bluuebunny/crossref_metadata_2025 huggingface dataset:
Calcite cementation in shallow marine Eocene sandstones and constraints of early diagenesis
Authors: MOLENAAR N.
Published: December 2007

The Lower Eocene shallow marine Roda Sandstone Member forms part of the Paleogene fill of the Tremp–Graus Basin in the southern Spanish Pyrenees. It is composed of mixed siliciclastic–carbonate sandstones that were severely modified in composition and texture shortly after deposition during pauses in sedimentation. Moreover, part of the sand was lithified by an early marine fringe cement. This early diagenetic cement stabilized the sandstone framework and prevented mechanical compaction. Where early cement was absent, mechanical compaction severely reduced the primary porosity during a first burial phase. Ductile grains were squeezed between rigid grains, obstructing pore connections. This caused the development of distinct porosity patterns in the sandstone bodies. After the first burial phase, two major phases of uplift and erosion resulted in the truncation of the Roda Sandstone Member in the northern part of the area studied. After the erosional phases, the sandstones were buried again. Recharge of the sandstone bodies with fresh water caused replacement of aragonite and high–magnesian calcite by low–magnesian calcite. Simultaneously, a second generation of sparry calcite cement was precipitated. Replacement and cementation were completed first in the most porous and permeable levels represented by those parts of the sandstone that contained the early cement. The intervals compacted during the first burial were cemented later or cementation was completed later.
Soil gas emanations as precursory indicators of volcanic eruptions
Authors: BAUBRON J.-C. , ALLARD P. , SABROUX J.-C. , TEDESCO D. , TOUTALN J.-P.
Published: December 2007

Field measurements conducted on several active volcanoes in Italy, the Lesser Antilles, and Indonesia demonstrate the common Occurrence of diffuse soil gas emanations from the volcanic piles, at distances from active craters or fumarolic zones. These emanations consist essentially of carbon dioxide and rare gases and their genetic link with crater fumaroles and/or magma degassing at depth can be verified both chemically and isotopically. We emphasize here the potential use of these fluids for continuous volcano monitoring and eruption forecasting.
Distribution of granite and possible Devonian sediments in part of the East Shetland Platform, North Sea
Authors: HOLLOWAY S. , REAY D. M. , DONATO J. A. , BEDDOE-STEPHENS B.
Published: December 2007

Seismic data on the East Shetland Platform, at about 59°50'N 1°12'E, image 4.7–6.6 km of folded possibly Devonian sediments partly coincident with a geophysical anomaly previously interpreted as a granite pluton at shallow depth. Seismic and potential field data constrain the possible distribution of granite, and well data indicate that shallow, lithologidly variable basement rocks may surround the deep ?Devonian basin. Geology Series Halibut Bank and Bressay Bank sheets. It shows the depth in metres below sea level to base Cretaceous, and the location of the northern end of seismicline FGS-64, illustrated in Fig. 3. Good control on the seismic reflectors down to base Jurassic is provided by well3/28-1.

Previous work
. Although there is a positive gravity anomaly centred upon the western margin of the East Shetland Platform in block 9/3, Donato & Tully (1982) showed that there is a negative residual gravity anomaly in this area of the East Shetland Platform, when a regional gravity field, based on a model of crustal thinning beneath the Viking Graben, and the gravity effect of the known Tertiary and Mesozoic strata are subtracted from the observed gravity field. They modelled this negative residual gravity anomaly as a granite batholith 40 km in diameter, buried beneath approximately 2 km of sediments, with its centre close to seismic line FGS-64 (Fig.2)

Donato & Tully (1982) also described an associated horseshoe-shaped positive magnetic anomaly around the margins of the negative residual gravity anomaly (Fig. 2). They drew an analogy with Chevoit granite, where similar
Crustal evolutionary model for the Variscides of Ireland and Wales from SWAT seismic data
Authors: LE GALL B.
Published: December 2007

The SWAT seismic reflection profiles recently acquired across the Celtic Sea demonstrate that the crust, which underlies the Munster and Pembroke Variscan foldbelts, contains extensive south-dipping reflections interpreted as Hercynian foreland-directed ramp thrusts largely involving the pre-Devonian basement. These large-scale crustal ramps developed without any intervening flat-lying decollement levels, and are thought to have originated in a deep infra-crustal decoupling zone not imaged on the SWAT profiles because it lies within the present-day layered lower crust at approximately 25 km depth. The pre-existing extensional basinal pattern is assumed to have highly influenced the geometry of these deeply rooted thrusts, and in particular that of the frontal ramp which emerges along a discontinuous N100°-trending thrust zone located above the faulted extensional margin of the Munster, Pembroke and Mendips Devonian basins. Shortening of the Irish and Welsh external zones is hence assigned to dominantly crustal stacking achieved along steep ramps dying out upwards, and giving way to mainly undisrupted folds in the thick overlying Devonian infill. In addition, a shallow thin-skinned fold-thrust system developed above an intra-Namurian master decollement still preserved in the footwall of the frontal ramp where it either stays blind (Ireland) or emerges (Pembroke) above a dominantly wrench-faulted Caledonian basement. Compiling SWAT seismic data and structural geology leads to a crustal evolutionary model for the Irish and South Welsh external Variscides from a Devonian basin template to a final deformation pattern.
Tectonics and seismic sequence stratigraphy
Authors: WILLIAMS GRAHAM D. , DOBB ANGELA
Published: December 2007

A two day meeting convened by Graham Williams (University of Keele) and Angela Dobb (Mobil North Sea Ltd) was held at the Geological Society in London on 6 and 7 February 1991.

