bluuebunny/crossref_metadata_2025 huggingface dataset:
Regarding test functions for multi-dimensional integration
Authors: Whiten W. J. , Kocis L.
Published: April 2007

Monte Carlo and quasi Monte Carlo (ie using low discrepancy sequences) methods (Bratley & Fox 1988, Joe & Sloan 1993, Krommer & Ueberhuber 1994, Lyness 1989, Niederreiter 1978, Sloan & Kachoyan 1987) are used to approximate an integral by the average value of function samples:[EQUATION 1]where v is the volume of integration (taken here to be the unit multi-dimensional cube) and x is a vector with an element for each of the dimensions of the multidimensional space. In the case of Monte Carlo the points x
p
are chosen at random, while in quasi Monte Carlo the points are chosen to cover the integration volume as uniformly as possible. For numerical integration over a large number of dimensions these two techniques are often the only methods available.
An example of error propagation reinterpreted as subtractive cancellation—revisited
Authors: Dukelow James S.
Published: April 2007

James Delaney, in his paper in
SIGNUM Newsletter
[1], convincingly demonstrates that the recursion[EQUATION]blows up because of catastrophic loss of precision due to subtractive cancellation. Values of I
n
calculated using this recursion are given in the second column of Table 1.
Saving time and space in spline calculations
Authors: Bush George C
Published: April 2007

There are many descriptions in the literature of the use of cubic splines for interpolation, approximating derivatives, etc. The purpose of this note is to explore some shortcuts in computation that are possible if the tabular points (knots) are equally spaced.
An alternative to Chan's deflation for bordered systems
Authors: Govaerts W , Pryce J D
Published: April 2007

In many contexts, notably in computing continuation curves near singular points, it is necessary to solve linear systems of the form[EQUATION]where
A
is
n
x
n
, b is
n
x 1,
c
is 1 x
n
, and
d
is a scalar. (Thus
x, f
are
n
-vectors and
y, g
are scalars.) The complete (
n
+ 1) x (
n
+ 1) matrix
M
is assumed to be well-conditioned, but
A
is expected to be singular or nearly so. In addition
A
is assumed to possess useful properties which may be lost if the augmented matrix
M
is dealt with directly:
e.g. A
might have a band structure which would be lost by pivoting too soon in the bottom row. Thus for efficiency's sake we wish to use a solver for systems with coefficient matrix
A
, but its likely ill-condition demands special care.
Compiling LISP procedures
Authors: Pumplin Bruce A
Published: April 2007

The programming language LISP is frequently the language of choice for the implementation of artificial intelligence (AI) systems, even though it has earned a reputation for being slow. This lack of speed is usually due to the fact that commonly available LISP implementations are interpretive in nature rather than compile and go. And we all know that interpreting source code is invariably slower than simply executing the compiled object code.
Symposium Versus Newsletter
Authors: Press Larry
Published: April 2007

Like most of our members, I was unable to attend our Symposium on Small Systems last December, but I have had a chance to read the Proceedings. I'm writing this note for two reasons: to say a little about the Proceedings in case others might want to order a copy and to speculate on how we can get future Symposium papers to the members at large.
Fast recognition of circular objects in digital images
Authors: Hill Frederick R.
Published: April 2007

Occasions arise when it become necessary to rapidly recognize circular objects in digital images. One such application involves the testing of manufacturing runs of antibiotics for potency. The procedure is fairly simple in that by measuring the zones of inhibition produced by diluted samples of the antibiotics on bacterial culture dishes, and comparing these measurements to a set of standard measurements, the potency of the particular run can easily be determined. The problem arises in that multiple sets of measurements need to be made to insure statistical significance and most drugs can only be produced in relatively small lots. The result is that literally thousands of measurements must be made every day in a typical laboratory. In this paper, we discuss an algorithm that can be implemented on an IBM PC using a variety of frame grabber video boards to measure the diameters of zones of inhibition quickly, and to reject data from zones which are not circular.
The JSP-Tutor: a computerized aid for teaching Jackson structured programming
Authors: Kokol Peter
Published: April 2007

In the article we briefly discuss the Jackson Structured Programming method and compare this method with the conventional approach to programming. Then we introduce a computerized tutor which helps in the teaching of JSP. The tutor supports all aspects of development in JSP in a "step-by-step" mode for laymen and a "normal" mode for the advanced user. It runs on the Graphic Partner computer under CPM or on the IBM Personal Computer under MS-DOS.
On a fast integer square root algorithm
Authors: Rolfe TImothy J.
Published: April 2007

The long-hand square root algorithm, when implemented in binary arithmetic, produces immediately the analytic result (as opposed to the successive approximations generated by the Newton-Raphson method). It also uses only addition, subtraction, and bits shifts; it is related to the binary integer division algorithm, but is in fact a simpler procedure.
Finding new mathematical identities via numerical computations
Authors: Bailey David H.
Published: April 2007

