bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of borehole temperature data in the Northeast German Basin: continuous logs versus bottom-hole temperatures
Authors: Förster Andrea
Published: November 2010

Temperature recordings from exploration boreholes for hydrocarbons and geothermal energy are evaluated to select the best-suitable data for determining formation temperature and heat flow in the Northeast German Basin. Repeated temperature logs measured in several boreholes allow a classification into equilibrium logs and perturbed logs. For the latter, a simple empirical correction is proposed based on mean annual ground-surface temperature, the estimated amount of temperature correction at total depth of log, and the depth-dependent cross-over point of temperature perturbation due to drilling. Analysis of bottom-hole temperatures (BHTs) showed that the uncorrected values deviate, on average, by as much as 22.2±10.2°C (1σ) from the formation temperature. BHTs corrected using the Horner-plot method are systematically too low by 1–2°C compared to values corrected using the exact solution to the full line-source equation. Both correction methods yield values that underestimate formation temperatures by as much as 9°C and 8°C, respectively. The large standard deviation (1σ) of about ±8°C indicates that a corrected BHT reflects (with 96% confidence, 2σ) formation temperature not better than ±16°C. However, using temperature logs in conjunction with the corrected BHTs allowed a prediction of formation temperatures with an error less than ±10°C at somewhat deeper depths than the log in several boreholes. The availability of continuous temperature logs as a prerequisite for a reduction of error of BHTs significantly reduced the quantity of useable corrected BHTs in the basin.
Arc magmatism and hydrocarbon generation in the northern Taranaki Basin, New Zealand
Authors: Stagpoole Vaughan , Funnell Rob
Published: November 2010

A Middle–Late Miocene andesitic arc named the Mohakatino Volcanic Centre is buried beneath younger sediments in the northern part of the Taranaki Basin, New Zealand’s primary oil production province. Volcanoes of the centre cover an area of about 3200 km
2
. An estimated 7000±3000 km
3
of andesite were erupted from the centre and between 1000 to 2500 km
3
of magma were intruded into the basement beneath the volcanic cones. The key element of the petroleum system altered by magmatism is the maturity of source rocks and the timing of expulsion, although volcanism also contributes to the formation of potential reservoirs and traps. In the northern Taranaki Basin, two periods of hydrocarbon expulsion occurred: following magmatism (14 Ma to about 8 Ma), and following renewed burial (since about 4 Ma). Thermal models indicate that Late Cretaceous terrestrial source rocks close to large magmatic intrusions became fully mature during magmatism. Overlying marine source rocks are modelled to still be generating and expelling hydrocarbons to the present day. Hence hydrocarbon expulsion and the charge history of this basin is partly governed by Miocene magmatism. Results are also relevant to many petroleum basins that contain similar andesitic arc volcanic rocks.
Infiltration of Late Palaeozoic evaporative brines in the Reelfoot rift: a possible salt source for Illinois basin formation waters and MVT mineralizing fluids
Authors: Rowan E. L. , de Marsily G.
Published: November 2010

Salinities and homogenization temperatures of fluid inclusions in Mississippi Valley-type (MVT) deposits provide important insights into the regional hydrology of the Illinois basin/Reelfoot rift system in late Palaeozoic time. Although the thermal regime of this basin system has been plausibly explained, the origin of high salinities in the basin fluids remains enigmatic. Topographically driven flow appears to have been essential in forming these MVT districts, as well as many other districts worldwide. However, this type of flow is recharged by fresh water making it difficult to account for the high salinities of the mineralizing fluids over extended time periods. Results of numerical experiments carried out in this study provide a possible solution to the salinity problem presented by the MVT zinc–lead and fluorite districts at the margins of the basin system.

Evaporative concentration of surface water and subsequent infiltration into the subsurface are proposed to account for large volumes of brine that are ultimately responsible for mineralization of these districts. This study demonstrates that under a range of geologically reasonable conditions, brine infiltration into an aquifer in the deep subsurface can coexist with topographically driven flow. Infiltration combined with regional flow and local magmatic heat sources in the Reelfoot rift explain the brine concentrations as well as the temperatures observed in the Southern Illinois and Upper Mississippi Valley districts.
A log correlation of the Rotliegend of the northern Cleaver Bank High: the search for controls on reservoir sand distribution
Authors: Bailey R. J. , Lloyd D. A.
Published: November 2010

Gamma ray log correlations of some 50 Open File wells were used to investigate the distribution and relative age of aeolian Leman Sandstone developments across the northern Cleaver Bank High. The correlations led to a sequence stratigraphic interpretation based on a depositional record of climatically forced fluctuations in the level of the Silverpit Formation playa lake system. This confirmed the widely reported diachroneity of the Leman Sandstone and identified the onlapped Base Permian palaeotopography and climatically forced, generally positive, changes in the water budget of the Silverpit Lake as the chief controls on aeolian sand distribution. However, a ‘1/f
n
’ power law distribution of changes in water budget is preferred to the idea of strictly cyclic climatic control. On this basis, the transgression of the northern Cleaver Bank High and the occurrence of aeolian and lacustrine end-member facies within depositional sequences of uniform thickness can be understood. Interval isochores were used to derive palaeotopographic maps of the Base Permian. Taken in conjunction with the observed facies of the onlapping depositional sequences, the maps locate under-explored basal aeolian Leman Sandstone play fairways.
Nested geological modelling of naturally fractured reservoirs
Authors: Cacas M. C. , Daniel J. M. , Letouzey J.
Published: November 2010

