bluuebunny/crossref_metadata_2025 huggingface dataset:
UK North Sea exploration: a future?
Authors: VINING B. A. , MABILLARD J. E. , VAN RIJSSEN P.
Published: April 2010

The UK sector of the North Sea is approaching a sharp decline in the production of oil and gas. This paper considers the role exploration can play in the future to arrest, in part, this decline. Whilst many of the major oil and gas provinces around the world have forecast significant production falls in the past, few have actually reached a terminal stage of decline. The regenerative capacity of these most prolific provinces has been driven by a complex interaction of legislative, economic, commercial and technical factors. The technical factors influencing future exploration in the North Sea are the focus of this paper.

The ability to assess the remaining exploration potential of a basin relies heavily on geostatistical methods such as creaming curves, field size distributions and economics. However, the reliability of analyses depends on the adequacy of relevant data and knowledge that together frame the degree of uncertainty and risk around any prediction. An analysis of the exploration history of the UK sector of the North Sea is presented in the context of a hierarchy, basin, play and prospect. The results clearly demonstrate the region to be in an advanced mature stage for known plays.

At present, our ability to identify and quantify remaining exploration potential is conditioned by our experience and our ability to imagine the future. As a result, the perceived future contribution from exploration of conventional plays in the North Sea appears limited. Any significant contribution from exploration would require a paradigm shift in our ability to define and economically pursue new plays and prospectivity. From a global perspective, a review of how large fields in new plays have been discovered in the past reveals some ideas that may be applied to the UK North Sea in the future.

The North Sea has a diverse stratigraphy with prolific source rocks, which are the fundamental ingredients required to develop new play concepts. However, in spite of the extensive data, technology and knowledge at our disposal, significant new play concepts are not forthcoming. The rhetorical question remains, are new plays not there, or are we not creative enough to conceive them?

‘Where oil is first found, in the final analysis, is in the minds of men’, Wallace E. Pratt 1952.
The technical challenges to exploration and development of the Kopervik fairway, Outer Moray Firth, UK
Authors: ARGENT J. , BLIGHT R. , COX P. , HARDY R. , LAW A. , SMALLWOOD J. R. , WALTER D.
Published: April 2010

Despite a number of targeted and serendipitous discoveries above deeper Jurassic targets in the 1970s and 1980s, the high-quality Albo-Aptian sand fairway of the Outer Moray Firth, informally known as the Kopervik fairway, still remained relatively unexplored until the late 1990s. Following the Hannay and Goldeneye discoveries in 1996, the renewed impetus in exploration drilling on the trend generated a series of commercial oil and gas discoveries. This most recent exploration phase proceeded with a high ratio of well success to failure, despite the significant technical challenges specific to the Kopervik reservoir sands. For the most part, the explorationist has to contend with a play fairway consisting of subtle trapping mechanisms. The recognition of these traps is hampered by the acoustically transparent nature of the sand, ambiguous seismic imaging and depth conversion issues. The subsequent development of this high permeability reservoir remains equally challenging. Many discoveries have low hydrocarbon column heights with an active aquifer and/or mixed phased fluids, which lead to well deliverability and fluid processing issues. In spite of the technical complications, these discoveries are now being swiftly developed by various operators along the trend. In this paper, we discuss how interest in the fairway was renewed only recently, review how the technical concept was developed in an attempt to reduce exploration risk, and how, following a number of early and surprising discoveries, the fairway was rapidly and effectively appraised. Finally, as an example, we review how the application of joint development concepts will lead to the commercialization of the fallow Cromarty Field and the neighbouring Atlantic discoveries.
Production from Muschelkalk carbonates (Triassic, NE Netherlands): unique play or overlooked opportunity?
Authors: PÖPPELREITER M. , BORKHATARIA R. , AIGNER T. , PIPPING K.
Published: April 2010

The Triassic Muschelkalk carbonates are a unique play in NW Europe, producing hydrocarbons onshore The Netherlands. This paper aims at a comprehensive description of these relatively unknown reservoirs and speculates on additional play potential outside of the current production areas. The Muschelkalk Formation consists of partially porous Lower and Upper Muschelkalk carbonates separated by tight Middle Muschelkalk evaporites. The 100 m thick Lower Muschelkalk holds 1.9 BCM gas in the De Wijk Field. The reservoir is a limestone–dolomite–marl succession producing from several decimetres thick calcisilitic dolo-mudstones encased in tight lime-mudstones. The reservoir shows a stratified architecture composed of 16 cycles with thin but laterally continuous porous units. Good reservoir quality facies are concentrated in the upper third of these cycles. Porosities vary from 6 to 27%, (average 12%) and permeabilities range from 0.01 to 32 mD (average 0.06 mD). The reservoir rocks represent inner ramp sediments of a storm-dominated epeiric ramp. The 50 m thick Upper Muschelkalk contains 0.8 BCM gas in the Coevorden Muschelkalk Field. The reservoir consists of several decimetres thick peloidal-oolitic dolo-grain to packstones of good permeability interbedded with lower permeability dolo-mudstones to wackestones. Porosity varies from 5 to 29% (average 15%) and permeability ranges from 0.01 to 57 mD (average 1 mD). The permeable dolo-grainstones occur chiefly around peak transgression and early regression of the Upper Muschelkalk. The producing Upper Muschelkalk deposits represent the inner ramp section of a storm-dominated homoclinal ramp. Numerous gas shows in the Lower and Upper Muschelkalk, scattered over the onshore territory of The Netherlands, suggest possible missed pay and upside potential. The highest reservoir potential occurs in grainy dolomitic inner ramp deposits. These are likely to be located close to the existing fields in the NE Netherlands. Additionally, currently unrecognized potential could be present in southern Germany and eastern Poland.
4D Ocean Bottom Seismic technology: an innovative tool for improved hydrocarbon recovery at Gullfaks
Authors: THOMPSON M. , DIGRANES P.
Published: April 2010