A recent development in computational mathematics is the use of high-precision numerical computations, together with advanced integer relation algorithms, to discover heretofore unknown mathematical identities. One of these new identities, a remarkable new formula for π, permits one to directly compute the
n
-th hexadecimal digit of π, without computing the first
n
- 1 digits, and without the need of multiple-precision arithmetic software.
Evaluation of two relational database management systems
Authors: McDermid Lindsay
Published: April 2007

The following document is an evaluation and comparison of two relational database management systems: UNIFY and iDB. UNIFY Release 3.1 runs on the NCR Tower iDB runs a version of Mistress under iDIS Release 1.6 on the Intel 310.
Basic and DOS jobstreams in IBM PC software documentation
Authors: Barnett Michael P.
Published: April 2007

This paper describes some applications of a programming technique that can be used to produce on-line and printed documentation of BASIC programs written for the IBM PC. The methodology helps to document the usage and other aspects of software, for purposes of review, instruction, reference and general information. The author has used the techniques:(1) to explain the usage of a program by reference to a succession of simplified versions which exclude unnecessary details,(2) to construct file driven adaptations of interactive programs for use in automated demonstrations, and to run these adaptations,(3) to capture sample displays of text and graphics that illustrate the actions of a program,(4) to print batches of programs in formats that are easy to read, and to perform other related cosmetic and editorial processes.
Job hunting in the modern market
Authors: Hodge H. K.
Published: April 2007

In the midst (October '85) of my most recent episode of voluntary unemployment, I have noticed a marked change in the manner of hiring data processing employees. Back when I broke into the field (1959), before there were computer science majors, companies were willing, even eager, to hire one off the street and teach him the ropes (or, more often, to let him learn the ropes by himself, since there were not that many people familiar with the equipment).
Architecture of a microcomputer based DSS generator
Authors: Saxena K. B. C. , Gulati D. V. , Kaul M.
Published: April 2007

A Decision Support System (DSS) is an interactive computer-based system used to support decision makers in their decision making activities. Normally, it is easier and quicker to build such systems using DSS generators (software packages) with related hardware.This paper describes the design and implementation of an experimental microcomputer-based DSS generator REGIMES. The system design is conceptually an extension of Sprague's model for organising decision support capabilities. The system is one of the first examples of an integrated DSS generator software implemented in BASIC on a personal computer providing multiple user interfaces, graphics, data base management and modelling capabilities.
Filestore structure of a single-user operating system
Authors: Ranai K.
Published: April 2007

This paper is a description of a filestore structure of a single-user operating system MICRODOS (see [Ranai, 1, 2]). A hybrid filestore structure of the random page map type (SOLO system see [Hansen, 5]) and the sequential chain linked type (OS6 system see [Stoy and Strachey, 3, 4]) was adopted for MICRODOS system.
Physical locking/anti-theft devices (LD) case study
Authors: Rushinek Avi , Rushinek Sara
Published: April 2007

The selection of computer systems can be a frustrating process. The overall satisfaction derived from a system depends on matching system specifications to user needs. This case study describes a Product Evaluation and Selection System (PESS) that correlates user needs to system specifications. This case illustrates the selection of LD. A recommendation report ranks the LD in descending order of their correlations to user needs. Implications for users, consultants and vendors are discussed and illustrated.
The ACM conference on the history of personal workstations
Authors: Press Larry
Published: April 2007

ACM held a conference on the history of personal workstations at Palo Alto, CA on January 9-10, 1986. There were presentations by thirteen pioneering researchers, primarily from projects funded by ARPA at MIT, the Stanford Research Institute, and the Xerox Palo Alto Research Center. The participants described their motivation, the systems they developed and the goals of the organizations where they worked. This paper summarizes and discusses the conference.
Line numbering for IBM DisplayWrite 3 legal documents
Authors: Higgins Donald S.
Published: April 2007

A public domain utility program has been developed to perform line numbering on IBM DisplayWrite 3 word processing legal documents without losing the text document's characteristics such as bolding and automatic line adjust. (1) Development of the line numbering program was made possible in large part due to the fact that the IBM PC DisplayWrite 3 package uses the published IBM Document Content Architecture. (2) The use of the Document Content Architecture (DCA) by IBM for its office products has proven to be of added value since it provides a well documented standard data base design upon which users can develop additional software to meet user requirements not currently met by existing vendor software. (3)
Microcomputer systems for low-earth-orbit satellite tracking and data acquisition
Authors: Diersing Robert J.
Published: April 2007