Because of the multiscaled character of fracture networks and their high degree of heterogeneity, characterization and modelling of fractured reservoirs requires different techniques to the well-established geostatistical methods derived for modelling rock heterogeneity. We have developed a method to improve the geological model used as an input of fractured reservoir fluid flow simulators, either in single or dual permeability simulations, as well as new specific procedures. The method is based on three nested models. The first, the ‘global geo-cellular fracture model’, considers fracture average property distribution at the scale of the reservoir. Location of the major faults as well as properties, such as horizon curvature, are taken into account. ‘The global discrete model’ considers the fault system at the same scale and algorithms generate realistic synthetic fault patterns using an object-orientated approach. The third model, the ‘local discrete model’, creates realistic synthetic fracture patterns at the decametre scale with another object-orientated procedure. These models are all constrained by hard data acquired from seismic, well imaging and logs. They can be constrained by output from deterministic approaches like structural evolution analyses and geomechanical modelling. Interrelationships between these models enable account to be taken of the complex interrelationships between fractures at different scales and rock material heterogeneity. Finally, this modelling approach makes the geological model used as an input of fractured reservoir fluid flow simulators more satisfying than conventional approaches.
Stochastic vector and tensor fields applied to strain modelling
Authors: Daly C.
Published: November 2010

In this paper a brief introduction to the theory of stochastic vector and tensor fields is given. Necessary and sufficient conditions for isotropic vector random fields are reviewed and necessary conditions for second order tensors are developed. These models increase the flexibility of the usual geostatistical models but at the cost of increased complexity. This complexity can be reduced to a manageable level for a class of tensor fields that are associated with strain. The potential for modelling fractures using strain models is briefly discussed.
Lithofacies characterization of fluvial sandstones from outcrop gamma-ray logs (Loranca Basin, Spain): the influence of provenance
Authors: Martinius A. W. , Geel C. R. , Arribas J.
Published: November 2010

Natural gamma spectral (NGS) log motifs and cluster analysis were used to characterize outcropping sandstone bodies formed in braided and high-sinuosity streams of the Tertiary Tórtola fluvial system of the Loranca Basin (Spain). Five coarse-grained lithofacies comprise these deposits and determine distinct NGS log motif. Cross-plots and cluster analysis of NGS log data of the lithofacies suggest three distinct clusters. These clusters reflect distinct values for sandstones with small sets of ripple lamination, cross-stratification, and conglomerates and pebbles. Ripple-laminated sandstones show the most variability in NGS signature, whereas conglomeratic sandstones show the most uniform signature. Such cluster analysis may be used to assign NGS log data points of unknown origin to a specific fluvial lithofacies under conditions of equal rock provenance and diagenetic history. A sedimentaclastic (i.e. sedimentary parent rock) origin of sediments appears to be the main control on detrital composition that, in turn, varies with grain size.
Reservoir parameters estimation from well log and core data: a case study from the North Sea
Authors: Yan Jun
Published: November 2010

In this paper we present an integrated approach to derive reservoir parameters from core and well-log data in clay–sand mixtures. This method is based on matching core and log data, and the linear and non-linear regressions are then used to build respective relationships between core and log data to determine formation parameters such as porosity, shale volume, clay content, permeability and fluid saturation. This information is then fed into a velocity prediction model to estimate seismic parameters such as elastic moduli, shear wave velocity and anisotropy coefficients. Finally, we test the method on real data from the North Sea and show that reservoir parameters can be accurately predicted.
Reservoir characterization of the Roar Gas Field, Danish North Sea
Authors: Vejbæk Ole Valdemar
Published: November 2010

The Roar Field consists of a gentle inversion anticline in which porosity, permeability and hydrocarbon saturation distributions in the Danian–Upper Cretaceous Chalk reservoir have been mapped using seismic data. The seismic data are inverted to support porosity prediction in a stochastic modelling approach. The uniform chalk matrix causes seismic impedance to correlate mainly with porosity and fluid content. Replacement of oil by water has negligible effect on seismic impedance but correction for fluid content in the gas cap is needed to increase correlation between seismic impedance and porosity. Porosity in excess of 40% is characteristic, probably reflecting early invasion of hydrocarbons. A slight tilting since Miocene times is suggested by higher porosity on the southwest flank. Permeability is generally below 10 mD in the reservoir and around 1 mD below. A slight south-dipping free water level is consistent with a regional water zone pressure gradient, if local high permeability is considered. A gas cloud that produces a velocity anomaly not apparent in well velocity data hampers depth conversion. The velocity anomaly is revealed from horizontal wells and has led to the identification of a new culmination at the north end 15 m shallower than the culmination at the south end; this has increased the estimated initial hydrocarbons in place from around 510 to 720×10
9
SCF gas. Analysis of uncertainty on hydrocarbon in-place calculations resulting from the characterization is limited to studying the effects of the gas cloud anomaly and the value added by the two horizontal wells on porosity field determination.
Cyclic water injection: improved oil recovery at zero cost
Authors: Surguchev Leonid , Koundin Alexander , Melberg Oddbjørn , Rolfsvåg Trond A. , Menard Wendell P.
Published: November 2010

Cyclic injection is a process that improves waterflooding efficiency in heterogeneous reservoirs. The concept of cyclic injection is based on (1) pulsed injection and (2) alternating waterflood patterns. Cyclic injection has been successfully applied in a number of sandstone and carbonate oil fields in Russia. In the rest of the world, pulsed injection has had limited application, and only in naturally fractured reservoirs. Although changing the waterflood patterns is a common approach to deal with increasing water cuts, a more systematic approach with both pulsed injection and alternating flow directions is not.