The Gullfaks Oil Field is located in the Norwegian sector of the Northern North Sea. Time-lapse (4D) seismic data have been used at Gullfaks since 1995 and have contributed significantly to the reservoir management of the field. Permanent field installations limit the area where new marine streamer surveys can be acquired; this restriction affects in 25% of the field. In 2001 an Ocean Bottom Seismic (OBS) pilot survey was acquired around the Gullfaks C (GFC) platform, to test whether the OBS technology could cover the ‘shadow zones’ around the permanent installations. The results from the 2001 OBS survey clearly show that the OBS data cover the ‘shadow zone’ and provide new 4D information around the GFC platform. Within the OBS area two new wells have been successfully drilled based on updated 4D information comparing streamer data from 1999 and OBS data from 2001. Based on the experience from the 2001 survey a new OBS survey was acquired in 2003 to cover the areas around the GFA and GFB platforms.
In situ
stresses in the North Sea and their applications: petroleum geomechanics from exploration to development
Authors: HILLIS R. R. , NELSON E. J.
Published: April 2010

Present-day maximum horizontal stress (σ
H
) is oriented northwest–southeast onshore North West Europe, reflecting the first-order control on intraplate stresses exerted by plate boundary forces. Stresses associated with deglaciation appear to influence the stress regime in the Northern North Sea, with σ
H
oriented E–W and a contemporary stress regime close to the transition between strike-slip and reverse faulting, i.e. σ
H
> σ
v
~ σ
h
(where σ
v
and σ
h
are vertical and minimum horizontal stress respectively). Maximum horizontal stress orientations are highly variable in the Central North Sea and the stress regime within the sedimentary sequence appears to be detached from that in the basement. The stress regime in the sedimentary sequence of the Central North Sea is predominantly one of normal faulting with almost isotropic horizontal stresses (σ
v
> σ
H
~ σ
h
).

Geomechanical risking of the likelihood of seal breach due to fracturing should incorporate the risk of reactivating sealing faults or fracturing intact cap seal rocks in shear or in tension. The risk of fracture-related seal breach is considered for stress regimes representative of the Northern and Central North Seas. Generally, reactivation of optimally oriented faults and/or shear fracturing of intact cap rock are the most likely mechanisms of fracture-related seal breach. However, in the Central North Sea overpressured scenario, tensile failure is the most likely mechanism of fracture-related seal breach.

In situ
stress data have value throughout the life cycle of a field. The implications of the stress regimes representative of the Northern and Central North Seas for naturally fractured reservoirs, wellbore stability, water flooding and fracture stimulation are analysed. These issues are stress-sensitive and the conclusions with respect to each issue differ significantly between the Northern and the Central North Sea because of their differing stress regimes.
Can UK coal resources contribute to a gas renaissance?
Authors: JONES N. S. , HOLLOWAY S. , CREEDY D. P. , GARNER K.
Published: April 2010

The predicted shortage of indigenous UK natural gas coincides with the continuing decline of the UK deep coal mining industry. Significant capacity has been lost through mine closures over the last few years as a result of competition from cheaper sources of coal from overseas and changes to the UK energy market. It is unlikely that any new large underground mines will be developed in the UK in the short or medium term. There are, however, still vast untouched coal resources in the UK that represent a significant energy resource. Increased awareness of the potential for clean energy from coal seams, advances in technology and recognition of the environmental benefits has seen a revival of interest in the potential to release some of the energy value of UK coal via alternative, non-mining technologies such as coalbed methane production and underground coal gasification. If successful, these could supplement declining conventional UK natural gas production. The utilization of clean energy from coal seams is supported by the UK Government through its Cleaner Fossil Fuels Programme.

There is some activity in this field already. Methane is being drained from most of the remaining deep mines and utilized as fuel for electricity generation or on-site boilers. Drained gas that is not utilized is conventionally vented, but at one mine this gas is now flared to reduce greenhouse gas emissions. Methane is also being produced from abandoned mines, but the present low electricity and gas prices have adversely affected its economics. For the longer-term future, there is potential for virgin coalbed methane production and underground coal gasification. The UK has coalbed methane resources estimated to be in the order of 2.9 × 10
12
m
3
CH
4
. However, the limited exploratory drilling for coalbed methane in unmined areas undertaken to date has not led to commercial production – the major barriers are perceived to be low seam permeability, drilling and completion costs, together with planning and access issues. Initial research suggests there is very large potential for underground coal gasification providing the environmental and perceived safety issues surrounding the application of this technology can be overcome.
Seismic characteristics and distribution of volcanic intrusions and hydrothermal vent complexes in the Vøring and Møre basins
Authors: PLANKE S. , RASMUSSEN T. , REY S. S. , MYKLEBUST R.
Published: April 2010