This article describes two microcomputer systems used for low-earth-orbit satellite tracking and data acquisition. The systems were developed for use with spacecraft operated in the Amateur Satellite Service but could be adapted for use with other satellites. After some background information on the Amateur Satellite Service and the spacecraft currently in operation, the details of each system are presented. The article concludes with the plans for continued development of the systems to perform new functions such as a gateway to the JAS-1 store-and-forward packet radio satellite. December of 1986 will be the twenty-fifth anniversary of the launch of the first amateur radio satellite.
Response to Keith Wayland's observation in the last sentence of his letter to H. K. Hodge
Authors: Koehler Vincent
Published: April 2007

This is in response to Keith Wayland's observation in the last sentence of his letter to H. K. Hodge that if N has K non-zero bits in binary form then N! has N-K trailing binary zeros. Here is a proof of that statement, by induction of course.
ISD OSI & OIS
Authors: Wong K. W.
Published: April 2007

This paper discusses the role of computer message systems in an automated office. Relationships between office automation and computer networks are identified. The paper also reports the status of the current development of message systems and related standards.
RANDOM THOUGHTS
Authors: Hodge H. K.
Published: April 2007

I saw in the newspaper the other day that Texas expects the demand for systems analysts to grow by 46% in the next few years. That led me to wonder (once again) just what constitutes a systems analyst; or rather, what should a systems analyst be, as opposed to the examples I have met of what they are.
Possible evolution strategies: single centralized system versus multi-processor architectures
Authors: Ferrara Fabrizio Massimo
Published: April 2007

The technological evolution and the increasing number of the hardware and software products available on the market make a wide range of possible solutions available to the system designer when defining the architecture to be used for implementing new computer--supported applications.
Series reversion as the reversed chain rule
Authors: Lawson Charles L.
Published: April 2007

I recently had occasion to extend a derivative-computation package I had written in 1971 to add the capability of dealing with a function defined implicitly. This led me to see the duality between Taylor series reversion and the chain rule of differentiation of a composite function. I was also struck with the compactness with which these algorithms could be expressed in a programming language, which in my case was Fortran 77. The basic ideas involved will probably not be new to persons who have worked on computerization of symbolic mathematics or other approaches to derivative computation, however, I think this may be of interest to many readers of this newsletter as an instance of a very small body of code implementing a mathematical transformation that might a priori be thought to be somewhat complicated.
Decomposing a sequence of matrices that differ only in one submatrix
Authors: Proskurowski Wlodzimierz
Published: April 2007

This paper is a development of a project assigned to a graduate class in Numerical Methods in the Fall Semester 1980 at USC. This approach to teaching shows some similarities with the Claremont Mathematics Clinic, see [4].
Some tests of the numerical procedures of Pascal-SC
Authors: Arone Z. , Jansen P. , Weidner P.
Published: April 2007

PASCAL-SC is an extended version of PASCAL, which is intended to be more usable for engineering purposes. It is distributed by Wiley-Teubner (see [1]). PASCAL-SC retains the features of standard PASCAL, and has some additional useful capabilities.
Some shared memory is desirable in parallel sparse matrix computation
Authors: George Alan , Ng Esmond
Published: April 2007

Over the past few years a number of algorithms for solving large sparse systems of equations on distributed-memory multiprocessors have been developed. In this article the authors point out that the properties of sparse matrix problems generally, along with the characteristics of these parallel algorithms for solving them, lead to inefficient use of memory. An example is presented to show that a (relatively small) amount of shared memory on an otherwise pure distributed-memory multiprocessor is very desirable when it is being used to execute these parallel algorithms.
Generations of permutations with non-unique elements
Authors: Rolfe T. J.
Published: April 2007

We wish to generate all unique permutations of a list of elements with possibly repeated items. We develop four algorithms to generate permutations, two from Knuth's
Art of Computer Programming
and two of our own devising. The last one developed also gives a numbering scheme for permutations that can be inverted to regenerate original permutations.
Caching on a microcomputer: an implementation
Authors: Wood Percy G.
Published: April 2007

In the constant search for improvements in computer system throughput, many developments have occurred. One of the 'hot' areas in recent years has been the idea of a cache. Caches are high-speed memory areas used for transient storage. They have been used for pre-fetching and holding instructions for fast access by the central processing unit and for holding output destined for a printer (spooling), as well as acting as an intermediate step in disk access.
IMCL language and its implementation on the personal computer
Authors: Kokol P. , Vucelic B. , Mernik M. , Rozman I. , Zumer V.
Published: April 2007

The use of traditional industrial controllers has been a common practice for successfully controlling processes in industrial plants for a long time. However, these old-fashioned controllers (Figure 1) are unfortunately inflexible and much too slow and unreliable for critical applications, and not "user friendly." Still worse, programming them is tedious, lengthy and difficult. LSI and VLSI technology with their 16- and 32-bit processors has permitted a new approach to the design and use of industrial controllers (Figure 2). The shift from MAD (Manually Aided Design) to CAD has been the most important result of this shift to date. But finally, newly emerging concepts of parallel computing, applicative languages and non-yon Neumann architecture have awakened our hopes of employing the computer to liberate the human (Figure 3).
The use of forward difference equations in animation of physical phenomena
Authors: Cynar Sandra J.
Published: April 2007

