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The presence of weak planes in rock fabric along with interactions of clay minerals with aqueous fluids are the major causes of instability in shale formations. Reviewing the current state-of-the art of wellbore stability models indicates that the interaction of aqueous fluids with clay minerals has been ignored or over-simplified due to the complexity of the processes. In this paper, a diffusion-sorption model, which is considered to be a unified model for all shale types, is integrated with a wellbore stability model. The coupled transport equations are solved using a finite difference method to determine pore pressure and moisture content in the vicinity of the borehole. The wellbore stability is analyzed using the modified Jaeger's criterion, which considers shale to be an isotropic body containing one set of weakness planes. Using field data, a comparison between the anisotropic failure model and isotropic failure model is presented. The results indicate that the wellbore is less stable when bedding planes are considered. The sensitivity analysis shows that the extent of failure zone in the vicinity of borehole is primarily governed by the orientation of wellbore trajectory with respect to the bedding planes. Furthermore, it is shown that the intrinsic rock strength anisotropy can be a significant parameter for failure analysis when shear failure along the bedding plane is not a major concern. The presented model predicts the instantaneous moisture content around the borehole, which is used as an index for estimation of rock strength both in shale matrix and along weakness planes. The simulation results shows that shale-fluid interaction affects borehole stability at early times.

Understanding the interaction of drilling fluid with a shale formation is a critical step to properly describe pore pressure distribution, which directly affects wellbore stability. In this study, the moisture adsorption to shale surfaces is investigated to identify the proper isotherm type curve. It is shown that the moisture content of shale is correlated with water activity using a multilayer adsorption theory. It is found that the GAB model (developed by Guggenheim, Anderson and De Boer) fairly well describes the adsorption process for the selected shale types. Accordingly, the moisture content is correlated with water activity through the GAB model, which is incorporated into the transport equations. The adsorption parameter signifies the characteristic of a specific shale that interacts with aqueous fluids and can be introduced as an index to characterize different shale formations. In this study, the constitutive equations are generalized to consider the case of non-ideal solutions. The coupled transport equations are solved using a finite difference method and numerical computations are conducted to predict the stability of the wellbore. Having developed a transient model that predicts the instantaneous moisture content around the wellbore, it is possible to update the rock compressive strength as a function of its moisture content using available empirical correlations in the literature. The results of this analysis indicate that the range of safe mud weight reduces substantially due to moisture adsorption. Comparisons of several compressive failure criteria indicate that stability reduction of the wellbore due to moisture transport is a common pattern based on the selected criteria. The results of this investigation assist in drilling fluid optimization and address wellbore stability issues in troublesome shale formations.

Routine measurement of hydraulic diffusivity of ultralow permeability rocks, such as shale, is a prolonged process. This study explores the effects of a sorptive characteristic of the porous medium on hydraulic diffusivities of shale rocks. The examined rock types include Mancos Shale, Catoosa Shale, Eagle Ford Shale, and core samples from the Gulf of Mexico. First, the adsorption isotherms of the selected shale rocks were obtained. Then, the hydraulic properties of the selected shale rocks were determined using Shale/Fluid Interaction Testing Cell, which employs pore pressure transmission technique. The experimental results show that the moisture content of shale is correlated with water activity using a multilayer adsorption theory. It is found that the adsorption isotherms of various shale formations can be scaled using their respective cation exchange capacity (CEC) into a single adsorption curve. Analyzing the transient pore pressure response in the downstream side of shale sample allows calculating the transport coefficients of shale samples. Hydraulic properties of shales are obtained by matching the pore pressure history with one-dimensional coupled fluid flow model. The experimental results indicate that sorptive properties can be inversely related to the hydraulic diffusivity of shale rocks. It is found that with an increase in the magnitude of sorption potential of shale, the hydraulic diffusivity decreases. This study is useful for shale characterization and provides a correlation, which can have various applications including, but not limited to, wellbore stability prediction during well planning.

