bluuebunny/crossref_metadata_2025 huggingface dataset:
Shape optimization of turbine blades with the integration ofaerodynamics and heat transfer
Authors: Rajadas J. N. , Chattopadhyay A. , Pagaldipti N. , Zhang S.
Published: September 2005

A multidisciplinary optimization procedure, with the integration of aerodynamic and heat transfer criteria, has been developed for the design of gas turbine blades. Two different optimization formulations have been used. In the first formulation, the maximum temperature in the blade section is chosen as the objective function to be minimized. An upper bound constraint is imposed on the blade average temperature and a lower bound constraint is imposed on the blade tangential force coefficient. In the second formulation, the blade average and maximum temperatures are chosen as objective functions. In both formulations, bounds are imposed on the velocity gradients at several points along the surface of the airfoil to eliminate leading edge velocity spikes which deteriorate aerodynamic performance. Shape optimization is performed using the blade external and coolant path geometric parameters as design variables. Aerodynamic analysis is performed using a panel code. Heat transfer analysis is performed using the finite element method. A gradient based procedure in conjunction with an approximate analysis technique is used for optimization. The results obtained using both optimization techniques are compared with a reference geometry. Both techniques yield significant improvements with the multiobjective formulation resulting in slightly superior design.
An algorithm for model reduction in large electric power systems
Authors: Zečević A. I. , Gačić N.
Published: September 2005

Model reduction has become an important issue in the analysis of electric power systems, due to their constantly increasing size and complexity. In this paper we present a decomposition algorithm which is capable of reducing the number of equations in the model, while preserving the potential for parallel computation. A variety of experimental results are provided to illustrate the performance of the algorithm.
On deterministic approximation of Markov processes by ordinary differential equations
Authors: Rozonoer L. I.
Published: September 2005

For a class of Markov processes on the integer multidimensional lattice, it is shown that the evolution of the mean values of some random variables can be approximated by ordinary differential equations. To illustrate the approach, a Markov model of a chemical reaction is considered
Nonnegativity of uncertain polynomials
Authors: Šiljak Dragoslav D. , Šiljak Matija D.
Published: September 2005

The purpose of this paper is to derive tests for robust nonnegativity of scalar and matrix polynomials, which are algebraic, recursive, and can be completed in finite number of steps. Polytopic families of polynomials are considered with various characterizations of parameter uncertainty including affine, multilinear, and polynomic structures. The zero exclusion condition for polynomial positivity is also proposed for general parameter dependencies. By reformulating the robust stability problem of complex polynomials as positivity of real polynomials, we obtain new sufficient conditions for robust stability involving multilinear structures, which can be tested using only real arithmetic. The obtained results are applied to robust matrix factorization, strict positive realness, and absolute stability of multivariable systems involving parameter dependent transfer function matrices.
Robust stability and stabilization of a class of uncertain nonlinear systems with delays
Authors: Mahmoud Magdi S.
Published: September 2005

A class of nonlinear systems with norm‐bounded uncertainties and state‐delay is considered. Two criteria are developed for the robust stability analysis: one is delay‐independent and the other is delay‐dependent. Methods for robust feedback synthesis are then examined. It is established that linear memoryless controllers are capable of guaranteeing the delay‐dependent and delay‐independent stabilizability of the closed‐loop systems. All the results are expressed in the form of linear matrix inequalities which can be solved by efficient and numerically‐stable routines. The developed theory is applied to the stability robustness problem of an industrial jacketed continuous stirred tank reactor.
The hybersonic navier‐stokes approximation for the normal shock structure of a perfect gas with the Sutherland viscosity law: Review and extension
Authors: Bush W. B. , Krishnamurthy L.
Published: September 2005

By means of a four‐region asymptotic analysis, a uniformly valid description of the
Sutherland‐viscosity‐law Navier‐Stokes structure of the normal shock wave in the hypersonic approximation is obtained.
Emergency control of unstable behavior of nonlinear systems induced by fault
Authors: Pinsky Mark A. , Basin Michael V.
Published: September 2005

This paper presents the emergency control approach intended to urgently return to the stability basin the system states affected by abrupt changes in certain system coefficients on a short time interval. Because of its short duration, the modeling of both the fault and controller involves δ
‐functions significantly simplifying analysis and control of fault phenomena. The design of an mergency controller is based on the technique for computing fault‐induced jumps of the system states, which is described in the paper. An emergency controller instantaneously returning states of a sample nonlinear system to its stability basin is designed.
Theory and computation of disturbance invariant sets for discrete‐time linear systems
Authors: Kolmanovsky Ilya , Gilbert Elmer G.
Published: September 2005

This paper considers the characterization and computation of invariant sets for
discrete‐time, time‐invariant, linear systems with disturbance inputs whose values are confined to a specified compact set but are otherwise unknown. The emphasis is on determining maximal disturbance‐invariant sets X that belong to a specified subset
Γ
of the state space. Such d‐invariant sets have important applications in control problems where there are pointwise‐in‐time state constraints of the form
χ(t) ∈ Γ
. One purpose of the paper is to unite and extend in a rigorous way disparate results from
the prior literature. In addition there are entirely new results. Specific contributions include: exploitation of the Pontryagin set difference to clarify conceptual matters and simplify mathematical developments, special properties of maximal invariant sets and conditions for their finite determination, algorithms for generating concrete representations of maximal invariant sets, practical computational questions, extension of the main results to general Lyapunov stable systems, applications of the computational techniques to the bounding of state and output response. Results on Lyapunov stable
systems are applied to the implementation of a logic‐based, nonlinear multimode regulator. For plants with disturbance inputs and state‐control constraints it enlarges the constraint‐admissible domain of attraction. Numerical examples illustrate the various theoretical and computational results.
A model of frontal polymerization including the gel effect
Authors: Goldfeder P. M. , Volpert V. A.
Published: September 2005