In the entertainment industry graphical images are often produced without adherence to physically accurate models. This is usually the case because there is a need to reduce production time and costs. The physical scientist, on the other hand, must produce graphical images that are accurate simulations of the physical phenomena they are attempting to visualize. Frequently the data that an accurate simulation produces can be difficult to use for rendering the animation. This paper describes the use of numerical methods to minimize the number of keyframes for an accurate animation.
PC-based software: the future is now
Authors: Nord Jeretta Horn , Nord G. Daryl , Aukerman Richard A.
Published: April 2007

Since the conception of the electronic computer, software technology has evolved through four stages or generations: machine, assembler, high-level or third generation (3GL), and fourth generation languages (4GL). The fourth generation of software is non-procedural in nature; that is, 4GL's employ a small set of powerful commands that tell the computer what to do, as opposed to procedural languages that tell the computer how to do it. Fourth generation languages may also include procedural capabilities which can be combined with non-procedural code. With the focus shifting from how to what, 4GL's allow nonprofessional programmers to get results, are typically user-friendly, and may of them include a database management system. In addition, less code is required using fourth generation software; therefore: debugging is reduced, it is easier to understand and maintain another's code, and results can be obtained in less time. As the gap between people and computers decreases through the use of fourth generation software, productivity is and will continue to be greatly enhanced. This concept, which is often referred to as end-user computing, is gaining momentum with the advent of PC-based microcomputer 4GL's.
Comandos
Authors: Balter R.
Published: April 2007

Pages are missing from the print and online versions of this paper
Some statistics on Gaussian elimination with partial pivoting
Authors: Macleod A. J.
Published: April 2007

There has recently been an upsurge of work on the (by now) classical problem of the stability of Gaussian elimination e.g., the papers of Trefethen & Schreiber [5], and Higham and Higham [2]. This short note describes some experimental results in this area derived by the author. They are described more fully in a technical report [4].
Comment on "Integer Arithmetic" by Hodge
Authors: Schnebly Dexter A.
Published: April 2007

I was very interested in H. K. Hodge's article on "INTEGER ARITHMETIC" in the last PC NOTES. It got me to thinking about the N! values, etc. As I thought about it I came up with the following. (This material is most likely in a textbook somewhere but Heaven forbid that a software type should look something up.)
The neXT computer
Authors: Dietrich T.
Published: April 2007

What's NeXT? NeXT
is
Steve Jobs. In September of 1985 Jobs was stripped of his authority at the very company he and his friend Steve Wozniak had created - Apple Computer, Inc. Apple Computer, one of the most successful computer companies ever, is viewed by many as
the
company that got the personal computer industry rolling. In fact, Apple's first computer, the Apple 1, was introduced in 1976' - almost six years before IBM introduced its infamous PC.
Activation of 5-HT1Areceptors in the paragigantocellularis lateralis decreases shivering during cooling in the conscious piglet
Authors: Hoffman J. M. , Brown J. W. , Sirlin E. A. , Benoit A. M. , Gill W. H. , Harris M. B. , Darnall R. A.
Published: April 2007

Activation of 5-HT1Areceptors in the medullary raphé decreases sympathetic outflow to thermoregulatory mechanisms, including brown adipose tissue (BAT), thermogenesis, and peripheral vasoconstriction when these mechanisms are previously activated with leptin, prostaglandins, or cooling. These same mechanisms are also inhibited during rapid eye movement (REM) sleep. It is not known whether shivering is also modulated by medullary raphé neurons. We previously showed in the conscious piglet that activation of 5-HT1Areceptors with 8-OH-DPAT (DPAT) in the paragigantocellularis lateralis (PGCL), a medullary region lateral to the midline raphé that contains 5-HT neurons, decreases heart rate, body temperature and muscle activity during non-rapid eye movement (NREM) sleep. We therefore hypothesized that activation of 5-HT1Areceptors in the PGCL would also attenuate shivering and peripheral vasoconstriction during cooling. During REM sleep in a cool environment, shivering, carbon dioxide production, and body temperature decreased, and ear capillary blood flow and ear skin temperature increased. Shivering associated with rapid cooling was attenuated after dialysis of DPAT into the PGCL. In animals maintained in a continuously cool environment, dialysis of DPAT into the PGCL attenuated shivering and decreased body temperature, but there were no significant increases in ear capillary blood flow or ear skin temperature. We conclude that both naturally occurring REM sleep and exogenous activation of 5-HT1Areceptors in the PGCL are associated with a suspension of shivering during cooling. Our data are consistent with the hypothesis that 5-HT neurons in the PGCL facilitate oscillating spinal motor circuits involved in shivering but are less involved in modulating sympathetically mediated thermoregulatory mechanisms.
Insulin-like growth factor I stimulates recovery of bone lost after a period of skeletal unloading
Authors: Boudignon Benjamin M. , Bikle Daniel D. , Kurimoto Pam , Elalieh Hashem , Nishida Shigeki , Wang Yongmei , Burghardt Andrew , Majumdar Sharmila , Orwoll Benjamin E. , Rosen Clifford , Halloran Bernard P.
Published: April 2007