A number of poly(vinylamine) (PVAm) samples with different molecular weight were synthesized following basically the same method as described by Hart. For PVAm and the intermediate macromolecular product, poly(tert-butyl vinylcarbamate) (PBVC), relations between the limiting viscosity number [η] and the number average molecular weight as determined by osmotic measurements are proposed. For two high molecular weight samples of PVAm also the weight average molecular weight was determined by light-scattering measurements.

In anti-cancer therapy, current investigations explore the possibility of two different strategies to target tumor vasculature: one aims at interfering with angiogenesis, the process involving the outgrowth of new blood vessels from pre-existing vessels, while the other directs at affecting the already established tumor vasculature. However, the majority of in vitro model systems currently available examine the process of angiogenesis, while the current focus in anti-vascular therapies moves towards exploring the benefit of targeting established vasculature as well. This urges the need for in vitro systems that are able to differentiate between the effects of compounds on angiogenesis as well as on established vasculature. To achieve this, we developed an in vitro model in which effects of compounds on different vascular targets can be studied specifically. Using this model, we examined the actions of the fumagillin derivate TNP-470, the MMP-inhibitor marimastat and the recently developed tubulin-binding agent Ang-510. We show that TNP-470 and marimastat solely inhibited angiogenesis, whereas Ang-510 potently inhibited angiogenesis and caused massive disruption of newly established vasculature. We show that the use of this in vitro model allows for specific and efficient screening of the effects of compounds on different vascular targets, which may facilitate the identification of agents with potential clinical benefit. The indicated differences in the mode of action between marimastat, TNP-470 and Ang-510 to target vasculature are illustrative for this approach. (C) 2009 Elsevier Inc. All rights reserved.

Osteoclast-devoid bone explants were cultured together with embryonic liver as a source of osteoclast precursors, but separated from each other by a filter. Cells migrated through the filter toward the calcified matrix and acquired the characteristics of mature, tartrate-resistant acid phosphatase-positive (TRAP+) osteoclasts upon contact with the bone explant. Migration and attachment could be visualized separately. Progressive reduction of filter pore size resulted in progressive reduction of resorption because the use of smaller pores made it increasingly difficult for cells to pass. Indeed, the use of 0.22-micron filters, through which no cells can pass, but which still allow full passage of medium, completely blocked the resorption. When migrating cells from fetal liver were arrested for 10 days by using a combination of filters with different pore sizes, the arrested cells showed a tendency to fuse just opposite the mineralized matrix. Furthermore, a great number of the arrested cells expressed the macrophage-specific cell-surface antigen F4/80 and showed acid phosphatase activity, but none of these cells were tartrate resistant. The acquisition of tartrate-resistant acid phosphatase activity upon contact with the bone explant and subsequent resorption of this explant could be prevented by exposure of the system to the bisphosphonate dimethyl-APD (Me2-APD), whereas migration of cells through the filter was not affected. We suggest that the bisphosphonate interferes with a matrix factor that is essential for the attachment and subsequent transformation of the osteoclast precursor into the mature phenotype.

This study investigates shale–fluid interactions through experimental approaches under simulated in situ conditions to determine the effects of bedding plane orientation on fluid flow through shale. Current wellbore stability models are developed based on isotropic conditions, where fluid transport coefficients are only considered in the radial direction. This paper also presents a novel mathematical method, which takes into account the three-dimensional coupled flow of water and solutes due to hydraulic, chemical, and electrical potential imposed by the drilling fluid and/or the shale formation. Numerical results indicate that the presence of microfissures can change the pore pressure distribution significantly around the wellbore and thus directly affect the mechanical strength of the shale.

Petroleum transportation pipelines are occasionally plugged by gas hydrate. Such plugs can be very costly because of delayed production and complicated removal procedures. The objective of this work was to develop a prototype computer program, with a collection of calculation modules, that could be useful in connection with the removal of hydrate plugs, and that could be extended in future to a more comprehensive tool. The program presently consists of five calculation modules. Most of the focus of this paper will be on the first of these-a module that can be used to analyze pressure time series to monitor plug dissociation progress.