The aim of the meeting was to address the problems of the interaction between eustacy, sediment supply rate and tectonics in seismically imaged basin sequences. The meeting discussed the importance of tectonics in generating recognizable sequence boundaries on both a regional and local scale. It was felt that eustacy as the dominant factor in controlling basin stratigraphy has been overplayed in the past. There were 190 participants at the conference representing the oil industry and academia. Some 21 oral presentations were given covering theoretical aspects of sequence stratigraphy, numerical modelling and field analogues. Case histories from Europe, North America, Africa and the UK were presented.

Basin scale numerical modelling

In the simplest case stratigraphy in extensional basins and passive margins may be subdivided into pre-, syn- and post-rift sequences representing stratigraphic fill related to a single rifting event. A widely recognized unconformity or megasequence boundary between syn- and post-rift sequences is referred to as the ‘breakup unconformity’.

Numerical modelling on a basin scale in extensional regimes has been carried out by
M. J. Newall
and
N. J. Kusznir
(Shell Research, Liverpool) who concentrated on the post-rift subsidence history and palaeobathymetric evolution of Snorre, Magnus and other areas of the northern North Sea Basin. Subsidence resulting from thermal effects, compaction and sediment loading has been numerically modelled using flexural
A Middle Pleistocene palaeovalley-fill west of the Malvern Hills
Authors: BARCLAY W. J. , BRANDON A. , ELLISON R. A. , MOORLOCK B. S. P.
Published: December 2007

New sections and detailed mapping of the Pleistocene deposits on the west side of the Malvern Hills show that the area occupied by ice during a pre-Devensian glaciation was greater than previously envisaged. The deposits associated with the glaciation occur in a palaeovalley and comprise lacustrine silts and clays and till. They are considered to be of Anglian age as they are locally overlain non-sequentially by newly described silts of probable late Anglian to early Hoxnian age, the most westerly record of such deposits in southern Britain. Gravels underlying the glacigenic deposits are thought to have been laid down by a southward-flowing river either earlier in the Anglian or during a preceding stage. Deposits formed during two post-Hoxnian episodes of gelifluction are correlated with similar deposits on the east side of the Malvern Hills. The younger gelifluctate is probably late Devensian in age and the older, much dissected deposit is attributable to periglacial processes during an earlier Devensian or Wolstonian cold period.
A return to William Smith
Authors: Fyfe William Sefton
Published: December 2007

I was
deeply honoured
when the Geological Society invited me to give the William Smith Lecture for 1970. It was an invitation rather easy to accept but when I contemplated the work of William Smith himself, I began to feel more and more inadequate for the task. What could a chemical-geologist say that might do honour to a man who was one who established geology as a rigorous science and who founded stratigraphy and geological mapping, the heart of all geology?

I think that as most of us grow a little older, we find that our new thoughts or the stage of thinking we have reached is often only that of workers long ago. For this reason when I pondered the subject of this lecture I looked a little at some of the writing of Smith himself and found again that my own present trend of thinking and plans for future working, were simply echoes from Smith. This man, who as Lyell states was ‘unassisted by advantage of wealth or station in society’ could have been the author of many parts of our present so-called ‘forward looks’.

I think it is perhaps justifiable here to quote a few of William Smith’s remarks from the 1815 memoir which accompanied his map of the strata of England:

“The wealth of a country primarily consists in the industry of its inhabitants, and in its vegetable and mineral productions; the application of the latter of which to the purposes of manufacture, within memory, has
Letters to the Editor
Authors: Lawson J. D. , Halstead L. Beverly , Turner Susan
Published: December 2007

Sir

I am in sympathy with many of the views expressed by Westoll
et al.
in their letter on the Silurian-Devonian boundary published in vol. 127 part 3 of the
Journal
, and in particular with their contention that the claims of a boundary at the base of the
M. ultimus
Zone were not given sufficient consideration by the Silurian-Devonian Committee of the International Commission on Stratigraphy. Nevertheless, this committee finally voted almost unanimously in favour of a boundary at the base of the
M. uniformis
Zone and I believe that a world-wide referendum of interested geologists would also show overwhelming support for this boundary. It is not popular in Britain because of the extreme difficulty in recognising the equivalent level in our continental development but it is not to be expected that a chronostratigraphic boundary will be an easily mappable horizon throughout the world. We tolerate in this country a Permian-Triassic boundary which lies somewhere in the middle of our New Red Sandstone and we must now come to accept a Silurian-Devonian boundary which can only be vaguely positioned within hundreds of feet of poorly exposed and sparsely fossiliferous Old Red Sandstone. Stratigraphical boundaries are essentially arbitrary and the most important criterion is international uniformity in usage. This uniformity can only be achieved by the sacrifice of individual and national preferences and I consider that the interests of stratigraphy are best served in this instance by acquiescence in the international decision on the
M. uniformis
boundary.