IGF-I stimulates osteoblast proliferation, bone formation, and increases bone volume in normal weight-bearing animals. During skeletal unloading or loss of weight bearing, bone becomes unresponsive to the anabolic effects of insulin-like growth factor I (IGF-I). To determine whether skeletal reloading after a period of unloading increases bone responsiveness to IGF-I, we examined bone structure and formation in response to IGF-I under different loading conditions. Twelve-week-old rats were divided into six groups: loaded (4 wk), unloaded (4 wk), and unloaded/reloaded (2/2 wk), and treated with IGF-I (2.5 mg·kg−1·day−1) or vehicle during the final 2 wk. Cortical bone formation rate (BFR), cancellous bone volume and architecture in the secondary spongiosa (tibia and vertebrae), and total volume and calcified volume in the primary spongiosa (tibia) were assessed. Periosteal BFR decreased during unloading, remained low during reloading in the vehicle-treated group, but was dramatically increased in IGF-I-treated animals. Cancellous bone volume decreased with unloading and increased with reloading, but the effect was exaggerated in the tibia of IGF-I-treated animals. Total and calcified volumes in the primary spongiosa decreased during unloading in the vehicle-treated animals. IGF-I treatment prevented the loss in volume. These data show that reloading after a period of skeletal unloading increases bone responsiveness to IGF-I, and they suggest that IGF-I may be of therapeutic use in patients who have lost bone as a consequence of prolonged skeletal disuse.
Synaptic Amplification Versus Bistability in Motoneuron Dendritic Processing: A Top-Down Modeling Approach
Authors: Shapiro Nicholas P. , Lee Robert H.
Published: April 2007

Motoneurons have been shown to exhibit both bistable firing and synaptic amplification. Both of these behaviors have generally been attributed to a single mechanism—dendritic plateau potentials based on L-type Ca2+ conductances. However, our recent discovery of a fast-amplification mode calls this into question. Here we examine the possibility that two mechanisms underlie these behaviors, one being a slow-mode bistability mechanism (i.e., the L-type Ca2+-conductance–based dendritic plateaus) and the other being a theoretical fast-mode amplification mechanism. A “top-down” motoneuron model that encapsulated these and other hypotheses was developed in which these mechanisms could be explored. The resulting final model simultaneously exhibits synaptic amplification, plateau potential formation, bistable firing patterns, and current–voltage ( I– V) and frequency–current ( F– I) hystereses. This model suggests that amplification and plateaus are mutually exclusive in the same dendrite/dendritic branch. Thus we predict that plateau generation does not occur in all dendritic branches. This could be readily accomplished by a large degree of variation in the density of L-type Ca2+ channels believed to underlie plateau formation in these cells with the added benefit of spreading plateau onset over a wider voltage range, as is observed experimentally.
Factors Affecting the Common Modulation of Bilateral Motor Unit Discharge in Human Soleus Muscles
Authors: Mochizuki G. , Ivanova T. D. , Garland S. J.
Published: April 2007

The purpose of this study was to determine the factors that influence the co-modulation of motor unit discharge rate in soleus muscles of both legs during upright standing. Single motor units were recorded from the left and right soleus muscles under three experimental conditions: standing quietly with the eyes open and closed, standing with the eyes closed while vibration was applied to one Achilles tendon, and swaying voluntarily or producing variable low-force isometric contractions at a frequency of 0.05 Hz. Correlations in motor unit discharge rate between left and right soleus motor units were assessed using common drive analysis. The results showed that common drive to motoneurons of the two muscles did not differ between standing with the eyes open or closed, but there was an order effect with the second task having significantly lower common drive than the first. Common drive was also significantly lower when vibration was applied to one leg compared with when no vibration was applied. Common drive was higher as subjects swayed anteriorly as compared with when they swayed posteriorly. There were no significant differences in common drive across phases of the variable isometric force contraction. Common drive was higher during voluntary sway than during variable force production; both of these values were significantly lower than those derived from the quiet standing task. These results suggest that proprioceptive and sub-cortical inputs contribute to the co-modulation of the firing rate of soleus motor unit pairs of the left and right leg during standing posture.
Salmonella typhimurium Lacking Ribose Chemoreceptors Localize in Tumor Quiescence and Induce Apoptosis
Authors: Kasinskas Rachel W. , Forbes Neil S.
Published: April 2007