A voluminous magmatic complex was emplaced in the Vøring and Møre basins during Paleocene/Eocene continental rifting and break-up in the NE Atlantic. This intrusive event has had a significant impact on deformation, source-rock maturation and fluid flow in the basins. Intrusive complexes and associated hydrothermal vent complexes have been mapped on a regional 2D seismic dataset (
c
.150 000 km) and on one large 3D survey. The extent of the sill complex is at least 80 000 km
2
, with an estimated total volume of 0.9 to 2.8 × 10
4
km
3
. The sheet intrusions are saucer-shaped in undeformed basin segments. The widths of the saucers become larger with increasing emplacement depth. More varied intrusion geometries are found in structured basin segments. Some 734 hydrothermal vent complexes have been identified, although it is estimated that 2–3000 vent complexes are present in the basins. The vent complexes are located above sills and were formed as a direct consequence of the intrusive event by explosive eruption of gases, liquids and sediments, forming up to 11 km wide craters at the seafloor. The largest vent complexes are found in basin segments with deep sills (3–9km palaeodepth). Mounds and seismic seep anomalies located above the hydrothermal vent complexes suggest that the vent complexes have been re-used for vertical fluid migration long after their formation. The intrusive event mainly took place just prior to, or during, the initial phase of massive break-up volcanism (55.0–55.8Ma). There is also evidence for a minor Upper Paleocene volcanic event documented by the presence of 20 vent complexes terminating in the Upper Paleocene sequence and the local presence of extrusive volcanic rocks within the Paleocene sequence.
Evidence for a major sediment input point into the Faroe–Shetland Basin from the Kangerlussuaq region of southern East Greenland
Authors: LARSEN M. , WHITHAM A. G.
Published: April 2010

Studies of the sedimentary succession in Kangerlussuaq, southern East Greenland suggest that a prominent sediment input point existed in the region in the Late Cretaceous–Palaeogene, which was controlled by a major northwest–southeast-oriented fault lineament. The presence of this sediment transfer path is supported by a number of observations. Firstly, the Cretaceous succession thickens towards the fault. This apparent thickening is due to post-depositional erosion of the succession and indicates a Late Maastrichtian–Palaeogene downthrow to the southwest. Secondly, Palaeogene sediments, which underlie the thick plateau basalt succession, are thickest along the axis of the sub-basin lying west of the fault and show south and southeasterly palaeocurrents parallel to the fault in the Christian IV Gletscher lineament. Thirdly, the Palaeogene volcanic succession shows important changes across the fault lineament. To the east of the lineament subaerial plateau basalts rest directly on basement or Palaeogene fluvial sediments, whereas to the west the basal lavas are interbedded with marine sediments and hyaloclastite foreset breccias up to 300m thick. With a pre-drift position less than 100 km from the present-day Faroe Islands, this new information has an important impact on our understanding of reservoir distribution in the Faroes area. Most models for the Palaeogene infill of the Faroe–Shetland Basin show basinal sands sourced from the Shetland Platform thinning northwestwards. If the Kangerlussuaq region was a major sediment input point then northwestward thickening sand bodies might be anticipated, radically altering the prospectivity of the Palaeogene section in areas towards the Faroe Islands.
Deep-water clastic reservoirs: a leading global play in terms of reserve replacement and technological challenges
Authors: HURST A. , FRASER A. J. , FRASER S. I. , HADLER-JACOBSEN F.
Published: April 2010

Experience from the exploration for, and development of, deep-water clastic reservoirs offshore NW Europe has provided an important testing ground for new technology and has subsequently been applied globally. In NW Europe, Upper Jurassic, Lower Cretaceous and Paleogene intervals have proven play fairways, all of which retain exploration potential. Ancient, particularly Tertiary, passive margins are identified as the main areas of current global deep-water exploration interest; a review of play characteristics is given. Innovative geophysical data and data analysis play an important role in deep-water clastic reservoir geology. The roles of AVO and seismic inversion are emphasized in the context of direct hydrocarbon indication and reservoir delineation. In areas of modern deep water, when drilling for ancient deep-water clastic targets, the importance of acquiring the right data at the right time is critical to creating robust predictive models.
Modelling the Central North Sea pressure history
Authors: SWARBRICK R. E. , SELDON B. , MALLON A. J.
Published: April 2010

High pore pressures in compartmentalized Mesozoic reservoirs in the Central North Sea are a challenge to predict using conventional porosity-based methods applied to shale mudrocks. Porosity and effective stress relationships, which work well in young and rapidly deposited basins such as Tertiary deltas, are not readily applicable to older, high-temperature sediments, and cannot be applied to non-reservoir chalk carbonates in which diagenesis is the principal control on porosity change. Basin modelling offers an alternative and complementary approach to conventional pressure prediction. New compaction and fluid flow relationships have been applied in commercial basin modelling software to model a 74 km 2D profile across the Central North Sea extending from the Fulmar Field in Block 30/16 across the Judy-Joanne High (Block 30/7) to the UK-Norwegian border in Block 30/8. The resulting models also tested chemical compaction simulation as a way to handle porosity change in non-reservoir chalks. The models were calibrated using porosity and permeability data collected as part of the study. When rock property data were satisfactorily matched, predicted pore pressures were compared with pore pressure measurements from multiple reservoirs in several boreholes. The model results closely match actual pressures from thin base-Tertiary reservoirs, which are likely to be close to their equilibrium with overlying shale mudrocks. The models underestimate the pore pressures in the deeply buried Mesozoic reservoirs. We interpret the deep pressures in relation to the contribution to overpressure from compaction disequilibrium (principally Tertiary sediment loading) relative to other, fluid inflation processes, such as gas generation. Future modelling, incorporating new data on fluid volume change when kerogen generates gas or oil cracks to gas, is now necessary to examine the magnitude of overpressure from these secondary sources.
Modelling seismic response from North Sea chalk reservoirs resulting from changes in burial depth and fluid saturation
Authors: VEJBÆK O. V. , RASMUSSEN R. , JAPSEN P. , BRUUN A. , PEDERSEN J. M. , MARSDEN G. , FABRICIUS I. L.
Published: April 2010