Summary This paper describes continuing efforts to develop a water-based drilling fluid that will provide the osmotic membrane behavior and wellbore stability of an oil-based drilling fluid. A pore-pressure-transmission technique in use for several years as a tool to measure osmotic behavior has been refined for improved measurement of changes in shale permeability and pore pressure in response to interaction with drilling fluids. Conventional invert-emulsion and water-based drilling fluids containing selected additives were tested with outcrop and preserved shale specimens using an innovative screening method. Observed pressure differences across each shale specimen were compared with the values predicted by osmotic theory. From this comparison, an empirical concept of "membrane efficiency" was developed. Three distinct types of "membranes" are postulated to describe the interaction of various drilling fluids with shales. Type 1 membranes are generally characterized by coupled flows of water and solutes between fluid and shale. Type 2 membranes greatly reduce the near-wellbore permeability of shale and restrict the flow of both water and solutes. Type 3 membranes transport water more selectively, but shale permeability and fluid chemistry may alter performance measurements. Invert-emulsion fluids tend to form efficient, Type 3 membranes; however, under certain conditions, these fluids can yield lower capillary pressures than described previously and invade the interstitial fabric of high-permeability shales. Several water-based mud formulations were prepared that achieve approximately one-quarter to one-half the measured osmotic pressure of a typical oil-based mud (OBM). Fluid additives that supplement or reinforce a Type 1 membrane, such as saccharide polymers (especially in combination with calcium, magnesium, or aluminum salts), can induce relatively high efficiencies. As expected, fluids that form a Type 2 membrane, such as silicate and aluminate muds, provide the highest membrane efficiencies.

The ribosomal frameshifting signal present in the genomic RNA of the coronavirus infectious bronchitis virus (IBV) contains a classic hairpin-type RNA pseudoknot that is believed to possess coaxially stacked stems of 11 bp (stem 1) and 6 bp (stem 2). We investigated the influence of stem 1 length on the frameshift process by measuring the frameshift efficiency in vitro of a series of IBV-based pseudoknots whose stem 1 length was varied from 4 to 13 bp in single base-pair increments. Efficient frameshifting depended upon the presence of a minimum of 11 bp; pseudoknots with a shorter stem 1 were either non-functional or had reduced frameshift efficiency, despite the fact that a number of them had a stem 1 with a predicted stability equal to or greater than that of the wild-type IBV pseudoknot. An upper limit for stem 1 length was not determined, but pseudoknots containing a 12 or 13 bp stem 1 were fully functional. Structure probing analysis was carried out on RNAs containing either a ten or 11 bp stem 1; these experiments confirmed that both RNAs formed pseudoknots and appeared to be indistinguishable in conformation. Thus the difference in frameshifting efficiency seen with the two structures was not simply due to an inability of the 10 bp stem 1 construct to fold into a pseudoknot. In an attempt to identify other parameters which could account for the poor functionality of the shorter stem 1-containing pseudoknots, we investigated, in the context of the 10 bp stem 1 construct, the influence on frameshifting of altering the slippery sequence-pseudoknot spacing distance, loop 2 length, and the number of G residues at the bottom of the 5'-arm of stem 1. For each parameter, it was possible to find a condition where a modest stimulation of frameshifting was observable (about twofold, from seven to a maximal 17 %), but we were unable to find a situation where frameshifting approached the levels seen with 11 bp stem 1 constructs (48-57 %). Furthermore, in the next smaller construct (9 bp stem 1), changing the bottom four base-pairs to G.C (the optimal base composition) only stimulated frameshifting from 3 to 6 %, an efficiency about tenfold lower than seen with the 11 bp construct. Thus stem 1 length is a major factor in determining the functionality of this class of pseudoknot and this has implications for models of the frameshift process.