The effectiveness of most chemotherapeutics is limited by their inability to penetrate deep into tumor tissue and their ineffectiveness against quiescent cells. Motile Salmonella typhimurium, which are specifically attracted to compounds produced by quiescent cancer cells, could overcome this therapeutic barrier. We hypothesized that individual chemoreceptors target S. typhimurium to specific tumor microenvironments. To test this hypothesis, we used time-lapse fluorescent microscopy and tumor cylindroids to quantify the accumulation of chemotaxis machinery knockouts, including strains lacking individual cell surface chemoreceptors, chemotaxis signal transduction pathway enzymes, and the flagella and motor assemblies. To measure the extent of apoptosis induced by individual bacterial strains, caspase-3 activity was measured as a function of time. Our results showed how chemoreceptors directed bacterial chemotaxis within cylindroids: the aspartate receptor initiated chemotaxis toward cylindroids, the serine receptor initiated penetration, and the ribose/galactose receptor directed S. typhimurium toward necrosis. In addition, strains lacking proper flagella constructs, signal transduction proteins, or active motor function did not chemotax toward tumor cylindroids, indicating that directed chemotaxis is necessary to promote accumulation in tumors. By deleting the ribose/galactose receptor, bacterial accumulation localized to tumor quiescence and had a greater individual effect on inducing apoptosis than wild-type S. typhimurium. This new understanding of the mechanisms of Salmonella migration in tumors will allow for the development of bacterial therapies with improved targeting to therapeutically inaccessible regions of tumors. [Cancer Res 2007;67(7):3201–9]
Peroxisome Proliferator-Activated Receptor γ–Independent Suppression of Androgen Receptor Expression by Troglitazone Mechanism and Pharmacologic Exploitation
Authors: Yang Chih-Cheng , Wang Yu-Chieh , Wei Shuo , Lin Li-Fang , Chen Chang-Shi , Lee Cheng-Chun , Lin Cheng-Chieh , Chen Ching-Shih
Published: April 2007

Previously, we showed that the peroxisome proliferator-activated receptor γ (PPARγ) agonist troglitazone at high doses was able to suppress androgen receptor (AR) expression in LNCaP prostate cancer cells independently of PPARγ. Pharmacologic exploitation of this finding led to STG28, a PPARγ-inactive analogue of troglitazone with substantially higher potency in AR repression. Considering the pivotal role of AR in prostate tumorigenesis, this study investigates the mechanism by which troglitazone and derivatives suppress AR expression in LNCaP cells. Reverse transcription-PCR and reporter gene assays indicate that this drug-induced AR repression occurs at both mRNA and protein levels. Evidence suggests that troglitazone and derivatives mediate the transcriptional repression of AR by facilitating the ubiquitin-dependent proteasomal degradation of the transcriptional factor Sp1. These agents also cause the proteolysis of two proteins that regulate Sp1-mediated transcription (i.e., the TATA-binding protein–associated factor TAFII250 and cyclin D1). However, their involvement in the transcriptional repression of AR is refuted by the finding that small interfering RNA knockdown of these two regulatory proteins does not cause AR down-regulation. STG28 does not cause significant reduction in Sp1 or AR expression in normal prostate epithelial cells. This discriminatory effect underscores the differential susceptibility of malignant versus normal cells to the inhibitory effect of STG28 on cell viability. From a translational perspective, STG28 provides a proof of principle that potent AR-ablative agents could be developed through structural modifications of troglitazone. Moreover, as the control of Sp1 degradation remains unclear, STG28 represents a unique pharmacologic probe to investigate the ubiquitin-proteasome system that regulates Sp1 proteolysis. [Cancer Res 2007;67(7):3229–38]
Evidences that Leptin Up-regulates E-Cadherin Expression in Breast Cancer: Effects on Tumor Growth and Progression
Authors: Mauro Loredana , Catalano Stefania , Bossi Gianluca , Pellegrino Michele , Barone Ines , Morales Sara , Giordano Cinzia , Bartella Viviana , Casaburi Ivan , Andò Sebastiano
Published: April 2007