Cyclic injection has the greatest potential for improved recovery in heterogeneous, high-permeability-contrast sandstones and in naturally fractured carbonates and dolomites. The efficiency of the process is high in preferentially water-wet rocks saturated with compressible fluids. Capillary pressures and relative permeability effects are responsible for the improved cyclic oil displacement at the micro level. Improved sweep of the less permeable layers in communication with more permeable thief zones, better horizontal sweep achieved by changing waterflood patterns, and alternating the dominance between gravity and viscous forces are the key effects of cyclic injection on the macro level.

The potential of cyclic injection at the Lower Tilje/Åre formations of the Heidrun Field in the Norwegian Sea has been evaluated. Some of the reservoir levels are highly heterogeneous, with large permeability contrasts vertically and horizontally. The current drainage strategy for these formations is water injection, with gas lift in producers when needed. Cyclic injection will improve waterflooding efficiency at virtually zero additional cost. Improved sweep, accelerated oil production, and reduced water cut are the main positive effects expected from cyclic waterflooding. The reserves are predicted to increase by 5 to 6% from the targeted reservoirs at Heidrun after 10 years of cyclic waterflooding.
Core and seismic observations of overpressure-related deformation within Eocene sediments of the Outer Moray Firth, UKCS
Authors: Hillier R. D. , Cosgrove J. W.
Published: November 2010

Cores from the Eocene Alba Field of the Outer Moray Firth, UKCS contain sandstone injections and bedding-parallel fibrous ‘beef’ veins. Both of these features are associated with high fluid pressure and the process of hydraulic fracturing. The orientation of the hydraulic fractures (along which sand injection occurred, or calcite precipitated) was controlled by the interplay of the stress field and the intrinsic anisotropy of the sediments. Seismic sections indicate that sand injection occurred on a larger scale than is apparent from the cores. Interpreted dykes (400 m long by 30 m wide) emanate from the margins of the Alba channel sandstone along fault planes. An analogy is drawn between these dykes, and the peripheral dykes formed at the margins of laccoliths as a result of the flexing and subsequent fracturing of the overlying strata. ‘Decompacting’ of ptygmatically folded dykes suggests that the process of hydraulic fracturing and sandstone intrusion initiated between burial depths of 40 to 400 m below seabed.
Using Shale Gouge Ratio (SGR) to model faults as transmissibility barriers in reservoirs: an example from the Strathspey Field, North Sea
Authors: Harris D. , Yielding G. , Levine P. , Maxwell G. , Rose P. T. , Nell P.
Published: November 2010

Since the onset of production in 1993, extraction and injection in Strathspey has focused on the central region of the field, around the ‘Central Fault’. Analysis of RFT measurements from intermittent, but regular drilling on either side of this fault has allowed reconstruction of footwall/hanging wall pore-pressure fields for particular time instances. Comparison of these similar age pressure fields shows the Central Fault capable of maintaining up to 1300 psi pressure differentials. The results of the pressure analysis were used to calibrate a fault seal attribute, termed Shale Gouge Ratio (SGR) which is an estimate of clay concentration within fault gouge, mapped across the surface of the Central Fault. The calibration showed that as SGR increases, so does the measured pressure differential across the fault. This positive relationship between SGR and pressure differential suggests SGR is a guide to potential fluid-flow resistance exerted by faults. We therefore suggest that SGR can potentially be used as a guide to defining differences in permeability within and between faults in a given field. This ‘scaleability’ of SGR as an indicator of fault permeability within a field could provide hitherto unachievable flexibility in the systematic modelling of the hydraulic behaviour of faults during fluid flow simulations.
Injected and remobilized Eocene sandstones from the Alba Field, UKCS: core and wireline log characteristics
Authors: Duranti Davide , Hurst Andrew , Bell Chris , Groves Sheila , Hanson Rex
Published: November 2010

Depositional and remobilized sandstone units are identified in core from the Eocene sand-rich deep-water Nauchlan Member and termed stratified and unstratified facies, respectively. The unstratified facies association records an increased intensity of sand remobilization, and inferred fluidization, upward. Unstratified facies have lower average porosity and permeability than stratified facies. Bulk density and acoustic velocity are higher in unstratified facies than in stratified facies. The general geometric relations of the reservoir can be inferred from a correct identification of the facies. Correlation of borehole data with (3D PS) seismic data enables the seismic to be used as a lithology indicator. A modified interpretation of sandbody geometry is made that incorporates sand injection features and provides a more accurate reservoir model.
An experimental study of the texture of deformation bands: effects on the porosity and permeability of sandstones
Authors: Lothe A. E. , Gabrielsen R. H. , Hagen N. Bjørnevoll , Larsen B. T.
Published: November 2010

We have investigated the texture and formation of deformation bands in relation to permeability and porosity. Video image analysis of the Brumunddal sandstone showed a decrease in the number of large pores in the deformed zones. The frequency of small pores is increasing in the intermediate zone, compared to the undeformed rock and the central zone of a deformation band.