The ribosomal frameshifting signal present in the genomic RNA of the coronavirus infectious bronchitis virus (IBV) contains a classic hairpin-type RNA pseudoknot that is believed to possess coaxially stacked stems of 11 bp (stem 1) and 6 bp (stem 2). We investigated the influence of stem 1 length on the frameshift process by measuring the frameshift efficiency in vitro of a series of IBV-based pseudoknots whose stem 1 length was varied from 4 to 13 bp in single base-pair increments. Efficient frameshifting depended upon the presence of a minimum of 11 bp; pseudoknots with a shorter stem 1 were either non-functional or had reduced frameshift efficiency, despite the fact that a number of them had a stem 1 with a predicted stability equal to or greater than that of the wild-type IBV pseudoknot. An upper limit for stem 1 length was not determined, but pseudoknots containing a 12 or 13 bp stem 1 were fully functional. Structure probing analysis was carried out on RNAs containing either a ten or 11 bp stem 1; these experiments confirmed that both RNAs formed pseudoknots and appeared to be indistinguishable in conformation. Thus the difference in frameshifting efficiency seen with the two structures was not simply due to an inability of the 10 bp stem 1 construct to fold into a pseudoknot. In an attempt to identify other parameters which could account for the poor functionality of the shorter stem 1-containing pseudoknots, we investigated, in the context of the 10 bp stem 1 construct, the influence on frameshifting of altering the slippery sequence-pseudoknot spacing distance, loop 2 length, and the number of G residues at the bottom of the 5'-arm of stem 1. For each parameter, it was possible to find a condition where a modest stimulation of frameshifting was observable (about twofold, from seven to a maximal 17 %), but we were unable to find a situation where frameshifting approached the levels seen with 11 bp stem 1 constructs (48-57 %). Furthermore, in the next smaller construct (9 bp stem 1), changing the bottom four base-pairs to G.C (the optimal base composition) only stimulated frameshifting from 3 to 6 %, an efficiency about tenfold lower than seen with the 11 bp construct. Thus stem 1 length is a major factor in determining the functionality of this class of pseudoknot and this has implications for models of the frameshift process.

Eukaryotic ribosomal frameshift signals generally contain two elements, a heptanucleotide slippery sequence (XXXYYYN) and an RNA secondary structure, often an RNA pseudoknot, located downstream. Frameshifting takes place at the slippery sequence by simultaneous slippage of two ribosome-bound tRNAs. All of the tRNAs that are predicted to decode frameshift sites in the ribosomal A-site (XXXYYYN) possess a hypermodified base in the anticodon-loop and it is conceivable that these modifications play a role in the frameshift process. To test this, we expressed slippery sequence variants of the coronavirus IBV frameshift signal in strains of Escherichia coli unable to modify fully either tRNA(Lys) or tRNA(Asn). At the slippery sequences UUUAAAC and UUUAAAU (underlined codon decoded by tRNA(Asn), anticodon 5' QUU 3'), frameshifting was very inefficient (2 to 3%) and in strains deficient in the biosynthesis of Q base, was increased (AAU) or decreased (AAC) only two-fold. In E. coli, therefore, hypomodification of tRNA(Asn) had little effect on frameshifting. The situation with the efficient slippery sequences UUUAAAA (15%) and UUUAAAG (40%) (underlined codon decoded by tRNA(Lys), anticodon 5' mnm5s2UUU 3') was more complex, since the wobble base of tRNA(Lys) is modified at two positions. Of four available mutants, only trmE (s2UUU) had a marked influence on frameshifting, increasing the efficiency of the process at the slippery sequence UUUAAAA. No effect on frameshifting was seen in trmC1 (cmnm5s2UUU) or trmC2 (nm5s2UUU) strains and only a very small reduction (at UUUAAAG) was observed in an asuE (mnm5UUU) strain. The slipperiness of tRNA(Lys), therefore, cannot be ascribed to a single modification site on the base. However, the data support a role for the amino group of the mnm5 substitution in shaping the anticodon structure. Whether these conclusions can be extended to eukaryotic translation systems is uncertain. Although E. coli ribosomes changed frame at the IBV signal (UUUAAAG) with an efficiency similar to that measured in reticulocyte lysates (40%), there were important qualitative differences. Frameshifting of prokaryotic ribosomes was pseudoknot-independent (although secondary structure dependent) and appeared to require slippage of only a single tRNA.