Frontal polymerization is a process in which a spatially localized reaction zone propagates into a monomer, converting it into a polymer. This new approach to polymer production
requires both theoretical and experimental study. Agreement between the existing theoretical and experimental work done on this subject has generally been fairly good. However, experimental results tend to show a higher degree of conversion than theoretical results. The reason for this discrepancy may be attributed to an autoacceleration of the polymerization rate which occurs when conversion has reached a certain point. This autoacceleration is due to a decrease in the termination rate caused by a phenomenon known as the gel effect. In this paper, we develop a mathematical model of the frontal polymerization process, taking the gel effect into consideration. Specifically, we determine how it will affect the degree of conversion, maximum temperature, and propagation velocity of the system.
On absolute stability of nonlinear systems with small delays
Authors: Gil M. I. , Ailon A. , Ahn B. H.
Published: September 2005

Nonlinear nonautonomous retarded systems with separated autonomous linear parts
and continuous nonlinear ones are considered. It is assumed that deviations of the argument are sufficiently small. Absolute stability conditions are derived. They are formulated in terms of eigenvalues of auxiliary matrices.
A colsed form solution of convective mass transfer model for intracellular calcium response of endothelial cells
Authors: Kumar Vineet , Pandey R. N. , Upadhyay S. N.
Published: September 2005

Endothelial cells, lining the entire vascular system, respond to change in concentration of specific agonist like adenosine triphosphate (ATP) by increasing cytosolic
Ca2+
concentration, producing prostacyclin, endothelium derived relaxing factor and ecto‐enzymes. Three different ecto‐enzymes metabolize ATP in three steps (ATP
→
ADP
→
AMP
→
adenosine )
. Normally experiments with endothelium are carried out in a rectangular flow chamber provided with a cell surface at one of its walls and feed stream containing ATP. The ATP concentration near the cell surface depends upon two factors, rate of its degradation and the rate at which it reaches from upstream.
Closed form solutions for the concentration profile of ATP in such a flow chamber indicates that concentration near the cell surface is lower than the bulk concentration depending on the activity of ecto‐enzymes and it increases with increase in tangential flow rate (shear stress). This indicates that shear induced response of endothelial cell (at least for low shear rate) may be due to change in ATP concentration near the cell surface which is sensed by purinoreceptors instead of a mechanoreceptor. Several workers have tried to investigate this problem analytically. Unfortunately, solutions
obtained by these workers have limited success. In the present work, exact solution of the problem has been obtained in terms of a confluent hypergeometric function. Solution of the transformed equation gives accurate results even in the entrance region of the flow chamber which eliminates the need of solutions based on approximate methods like perturbation or finite difference techniques.
The simplex method for nonlinear sliding mode control
Authors: Bartolini G. , Parodi F. , Utkin V. I. , Zolezzi T.
Published: September 2005

General nonlinear control systems described by ordinary differential equations with a prescribed sliding manifold are considered. A method of designing a feedback control law such that the state variable fulfills the sliding condition in finite time is based on the construction of a suitable simplex of vectors in the tangent space of the manifold. The convergence of the method is proved under an obtuse angle condition and a way to build the required simplex is indicated. An example of engineering interest is presented.
A dynamic model for crime control and policy evaluation
Authors: Ahmed N. U. , Rahim M. A.
Published: September 2005

The paper is concerned with the development of a rigorous mathematical model
describing the dynamics of criminal population subject to sentencing policies of any penal (legal) system. The model enables evaluation of the impact of preventive measures used in the society and correctional measures used by the penitentiaries. A performance index reflecting the effectiveness of such measures and the cost to the society for providing the same is introduced and the question of optimality discussed.
Controller design for bilinear systems with parametric uncertainties
Authors: Shi Peng , Shue Shyh-Pyng , Shi Yan , Agarwal Ramesh K.
Published: September 2005

This paper studies the problem of robust control of a class of uncertain bilinear continuous‐time systems. The class of uncertain systems is described by a state space model with time‐varying norm‐bounded parameter uncertainty in the state equation. We address the problem of robust H∞ control in which both robust stability and a prescribed H∞ performance are required to be achieved irrespective of the uncertainties. Both state feedback and output feedback controllers are designed. It has been shown that the above problems can be recast into H∞ syntheses for related bilinear systems without parameter uncertainty, which can be solved via a Riccati inequality approach. Two examples are given to show the potential of the proposed technique.
The effect of loss functions on empirical Bayes reliability analysis
Authors: Camara Vincent A. R. , Tsokos Chris P.
Published: September 2005

The aim of the present study is to investigate the sensitivity of empirical Bayes
estimates of the reliability function with respect to changing of the loss function. In addition to applying some of the basic analytical results on empirical Bayes reliability obtained with the use of the “popular” squared error loss function, we shall derive some expressions corresponding to empirical Bayes reliability estimates obtained with the Higgins–Tsokos, the Harris and our proposed logarithmic loss functions. The concept of efficiency, along with the notion of integrated mean square error, will be
used as a criterion to numerically compare our results.