Triaxial compression tests were performed on Red Wildmoor sandstone with constant confining pressure (8 MPa). Axial P-and S-wave velocities measured during loading showed structural changes in development of a deformation band:
Stage I
and
II
– closure of micro-cracks and pores and tighter grain packing parallel to the maximum stress direction and simultaneously dilation perpendicular to the maximum stress direction.
Stage III
– both the P-and the S-wave velocities decreased, reflecting tighter grain packing and development of micro-fractures. These observations are supported by permeability measurements taken before, under and after triaxial compression, with recovering of permeability due to elastic effect and static reduction due to tighter packing and ultimately grain size reduction. NMR images of oil-saturated samples after loading to failure show:
stage III
– grain size reduction;
stage IV
– secondary fracturing; and
stage V
– development of a slip plane.
Detailed analysis of probe permeameter and interval pressure transient test permeability measurements in a heterogeneous reservoir
Authors: Morton Kirsty , Thomas Simon , Corbett Patrick , Davies David
Published: November 2010

The goal of reservoir characterization is to generate models that allow the accurate prediction of future well performance and the estimation of reserves. Of particular importance to the characterization of permeability heterogeneity is an accurate understanding of vertical flow behaviour in a reservoir. Upscaling techniques applied to conventional core plug and probe permeameter permeability anisotropy are compared with Interval Pressure Transient Tests (IPTT) conducted with multiprobe formation testers. The aim is to investigate the scale of the dynamic permeability measurement and review the representivity of the IPTT estimate in a field example. We illustrate improvement in permeability anisotropy estimation by a combination of dynamic measurements with static measurements.

Further to this, we consider the permeability prediction from continuous downhole measurement. High-resolution measurements such as probe permeametry data and borehole imaging can produce the most complete data coverage at the well and have similar measurement scales. Predicted permeabilities are compared with IPTT results by upscaling to a length scale appropriate to the IPTT and the geometry of the formation.
Predicting distribution of remobilized aeolian facies using sub-surface data: the Weissliegend of the UK Southern North Sea
Authors: Strömbäck Anna C. , Howell John A.
Published: November 2010

Aeolian sandstones of the Permian Rotliegend Group comprise the principal gas reservoirs of the Southern North Sea Basin. The upper portion of the reservoir interval comprises a unit informally called the ‘Weissliegend’. This unit comprises mass-flow and
in-situ
soft-sediment deformed deposits formed when the Zechstein Sea catastrophically flooded the Rotliegend sand sea. The Weissliegend typically exhibits poorer reservoir properties than the underlying Rotliegend reservoirs and its thickness and distribution are notoriously difficult to map.

Hanging vertical sections on a regionally extensive, intra-Rotliegend super-surface has led to the recognition of a preserved topography at the top of the Rotliegend. The thickness differences within the unit between the super-surface and the top Rotliegend (termed here the Upper Aeolian Unit, UAU) represent the original dune topography modified by flood-related processes, and provide an insight into the nature and scale of the aeolian bedforms that existed within the basin prior flooding. The relationship between known Weissliegend distribution and this topography provides a predictive tool for understanding Weissliegend distribution.

Mapping the preserved topography reveals preserved bedforms up to 85 m high, with a bedform spacing of 8 to 10 km. The dunes deposited ‘transverse type’ strata but the scale and spacing of the bedforms are too big compared with modern transverse dunse. Instead a more complex model is proposed. The Weissliegend has highly variable thickness (0–26 m) and is commonly thicker within the interdune hollows.

The model for a preserved topography at the top of the Rotliegend is further supported by thickness trends in the overlying Zechstein units which increase into the proposed interdune lows.
Correlation of reservoir sandstones using quantitative heavy mineral analysis
Authors: Morton Andrew , O’B. Knox Robert W. , Hallsworth Claire
Published: November 2010

Heavy mineral analysis is one of a group of provenance-based methods that complement traditional biostratigraphic correlation of clastic reservoirs. A variety of processes give rise to stratigraphic changes in sediment composition, including source area uplift, unroofing, changes in climatic conditions, extent of alluvial storage on the floodplain and the interplay between different depositional systems. Heavy mineral analysis is a reliable and proven technique for the correlation of clastic successions because prolonged and extensive research has provided detailed understanding of the effects of processes that alter the original provenance signal during the sedimentary cycle, such as hydrodynamics and diagenesis. The technique has been successfully applied to a wide range of clastic reservoirs, from fluvial to deep marine and from Devonian to Tertiary, using a combination of different types of parameters (provenance-sensitive mineral ratios, mineral chemistry and grain morphology). The application of heavy mineral analysis as a non-biostratigraphic correlation tool has two limitations. The first is that valid correlations cannot be made in sequences with uniform provenance and sediment transport history, but this is a problem inherent with all provenance-based methods. The other is that the technique can be applied only to coarse clastic lithologies and is not suitable for fine-grained sediments or carbonates.
Influence of clay and silica on permeability and capillary entry pressure of chalk reservoirs in the North Sea
Authors: Røgen B. , Fabricius I. L.
Published: November 2010

The permeability and capillary entry pressure of chalk reservoirs are controlled by their porosity and specific surface area. Measured permeabilities are in the range 0.025–5.3 mD and are successfully predicted by use of the Kozeny equation. In this paper we focus on the factors that control specific surface area. Fifty-nine Tor and Ekofisk Formation chalk samples from five North Sea chalk reservoirs were investigated. All contain quartz and clay minerals, most commonly kaolinite and smectite, with trace amounts of illite. The contents of calcite and quartz are inversely correlated and both are independent of the content of clays. We thus infer that the main part of the silica is of biogenic origin.