A chemo-poro-elastic wellbore stability model considering the shale transverse isotropic effect is developed. In poroelastic theory, the pore fluid motion and solid structure deformation are coupled. Lubinski’s one-way coupling scheme is adopted in this study which assumed a rock has strong structure and the effect of solid skeleton deformation on fluid flow is negligible. It is found that normal stress along the cylindrical axis is affected by Young’s modulus on both the symmetrical plane and the axial direction. A Taguchi orthogonal simulation design strategy is adopted to reduce the number of simulations while still achieving meaningful results. Analysis of variance (ANOVA) is conducted and parameter contributions to the mud weight window have been investigated. It can be found that among the 11 parameters of interest, wellbore inclination angle, hydraulic conductivity and water activity of drilling fluid play the most important roles in determining the mud weight window. Knowledge of percentage contributions of the parameters in this chemo-poro-elastic wellbore stability model greatly helps drilling engineers identify the critical factors for wellbore stability control. This study also helps well trajectory design and drilling fluid optimization.

Hole cleaning is often more difficult during drilling of inclined wells. The resulting poor removal of cuttings can lead to problems such as borehole pack-off and excessive ECD, which are both difficult and expensive to resolve. Fluid sweeps are commonly implemented when normal circulation cannot adequately remove cuttings from the borehole. Field reports have indicated that specialized fibrous-type materials enhance cleaning performance when added to fluid sweeps. Yet, understanding of the behavior of this improvement remains inexact. This paper presents a comparative experimental investigation of the hole cleaning performances of fiber sweeps, conducted with different drill pipe rotation speeds and fiber concentrations. Experiments were carried out in an inclined flow loop apparatus with an inner rotating drill pipe. The hole cleaning performance of fiber-containing sweep fluids using different fiber concentrations (0%, 0.05%, 0.1%, and 0.2%, by weight) and varying drill pipe rotation speeds (0 to 90 rpm) was evaluated. Sweep efficiencies were compared in terms of the measurement of cuttings bed heights before and after circulating the sweep fluid. The results indicate that significant improvement associated with higher fiber content requires a commensurate increase in drill pipe rotation speed. With lower or no pipe rotation speed, increasing fiber concentration yields less dramatic returns. Pairing high fiber content with rapid pipe rotation resulted in enhanced performance over the control sweep, which contained no fiber, but relatively low concentrations did not surpass the control. With the increasing need in the industry to drill extended reach or otherwise inclined wells, there is greater potential to develop problems stemming from inadequate hole cleaning. This research gives insight into the specific interaction of sweep fiber and pipe rotation with the cuttings bed, and with each other. Deeper understanding of fiber sweeps would inform in-field decisions when dealing with poor hole cleaning.

The genomic RNA of human astrovirus serotype 1 (HAst-1) contains three open reading frames (ORFs), 1a, 1b, and 2. ORF 1b is located downstream of, and overlaps, 1a, and it has been suggested on the basis of sequence analysis that expression of ORF 1b is mediated through -1 ribosomal frameshifting. To examine this possibility, a cDNA fragment containing the 1a-1b overlap region was cloned within a reporter gene and placed under the control of the bacteriophage SP6 promoter in a recombinant plasmid. Synthetic transcripts derived from this plasmid, when translated in the rabbit reticulocyte lysate cell-free system, specified the synthesis of polypeptides whose size and antibody reactivity were consistent with an efficient -1 ribosomal frameshift event at the overlap region. The HAst-1 frameshift signal has two essential components, a heptanucleotide slippery sequence, A6C, and a stem-loop structure in the RNA. The presence of this structure was confirmed by complementary and compensatory mutation analysis and by direct structure probing with single- and double-stranded RNA-specific reagents. The HAst-1 frameshift signal, like that present at the overlap of the gag and pro genes of the retrovirus human T-cell lymphotrophic virus type II, does not involve the formation of an RNA pseudoknot.