It is shown that empirical Bayes reliability functions are in general sensitive to the choice of the loss function, and that the squared error loss does not always yield the best empirical Bayes reliability estimate.
Optimal recharge and driving strategies for a battery‐poweredelectric vehicle
Authors: Lee W. R. , Wang S. , Teo K. L.
Published: September 2005

A major problem facing battery‐powered electric vehicles is in their batteries: weight and charge capacity. Thus, a battery‐powered electric vehicle only has a short driving range. To travel for a longer distance, the batteries are required to be recharged frequently. In this paper, we construct a model for a battery‐powered electric vehicle, in which driving strategy is to be obtained such that the total travelling time between two locations is minimized. The problem is formulated as an optimization problem
with switching times and speed as decision variables. This is an unconventional
optimization problem. However, by using the control parametrization enhancing
technique (CPET), it is shown that this unconventional optimization is equivalent to a
conventional optimal parameter selection problem. Numerical examples are solved
using the proposed method.
Design of delay observer‐based controllers for uncertain time‐lag systems
Authors: Mahmoud Magdi S. , Zribi Mohamed
Published: September 2005

In this paper, the problem of designing observers and observer‐based controllers for a class of uncertain systems with input and state time lags is considered. We construct delay‐type observers in which both the instantaneous as well as the delayed measurements are utilized. Using feedback control based on the reconstructed state, the behavior of the closed‐loop system is investigated. It is established that the uncertain time‐lag system with delay observer‐based control is asymptotically stable. Expressions for the gain matrices are given based on two linear‐matrix inequalities. A numerical example is given to illustrate the theoretical developments.
A river water quality model for time varying BOD dischargeconcentration
Authors: Oppenheimer Seth F. , Adrian Donald Dean , Alshawabkeh Akram
Published: September 2005

We consider a model for biochemical oxygen demand (BOD) in a semi‐infinite river where the BOD is prescribed by a time varying function at the left endpoint. That is, we study the problem with a time varying boundary loading. We obtain the well‐posedness for the model when the boundary loading is smooth in time. We also obtain various qualitative results such as ordering, positivity, and boundedness. Of greatest interest, we show that a periodic loading function admits a unique asymptotically attracting periodic solution. For non‐smooth loading functions, we obtain weak solutions. Finally, for certain special cases, we show how to obtain explicit solutions in the form of infinite series.
Asymptotic analysis of the structure of a steady planardetonation: Review and extension
Authors: Bush W. B. , Krishnamurthy L.
Published: September 2005

The structure of a steady planar Chapman–Jouguet detonation, which is supported by a direct first‐order one‐step irreversible exothermic unimolecular reaction, subject to Arrhenius kinetics, is examined. Solutions are studied, by means of a limit‐process‐expansion analysis, valid for Λ, proportional to the ratio of the reaction rate to the
flow rate, going to zero, and for β, proportional to the ratio of the activation temperature to the maximum flow temperature, going to infinity, with the product Λβ1/2 going to zero. The results, essentially in agreement with the Zeldovich–von Neumann–Doring model, show that the detonation consists of (1) a three‐region upstream shock‐like zone, wherein convection and diffusion dominate; (2) an exponentially thicker five‐region downstream deflagration‐like zone, wherein convection and reaction dominate; and (3) a transition zone, intermediate to the upstream and downstream zones, wherein convection, diffusion, and reaction are of the same order of magnitude. It is in this transition zone that the ideal Neumann state is most closely approached.
Optimal control for a BMAP/G/1 queue with two service modes
Authors: Dudin Alexander N. , Nishimura Shoichi
Published: September 2005

Queueing models with controllable service rate play an important role in telecommunication systems. This paper deals with a single‐server model with a batch Markovian arrival process (BMAP) and two service modes, where switch‐over times are involved when changing the service mode. The embedded stationary queue length distribution and the explicit dependence of operation criteria on switch‐over levels and derived.
Similarity transformations of MAPs
Authors: Andersen Allan T. , Barker V. A. , Nielsen Bo Friis
Published: September 2005

We introduce the notion of similar Markovian Arrival Processes (MAPs) and show that the event stationary point processes related to two similar MAPs are stochastically equivalent. This holds true for the time stationary point processes too. We show that several well known stochastical equivalences as e.g. that between the H2 renewal process and the Interrupted Poisson Process (IPP) can be expressed by the similarity transformations of MAPs. In the appendix the valid region of similarity transformations for two‐state MAPs is characterized.
Multiple objective optimization of hydro‐thermal systems using Ritz′s method
Authors: Arnáu L. Bayón , Rodríguez P. Suárez
Published: September 2005

This paper examines the applicability of the Ritz method to multi‐objective optimization of hydro‐thermal systems. The algorithm proposed is aimed to minimize an objective functional that incorporates the cost of energy losses, the conventional fuel cost and the production of atmospheric emissions such as NOx and SO2 caused by the operation of fossil‐fueled thermal generation. The formulation includes a general layout of hydro‐plants that may form multi‐chains of reservoir network.