My support for the
The Badenian evaporite basin of the northern Carpathian Foredeep as a model of a meromictic selenite basin
Authors: Bąbel M. , Bogucki A.
Published: December 2007

The hydrography and brine flow patterns in the Middle Miocene (Badenian) evaporite basin of the northern Carpathian Foredeep (in Ukraine, Poland and the Czech Republic) are reconstructed based on studies of the peculiar, conformably oriented, bottom-grown gypsum crystals present in the selenite deposits along the basin margin. The crystal apices are turned in a similar horizontal direction that is interpreted as the product of consistent flow of the bottom brines during crystal formation. Similarly the regular millimetre-scale growth zoning in these crystals presumably reflects the annual stratification-mixing pattern in the brine column typical of monomictic basins. In the central, deeper parts of the basin deposition was dominated by Na-chloride, and the selenitic facies are lacking. These central areas are interpreted as being meromictic during the oriented selenite deposition. The permanent pycnocline separated a mixolimnion, at the surface, from an anoxic (euxinic) monimolimnion, at the bottom, where direct evaporative crystallization of gypsum was not possible. The mixolimnion, which extended far onto the shallow margin of the basin, showed only a seasonal (annual) pycnocline and monomictic hydrography. Oriented selenites grew just in this mixolimnetic marginal zone, under predominantly counterclockwise (cyclonic) flow.
Evidence of vanished evaporites in Neoarchaean carbonates of South Africa
Authors: Gandin A. , Wright D. T.
Published: December 2007

A detailed sedimentological and petrographic analysis of the Neoarchaean Campbellrand and Malmani carbonates of South Africa provides evidence that collectively indicates the former existence of evaporites and the early replacement of primary sulphate deposits by calcite. Diagenetic disruption of sedimentary structures, solution collapse breccias, cross-cutting relationships, corrosion surfaces, pseudomorphs of displacive nucleation cones, flowage and nodular structures are all characteristic of evaporites and their ductile behaviour. In thin section, rosettes of length-slow chalcedony around the heads of the silicified stromatolites also testify to the former presence of sulphates. Calcite, in the unusual form of herringbone/flamboyant spar in ‘cuspate’ and nodular facies, may preserve the fold shapes of enterolithic gypsum, picked out by deformed trails of degraded organic matter and dolomitized clusters of filaments. Subvertical columns of compressed organic material in a matrix of herringbone/flamboyant calcite appear to be the result of squeezing and compression between adjacent sulphate nodules. Carbonate replacement of evaporites was largely driven by bacterial sulphate reduction in sapropels and microbialites during early diagenesis. The petrographic evidence indicates that the replacive herringbone/flamboyant calcite precipitated after enterolithic and nodular structures formed, the sulphate having been used up before the enclosed organic material was totally consumed.
A comparison between deterministic and stochastic fault seal techniques
Authors: Dee S. J. , Yielding G. , Freeman B. , Bretan P.
Published: December 2007

Traditionally, the analysis of fault seal has been purely deterministic or a combination of deterministic and stochastic methods. In a deterministic model, prediction of the locations of reservoir overlaps is made from the static model of the reservoir horizon and fault geometry. The principal aim is to map faulted reservoir overlaps and determine their sealing character. This is usually performed using a predictive algorithm such as the shale gouge ratio (SGR) that relates the shale content of the formations that have moved past a point on the fault zone to the sealing capacity of the fault rock.

Deterministic fault seal studies are sensitive to the uncertainties associated with mapping of horizons in proximity to faults and the inherent uncertainty in a static fault interpretation in both position and fault zone complexity. Uncertainty in the static structure model can be addressed by convolving uncertainty in throw magnitude with juxtapositions at the fault. However, this does not address the uncertainty in the distribution of reservoirs on either side of the fault. With stochastic models multiple realizations of the stratigraphy can be tested. Stochastic models capture the uncertainty in the position of the reservoir at the fault by allowing multiple realizations of stacking geometries, where the principal assumption is that these stacked reservoir zones are laterally continuous covering the entire likely fill area.

Despite the conceptual differences between these two approaches to fault seal analysis, comparison of the predictions they make on the Ling Gu field shows a surprising degree of conformity. The cut-off used to determine the number of sand and shale beds in the stochastic workflow appears to account for seal by fault zone materials, since a conservative cut-off implies fewer sand beds with lower probability of leak and correlates with more shale in the section and higher SGR values.
Static and dynamic connectivity in bed-scale models of faulted and unfaulted turbidites
Authors: Manzocchi T. , Walsh J. J. , Tomasso M. , Strand J. , Childs C. , Haughton P. D. W.
Published: December 2007

A range of unfaulted and faulted bed-scale models with sheet-like or lobate bed geometries and faults of comparable sizes to beds have been built and analysed in terms of bed connectivity and fractional permeability assuming permeable sands and impermeable shales and shale smears. A new method has been devised allowing amalgamation ratio to be included explicitly as model input and this property, rather than net:gross ratio, is found to be the dominant control on the connectivity of unfaulted sequences. At the geometrically representative scales considered (horizontal distances of >1 km for beds up to
c
. 1 m thick and faults up to
c
. 5 m throw), faulted sequences rarely have lower connectivities than their unfaulted sedimentological equivalents irrespective of whether fault rock properties are included. Models containing stochastically placed shale smears associated with each faulted shale horizon are generally better connected than if deterministic Shale Gouge Ratio cut-offs are applied. Despite the complex interactions between geological input and connectivity of the faulted sequences, the flow properties at representative scales are controlled by three geometrical variables describing connectivity, anisotropy and resolution. If two different faulted or unfaulted systems have identical values of these three variables they will have the same equivalent flow properties.
Three-dimensional upscaling of fault damage zones for reservoir simulation
Authors: Harris S. D. , Vaszi A. Z. , Knipe R. J.
Published: December 2007