The specific surface area of the chalk is mainly controlled by clay content. The specific surface area of calcite is determined by the individual calcite crystal size and is not dependent on stratigraphic variations in fossil size. The specific surface area of calcite increases with increasing content of quartz and clays. These constituents may inhibit recrystallization of calcite and thus preserve high specific surface area. Our data accord with the following specific surface areas (m
2
g
−1
): calcite between 0.5 and 3.5, quartz about 5, kaolinite about 15, and smectite about 60.
Changes in matrix thermal conductivity of clays and claystones as a function of compaction
Authors: Waples Douglas W. , Tirsgaard Henrik
Published: November 2010

Vertical matrix thermal conductivities of clays and claystones in onshore Denmark decrease with decreasing porosity, probably because of increasing orientation of highly anisotropic clay platelets during compaction. The relationship between vertical matrix conductivity
λ
vm
and porosity for this dataset can be expressed as either
λ
vm
=2.544exp(0.943
φ
) or
λ
vm
=2.749exp (0.637
φ
), depending upon the statistical methods used to analyse the data. Using the first equation the vertical matrix conductivity of the Danish clays and claystones is found to be about 4.9 W m
−1
K
−1
in highly porous sediments, decreasing to 2.54 W m
−1
K
−1
when porosity reaches zero. Using the second equation the vertical matrix conductivity of the Danish clays and claystones is about 4.3 W m
−1
K
−1
in highly porous sediments, decreasing to about 2.75 W m
−1
K
−1
at zero porosity. Anisotropy varies from an assumed value of 1.02 in highly porous clays to 2.44 at zero porosity using the first equation, and 1.87 at zero porosity using the second equation. These values agree well with measured data.

This phenomenon is probably common or universal in fine-grained clay-rich sediments, and this method of data analysis could probably be applied to most or all claystone datasets. However, the equations derived in this study will be most appropriate for shales and claystones with comparatively high quartz contents similar to those of the samples analysed. Other specific relationships will probably exist for clay-rich shales and more-pure claystones.
ILK mediates the effects of strain on intestinal epithelial wound closure
Authors: Yuan Lisi , Sanders Matthew A. , Basson Marc D.
Published: November 2010

The intestinal epithelium is subjected to repetitive deformation during normal gut function by peristalsis and villous motility. Such repetitive strain promotes intestinal epithelial migration across fibronectin in vitro, but signaling mediators for this are poorly understood. We hypothesized that integrin-linked kinase (ILK) mediates strain-stimulated migration in intestinal epithelial cells cultured on fibronectin. ILK kinase activity increased rapidly 5 min after strain induction in both Caco-2 and intestinal epithelial cell-6 (IEC-6) cells. Wound closure in response to strain was reduced in ILK small interfering RNA (siRNA)-transfected Caco-2 cell monolayers when compared with control siRNA-transfected Caco-2 cells. Pharmacological blockade of phosphatidylinositol-3 kinase (PI3K) or Src or reducing Src by siRNA prevented strain activation of ILK. ILK coimmunoprecipitated with focal adhesion kinase (FAK), and this association was decreased by mutation of FAK Tyr925 but not FAK Tyr397. Strain induction of FAK Tyr925 phosphorylation but not FAK Tyr397 or FAK Tyr576 phosphorylation was blocked in ILK siRNA-transfected cells. ILK-Src association was stimulated by strain and was blocked by the Src inhibitor PP2. Finally, ILK reduction by siRNA inhibited strain-induced phosphorylation of myosin light chain and Akt. These results suggest a strain-dependent signaling pathway in which ILK association with FAK and Src mediates the subsequent downstream strain-induced motogenic response and suggest that ILK induction by repetitive deformation may contribute to recovery from mucosal injury and restoration of the mucosal barrier in patients with prolonged ileus. ILK may therefore be an important target for intervention to maintain the mucosa in such patients.
Lactose maldigestion during methotrexate-induced gastrointestinal mucositis in a rat model
Authors: Fijlstra M. , Rings E. H. H. M. , Verkade H. J. , van Dijk T. H. , Kamps W. A. , Tissing W. J. E.
Published: November 2010

Patients with chemotherapy-induced gastrointestinal mucositis suffer from anorexia, diarrhea, and stomach pain, often causing weight loss and malnutrition. When the intestinal function during mucositis would be known, a rational feeding strategy might improve the nutritional state, accelerate recuperation, and increase survival of mucositis patients. We developed a methotrexate (MTX)-induced mucositis rat model to study nutrient digestion and absorption. To determine lactose digestion and absorption of its derivative glucose during mucositis, we injected Wistar rats intravenously with MTX (60 mg/kg) or 0.9% NaCl (controls). Four days later, we orally administered trace amounts of [1-13C]lactose and [U-13C]glucose and quantified the appearance of labeled glucose in the blood for 3 h. Finally, we determined plasma citrulline level and harvested the small intestine to assess histology, myeloperoxidase level, glycohydrolase activity, immunohistochemical protein, and mRNA expression. MTX-treated rats showed profound villus atrophy and epithelial damage. During the experimental period, the absorption of lactose-derived [1-13C]glucose was 4.2-fold decreased in MTX-treated rats compared with controls ( P < 0.01). Lactose-derived [1-13C]glucose absorption correlated strongly with villus length (rho = 0.86, P < 0.001) and with plasma citrulline level (rho = 0.81, P < 0.001). MTX treatment decreased jejunal lactase activity (19.5-fold, P < 0.01) and immunohistochemical protein and mRNA expression (39.7-fold, P < 0.01) compared with controls. Interestingly, MTX treatment did not affect the absorption of [U-13C]glucose during the experimental period. We conclude that lactose digestion is severely decreased during mucositis while glucose absorption is still intact, when supplied in trace amounts. Plasma citrulline level might be a useful objective, noninvasive marker for lactose maldigestion during mucositis in clinic.
Interactions between the consumption of a high-fat diet and fasting in the regulation of fatty acid oxidation enzyme gene expression: an evaluation of potential mechanisms
Authors: Frier Bruce C. , Jacobs René L. , Wright David C.
Published: November 2010