Time‐delays are included and the electric network is considered by using the active power balance equation. The volume of water discharge for each hydro‐plant is a given constant amount from the optimization interval. The generic minimization algorithm, which is not difficult to construct on the basis of the Ritz method, has certain advantages in comparison with the conventional methods.
Optimal hysteretic control for a BMAP/SM/1/N queue with two operation modes
Authors: Dudin Alexander N. , Nishimura Shoichi
Published: September 2005

We consider BMAP/SM/1 type queueing system with finite buffer of size N. The system has two operation modes, which are characterized by the matrix generating function of BMAP‐input, the kernel of the semi‐Markovian service process, and utilization cost. An algorithm for determining the optimal hysteresis strategy is presented.
Stochastic algorithms for buffer allocation in reliable production lines
Authors: Spinellis Diomidis D. , Papadopoulos Chrissoleon T.
Published: September 2005

The allocation of buffers between workstations is a major optimization problem faced by manufacturing systems designers. It entails the determination of optimal buffer allocation plans in production lines with the objective of maximizing their throughput. We present and compare two stochastic approaches for solving the buffer allocation problem in large reliable production lines. The allocation plan is calculated subject to a given amount of total buffer slots using simulated annealing and genetic algorithms. The throughput is calculated utilizing a decomposition method.
Risk‐sensitive control of stochastic hybrid systems on infinitetime horizon
Authors: Runolfsson Thordur
Published: September 2005

A risk‐sensitive optimal control problem is considered for a hybrid system that consists of continuous time diffusion process that depends on a discrete valued mode variable that is modeled as a Markov chain. Optimality conditions are presented and conditions for the existence of optimal controls are derived. It is shown that the optimal risk‐sensitive control problem is equivalent to the upper value of an associated stochastic differential game, and insight into the contributions of the noise input and mode variable to the risk sensitivity of the cost functional is given. Furthermore, it is shown that due to the mode variable risk sensitivity, the equivalence relationship that has been observed between risk‐sensitive and H∞ control in the nonhybrid case does not hold for stochastic hybrid systems.
Bottlenecks with respect to due‐time performance in pull serialproduction lines
Authors: Li Jingshan , Meerkov Semyon M.
Published: September 2005

In this work, serial production lines with finished goods buffers operating in the pull regime are considered. The machines are assumed to obey Bernoulli reliability model. The problem of satisfying customers demand is addressed. The level of demand satisfaction is quantified by the due‐time performance (DTP), which is defined as the probability to ship to the customer a required number of parts during a fixed time interval. Within this scenario, the definitions of DTP bottlenecks are introduced and a method for their identification is developed.
Nonlinear robust hierarchical control for nonlinear uncertainsystems
Authors: Leonessa Alexander , Haddad Wassim M. , Chellaboina Vijaysekhar
Published: September 2005

A nonlinear robust control‐system design framework predicated on a hierarchical switching controller architecture parameterized over a set of moving nominal system equilibria is developed. Specifically, using equilibria‐dependent Lyapunov functions, a hierarchical nonlinear robust control strategy is developed that robustly stabilizes a given nonlinear system over a prescribed range of system uncertainty by robustly stabilizing a collection of nonlinear controlled uncertain subsystems. The robust switching nonlinear controller architecture is designed based on a generalized (lower semicontinuous) Lyapunov function obtained by minimizing a potential function over a given switching set induced by the parameterized nominal system equilibria. The proposed framework robustly stabilizes a compact positively invariant set of a given nonlinear uncertain dynamical system with structured parametric uncertainty. Finally, the efficacy of the proposed approach is demonstrated on a jet engine propulsion control problem with uncertain pressure‐flow map data.
The Bisphosphonate YM529 Inhibits Osteolytic and Osteoblastic Changes and CXCR-4–Induced Invasion in Prostate Cancer
Authors: Miwa Sotaro , Mizokami Atsushi , Keller Evan T. , Taichman Russell , Zhang Jian , Namiki Mikio
Published: October 2005

Bisphosphonates are useful for the treatment of prostate cancer bone metastasis. However, the role of bisphosphonate on the development of the osteoblastic component of prostate cancer bone metastases is not defined. In the present study, the third-generation bisphosphonate, YM529 (minodoronate), was tested for its effects on the osteolytic PC-3 and novel osteoblastic LNCaP-SF cell lines. YM529 inhibited both osteolytic and osteoblastic changes in an intratibial tumor injection murine model. In vitro, YM529 inhibited both the proliferation and the invasion of both prostate cancer cell lines. The stromal cell–derived factor-1 (or CXCL12)/CXCR-4 pathway is believed to play an important role in the development of prostate cancer bone metastases. Thus, we determined if YM529 affected this pathway. YM529 suppressed CXCR-4 expression in PC-3 and LNCaP-SF in vitro and in vivo and this was associated with decreased in vitro invasion. These results suggest that YM529 may inhibit cancer cell invasion into the bone matrix by repressing the expression of CXCR-4 in bone metastasis lesions.
Down-Regulation of Vascular Endothelial Cell Growth Factor-C Expression Using Small Interfering RNA Vectors in Mammary Tumors Inhibits Tumor Lymphangiogenesis and Spontaneous Metastasis and Enhances Survival
Authors: Chen Zhengtang , Varney Michelle L. , Backora Matthew W. , Cowan Kenneth , Solheim Joyce C. , Talmadge James E. , Singh Rakesh K.
Published: October 2005