Major faults are surrounded by damage zones of minor faults that, in siliclastic rocks, can form barriers to flow in their own right. Reservoir flow simulation, now a routine part of reservoir management, requires equivalent hydraulic parameters on the scale of the whole fault. Geological models of structurally complex reservoirs, from which flow simulator grids are generated, require information on the 3D characteristics of fault populations. Here, 3D stochastic models of fault damage zone (FDZ) architecture are generated based on fault population statistics (offset, orientation, length, thickness, spatial distribution) measured from seismic, outcrop and core data. These FDZ models provide input to a 3D discrete fault flow model (DFFM) and we consider the case when the minor faults have permeabilities (isotropic) that are several orders of magnitude lower than the host rock, and thus form partial barriers to flow. The DFFM is used to determine and characterize the impact of the parameters defining the FDZ on the predicted bulk FDZ permeability, connectivity, ‘efficiency’ as a barrier or retarder to flow, and the ‘effective’ fault rock throw to thickness relationship for the FDZ. The latter of the summary results presented provides a means for incorporating FDZs into conventional production simulation package models of structurally complex reservoirs.
The modelling of fractured reservoirs: constraints and potential for fracture network geometry and hydraulics analysis
Authors: Mäkel G. H.
Published: December 2007

The interconnectedness of a subsurface fracture system depends on five fracture and fracture set geometry characteristics: density, orientation, dimensions (height and length), connectivity and aperture. Orientation and density can be determined with some degree of accuracy but the uncertainty ranges associated with the other characteristics will be large. Calibration with dynamic indicators will bring out the hydraulic properties of the network and can help to reduce uncertainty in the geometric characteristics. The fracture network geometry in the inter-well space can be described through geostatistical analysis but more commonly it is derived from seismic data, through edge detection or the analysis and calibration of seismic velocity anisotropy attributes or curvature analysis. Geomechanical analysis is necessary to evaluate the impact on network conductivity of the changing stress state in the reservoir. Using percolation theory, a qualitative assessment can be made of how the conductivity and interconnectedness of the fracture network is developed in terms of network clusters. This integrated analysis of static and dynamic fracture data leads to the formulation of conceptual models and a set of modelling rules. A Digital (Discrete) Fracture Network model, based on these concept(s), rules and inter-well interpolation data, can then be analysed in terms of expected network cluster size, distribution and hydraulics. This provides a control on the expectations embedded in the concepts prior to dynamic modelling. The uncertainties are normally quite large and very seldom will they allow construction of the definitive fracture model. The systematic and integrated analysis of fracture network geometry, constrained with dynamic indicators and subsequent network cluster analysis, are necessary preparatory steps for construction and analysis of dynamic models.
Numerical simulation of multi-phase fluid flow in structurally complex reservoirs
Authors: Matthäi S. K. , Geiger S. , Roberts S. G. , Paluszny A. , Belayneh M. , Burri A. , Mezentsev A. , Lu H. , Coumou D. , Driesner T. , Heinrich C. A.
Published: December 2007

Realistic simulation of structurally complex reservoirs (SCR) is challenging in at least three ways: (1) geological structures must be represented and discretized accurately on vastly different length scales; (2) extreme ranges and discontinuous variations of material properties have to be associated with the discretized structures and accounted for in the computations; and (3) episodic, highly transient and often localized events such as well shut-in have to be resolved adequately within the overall production history, necessitating a highly adaptive resolution of time. To facilitate numerical experiments that elucidate the emergent properties, typical states and state transitions of SCRs, an application programmer interface (API) called complex systems modelling platform (CSMP++) has been engineered in ANSI/ISO C++. It implements a geometry and process-based SCR decomposition in space and time, and uses an algebraic multigrid solver (SAMG) for the spatio-temporal integration of the governing partial differential equations. This paper describes a new SCR simulation workflow including a two-phase fluid flow model that is compared with ECLIPSE in a single-fracture flow simulation. Geologically realistic application examples are presented for incompressible 2-phase flow, compressible 3-phase flow, and pressure-diffusion in a sector-scale model of a structurally complex reservoir.
Water in Nonpolar Confinement: From Nanotubes to Proteins and Beyond
Authors: Rasaiah Jayendran C. , Garde Shekhar , Hummer Gerhard
Published: December 2007

Water molecules confined to nonpolar pores and cavities of nanoscopic dimensions exhibit highly unusual properties. Water filling is strongly cooperative, with the possible coexistence of filled and empty states and sensitivity to small perturbations of the pore polarity and solvent conditions. Confined water molecules form tightly hydrogen-bonded wires or clusters. The weak attractions to the confining wall, combined with strong interactions between water molecules, permit exceptionally rapid water flow, exceeding expectations from macroscopic hydrodynamics by several orders of magnitude. The proton mobility along 1D water wires also substantially exceeds that in the bulk. Proteins appear to exploit these unusual properties of confined water in their biological function (e.g., to ensure rapid water flow in aquaporins or to gate proton flow in proton pumps and enzymes). The unusual properties of water in nonpolar confinement are also relevant to the design of novel nanofluidic and molecular separation devices or fuel cells.
Activation of 5-HT1Areceptors in medullary raphé disrupts sleep and decreases shivering during cooling in the conscious piglet
Authors: Brown J. W. , Sirlin E. A. , Benoit A. M. , Hoffman J. M. , Darnall R. A.
Published: December 2007