Changes in seismic response caused by variation in degree of compaction and fluid content in North Sea chalk reservoirs away from a wellbore are investigated by forward modelling. The investigated seismic response encompasses reflectivity, AVO and acoustic impedance. Synthetic seismic data are calculated on the basis of well data from the South-Arne and Dan fields, Danish North Sea and compared to field records. Seismic response predictions are based on three main tools: (1) saturation modelling, (2) compaction/decompaction modelling and (3) rock physics.

Hydrocarbon saturation in North Sea chalk is strongly affected by capillary forces and transition zones in the order of 50 m are common. Advanced saturation height modelling is applied, which has proved robust for the prediction of saturation profiles in Danish chalk.

Compaction modelling relies on exponential decay of porosity with depth, where abnormal fluid pressures are accounted for. A new set of compaction parameters is presented based on a normal velocity–depth trend and a velocity–porosity transform for North Sea chalk. The parameters appear to allow fairly precise predictions of abnormal fluid pressures from observed average porosity. Based on this, the relative contribution to porosity preservation by abnormal fluid pressure and early hydrocarbon invasion may be estimated.

Rock physics theory is applied to obtain all necessary parameters for the complete set of elastic parameters for seismic modelling.

Modelling results of importance in the search for subtle traps include: (1) correlation of reflectivity with porosity; (2) primary sensitivity of acoustic impedance is to porosity variation rather than hydrocarbon saturation; (3) the Poisson ratio is very sensitive to hydrocarbon saturation at high porosity, depending on fluid density contrasts. In addition, compaction modelling shows a clear effect of porosity preservation by hydrocarbons in the South-Arne Field, whereas this effect is negligible in the Dan Field. In both fields seismic signatures in field records originating from fluid changes are identified.
Automated interpretation of geological fault surfaces imaged in 3D seismic data
Authors: GIBSON D. , TURNER J. P. , SPANN M. S. , WRIGHT T. D.
Published: April 2010

A novel approach to the automatic extraction of geological faults from 3D seismic data is described and comparisons of manually and automatically picked fault geometries interpreted from a high-quality 3D seismic dataset are presented. Based on the premise that faults introduce discontinuities to otherwise coherent layers (horizons) in seismic data volumes, prototype software has been developed that employs a coherency measure to detect points of significant discontinuity. An iterative highest confidence first merging strategy then groups clusters of ‘faulty’ points to form many planar segments, or patches, of larger fault surfaces. Because a planar model cannot reflect the curvature and localized irregularities that characterize real fault surfaces, the 3D fault surface geometry is generated using a combined parametric and residual field model to link the fault patches. The parametric model, in our case a planar model, represents the basic structure of the fault surface whilst the residual field models the surface deviation from the planar model. This is one of the few projects of this kind that combines expertise
from computer vision and structural geology. We conclude with a discussion on how empirical structural geological criteria
describing the geometry of natural fault systems will be integrated with the autopicking software to optimize the geological
validity of the interpreted fault geometry.
Extrusive and intrusive magmatism in the North Rockall Trough
Authors: THOMSON K.
Published: April 2010

Opacity-rendering techniques applied to 3D seismic data from the North Rockall Trough demonstrate that a range of volcanic features indicative of eruptive style can be recognized. The data reveal a complex terrain containing a range of volcanic features, with lava flows originating from discrete volcanic centres up to 4km wide, contemporaneous normal faults, linear fissures a few kilometres long, ring dykes and inflation ridges. Lava flow morphologies indicative of tube-fed inflated sheet flows, intracanyon flows and elongate subaerial flows that enter water downslope to produce a large hyaloclastic delta are observed. Opacity rendering of doleritic sills reveals a branching hierarchy of magma tubes originating from the centre of the sill and climbing upwards and outwards to produce the distinctive ‘saucer-shaped’ morphology. The results show that magma flow within the area under investigation was complex with magma conduits widely distributed across the region. This suggests that the diagenetic effects associated with contact metamorphism and hydrothermal alteration would be widespread, although reduced in magnitude, compared to an area of similar dimensions surrounding a localized high magma volume conduit such as the Skye Central Complex.