The consumption of high-fat diets (HFDs) and fasting are known to increase the expression of enzymes involved in fatty acid oxidation (FAO). However, it has been reported that the ability of physiological stressors to induce enzymes of FAO in skeletal muscle is blunted with obesity. In this regard, we sought to explore the effects and potential mechanisms of an HFD on the expression of FAO enzymes in the fed and fasted state. The consumption of an HFD increased the mRNA expression or protein content of medium-chain acyl-CoA dehydrogenase (MCAD), uncoupling protein-3 (UCP3), and pyruvate dehydrogenase kinase 4 (PDK4) in the fed state. Fasting increased the mRNA expression of PDK4, MCAD, and UCP-3, and the protein content of UCP-3 in chow but not HFD rats. HFDs did not increase carnitine palmitoyl transfer-1 (CPT-1) mRNA levels in the fed state and the effects of fasting were markedly reduced compared with chow-fed rats. The expression of peroxisome-proliferator-activated receptor-γ coactivator-1β (PGC-1β) was increased in muscle from HFD rats in the fed state, while PGC-1-related coactivator (PRC) was increased with fasting in chow-fed but not HFD rats. Plasma fatty acid levels were elevated in the fed state from HFD rats but not increased further with fasting, whereas fasting increased plasma fatty acids in chow-fed animals. Fasting-mediated increases in plasma epinephrine, and the activation of PKA and AMPK in skeletal muscle were similar between chow and HFD rats. p38 MAPK phosphorylation was increased with fasting in chow-fed but not HFD rats. Our findings suggest that a blunted effect of fasting on the induction of PDK4, MCAD, and UCP3 in skeletal muscle from HFD rats is likely a result of already elevated levels of these enzymes, the induction of which is associated with increases in plasma fatty acid and PGC-1β. On the other hand, a blunted induction of PRC and CPT-1 mRNA may be explained by decreases in p38 MAPK signaling.
Changes in ventral respiratory column GABAaR ε- and δ-subunits during hibernation mediate resistance to depression by EtOH and pentobarbital
Authors: Hengen K. B. , Gomez T. M. , Stang K. M. , Johnson S. M. , Behan M.
Published: November 2010

During hibernation in the 13-lined ground squirrel, Ictidomys tridecemlineatus , the cerebral cortex is electrically silent, yet the brainstem continues to regulate cardiorespiratory function. Previous work showed that neurons in slices through the medullary ventral respiratory column (VRC) but not the cortex are insensitive to high doses of pentobarbital during hibernation, leading to the hypothesis that GABAA receptors (GABAAR) in the VRC undergo a seasonal modification in subunit composition. To test whether alteration of GABAAR subunits are responsible for hibernation-associated pentobarbital insensitivity, we examined an array of subunits using RT-PCR and Western blots and identified changes in ε- and δ-subunits in the medulla but not the cortex. Using immunohistochemistry, we confirmed that during hibernation, the expression of ε-subunit-containing GABAARs nearly doubles in the VRC. We also identified a population of δ-subunit-containing GABAARs adjacent to the VRC that were differentially expressed during hibernation. As δ-subunit-containing GABAARs are particularly sensitive to ethanol (EtOH), multichannel electrodes were inserted in slices of medulla and cortex from hibernating squirrels and EtOH was applied. EtOH, which normally inhibits neuronal activity, excited VRC but not cortical neurons during hibernation. This excitation was prevented by bicuculline pretreatment, indicating the involvement of GABAARs. We propose that neuronal activity in the VRC during hibernation is unaffected by pentobarbital due to upregulation of ε-subunit-containing GABAARs on VRC neurons. Synaptic input from adjacent inhibitory interneurons that express δ-subunit-containing GABAARs is responsible for the excitatory effects of EtOH on VRC neurons during hibernation.
Key roles of endothelin-1 and p38 MAPK in the regulation of atrial stretch response
Authors: Kerkelä Risto , Ilves Mika , Pikkarainen Sampsa , Tokola Heikki , Ronkainen Veli-Pekka , Majalahti Theresa , Leppäluoto Juhani , Vuolteenaho Olli , Ruskoaho Heikki
Published: November 2010