Tumor production of vascular endothelial cell growth factor (VEGF)-C is associated with tumor lymphangiogenesis and lymph node metastasis. In this study, we examined the effects of small interfering RNA (siRNA)–mediated inhibition of VEGF-C on murine mammary tumor growth, metastasis, and survival. The mRNA and protein expression of VEGF-C in murine mammary tumor cells stably transfected with a VEGF-C siRNA vector were significantly lower compared with VEGF-C-control vector-transfected cells. Cl66-siVEGFC tumors had lower levels of lymphangiogenesis and lymph node and spontaneous lung metastasis than Cl66-control tumors. However, we did not observe significant differences in primary tumor growth and experimental lung metastasis between mice injected with Cl66-siVEGFC and Cl66-control cells. In addition, mice bearing Cl66-siVEGFC tumors lived significantly longer than mice bearing Cl66-control tumors. Furthermore, our data suggest that inhibition of VEGF-C modulates immune cell infiltration and their function, which might be critical in tumor immunity. In summary, our data show that inhibition of VEGF-C expression using siRNA-mediated gene silencing vectors reduces lymphangiogenesis and lymph node and spontaneous lung metastasis, and enhances survival.
Retention of Intrinsic Stem Cell Hierarchies in Carcinoma-Derived Cell Lines
Authors: Locke Matthew , Heywood Matthew , Fawell Stuart , Mackenzie Ian C.
Published: October 2005

Recent work indicates that the growth and behavior of cancers are ultimately determined by a small subpopulation of malignant stem cells and that information about the properties of these cells is urgently needed to enable their targeting for therapeutic elimination. A key feature of normal stem cells is their asymmetrical division, the mechanism that allows stem cell self-renewal while producing hierarchies of amplifying and differentiating cells that form the bulk of the tissue. Most cancer deaths result from epithelial malignancies, but the extent to which the hierarchical proliferative stem and amplifying cell patterns of normal epithelia are actually retained in epithelial malignancies has been unclear. Here we show that even cell lines generated from carcinomas consistently produce in vitro colony patterns unexpectedly similar to those produced by the stem and amplifying cells of normal epithelia. From the differing types of colony morphologies formed, it is possible to predict both the growth potential of their constituent cells and their patterns of macromolecular expression. Maintenance of a subpopulation of stem cells during passage of cell lines indicates that the key stem cell property of asymmetrical division persists but is shifted towards enhanced stem cell self-renewal. The presence of malignant epithelial stem cells in vivo has been shown by serial transplantation of primary cancer cells and the present observations indicate that stem cell patterns are robust and persist even in cell lines. An understanding of this behavior should facilitate studies directed towards the molecular or pharmacologic manipulation of malignant stem cell survival.
Up-regulation of Delta-like 4 Ligand in Human Tumor Vasculature and the Role of Basal Expression in Endothelial Cell Function
Authors: Patel Nilay S. , Li Ji-Liang , Generali Daniele , Poulsom Richard , Cranston David W. , Harris Adrian L.
Published: October 2005

The Notch signaling pathway and the delta-like 4 ligand (DLL4) play key roles in embryonic vascular development. Many of the pathways involved in embryonic vascular development also play important roles in tumor angiogenesis. In this study, we assessed the expression of DLL4 in primary renal cancer and investigated the biological function of DLL4 in primary endothelial cells. Using real-time quantitative PCR and in situ hybridization, we showed that the expression of DLL4 was up-regulated within the vasculature of clear cell-renal cell carcinoma almost 9-fold more than normal kidney and was correlated with the expression of vascular endothelial growth factor (VEGF). The expression of DLL4 in endothelial cells was up-regulated by VEGF and basic fibroblast growth factor synergistically, and by hypoxia through hypoxia-inducible factor 1α. Down-regulation of DLL4 expression with RNA interference led to decreased expression of HEY1 and EphrinB2, and the inhibition of endothelial cell proliferation, migration, and network formation, all of which are important processes in tumor angiogenesis. The inhibition of proliferation occurred via the induction of cell cycle arrest in G0-G1 by increased expression of p21 and decreased phosphorylation of retinoblastoma. We conclude that an optimal window of the DLL4 expression is essential for tumor angiogenesis and that selective modulation of the DLL4 expression within human tumors may represent a potential novel antiangiogenic therapy.
Pharmacologic Modulation of Glycogen Synthase Kinase-3β Promotes p53-Dependent Apoptosis through a Direct Bax-Mediated Mitochondrial Pathway in Colorectal Cancer Cells
Authors: Tan Jing , Zhuang Li , Leong Hui-Sun , Iyer N. Gopalakrishna , Liu Edison T. , Yu Qiang
Published: October 2005