Supplementary material:
The movies referred to in the article are available at
https://doi.org/10.6084/m9.figshare.c.4813002
Regulation of human skeletal muscle perfusion and its heterogeneity during exercise in moderate hypoxia
Authors: Heinonen Ilkka H. , Kemppainen Jukka , Kaskinoro Kimmo , Peltonen Juha E. , Borra Ronald , Lindroos Markus , Oikonen Vesa , Nuutila Pirjo , Knuuti Juhani , Boushel Robert , Kalliokoski Kari K.
Published: April 2010

Although many effects of both acute and chronic hypoxia on the circulation are well characterized, the distribution and regulation of blood flow (BF) heterogeneity in skeletal muscle during systemic hypoxia is not well understood in humans. We measured muscle BF within the thigh muscles of nine healthy young men using positron emission tomography during one-leg dynamic knee extension exercise in normoxia and moderate physiological systemic hypoxia (14% O2 corresponding to ∼3,400 m of altitude) without and with local adenosine receptor inhibition with femoral artery infusion of aminophylline. Systemic hypoxia reduced oxygen extraction of the limb but increased muscle BF, and this flow increment was confined solely to the exercising quadriceps femoris muscle. Exercising muscle BF heterogeneity was reduced from rest ( P = 0.055) but was not affected by hypoxia. Adenosine receptor inhibition had no effect on capillary BF during exercise in either normoxia or hypoxia. Finally, one-leg exercise increased muscle BF heterogeneity both in the resting posterior hamstring part of the exercising leg and in the resting contralateral leg, whereas mean BF was unchanged. In conclusion, the results show that increased BF during one-leg exercise in moderate hypoxia is confined only to the contracting muscles, and the working muscle hyperemia appears not to be directly mediated by adenosine. Increased flow heterogeneity in noncontracting muscles likely reflects sympathetic nervous constraints to curtail BF increments in areas other than working skeletal muscles, but this effect is not potentiated in moderate systemic hypoxia during small muscle mass exercise.
On Steady MHD Thermally Radiating and Reacting Thermosolutal Viscous Flow through a Channel with Porous Medium
Authors: Mebine Promise , Gumus Rhoda H.
Published: April 2010

This paper investigates steady‐state solutions to MHD thermally radiating and reacting thermosolutal viscous flow through a channel with porous medium. The reaction
is assumed to be strongly exothermic under generalized Arrhenius kinetics, neglecting
the consumption of the material. Approximate solutions are constructed for the governing
nonlinear boundary value problem using WKBJ approximations. The results,
which are discussed with the aid of the dimensionless parameters entering the problem,
are seen to depend sensitively on the parameters.
Variational Iteration Method for Initial and Boundary Value Problems Using He′s Polynomials
Authors: Mohyud-Din Syed Tauseef , Yildirim Ahmet , Hosseini M. M.
Published: April 2010

This paper outlines a detailed study of the coupling of He′s polynomials with correction functional of variational iteration method (VIM) for solving various initial and boundary value problems. The elegant coupling gives rise to the modified versions of VIM which is very efficient in solving nonlinear problems of diversified nature. It is observed that the variational iteration method using He′s polynomials (VIMHP) is very efficient, easier to implements, and more user friendly. Several examples are given to reconfirm the efficiency of the proposed VIMHP.
Latis: A Spatial Decision Support System to Assess Low-Impact Site Development Strategies
Authors: Wilkerson G. Wayne , McAnally William H. , Martin James L. , Ballweber Jeff A. , Pevey Kim Collins , Diaz-Ramirez Jairo , Moore Austin
Published: April 2010

Significant advances have been made in the use of spatial and hydrologic models to quantify the impact of Best Management Practices (BMPs) and Low-Impact Development (LID) practices on water quality. Further advances are the goal of this work to add selection of BMP/LID and calculation of implementation costs, all integrated into a spatial decision support system (DSS). The Hydrologic Simulation Program in FORTRAN (HSPF), an unsteady flow model, was combined with links to desktop spatial data analysis tools, a spreadsheet listing BMP/LID and their implementation, operation, and maintenance cost data. Testing of the DSS, named Latis, allowed improvements in direct design of BMP, and a survey of landscape and engineering practitioners provided the impetus for a simplified version, Latis-LIDIA.
Kinetic Assessment and Therapeutic Modulation of Metabolic and Inflammatory Profiles in Mice on a High-Fat and Cholesterol Diet
Authors: Engstrom Laura W. , Bober Loretta , Chen Shu-Cheng , Fine Jay S. , Li Ying , Stanton Michaela C. , Kinsley David , Cui Long , Jackson James V. , Rojas-Triana Alberto , Lundell Daniel , Laverty Maureen , Gustafson Eric L. , Jenh Chung-Her , Kowalski Timothy J. , Manfra Denise J.
Published: April 2010

The kinetics of metabolic and inflammatory parameters associated with obesity were evaluated in a murine diet-induced obesity (DIO) model using a diet high in fat and cholesterol. Cellular infiltration and mediator production were assessed and shown to be therapeutically modulated by the PPARgamma agonist rosiglitazone. C57BL/6 mice were maintained on a 45% fat/0.12% cholesterol (HF/CH) or Chow diet for 3, 6, 16, or 27 weeks. Flow cytometry was employed to monitor peripheral blood monocytes and adipose tissue macrophages (ATM). Gene expression and protein analysis methods were used to evaluate mediator production from total epididymal fat (EF), stromal vascular fraction (SVF), and sorted SVF cells. To investigate therapeutic intervention, mice were fed a HF/CH diet for 12 weeks and then a diet formulated with rosiglitazone (5 mg/kg) for an additional 6 weeks. A HF/CH diet correlated with obesity and a dramatic proinflammatory state. Therapeutic intervention with rosiglitazone attenuated the HF/CH induced inflammation. In addition, a novel population was found that expressed the highest levels of the pro-inflammatory mediators CCL2 and IL-6.
SKI-606 (Bosutinib) Blocks Prostate Cancer Invasion, Growth, and Metastasis In vitro and In vivo through Regulation of Genes Involved in Cancer Growth and Skeletal Metastasis
Authors: Rabbani Shafaat A. , Valentino Maria-Luisa , Arakelian Ani , Ali Suhad , Boschelli Frank
Published: April 2010