Activation of 5-HT1Areceptors in the medullary raphé decreases sympathetically mediated brown adipose tissue (BAT) thermogenesis and peripheral vasoconstriction when previously activated with leptin, LPS, prostaglandins, or cooling. It is not known whether shivering is also modulated by medullary raphé 5-HT1Areceptors. We previously showed in conscious piglets that activation of 5-HT1Areceptors with (±)-8-hydroxy-2-(dipropylamino)-tetralin (8-OH-DPAT) in the paragigantocellularis lateralis (PGCL), a medullary region lateral to the raphé that contains substantial numbers of 5-HT neurons, eliminates rapid eye movement (REM) sleep and decreases shivering in a cold environment, but does not attenuate peripheral vasoconstriction. Hoffman JM, Brown JW, Sirlin EA, Benoit AM, Gill WH, Harris MB, Darnall RA. Am J Physiol Regul Integr Comp Physiol 293: R518–R527, 2007. We hypothesized that, during cooling, activation of 5-HT1Areceptors in the medullary raphé would also eliminate REM sleep and, in contrast to activation of 5-HT1Areceptors in the PGCL, would attenuate both shivering and peripheral vasoconstriction. In a continuously cool environment, dialysis of 8-OH-DPAT into the medullary raphé resulted in alternating brief periods of non-REM sleep and wakefulness and eliminated REM sleep, as observed when 8-OH-DPAT is dialyzed into the PGCL. Moreover, both shivering and peripheral vasoconstriction were significantly attenuated after 8-OH-DPAT dialysis into the medullary raphé. The effects of 8-OH-DPAT were prevented after dialysis of the selective 5-HT1Areceptor antagonist WAY-100635. We conclude that, during cooling, exogenous activation of 5-HT1Areceptors in the medullary raphé decreases both shivering and peripheral vasoconstriction. Our data are consistent with the hypothesis that neurons expressing 5-HT1Areceptors in the medullary raphé facilitate spinal motor circuits involved in shivering, as well as sympathetic stimulation of other thermoregulatory effector mechanisms.
Molecular detection and immunological localization of gill Na+/H+exchanger in the dogfish (Squalus acanthias)
Authors: Claiborne James B. , Choe Keith P. , Morrison-Shetlar Alison I. , Weakley Jill C. , Havird Justin , Freiji Abe , Evans David H. , Edwards Susan L.
Published: December 2007

The dogfish ( Squalus acanthias) can make rapid adjustments to gill acid-base transfers to compensate for internal acidosis/alkalosis. Branchial Na+/H+exchange (NHE) has been postulated as one mechanism driving the excretion of H+following acidosis. We have cloned gill cDNA that includes an open reading frame coding for a 770-residue protein most homologous (∼71%) to mammalian NHE2. RT-PCR revealed NHE2 transcripts predominantly in gill, stomach, rectal gland, intestine, and kidney. In situ hybridization with an antisense probe against NHE2 in gill sections revealed a strong mRNA signal from a subset of interlamellar and lamellae cells. We developed dogfish-specific polyclonal antibodies against NHE2 that detected a ∼70-kDa protein in Western blots and immunologically recognized branchial cells having two patterns of protein expression. Cytoplasmic and apical NHE2 immunoreactivity were observed in cells coexpressing basolateral Na+-K+-ATPase. Other large ovoid cells more generally staining for NHE2 also were strongly positive for basolateral H+-ATPase. Gill mRNA levels for NHE2 and H+-ATPase did not change following systemic acidosis (as measured by quantitative PCR 2 h after a 1- or 2-meq/kg acid infusion). These data indicate that posttranslational adjustments of NHE2 and other transport systems (e.g., NHE3) following acidosis may be of importance in the short-term pH adjustment and net branchial H+efflux observed in vivo. NHE2 may play multiple roles in the gills, involved with H+efflux from acid-secreting cells, basolateral H+reabsorption for pHiregulation, and in parallel with H+-ATPase for the generation of HCO3−in base-secreting cells.
Low-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat
Authors: Krämer Stephanie , Wang-Rosenke Yingrui , Scholl Valeska , Binder Eva , Loof Tanja , Khadzhynov Dmytro , Kawachi Hiroshi , Shimizu Fujio , Diekmann Fritz , Budde Klemens , Neumayer Hans-H. , Peters Harm
Published: December 2007

Treatment options in human mesangioproliferative glomerulonephritis/sclerosis, mostly IgA nephropathy, are limited. Progressive mesangioproliferative nephropathy represents a major cause of end-stage kidney disease. The present study explores the efficacy of low-dose mTOR inhibition by rapamycin in a chronic-progressive model of mesangioproliferative glomerulosclerosis (cGS). cGS was induced by high-dose anti-thy1 antibody injection into uninephrectomized rats. Rapamycin administration (2.5 mg·kg−1·body wt−1) was started 10 days after antibody injection and continued until week 20. cGS was characterized by advancing proteinuria, increased blood pressure, marked tubulointerstitial and glomerular fibrosis, cell proliferation and round cell infiltration, and impaired renal function. Kruskal-Wallis and Mann-Whitney U-tests were used for statistical analysis. The course of chronic anti-thy1-induced glomerulosclerosis was significantly attenuated by low-dose rapamycin treatment. In week 20, this was demonstrated by improvements in proteinuria (−38%), systolic blood pressure (−16 mmHg), tubulointerstitial and glomerular histological matrix accumulation (−61 and −24%), transforming growth factor-β1 overexpression (−41 and −47%), collagen I deposition (−53 and −65%), cell proliferation (−90 and −76%), and leukocyte number (macrophages −52 and −53%; lymphocytes −58 and 51%), respectively. Rapamycin improved renal function as well (blood creatinine −0.68 mg/dl, urea −66.7 mg/day, and creatinine clearance +0.13 ml·min−1·100 g body wt−1). In conclusion, low-dose mTOR inhibition by rapamycin limits the progressive course of anti-thy1-induced renal disease toward chronic glomerulosclerosis, tubulointerstitial fibrosis, and renal insufficiency. Renoprotection by rapamycin involved significant beneficial effects on multiple key pathways in the progression of chronic renal disease, i.e., proteinuria, extracellular matrix accumulation, renal cell proliferation, and inflammatory cell infiltration.
Effects of Motor Training on the Recovery of Manual Dexterity After Primary Motor Cortex Lesion in Macaque Monkeys
Authors: Murata Yumi , Higo Noriyuki , Oishi Takao , Yamashita Akiko , Matsuda Keiji , Hayashi Motoharu , Yamane Shigeru
Published: December 2007