Activation of p53 tumor suppressor induces either cell cycle arrest or apoptosis through transcription-dependent and independent pathways; however, their relative roles in apoptosis induction and how these pathways are regulated remains elusive. Here, we report a unique role for glycogen synthesis kinase-3β (GSK-3β) in regulating p53 functions in human colorectal cancer cells. Pharmacologic modulation of GSK-3β markedly impaired p53-dependent transactivation of targets including p21 and Puma but promoted p53-dependent conformational activation of Bax, resulting in cytochrome c release, loss of mitochondrial membrane potential, and caspase-9 processing. Thus, p53-mediated damage response is converted from cell cycle arrest to apoptosis following exposure to a variety of chemotherapeutic agents. We found that this effect is associated with the modulation of inhibitory Ser9 phosphorylation of GSK-3β but not with the activating tyrosine phosphorylation. We further show that the induction of apoptosis is through a direct mitochondrial pathway that requires Bax but not Puma. Our results underscore the importance of transcription-independent mechanism in p53-induced apoptosis and indicate that GSK-3β plays distinct dual roles in regulating p53 pathways: promoting p53 transcriptional activity in the nucleus but suppressing p53-mediated direct apoptotic function at the mitochondria. Importantly, our data suggest that small-molecule inhibition of GSK-3β might represent a novel approach for modulating chemotherapy.
Inflammation in the Genesis and Perpetuation of Cancer: Summary and Recommendations from a National Cancer Institute–Sponsored Meeting
Authors: Peek Richard M. , Mohla Suresh , DuBois Raymond N.
Published: October 2005

The Inflammation and Cancer Think Tank Meeting was organized by the National Cancer Institute with the purpose of identifying research advances, gaps, and opportunities for the study and clinical application of the role of inflammation on tumorigenesis. The format of this meeting consisted of brief presentations that focused on concepts, with extensive discussion periods to allow participants to identify issues and barriers limiting progress in this area. The strong relationship between inflammation and cancer in the gastrointestinal tract prompted several presentations that were focused on carcinogenesis within this organ system; however, many of the same immune mediators that influence esophageal, gastric, and colorectal carcinoma were also shown to influence inflammation-related malignancies at other anatomic sites. This article summarizes the findings of this Think Tank Meeting, which highlight the intimate relationship between malignant cells and their inflammatory microenvironment and specifically address opportunities to manipulate the host immune response and therefore intervene at different points along the tumorigenic cascade.
Endoplasmic Reticulum Stress Signal Mediators Are Targets of Selenium Action
Authors: Wu Yue , Zhang Haitao , Dong Yan , Park Young-Mee , Ip Clement
Published: October 2005

A monomethylated selenium metabolite, called methylseleninic acid (MSA), has recently been shown to cause global thiol redox modification of proteins. These changes represent a form of cellular stress due to protein misfolding or unfolding. An accumulation of aberrantly folded proteins in the endoplasmic reticulum (ER) triggers a defined set of transducers to correct the defects or commit the cells to apoptosis if the rescue effort is exhausted. Treatment of PC-3 human prostate cancer cells with MSA was found to induce a number of signature ER stress markers: (a) the survival/rescue molecules such as phosphorylated protein kinase–like ER-resident kinase (phospho-PERK), phosphorylated eukaryotic initiation factor-2α (phospho-eIF2α), glucose-regulated protein (GRP)-78, and GRP94; and (b) the apoptotic molecules such as caspase-12, caspase-7, and CAAT/enhancer binding protein homologous protein or growth arrest DNA damage-inducible gene 153 (CHOP/GADD153). Additional evidence suggested that CHOP/GADD153 might be an important transcription factor in apoptosis induction by MSA. In general, a higher concentration of MSA was required to elicit the apoptotic markers compared with the rescue markers. The apoptotic markers increased proportionally with the dose of MSA, whereas the rescue markers failed to keep pace with the increasing challenge from MSA. GRP78 is the rheostat of the ER stress transducers. In GRP78-overexpressing cells, the ability of MSA to up-regulate phospho-PERK, phospho-eIF2α, GRP94, caspase-12, caspase-7, and CHOP/GADD153 was significantly muted. A generous supply of GRP78 would allow cells to cope better with ER stress, thereby improving the odds for survival and negating the commitment to apoptotic death. The present study thus provides strong evidence to support an important role of ER stress response in mediating the anticancer effect of selenium.
On Confidence Intervals for Genotype Relative Risks and Attributable Risks from Case Parent Trio Designs for Candidate-Gene Studies
Authors: Franke Daniel , Philippi Anne , Tores Frédéric , Hager Jörg , Ziegler Andreas , König Inke R.
Published: September 2005