In the current study, we have examined the efficacy of a Src/Abl kinase inhibitor SKI-606 (Bosutinib) for its effect on prostate cancer growth and skeletal metastasis. Treatment of highly invasive human prostate cancer cells PC-3 and DU-145 with different doses of SKI-606 decreased Src activation, cell proliferation, migration, and invasion as determined by Matrigel Boyden chamber invasion assay. For in vivo studies, PC-3 cells were inoculated through s.c. or i.t. route into male BALB/c nu/nu or Fox Chase severe combined immunodeficient mice, respectively. Experimental animals treated with SKI-606 developed tumors of a significantly smaller volume and a significant decrease (50%) in experimental skeletal lesion area. A marked increase (32%) in bone volume to tumor volume ratio was also seen by micro–computed tomography analysis of tibias from control and experimental groups of animals. Western blot analysis showed the ability of SKI-606 to significantly decrease the phosphorylation of signaling molecules (AKT, mitogen-activated protein kinase, focal adhesion kinase) and the expression of tumor progression–associated genes uPAR, MMP-2, MMP-9, N-cadherin, fibronectin, BMP-2 (bone morphogenetic protein 2), BMP-6 (bone morphogenetic protein 6), IL-8 (interleukin 8), and TGF-β (transforming growth factor β) in prostate cancer cells. SKI-606 is currently in clinical trials for breast cancer and chronic myelogenous leukemia. Results from these studies provide convincing evidence for evaluating its efficacy in prostate cancer patients. Mol Cancer Ther; 9(5); 1147–57. ©2010 AACR.
Development of Candidate Genomic Markers to Select Breast Cancer Patients for Dasatinib Therapy
Authors: Moulder Stacy , Yan Kai , Huang Fei , Hess Kenneth R. , Liedtke Cornelia , Lin Feng , Hatzis Christos , Hortobagyi Gabriel N. , Symmans W. Fraser , Pusztai Lajos
Published: April 2010

Patient selection is important for targeted therapies, yet phase I/II trials are often underpowered for developing predictors of drug response. The goal of this research was to define genomic predictors for dasatinib that could be prospectively tested in early-phase clinical trials.

Gene expression profiles of dasatinib-sensitive and dasatinib-resistant cell lines (n = 23) were compared to develop a dasatinib-sensitivity index (modified DS index). A Src pathway activity index (revised Src index) was defined using genes induced by the Src transfection of mammary epithelial cells and was optimized to be reproducible across cell lines and human specimens. A dasatinib target index was devised using the weighted sum of 19 kinases that bind to dasatinib with variable affinity. The performance of these prediction models was assessed in independent cell lines with known dasatinib sensitivity. The feasibility of applying these genomic tests to human samples was evaluated on 133 biopsies of primary breast cancers.

The modified DS index showed 90% accuracy in independent breast cancer cell lines (n = 12) and the target index, but not the revised Src index signature, also distinguished dasatinib-sensitive and dasatinib-resistant cells (P = 0.0024). The genomic predictors showed acceptable reproducibility in replicate cell line and human gene expression data. When all three predictors were applied to the same 133 patient samples, the predictors identified different patient subsets as potentially sensitive.

We defined three conceptually different potential predictors of dasatinib response that were reproducible across cell lines and human data. These candidate markers are being tested in a clinical trial to determine their utility. Mol Cancer Ther; 9(5); 1120–7. ©2010 AACR.
Effects of Thymoquinone in the Expression of Mucin 4 in Pancreatic Cancer Cells: Implications for the Development of Novel Cancer Therapies
Authors: Torres Maria P. , Ponnusamy Moorthy P. , Chakraborty Subhankar , Smith Lynette M. , Das Srustidhar , Arafat Hwyda A. , Batra Surinder K.
Published: April 2010

Pancreatic cancer is one of the most lethal cancers in the world, as it continues to be resistant to any therapeutic approaches. The high molecular weight glycoprotein mucin 4 (MUC4) is aberrantly expressed in pancreatic cancer and contributes to the regulation of differentiation, proliferation, metastasis, and the chemoresistance of pancreatic cancer cells. The absence of its expression in the normal pancreatic ductal cells makes MUC4 a promising target for novel cancer therapeutics. Natural products have been widely investigated as potential candidates in cancer therapies, and thymoquinone (TQ), extracted from the seeds of Nigella sativa, has shown excellent antineoplastic properties in some systems. In the present study, we evaluated the effect of TQ on pancreatic cancer cells and specifically investigated its effect on MUC4 expression. The MUC4-expressing pancreatic cancer cells FG/COLO357 and CD18/HPAF were incubated with TQ, and in vitro functional assays were done. The results obtained indicate that treatment with TQ downregulated MUC4 expression through the proteasomal pathway and induced apoptosis in pancreatic cancer cells by the activation of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase pathways. In agreement with previous studies, the decrease in MUC4 expression correlated with an increase in apoptosis, decreased motility, and decreased migration of pancreatic cancer cells. MUC4 transient silencing studies showed that c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase pathways are activated in pancreatic cancer cells, indicating that the activation of these pathways by TQ is directly related to the MUC4 downregulation induced by the drug. Overall, TQ has potential for the development of novel therapies against pancreatic cancer. Mol Cancer Ther; 9(5); 1419–31. ©2010 AACR.
Transient Abnormal Myelopoiesis Associated with Down Syndrome Presenting as Severe Hydrops Fetalis: A Case Report
Authors: Malin G.L. , Kilby M.D. , Velangi M.
Published: April 2010