To investigate the effects of postlesion training on motor recovery, we compared the motor recovery of macaque monkeys that had received intensive motor training with those that received no training after a lesion of the primary motor cortex (M1). An ibotenic acid lesion in the M1 digit area resulted in impairment of hand function, with complete loss of digit movement. In the monkeys that had undergone intensive daily training (1 h/day, 5 days/wk) after the lesion, behavioral indexes used to evaluate manual dexterity recovered to the same level as in the prelesion period after 1 or 2 mo of postlesion training period. Relatively independent digit movements, including precision grip (prehension of a small object with finger-to-thumb opposition), were restored in the trained monkeys. Although the behavioral indexes of manual dexterity recovered to some extent in the monkeys without the postlesion training, they remained lower than those in the prelesion period until several months after M1 lesion. The untrained monkeys frequently used alternate grip strategies to grasp a small object with the affected hand, holding food pellets between the tip of the index finger and the dorsum of the thumb. These results suggest that the recovery after M1 lesion includes both use-dependent and use-independent processes and that the recovery of precision grip can be promoted by intensive use of the affected hand in postlesion training.
Evidence for Microtubule Target Engagement in Tumors of Patients Receiving Ixabepilone
Authors: Zhuang Sen H. , Hung Y. Elizabeth , Hung Laura , Robey Robert W. , Sackett Dan L. , Linehan W. Marston , Bates Susan E. , Fojo Tito , Poruchynsky Marianne S.
Published: December 2007

Purpose: Microtubule-stabilizing agents, such as taxanes, have been shown to be effective anticancer drugs. α-Tubulin, a basic unit of microtubules, can undergo several posttranslational modifications after assembly into stabilized microtubules, including acetylation and detyrosination. These modifications have been observed in cell cultures after exposure to microtubule stabilizers. Our objective was to develop a straightforward and dependable assay to show tubulin target engagement in tumor tissue after treatment of patients with ixabepilone(BMS-247550; Ixempra).

Experimental Design: Levels of posttranslationally modified α-tubulin were assessed in lysates of cultured malignant cell lines, as well as in both tumor tissue and peripheral blood mononuclear cells derived from patients before and after treatment with ixabepilone. Modification-specific antibodies permitted quantitative Western blot analysis.

Results: In cultured cell lines, the levels of detyrosinated (glu-terminated) and acetylated α-tubulin increased after microtubule stabilization induced by ixabepilone. ixabepilone treatment also induced a 2-fold to 25-fold increase in detyrosinated α-tubulin levels in 11 of 13 serial biopsies and a 2-fold to 100-fold increase in acetylated α-tubulin in 11 of 12 serial biopsies obtained from patients receiving ixabepilone. Overall, little or no difference in tubulin modifications were observed between the before and after ixabepilone treatment in lysates from their peripheral blood mononuclear cells at the time point examined.

Conclusion: Assessing the levels of detyrosinated and/or acetylated α-tubulin seems to provide a simple and reliable assay to show target engagement by the microtubule-stabilizing agent ixabepilone. Such analyses may provide further understanding of therapeutic success or failure of microtubule-stabilizing agents in cancer therapy.
Angiogenesis-Promoting Gene Patterns in Alveolar Soft Part Sarcoma
Authors: Lazar Alexander J.F. , Das Parimal , Tuvin Daniel , Korchin Borys , Zhu Quansheng , Jin Zeming , Warneke Carla L. , Zhang Peter S. , Hernandez Vivian , Lopez-Terrada Dolores , Pisters Peter W. , Pollock Raphael E. , Lev Dina
Published: December 2007

Purpose: We examined a cohort of patients with alveolar soft part sarcoma (ASPS) treated at our institution and showed the characteristic ASPSCR1-TFE3 fusion transcript in their tumors. Investigation of potential angiogenesis-modulating molecular determinants provided mechanistic and potentially therapeutically relevant insight into the enhanced vascularity characteristic of this unusual tumor.

Experimental Design: Medical records of 71 patients with ASPS presenting at the University of Texas M.D. Anderson Cancer Center (1986-2005) were reviewed to isolate 33 patients with formalin-fixed paraffin-embedded material available for study. RNA extracted from available fresh-frozen and formalin-fixed paraffin-embedded human ASPS tumors were analyzed for ASPSCR1-TFE3 fusion transcript expression using reverse transcription-PCR and by angiogenesis oligomicroarrays with immunohistochemical confirmation.