Leptin, a cytokine mainly produced by adipocytes, seems to play a crucial role in mammary carcinogenesis. In the present study, we explored the mechanism of leptin-mediated promotion of breast tumor growth using xenograft MCF-7 in 45-day-old female nude mice, and an in vitro model represented by MCF-7 three-dimensional cultures. Xenograft tumors, obtained only in animals with estradiol (E2) pellet implants, doubled control value after 13 weeks of leptin exposure. In three-dimensional cultures, leptin and/or E2 enhanced cell-cell adhesion. This increased aggregation seems to be dependent on E-cadherin because it was completely abrogated in the presence of function-blocking E-cadherin antibody or EGTA, a calcium-chelating agent. In three-dimensional cultures, leptin and/or E2 treatment significantly increased cell growth, which was abrogated when E-cadherin function was blocked. These findings well correlated with an increase of mRNA and protein content of E-cadherin in three-dimensional cultures and in xenografts. In MCF-7 cells both hormones were able to activate E-cadherin promoter. Mutagenesis studies, electrophoretic mobility shift assay, and chromatin immunoprecipitation assays revealed that cyclic AMP–responsive element binding protein and Sp1 motifs, present on E-cadherin promoter, were important for the up-regulatory effects induced by both hormones on E-cadherin expression in breast cancer MCF-7 cells. In conclusion, the present study shows how leptin is able to promote tumor cell proliferation and homotypic tumor cell adhesion via an increase of E-cadherin expression. This combined effect may give reasonable emphasis to the important role of this cytokine in stimulating primary breast tumor cell growth and progression, particularly in obese women. [Cancer Res 2007;67(7):3412–21]
Gene and Protein Expression Profiling of Human Ovarian Cancer Cells Treated with the Heat Shock Protein 90 Inhibitor 17-Allylamino-17-Demethoxygeldanamycin
Authors: Maloney Alison , Clarke Paul A. , Naaby-Hansen Soren , Stein Rob , Koopman Jens-Oliver , Akpan Akunna , Yang Alice , Zvelebil Marketa , Cramer Rainer , Stimson Lindsay , Aherne Wynne , Banerji Udai , Judson Ian , Sharp Swee , Powers Marissa , deBilly Emmanuel , Salmons Joanne , Walton Michael , Burlingame Al , Waterfield Michael , Workman Paul
Published: April 2007

The promising antitumor activity of 17-allylamino-17-demethoxygeldanamycin (17AAG) results from inhibition of the molecular chaperone heat shock protein 90 (HSP90) and subsequent degradation of multiple oncogenic client proteins. Gene expression microarray and proteomic analysis were used to profile molecular changes in the A2780 human ovarian cancer cell line treated with 17AAG. Comparison of results with an inactive analogue and an alternative HSP90 inhibitor radicicol indicated that increased expression of HSP72, HSC70, HSP27, HSP47, and HSP90β at the mRNA level were on-target effects of 17AAG. HSP27 protein levels were increased in tumor biopsies following treatment of patients with 17AAG. A group of MYC-regulated mRNAs was decreased by 17AAG. Of particular interest and novelty were changes in expression of chromatin-associated proteins. Expression of the heterochromatin protein 1 was increased, and expression of the histone acetyltransferase 1 and the histone arginine methyltransferase PRMT5 was decreased by 17AAG. PRMT5 was shown to be a novel HSP90-binding partner and potential client protein. Cellular protein acetylation was reduced by 17AAG, which was shown to have an antagonistic interaction on cell proliferation with the histone deacetylase inhibitor trichostatin A. This mRNA and protein expression analysis has provided new insights into the complex molecular pharmacology of 17AAG and suggested new genes and proteins that may be involved in response to the drug or be potential biomarkers of drug action. [Cancer Res 2007;67(7):3239–53]
Nonsteroidal Anti-inflammatory Drugs Induce Colorectal Cancer Cell Apoptosis by Suppressing 14-3-3ε
Authors: Liou Jun-Yang , Ghelani Dipak , Yeh Sam , Wu Kenneth K.
Published: April 2007

To determine the role of 14-3-3 in colorectal cancer apoptosis induced by nonsteroidal anti-inflammatory drugs (NSAIDs), we evaluated the effects of sulindac on 14-3-3ε protein expression in colorectal cancer cells. Sulindac sulfide inhibited 14-3-3ε proteins in HT-29 and DLD-1 cells in a time- and concentration-dependent manner. Sulindac sulfone at 600 μmol/L inhibited 14-3-3ε protein expression in HT-29. Indomethacin and SC-236, a selective cyclooxygenase-2 (COX-2) inhibitor, exerted a similar effect as sulindac. Sulindac suppressed 14-3-3ε promoter activity. As 14-3-3ε promoter activation is mediated by peroxisome proliferator–activated receptor δ (PPARδ), we determined the correlation between 14-3-3ε inhibition and PPARδ suppression by NSAIDs. Sulindac sulfide inhibited PPARδ protein expression and PPARδ transcriptional activity. Overexpression of PPARδ by adenoviral transfer rescued 14-3-3ε proteins from elimination by sulindac or indomethacin. NSAID-induced 14-3-3ε suppression was associated with reduced cytosolic Bad with elevation of mitochondrial Bad and increase in apoptosis which was rescued by Ad-PPARδ transduction. Stable expression of 14-3-3ε in HT-29 significantly protected cells from apoptosis. Our findings shed light on a novel mechanism by which NSAIDs induce colorectal cancer apoptosis via the PPARδ/14-3-3ε transcriptional pathway. These results suggest that 14-3-3ε is a target for the prevention and therapy of colorectal cancer. [Cancer Res 2007;67(7):3185–91]
Fatty Acid Synthase Inhibition Activates AMP-Activated Protein Kinase in SKOV3 Human Ovarian Cancer Cells
Authors: Zhou Weibo , Han Wan Fang , Landree Leslie E. , Thupari Jagan N. , Pinn Michael L. , Bililign Tsion , Kim Eun Kyoung , Vadlamudi Aravinda , Medghalchi Susan M. , El Meskini Rajaa , Ronnett Gabriele V. , Townsend Craig A. , Kuhajda Francis P.
Published: April 2007