Instability issues often occur when water-based muds are applied to shale formations. Failure to predict the pore pressure accurately has been widely accepted as one of the major reasons causing shale instability. Water activity is a key factor to control the pore fluid moving in and out of the formation due to osmotic effects. Ideal and single-solute models have been developed in the past to predict the pore pressure by considering chemical osmotic effects. However, due to their complex nature, pore fluids/drilling fluids rarely behave as ideal solutions. A new model has been developed to predict pore pressure in shale formations that takes into account the non-ideality and multiple solutes of both drilling fluid and pore fluid. Transient pore pressure profiles and water activity are obtained from the coupled equations developed in this study. A Shale-Fluid Interaction Testing Cell (SFITC) has been developed in this study to test the interaction between the drilling fluid and the pore fluid. Parameters involved in the model, such as hydraulic conductivity, membrane efficiency and ion diffusion rate can be obtained through experimental data curve fitting. Model predictions have been compared with lab data and good agreement has been achieved. Water activity is found to be crucial for pore pressure control in shale formations. Simulation results explain the fact that salinity of drilling fluids has to be controlled in order to achieve shale stability. Results of this study can benefit drilling fluid design. Shale instability can be reduced by "balancing" the water activities of shale and drilling fluid. This can be achieved through changing the type of solutes and their concentrations based on information of the initial water activity of the shale. Wellbore stability models can obtain more accurate results by including the proposed pore pressure propagation model, which considers drilling fluid-induced chemical osmotic in-situ stress.

Acquisition of an invasive phenotype by cancer cells is a requirement for bone metastasis. Transformed epithelial cells can switch to a motile, mesenchymal phenotype by epithelial-mesenchymal transition (EMT). Recently, it has been shown that EMT is functionally linked to prostate cancer stem cells, which are not only critically involved in prostate cancer maintenance but also in bone metastasis. We showed that treatment with the non-peptide αv-integrin antagonist GLPG0187 dose-dependently increased the E-cadherin/vimentin ratio, rendering the cells a more epithelial, sessile phenotype. In addition, GLPG0187 dose-dependently diminished the size of the aldehyde dehydrogenase high subpopulation of prostate cancer cells, suggesting that αv-integrin plays an important role in maintaining the prostate cancer stem/progenitor pool. Our data show that GLPG0187 is a potent inhibitor of osteoclastic bone resorption and angiogenesis in vitro and in vivo. Real-time bioluminescent imaging in preclinical models of prostate cancer demonstrated that blocking αv-integrins by GLPG0187 markedly reduced their metastatic tumor growth according to preventive and curative protocols. Bone tumor burden was significantly lower in the preventive protocol. In addition, the number of bone metastases/mouse was significantly inhibited. In the curative protocol, the progression of bone metastases and the formation of new bone metastases during the treatment period was significantly inhibited. In conclusion, we demonstrate that targeting of integrins by GLPG0187 can inhibit the de novo formation and progression of bone metastases in prostate cancer by antitumor (including inhibition of EMT and the size of the prostate cancer stem cell population), antiresorptive, and antiangiogenic mechanisms.

The latest addition to SPE’s Monograph Series, Low Invasion Coring will help readers develop an understanding of how to apply the array of technologies required for successful completion of a low-invasion coring (LIC) project. This monograph addresses the principles of obtaining low-invasion cores and provides essential practical tips for engineering field LIC projects. Appendices provide detailed information on specific core-analysis procedures. .