Results: Similar to previous studies, actuarial 5- and 10-year survival rates were 74% and 51%, respectively, despite frequent metastasis. ASPSCR1-TFE3 fusion transcripts were identified in 16 of 18 ASPS samples. In the three frozen samples subjected to an angiogenesis oligoarray, 18 angiogenesis-related genes were up-regulated in tumor over adjacent normal tissue. Immunohistochemistry for jag-1, midkine, and angiogenin in 33 human ASPS samples confirmed these results. Comparison with other sarcomas indicates that the ASPS angiogenic signature is unique.

Conclusion: ASPS is a highly vascular and metastatic tumor with a surprisingly favorable outcome; therapeutically resistant metastases drive mortality. Future molecular therapies targeting overexpressed angiogenesis-promoting proteins (such as those identified here) could benefit patients with ASPS.
Influence of CYP3A4 Inhibition on the Steady-State Pharmacokinetics of Imatinib
Authors: van Erp Nielka P. , Gelderblom Hans , Karlsson Mats O. , Li Jing , Zhao Ming , Ouwerkerk Jan , Nortier Johan W. , Guchelaar Henk-Jan , Baker Sharyn D. , Sparreboom Alex
Published: December 2007

Purpose: To evaluate the effects of ritonavir, a potent inhibitor of CYP3A4, on the steady-state pharmacokinetics of imatinib.

Experimental Design: Imatinib pharmacokinetics were evaluated in cancer patients receiving the drug for at least 2 months, after which ritonavir (600 mg) was administered daily for 3 days. Samples were obtained on the day before ritonavir (day 1) and on the third day (day 4). The in vitro metabolism of imatinib with or without ritonavir and the effect of imatinib on 1-OH-midazolam formation rate, a probe for CYP3A4 activity, were evaluated with human CYP3A4 and pooled liver microsomes.

Results: In 11 evaluable patients, the geometric mean (95% confidence interval) area under the curve of imatinib on days 1 and 4 were 42.6 (33.0-54.9) μg·h/mL and 41.2 (32.1-53.1) μg·h/mL, respectively (P = 0.65). A population analysis done in NONMEM with a time-dependent covariate confirmed that ritonavir did not influence the clearance or bioavailability of imatinib. In vitro, imatinib was metabolized to the active metabolite CGP74588 by CYP3A4 and CYP3A5 and, to a lesser extent, by CYP2D6. Ritonavir (1 μmol/L) completely inhibited CYP3A4-mediated metabolism of imatinib to CGP74588 but inhibited metabolism in microsomes by only 50%. Imatinib significantly inhibited CYP3A4 activity in vitro.

Conclusion: At steady state, imatinib is insensitive to potent CYP3A4 inhibition and relies on alternate elimination pathways. For agents with complex elimination pathways that involve autoinhibition, interaction studies that are done after a single dose may not be applicable when drugs are administered chronically.
Hypoxia-Inducible Factor 1α in Clear Cell Renal Cell Carcinoma
Authors: Klatte Tobias , Seligson David B. , Riggs Stephen B. , Leppert John T. , Berkman Maria K. , Kleid Mark D. , Yu Hong , Kabbinavar Fairooz F. , Pantuck Allan J. , Belldegrun Arie S.
Published: December 2007

Purpose: Hypoxia-inducible factor-1α (HIF-1α) plays an important role in tumoral adaptation to hypoxic conditions by serving as a transcription factor for several crucial proteins, including vascular endothelial growth factor and carbonic anhydrase IX (CAIX). Here, we evaluated the significance of HIF-1α in renal cell carcinoma (RCC).

Experimental Design: Immunohistochemical analysis was done on a tissue microarray constructed from paraffin-embedded primary tumor specimens from 357 patients treated by nephrectomy for RCC. Nuclear expression was evaluated by a single pathologist who was blinded to outcome. The expression levels were associated with pathologic variables and survival.

Results: HIF-1α expression was greater in RCC than in benign tissue. Clear cell RCC showed the highest expression levels. In clear cell RCC, HIF-1α was significantly correlated with markers of apoptosis (p21, p53), the mammalian target of rapamycin pathway (pAkt, p27), CXCR3, and proteins of the vascular endothelial growth factor family. HIF-1α was correlated with CAIX and CAXII in localized, but not in metastatic RCC. HIF-1α expression predicted outcome in metastatic patients: patients with high HIF-1α expression (>35%) had significantly worse survival than patients with low expression (≤35%); median survival, 13.5 versus 24.4 months, respectively (P = 0.005). Multivariate analysis retained HIF-1α and CAIX expression as the strongest independent prognostic factors for patients with metastatic clear cell RCC.

Conclusions: HIF-1α is an important independent prognostic factor for patients with metastatic clear cell RCC. Because HIF-1α and CAIX are independently and differentially regulated in metastatic clear cell RCC, both tumor markers can be complementary in predicting prognosis.
Loss of Heterozygosity at D8S298 Is a Predictor for Long-term Survival of Patients with Tumor-Node-Metastasis Stage I of Hepatocellular Carcinoma
Authors: Pang Jin-Zhong , Qin Lun-Xiu , Ren Ning , Hei Zhen-Yu , Ye Qing-Hai , Jia Wei-Dong , Sun Bing-Sheng , Lin Guo-Ling , Liu Dao-Yong , Liu Yin-Kun , Tang Zhao-You
Published: December 2007

Purpose: Our previous studies have shown that chromosome 8p deletion correlates with metastasis of hepatocellular carcinoma (HCC). This study was to determine whether 8p deletion could be used in predicting the prognosis of patients with HCC, particularly in those with early stage of HCC.