We present a case of transient abnormal myelopoiesis (TAM) presenting as non-immune fetal hydrops (NIHF). Hydrops fetalis (HF) is a condition associated with very high perinatal mortality, especially when no treatable cause, such as fetal anaemia, exists. In fetuses prior to 24 weeks with NIHF, a chromosomal anomaly is a common association. TAM is a leukaemic condition, almost entirely limited to children with Down syndrome. The presentation of TAM prenatally is unusual but cases may present ultrasonographically with NIHF and associated fetal hepatosplenomegaly. We report a case presenting in this manner with NIHF detected at 29 weeks’ gestation and discuss the subsequent diagnosis and management of in utero TAM.
Speech Motor Development in Childhood Apraxia of Speech: Generating Testable Hypotheses by Neurocomputational Modeling
Authors: Terband H. , Maassen B.
Published: April 2010

Childhood apraxia of speech (CAS) is a highly controversial clinical entity, with respect to both clinical signs and underlying neuromotor deficit. In the current paper, we advocate a modeling approach in which a computational neural model of speech acquisition and production is utilized in order to find the neuromotor deficits that underlie the diversity of phonological and speech-motor symptoms of CAS. Based on existing approaches and behavioral data, we first generated specific hypotheses about the underlying deficits. These hypotheses were then tested in a series of computer simulations, and the resulting speech patterns were compared to the available behavioral data. Finally, the model was used to derive further predictions that can be tested empirically in behavioral experiments and possible new angles for clinical intervention.
Different Lip Asymmetry in Adults Who Stutter: Electromyographic Evidence during Speech and Non-Speech
Authors: Choo Ai Leen , Robb Michael P. , Dalrymple-Alford John C. , Huckabee Maggie-Lee , O’Beirne Greg A.
Published: April 2010

The present study examined whether abnormal cerebral control was evident in the lip movements of adult stutterers (AS) compared to non-stutterers (ANS), as demonstrated during speech and non-speech tasks. Electromyographic (EMG) activity during production of words with initial /f/ and /p/ phonemes, single-sentence production and lip pursing were measured. Differences between AS and ANS were evident in all tasks. For AS, the highest EMG amplitude was in the region of the left lower lip, which is indicative of greater right hemisphere participation. However, in ANS the right lower lip displayed the highest EMG amplitude, suggesting greater left hemisphere participation. Further, AS showed greater asynchronous lip activity than ANS for all tasks. These results support the hypotheses of reversed lateralization for speech and non-speech processing and reduced coordination of speech musculature in AS.
Quantification of Population Structure Using Correlated SNPs by Shrinkage Principal Components
Authors: Zou Fei , Lee Seunggeun , Knowles Michael R. , Wright Fred A.
Published: April 2010

Background/Aims: Association studies using unrelated individuals have become the most popular design for mapping complex traits. One of the major challenges of association mapping is avoiding spurious association due to population stratification. Principal component analysis (PCA) on genome-wide marker genotypes is one of the most popular population stratification control methods. It implicitly assumes that the markers are in linkage equilibrium, a condition that is rarely satisfied and that we plan to relax. Methods: We carefully examined the impact of linkage disequilibrium (LD) on PCA, and proposed a simple modification of the standard PCA to automatically adjust for the correlations among markers. Results: We demonstrated that LD patterns in genome-wide association datasets can distort the techniques for stratification control, showing ‘subpopulations’ reflecting localized LD phenomena rather than plausible population structure. We showed that the proposed method effectively removes the artifactual effect of LD patterns, and successfully recovers underlying population structure that is not apparent from standard PCA. Conclusion: PCA is highly influenced by sets of SNPs with high LD, obscuring the true population substructure. Our shrinkage PCA applies to all available markers, regardless of the LD patterns. The proposed method is easier to implement than most existing LD adjusted PCA methods.
Appraising the Plasticity of the Circle of Willis: A Model of Hemodynamic Modulation in Cerebral Arteriovenous Malformations
Authors: Chuang Yu-Ming , Guo Wanyuo , Lin Ching-Po
Published: April 2010