Scherag et al. [Hum Hered 2002;54:210–217] recently proposed point estimates and asymptotic as well as exact confidence intervals for genotype relative risks (GRRs) and the attributable risk (AR) in case parent trio designs using single nucleotide polymorphism (SNP) data. The aim of this study was the investigation of coverage probabilities and bias in estimates if the marker locus is not identical to the disease locus. Using a variety of parameter constellations, including marker allele frequencies identical to and different from the SNP at the disease locus, we performed an analytical study to quantify the bias and a Monte-Carlo simulation study for quantifying both bias and coverage probabilities. No bias was observed if marker and trait locus coincided. Two parameters had a strong impact on coverage probabilities of confidence intervals and bias in point estimates if they did not coincide: the linkage disequilibrium (LD) parameter δ and the allele frequency at the marker SNP. If marker allele frequencies were different from the allele frequencies at the functional SNP, substantial biases occurred. Further, if δ between the marker and the disease locus was lower than the maximum possible δ, estimates were also biased. In general, biases were towards the null hypothesis for both GRRs and AR. If one GRR was not increased, as e.g. in a recessive genetic model, biases away from the null could be observed. If both GRRs were in identical directions and if both were substantially larger than 1, the bias always was towards the null. When applying point estimates and confidence intervals for GRRs and AR in candidate gene studies, great care is needed. Effect estimates are substantially biased towards the null if either the allele frequencies at the marker SNP and the true disease locus are different or if the LD between the marker SNP and the disease locus is not at its maximum. A bias away from the null occurs only in uncommon study situations; it is small and can therefore be ignored for applications.
Adrenal Pathophysiology: Lessons from the Carney Complex
Authors: Groussin Lionel , Cazabat Laure , René-Corail Fernande , Jullian Eric , Bertherat Jérôme
Published: September 2005

The Carney complex (CNC) is a dominantly inherited syndrome responsible mainly for spotty skin pigmentation (lentiginosis), endocrine overactivity, and cardiac myxomas. Adrenocorticotropic hormone independent Cushing’s syndrome due to primary pigmented nodular adrenocortical disease (PPNAD) is a main characteristic of CNC. PPNAD is a very rare cause of Cushing’s syndrome due to a primary bilateral adrenal defect that can be also observed in some patients without other CNC manifestations nor familial history. One of the putative CNC genes, located on 17q22-24, has been identified as the regulatory subunit R1A of protein kinase A (PRKAR1A). Heterozygous inactivating mutations of PRKAR1A have been reported initially in about 45% of the CNC index cases and could be found in about 80% of the CNC families presenting mainly with Cushing’s syndrome. PRKAR1A is a key component of the cyclic AMP signaling pathway that has been implicated in endocrine tumorigenesis and could, at least partly, function as a tumor suppressor gene. Interestingly, patients with isolated PPNAD and no familial history of CNC can also present a germline de novo mutation of PRKAR1A. Somatic mutations of PRKAR1A have been found in PPNAD as a mechanism of inactivation of the wild-type allele, in a patient already presenting a germline mutation, and in a subset of sporadic secreting adrenocortical adenomas with clinical, hormonal, and pathological features quite similar to PPNAD. This review will summarize the recent findings on CNC from the perspective of the pathophysiology of adrenal Cushing’s syndrome and PPNAD.
Efficient Short-Term Control of Hypercortisolaemia by Low-Dose Etomidate in Severe Paediatric Cushing’s Disease
Authors: Greening J.E. , Brain C.E. , Perry L.A. , Mushtaq I. , Sales Marques J. , Grossman A.B. , Savage M.O.
Published: September 2005

Background: Paediatric Cushing’s disease (CD) is rare, but is associated with considerable morbidity and requires effective treatment. Control of hypercortisolaemia is recommended prior to definitive therapy by transsphenoidal pituitary surgery with selective adenomectomy. We describe a 6.2-year-old male with severe hypercortisolaemia and life-threatening complications of Cushing’s disease. Control of cortisol with metyrapone and ketoconazole was ineffective, and due to his deteriorating condition, the decision was taken to proceed to bilateral adrenalectomy. Methods: Low-dose IV infusion of etomidate, with dose titration according to serum cortisol levels, was administered. Results: Etomidate infusion (3.0 mg/h i.v.) decreased serum cortisol from 1,250 to 250 nmol/l within 24 h. Combined etomidate and hydrocortisone therapy was maintained to provide stable serum cortisol levels within the desired range for 12 days prior to successful bilateral adrenalectomy. Conclusion: In our experience, etomidate was effective and safe for short-term control of severe hypercortisolaemia in a severely ill child.
Prevalence of Vitamin D Deficiency in Isfahani High School Students in 2004
Authors: Moussavi Mohammad , Heidarpour Reza , Aminorroaya Ashraf , Pournaghshband Zahra , Amini Massoud
Published: September 2005

Background and Aims: Vitamin D is important for calcium absorption and bone growth. Hypovitaminosis and vitamin D deficiency have been observed in developed and developing countries including several in the Middle East. The prevalence of vitamin D deficiency was investigated in Isfahani male and female high school students in Iran in 2004. Methods: In a cross-sectional study, 318 students (153 boys and 165 girls) aged 14–18 years were selected by multistage random sampling. Data were collected by interview and serum 25-hydroxyvitamin D (25-OHD) and parathyroid hormone (PTH) levels were measured. Vitamin D deficiency was defined as serum 25-OHD <20 and <32 ng/ml in which the mean serum PTH began to increase in our population. Results: The prevalence of vitamin D deficiency according to 25-OHD <20 ng/ml in all subjects was 46.2% (72.1% in females and 18.3% in males). Vitamin D deficiency in female students was about four times more common than in males (OR = 3.9, 95% CI = 1.88–3.91, p < 0.001). According to 25-OHD <32 ng/ml, the prevalence of vitamin D deficiency in all students was 72.2% (95.2% in females and 49% in males). Conclusions: Vitamin D deficiency is common in high school students, especially in girls. Avoidance of sunshine or inadequate dietary intake of vitamin D may be the main causes.
Genetic Analysis of Tall Stature
Authors: Kant S.G. , Wit J.M. , Breuning M.H.
Published: September 2005