Experimental Design: A total of 131 patients with tumor-node-metastasis (TNM) stage I of HCC who underwent curative liver resection were enrolled. Loss of heterozygosity (LOH) was examined using 10 microsatellite markers at chromosome 8p, as well as 14 microsatellites at chromosome 1p, 17p, 4q, 13q, and 16q, and their association with 5-year overall survival (OS) and disease-free survival (DFS) of patients was analyzed.

Results: In the entire cohort of patients, the mean LOH frequency at these 24 loci was 43.2%; LOH frequencies at D8S298 and D1S199 were 31.5% and 33.7%, respectively. LOH at D8S298 was associated with a worse 5-year OS (P = 0.008) and DFS (P = 0.038) in patients with TNM stage I of HCC. Likewise, the patients with LOH at D1S199 had a worse 5-year OS (P < 0.001) and DFS (P = 0.014) compared with those without LOH at D1S199. In multivariate analyses, LOH at D8S298 was an independent predictor of decreased DFS (hazard ratio, 0.372; 95% 95% confidence interval, 0.146-0.948; P = 0.038), whereas LOH at D1S199 was an independent predictor of decreased OS (hazard ratio, 0.281; 95% confidence interval, 0.123-0.643; P = 0.003).

Conclusions: LOH at D8S298 and D1S199 is independently associated with a worse survival in patients with TNM stage I of HCC after curative resection and could serve as novel prognostic predictors for this subgroup of patients.
l-Arginine Reduces Cell Proliferation and Ornithine Decarboxylase Activity in Patients with Colorectal Adenoma and Adenocarcinoma
Authors: Ma Qingyong , Wang Yunjian , Gao Xiaopeng , Ma Zhenhua , Song Zhengjun
Published: December 2007

Purpose: Evidence suggests that the majority of colorectal carcinomas arise from adenomas, and l-arginine suppresses colorectal tumorigenesis. We suppose that l-arginine may inhibit the process of carcinogenesis from colorectal adenoma to adenocarcinoma. The aim of this study was to investigate the effects of l-arginine on the formation and development of colorectal tumors.

Experimental Design: We selected 60 patients with colorectal cancer and 60 patients with colorectal adenoma (CRA) and divided them into four groups of 30 patients each. We gave 30 g (120 mL) of l-arginine everyday for 3 days to the test groups, whereas l-arginine was substituted by 5% glucose in the control groups. The expression of the proliferating cell nuclear antigen, survivin, and nitric oxide synthase was examined immunohistochemically, and ornithine decarboxylase (ODC) activity was examined spectrophotometrically. Serum nitric oxide (NO) was detected by the Griess assay.

Results: In patients with CRA, the proliferating cell nuclear antigen and survivin labeling indexes and ODC activity of the tumor and paratumor mucosa in the l-arginine–treated group after l-arginine treatment were significantly lower as compared with the corresponding pretreatment values (P < 0.01). Moreover, inducible nitric oxide synthase expression in the tumor markedly increased after l-arginine treatment (P < 0.05). Serum NO levels in the patients with colorectal cancer were markedly higher than those in the patients with CRA, and l-arginine treatment was responsible for this increase (P < 0.05).

Conclusions: Our results show that l-arginine can restrain crypt cell hyperproliferation and the expression of survivin, an inhibitor of apoptosis protein. This suggests that l-arginine can block the formation and development of colorectal tumors, and this effect might be related to the increased serum NO concentration and decreased ODC activity.
PAM4-Reactive MUC1 Is a Biomarker for Early Pancreatic Adenocarcinoma
Authors: Gold David V. , Karanjawala Zarir , Modrak David E. , Goldenberg David M. , Hruban Ralph H.
Published: December 2007

Purpose: The anti-MUC1 monoclonal antibody (MAb), PAM4, has a high specificity for pancreatic adenocarcinoma compared with other cancers, normal tissues, or pancreatitis. In order to assess its role in early pancreatic cancer development, we examined the expression of the PAM4-reactive MUC1 in the noninvasive precursor lesions, pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN).

Experimental Design: Tissue microarrays prepared from formalin-fixed, paraffin-embedded specimens were assessed by immunohistology for expression of the PAM4-reactive, non–variable number of tandem repeats (VNTR), MUC1 epitope, and the VNTR epitope bound by the MA5 MAb.

Results: The PAM4-reactive MUC1 epitope was not detected in normal pancreas but was expressed in 87% (48 of 55) of invasive pancreatic adenocarcinomas, including early stage 1 disease: PAM4 labeled 94% (44 of 47) of the earliest PanIN lesions, PanIN-1A and 1B, along with 91% (10 of 11) of PanIN-2, 40% (2 of 5) of PanIN-3, and 86% (31 of 36) of intraductal papillary mucinous neoplasia lesions. A mostly diffuse pattern of labeling was observed. A second, unrelated, anti-MUC1 MAb, MA5, showed considerably less sensitivity with early PanIN-1 lesions; only 61% (25 of 41) were positive and the labeling did not differentiate normal pancreas from PanINs.

Conclusions: The results suggest that expression of the PAM4-reactive antigen may represent an early event in the development of invasive pancreatic adenocarcinoma, and is unrelated to the VNTR peptide core epitopes of MUC1. Detection of this biomarker using immunohistology, in vitro immunoassays, and in vivo antibody–based imaging may provide new opportunities for the early detection and improved diagnosis of pancreatic cancer.