Mechanisms regulating stretch response in the left ventricle are investigated in detail but not well understood in atrial myocardium. Hypertrophic growth of atrial myocardium contributes to the pathogenesis of atrial fibrillation. In this study, we sought to elucidate mechanisms of stretch-induced activation of key signaling pathways and hypertrophy-associated genes in rat atria. Stretching of isolated atria induced a rapid increase in phosphorylation of p38 MAPK and ERK and induced a p38 MAPK-dependent increase in DNA binding activity of transcription factors Elk-1 and GATA-4. Inhibition of the ERK pathway had no effect on the cardiac transcription factors studied. Stretch-induced increase in atrial contractile function was substantially enhanced by inhibition of p38 MAPK. p38 MAPK also regulated stretch-induced increase in c-fos, β-myosin heavy chain, B-type natriuretic peptide mRNA levels, and atrial natriuretic peptide secretion in isolated atria. Various autocrine/paracrine factors are known to mediate the stretch response in the left ventricle. Stretching of isolated atria resulted in a robust increase in endothelin-1 (ET-1) mRNA levels, while apelin and adrenomedullin signaling cascades were downregulated. Administration of mixed ETA/Breceptor antagonist bosentan attenuated the stretch-induced activation of GATA-4 in isolated atria, whereas ANG II receptor type-1 antagonist CV-11974 had no effect. Moreover, analysis of RNA from intact atrial and ventricular myocardium revealed significantly higher mRNA levels of ETAreceptor and ET converting enzyme-1 in atrial compared with ventricular myocardium. In conclusion, our findings identify the local ET-1 system and p38 MAPK as key regulators of load-induced hypertrophic response in isolated rat atria.
Changes in angiotensin receptors expression play a pivotal role in the renal damage observed in spontaneously hypertensive rats
Authors: Landgraf Sharon S. , Wengert Mira , Silva Jaqueline S. , Zapata-Sudo Gisele , Sudo Roberto T. , Takiya Christina Maeda , Pinheiro Ana Acacia S. , Caruso-Neves Celso
Published: November 2010

The renal renin-angiotensin system plays a central role in the development of hypertension. The aim of this work was to verify the expression of angiotensin II receptors AT1R and AT2R in the microsomal fraction of renal cortex and correlate this with the development of hypertension and renal damage in spontaneously hypertensive rats (SHR) using Wistar-Kyoto rats (WKY) as controls. AT1R expression increased (126%) and AT2R expression decreased (66%) in 4-wk-old SHR; AT2expression decreased in 14-wk-old SHR (61%) compared with respective age-matched WKY. These modifications were correlated to the increase in protein kinase C activity and decrease in protein kinase A activity. Four-week-old SHR showed large accumulations of macrophages in kidney glomerulus and the tubulointerstitial area, dense cortical collagen deposition, and arterial proliferative changes in the walls of arterioles and medium-sized vessels. Similar modifications were also observed in 14-wk-old SHR. Four-week-old SHR treated with losartan (30 mg·kg−1·day−1) or hydralazine (15 and 30 mg·kg−1·day−1) by gavage for 10 wk did not develop hypertension. The decrease in AT2R expression and renal damage observed in SHR remained even after treatment with hydralazine. On the other hand, losartan treatment prevented the modifications observed in 14-wk-old SHR, indicating that renal injuries are caused specifically by AT1rather than an increase in blood pressure. Our results indicate that the imbalance in AT1R and AT2R expression is associated with an inflammatory process that contributes to renal injury in adult SHR and to the development of hypertension.
Common Synaptic Input to the Human Hypoglossal Motor Nucleus
Authors: Laine Christopher M. , Bailey E. Fiona
Published: November 2010

The tongue plays a key role in various volitional and automatic functions such as swallowing, maintenance of airway patency, and speech. Precisely how hypoglossal motor neurons, which control the tongue, receive and process their often concurrent input drives is a subject of ongoing research. We investigated common synaptic input to the hypoglossal motor nucleus by measuring the coordination of spike timing, firing rate, and oscillatory activity across motor units recorded from unilateral (i.e., within a belly) or bilateral (i.e., across both bellies) locations within the genioglossus (GG), the primary protruder muscle of the tongue. Simultaneously recorded pairs of motor units were obtained from 14 healthy adult volunteers using tungsten microelectrodes inserted percutaneously into the GG while the subjects were engaged in volitional tongue protrusion or rest breathing. Bilateral motor unit pairs showed concurrent low frequency alterations in firing rate (common drive) with no significant difference between tasks. Unilateral motor unit pairs showed significantly stronger common drive in the protrusion task compared with rest breathing, as well as higher indices of synchronous spiking (short-term synchrony). Common oscillatory input was assessed using coherence analysis and was observed in all conditions for frequencies up to ∼5 Hz. Coherence at frequencies up to ∼10 Hz was strongest in motor unit pairs recorded from the same GG belly in tongue protrusion. Taken together, our results suggest that cortical drive increases motor unit coordination within but not across GG bellies, while input drive during rest breathing is distributed uniformly to both bellies of the muscle.
An Illegitimate microRNA Target Site within the 3′ UTR of MDM4 Affects Ovarian Cancer Progression and Chemosensitivity
Authors: Wynendaele Jessika , Böhnke Anja , Leucci Eleonora , Nielsen Søren Jensby , Lambertz Irina , Hammer Stefanie , Sbrzesny Nadja , Kubitza Dana , Wolf Anja , Gradhand Elise , Balschun Katharina , Braicu Ioana , Sehouli Jalid , Darb-Esfahani Silvia , Denkert Carsten , Thomssen Christoph , Hauptmann Steffen , Lund Anders , Marine Jean-Christophe , Bartel Frank
Published: November 2010