Tall stature is less often experienced as an important problem than short stature. However, a correct diagnosis may be of eminent importance, especially when interventions are planned, or to know the natural history. Overgrowth can be caused by endocrine disorders and skeletal dysplasias, but also by several genetic syndromes. Despite a systematic diagnostic approach, there will be patients with tall stature who do not fit a known diagnosis. In this group of patients possibilities of genetic analysis do exist, but are not common practice. The FMR1 gene should be analyzed in patients with tall stature and mental retardation, and in these patients the NSD1 gene can be considered whenever some features of Sotos syndrome do exist. In tall patients without mental retardation and some features of Sotos or Beckwith-Wiedemann syndrome it may still be useful to look for mutations in the NSD1 gene, but also for changes in the 11p15 region. The various possibilities are discussed and placed in a flowchart.
Role of Palliative Endoscopic Drainage in Patients with Malignant Biliary Obstruction
Authors: Hammarström Lars-Erik
Published: September 2005

Background: Endoscopic biliary drainage for malignant obstructive jaundice is a viable palliative alternative, but its role and cost-effectiveness compared to percutaneous drainage or surgical bypass are subject to debate. Aim: To review the evidence in the literature with regard to the settings in which endoscopic drainage favorably compares with and affords palliation and quality of life comparable to percutaneous drainage or surgical bypass in malignant obstructive jaundice patients. Method: Using PubMed, Embase, Current Contents, and Medline, a literature search was performed for papers published from 1979 to April 2004. All retrieved papers comparing endoscopic drainage with percutaneous or surgical drainage, with special reference to the level of obstruction, were rated according to the strength of evidence and carefully analyzed. Results and Conclusions: Palliative drainage affords improved quality of life. The outcome of endoscopic and percutaneous drainage was similar, but data were few and inconsistent. Due to fewer late complications, surgical bypass is an alternative to metal stents (Wallstent™) which remain patent longer than plastic stents (large-bore polyethylene), with an overall median of 180 and 109 days, respectively, in patients who survive longer than about 6 months, which cannot be accurately predicted though. Overall early and late morbidity, stent patency, and survival were similar in patients treated for hilar compared to distal obstruction.
A Novel, Easy, and Safe Technique to Repair a Stoma Prolapse Using a Surgical Stapling Device
Authors: Hata Fumitake , Kitagawa Shingo , Nishimori Hidefumi , Furuhata Tomohisa , Tsuruma Tetsuhiro , Ezoe Eiri , Ishiyama Gentaro , Ohno Keisuke , Fukui Rika , Yanai Yoshiyuki , Yasoshima Takahiro , Koichi Hirata
Published: September 2005

A stoma prolapse is one of the late complications and often occurs when the stoma is made in an emergency situation. This complication is not lethal, but causes irritable stoma, skin trouble, and difficulty in stoma care. We herein report the case of a 48-year-old female with an end colostomy that was created as an emergency operation 4 months before. On admission, her colostomy protruded approximately 20 cm from the skin with marked redness, swelling, and erosion; it was impossible to treat manually. We repaired the prolapse successfully in a simple procedure with a Proximate Linear Cutter 100. Briefly, under mild sedation, the instrument was diagonally inserted into the prolapsed stoma and applied twice on both sides. Then, the base of each divided tissue was stapled and cut with the same device. Finally, the prolapse was completely repaired without major bleeding and severe pain. We have applied this novel technique successfully in 5 further cases, and there have been no complications or recurrences. This technique can be performed without spinal or general anesthesia and seems to be a very useful procedure for patients with prolapse of a stoma.
Genetic Association of CDC2 with Cerebrospinal Fluid Tau in Alzheimer’s Disease
Authors: Johansson Annica , Zetterberg Henrik , Hampel Harald , Buerger Katharina , Prince Jonathan A. , Minthon Lennart , Wahlund Lars-Olof , Blennow Kaj
Published: September 2005

We have recently reported that a polymorphism in the cell division cycle (CDC2) gene, designated Ex6 + 7I/D, is associated with Alzheimer’s disease (AD). The CDC2 gene is located on chromosome 10q21.1 close to the marker D10S1225 linked to AD. Active cdc2 accumulates in neurons containing neurofibrillary tangles (NFT), a process that can precede the formation of NFT. Therefore, CDC2 is a promising candidate susceptibility gene for AD. We investigated the possible effects of the CDC2 polymorphism on cerebrospinal fluid (CSF) biomarkers in AD patients. CDC2 genotypes were evaluated in relation to CSF protein levels of total tau, phospho-tau and β-amyloid(1–42) in AD patients and control individuals, and in relation to the amount of senile plaques and NFT in the frontal cortex and in the hippocampus in patients with autopsy-proven AD and controls. The CDC2 Ex6 + 7I allele was associated with a gene dose-dependent increase of CSF total tau levels (F2, 626 = 7.0, p = 0.001) and the homozygous CDC2 Ex6 + 7II genotype was significantly more frequent among AD patients compared to controls (p = 0.006, OR = 1.57, 95% CI 1.13–2.17). Our results provide further evidence for an involvement of cdc2 in the pathogenesis of AD.