites within its NH2-terminal region. One of these phosphorylation sites (mouse Ser18 and human Ser15) is a substrate for the ataxia telangiectasia–mutated (ATM) and ATM-related (ATR) protein kinases. Studies of p53S18A mice (with a germ-line mutation that replaces Ser18 with Ala) have indicated that ATM/ATR phosphorylation of p53 Ser18 is required for normal DNA damage–induced PUMA expression and apoptosis but not for DNA damage–induced cell cycle arrest. Unlike p53-null mice, p53S18A mice did not succumb to early-onset tumors. This finding suggested that phosphorylation of p53 Ser18 was not required for p53-dependent tumor suppression. Here we report that the survival of p53S18A mice was compromised and that they spontaneously developed late-onset lymphomas (between ages 1 and 2 years). These mice also developed several malignancies, including fibrosarcoma, leukemia, leiomyosarcoma, and myxosarcoma, which are unusual in p53 mutant mice. Furthermore, we found that lymphoma development was linked with apoptotic defects. In addition, p53S18A animals exhibited several aging-associated phenotypes early, and murine embryonic fibroblasts from these animals underwent early senescence in culture. Together, these data indicate that the ATM/ATR phosphorylation site Ser18 on p53 contributes to tumor suppression in vivo. [Cancer Res 2007;67(24):11696–703]
Induction of Apoptosis in Plasma Cells by B Lymphocyte–Induced Maturation Protein-1 Knockdown
Authors: Lin Fan-Ru , Kuo Hui-Kai , Ying Hsia-Yuan , Yang Fu-Hung , Lin Kuo-I
Published: December 2007

B lymphocyte–induced maturation protein-1 (Blimp-1) is a transcriptional repressor that plays an important role during plasmacytic differentiation and is expressed in normal and transformed plasma cells. We here investigated the importance of continuous Blimp-1 expression. We found that knockdown of Blimp-1 expression by lentiviral vector-delivered short hairpin RNA causes apoptosis in multiple myeloma cell lines and plasmacytoma cells, indicating that continued expression of Blimp-1 is required for cell survival. We examined the mechanism underlying Blimp-1 knockdown-mediated apoptosis and found that the Blimp-1 knockdown neither reversed the phenotypic markers of plasma cells nor caused cell cycle arrest. Instead, our results show that knockdown of Blimp-1 induced the proapoptotic protein Bim, reduced the antiapoptotic protein Mcl-1, and activated caspase-9 and caspase-3. We further link apoptosis in transformed plasma cells mediated by proteasome inhibitors, the effective therapeutic agent for multiple myeloma patients, with reduced expression of Blimp-1. Lastly, we show that Blimp-1–dependent cell survival may act downstream of IFN regulatory factor 4 (IRF4) because IRF4 knockdown leads to down-regulation of Blimp-1 and apoptosis in multiple myeloma cells and plasmacytoma cells. Together, our data suggest that Blimp-1 ensures the survival of transformed plasma cells. [Cancer Res 2007;67(24):11914–23]