Overexpression of MDM4 (also known as MDMX or HDMX) is thought to promote tumorigenesis by decreasing p53 tumor suppressor function. Even modest decrease in Mdm4 levels affects tumorigenesis in mice, suggesting that genetic variants of MDM4 might have similar effects in humans. We sequenced the MDM4 gene in a series of ovarian cancer cell lines and carcinomas to identify mutations and/or single nucleotide polymorphisms (SNPs). We identified an SNP (SNP34091) in the 3′-UTR of MDM4 that creates a putative target site for hsa-miR-191, a microRNA that is highly expressed in normal and tumor tissues. Biochemical evidence supports specific miR-191–dependent regulation of the MDM4-C, but not MDM4-A, variant. Consistently, the A-allele was associated with statistically significant increased expression of MDM4 mRNA and protein levels in ovarian carcinomas. Importantly, the wild-type genotype (A/A) is more frequent (57.8% vs. 42.2% for A/C and C/C, respectively) in patients with high-grade carcinomas than in patients with low-grade carcinomas (47.2% vs. 52.5% for A/A and A/C + C/C, respectively). Moreover, A/A patients who do not express the estrogen receptor had a 4.2-fold [95% confidence interval (CI) = 1.2–13.5; P = 0.02] increased risk of recurrence and 5.5-fold (95% CI = 1.5–20.5; P = 0.01) increased risk of tumor-related death. Unexpectedly, the frequency of p53 mutations was not significantly lower in A/A patients. We conclude that acquisition of an illegitimate miR-191 target site causes downregulation of MDM4 expression, thereby significantly delaying ovarian carcinoma progression and tumor-related death. Importantly, these effects appear to be, at least partly, independent of p53. Cancer Res; 70(23); 9641–9. ©2010 AACR.
VEGF-PET Imaging Is a Noninvasive Biomarker Showing Differential Changes in the Tumor during Sunitinib Treatment
Authors: Nagengast Wouter B. , Lub-de Hooge Marjolijn N. , Oosting Sjoukje F. , den Dunnen Wilfred F.A. , Warnders Frank-Jan , Brouwers Adrienne H. , de Jong Johan R. , Price Patricia M. , Hollema Harry , Hospers Geke A.P. , Elsinga Philip H. , Hesselink Jan Willem , Gietema Jourik A. , de Vries Elisabeth G.E.
Published: November 2010

Non-invasive imaging of angiogenesis could ease the optimization of antiangiogenesis treatments for cancer. In this study, we evaluated the role of VEGF-PET as a biomarker of dynamic angiogenic changes in tumors following treatment with the kinase inhibitor sunitinib. The effects of sunitinib treatment and withdrawal on the tumor was investigated using the new VEGF-PET tracer 89Zr-ranibizumab as well as 18F-FDG PET, and 15O-water PET in mouse xenograft models of human cancer. The obtained imaging results were compared with tumor growth, VEGF plasma levels and immunohistologic analyzes. In contrast to 18F-FDG and 15O-water PET, VEGF-PET demonstrated dynamic changes during sunitinib treatment within the tumor with a strong decline in signal in the tumor center and only minimal reduction in tumor rim, with a pronounced rebound after sunitinib discontinuation. VEGF-PET results corresponded with tumor growth and immunohistochemical vascular- and tumor- markers. Our findings highlight the strengths of VEGF-PET imaging to allow serial analysis of angiogenic changes in different areas within a tumor. Cancer Res; 71(1); 143–53. ©2010 AACR.
Differential Contextual Responses of Normal Human Breast Epithelium to Ionizing Radiation in a Mouse Xenograft Model
Authors: Coates Philip J. , Virginia M. , Appleyard C.L. , Murray Karen , Ackland Caroline , Gardner June , Brown Douglas C. , Adamson Dougal J.A. , Jordan Lee B. , Purdie Colin A. , Munro Alastair J. , Wright Eric G. , Dewar John A. , Thompson Alastair M.
Published: November 2010

Radiotherapy is a key treatment option for breast cancer, yet the molecular responses of normal human breast epithelial cells to ionizing radiation are unclear. A murine subcutaneous xenograft model was developed in which nonneoplastic human breast tissue was maintained with the preservation of normal tissue architecture, allowing us to study for the first time the radiation response of normal human breast tissue in situ. Ionizing radiation induced dose-dependent p53 stabilization and p53 phosphorylation, together with the induction of p21(CDKN1A) and apoptosis of normal breast epithelium. Although p53 was stabilized in both luminal and basal cells, induction of Ser392-phosphorylated p53 and p21 was higher in basal cells and varied along the length of the ductal system. Basal breast epithelial cells expressed ΔNp63, which was unchanged on irradiation. Although stromal responses themselves were minimal, the response of normal breast epithelium to ionizing radiation differed according to the stromal setting. We also demonstrated a dose-dependent induction of γ-H2AX foci in epithelial cells that was similarly dependent on the stromal environment and differed between basal and luminal epithelial cells. The intrinsic differences between human mammary cell types in response to in vivo irradiation are consistent with clinical observation that therapeutic ionizing radiation is associated with the development of basal-type breast carcinomas. Furthermore, there may be clinically important stromal–epithelial interactions that influence DNA damage responses in the normal breast. These findings demonstrate highly complex responses of normal human breast epithelium following ionizing radiation exposure and emphasize the importance of studying whole-tissue effects rather than single-cell systems. Cancer Res; 70(23); 9808–15. ©2010 AACR.