Objectives: Cerebral arteriovenous malformations (AVMs) harbor a network of abnormal vasculatures, namely the nidus between arterial and venous components. The pressure gradient between these two components results in abnormal high-velocity arteriovenous shunts flowing through the nidus and alternate intracranial hemodynamics. This study hypothesizes that the flow patterns of the circle of Willis (CoW) are modulated by the alternation of intracranial hemodynamics occurring in cerebral AVMs. The flow patterns of the CoW before and after AVMs had been corrected and the arteriovenous shunts closed by radiosurgery were assessed to validate the hypothesis. Patients and Methods: Fifty patients (32 men and 18 women; mean age 35.8 ± 4.2, range 23–52 years) with cerebral AVMs previously treated by radiosurgery were retrospectively investigated. This investigation used magnetic resonance angiography, performed prior to and after AVM surgery, to assess the CoW flow patterns. Results: The CoW flow patterns in nearly half of the subjects (20/50, 40%) altered after the AVMs had been corrected. The alterations included: (1) decreased size or ceased flow patterns in the CoW vascular segment: ipsilateral A1 (n = 1) of the anterior cerebral artery (ACA), ipsilateral posterior communicating artery (PCoA) segment (n = 7), contralateral PCoA collateral (n = 4), bilateral PCoA (n = 2); (2) increased size or opening of the previous ‘hypoplastic’ segment of CoW: ipsilateral A1 of ACA (n = 1), contralateral PCoA (n = 2), bilateral PCoA (n = 1), and (3) biphasic alteration of the CoW: ceased ipsilateral PCoA segment and opening ipsilateral A1 of the ACA (n = 1), ceased ipsilateral PCoA and opening contralateral P1 of the posterior cerebral artery (n = 1). Conclusion: The plasticity of the flow patterns in the CoW are modulated by intracranial hemodynamics as shown by the AVM model. The calibers of CoW arterial segments are not a static feature. Willisian collateralization with recruitment of the CoW segment may cease, or hypoplastic segments may reopen after closing arteriovenous shunts of the AVM.
Genome-Wide Conditional Search for Epistatic Disease-Predisposing Variants in Human Association Studies
Authors: Wang Gao , Yang Yaning , Ott Jurg
Published: April 2010

Genome-wide search for new disease variants, based on well-established variants, has a long history in linkage analysis but is less well-known in genetic case-control association studies. We developed a simple yet highly efficient conditional search method that can find new variants, which are associated with a disease only through epistatic interaction with another variant and do not necessarily have a direct association effect. Our approach is analogous to partitioning of χ2 in a hierarchical design, which is a well-established statistical technique. Applied to previously published data on age-related macular degeneration, our method found two single-nucleotide polymorphisms with genome-wide significant epistatic interaction that could not be found based only on direct main effects.
Health Heritage©, a Web-Based Tool for the Collection and Assessment of Family Health History: Initial User Experience and Analytic Validity
Authors: Cohn W.F. , Ropka M.E. , Pelletier S.L. , Barrett J.R. , Kinzie M.B. , Harrison M.B. , Liu Z. , Miesfeldt S. , Tucker A.L. , Worrall B.B. , Gibson J. , Mullins I.M. , Elward K.S. , Franko J. , Guterbock T.M. , Knaus W.A.
Published: April 2010

A detailed family health history is currently the most potentially useful tool for diagnosis and risk assessment in clinical genetics. We developed and evaluated the usability and analytic validity of a patient-driven web-based family health history collection and analysis tool. Health Heritage© guides users through the collection of their family health history by relative, generates a pedigree, completes risk assessment, stratification, and recommendations for 89 conditions. We compared the performance of Health Heritage to that of Usual Care using a nonrandomized cohort trial of 109 volunteers. We contrasted the completeness and sensitivity of family health history collection and risk assessments derived from Health Heritage and Usual Care to those obtained by genetic counselors and genetic assessment teams. Nearly half (42%) of the Health Heritage participants reported discovery of health risks; 63% found the information easy to understand and 56% indicated it would change their health behavior. Health Heritage consistently outperformed Usual Care in the completeness and accuracy of family health history collection, identifying 60% of the elevated risk conditions specified by the genetic team versus 24% identified by Usual Care. Health Heritage also had greater sensitivity than Usual Care when comparing the identification of risks. These results suggest a strong role for automated family health history collection and risk assessment and underscore the potential of these data to serve as the foundation for comprehensive, cost-effective personalized genomic medicine.
Frequency of Sinus Disease in Normal Subjects and Patients with Benign Paroxysmal Positional Vertigo
Authors: Cohen H.S. , Stewart M.G. , Brissett A.E. , Olson K.L. , Takashima M. , Sangi-Haghpeykar H.
Published: April 2010

Background/Aims: To determine if patients with benign paroxysmal positional vertigo (BPPV) have a higher frequency of rhinosinusitis than people with normal vestibular function. Methods: The subjects were 52 patients with BPPV and 46 normal people. Every subject had a sinus CT scan, a blood draw for IgE and a rhinologic examination by an otolaryngologist. Results: The frequency of rhinosinusitis based on physician diagnosis was 49% and based on CT scan findings 59%. This difference approached significance (p = 0.08). The observed frequency of rhinosinusitis was higher than predicted by survey data about the southern US region. The data trended toward higher prevalence of rhinosinusitis (by physician diagnosis) in the BPPV patients versus controls (58 vs. 39%, p = 0.06). Conclusion: BPPV patients have a higher frequency of sinus disease compared to people with normal vestibular systems, perhaps due to age differences, but physiologic factors may also be involved. The higher frequency of rhinosinusitis in this geographical area than reported rates based on survey data raises concerns about the usefulness of questionnaire data for estimating population prevalence.