Fatty acid synthase (FAS), the enzyme responsible for the de novo synthesis of fatty acids, is highly expressed in ovarian cancers and most common human carcinomas. Inhibition of FAS and activation of AMP-activated protein kinase (AMPK) have been shown to be cytotoxic to human cancer cells in vitro and in vivo. In this report, we explore the cytotoxic mechanism of action of FAS inhibition and show that C93, a synthetic FAS inhibitor, increases the AMP/ATP ratio, activating AMPK in SKOV3 human ovarian cancer cells, which leads to cytotoxicity. As a physiologic consequence of AMPK activation, acetyl-CoA carboxylase (ACC), the rate-limiting enzyme of fatty acid synthesis, was phosphorylated and inhibited whereas glucose oxidation was increased. Despite these attempts to conserve energy, the AMP/ATP ratio increased with worsening cellular redox status. Pretreatment of SKOV3 cells with compound C, an AMPK inhibitor, substantially rescued the cells from C93 cytotoxicity, indicating its dependence on AMPK activation. 5-(Tetradecyloxy)-2-furoic acid, an ACC inhibitor, did not activate AMPK despite inhibiting fatty acid synthesis pathway activity and was not significantly cytotoxic to SKOV3 cells. This indicates that substrate accumulation from FAS inhibition triggering AMPK activation, not end-product depletion of fatty acids, is likely responsible for AMPK activation. C93 also exhibited significant antitumor activity and apoptosis against SKOV3 xenografts in athymic mice without significant weight loss or cytotoxicity to proliferating cellular compartments such as bone marrow, gastrointestinal tract, or skin. Thus, pharmacologic FAS inhibition selectively activates AMPK in ovarian cancer cells, inducing cytotoxicity while sparing most normal human tissues from the pleiotropic effects of AMPK activation. [Cancer Res 2007;67(7):2964–71]
Isoleucine, an Essential Amino Acid, Prevents Liver Metastases of Colon Cancer by Antiangiogenesis
Authors: Murata Kazumoto , Moriyama Masami
Published: April 2007

In spite of recent advances in the treatment of colon cancer, multiple liver metastases of colon cancer are still difficult to treat. Some chemotherapeutic regimens have been reported to be efficient, but there is a high risk of side effects associated with these. Here, we show that isoleucine, an essential amino acid, prevents liver metastases in a mouse colon cancer metastatic model. Because isoleucine is a strong inducer of β-defensin, we first hypothesized that it prevented liver metastases via the accumulation of dendritic cells or memory T cells through up-regulation of β-defensin. However, neither β-defensin nor immunologic responses were induced by isoleucine in both mouse livers and spleens. Furthermore, isoleucine prevented liver metastasis in nude mice, which lack T cells and natural killer T cells. Finally, we discovered a novel mechanism of isoleucine: down-regulation of angiogenesis via inhibition of vascular endothelial growth factor, partially through the mammalian target of the rapamycin pathway, independent of hypoxia-inducible factor 1-α. Importantly, isoleucine is safe for administration to humans because it does not affect cell viability. Isoleucine could be a novel prophylactic drug for the prevention of liver metastases of colon cancer. [Cancer Res 2007;67(7):3263–8]
IFN-γ Enhances the Antimyeloma Activity of the Fully Human Anti–Human Leukocyte Antigen-DR Monoclonal Antibody 1D09C3
Authors: Carlo-Stella Carmelo , Guidetti Anna , Di Nicola Massimo , Lavazza Cristiana , Cleris Loredana , Sia Daniela , Longoni Paolo , Milanesi Marco , Magni Michele , Nagy Zoltan , Corradini Paolo , Carbone Antonino , Formelli Franca , Gianni Alessandro M.
Published: April 2007

To investigate the therapeutic activity of the fully human anti–HLA-DR antibody 1D09C3 in multiple myeloma (MM), we reevaluated HLA-DR expression on CD138+ cells, analyzed the capacity of IFN-γ to up-regulate HLA-DR expression on MM cell lines, and tested the in vitro and in vivo activity of 1D09C3 alone or in combination with IFN-γ. CD138+HLA-DR+ cells were detected in 31 of 60 patients, with 15 of 60 patients having ≥20% CD138+HLA-DR+ cells (median, 50%; range, 23–100). Because primary plasma cells cannot be efficiently cultured in vitro, we used a panel of MM cell lines with a dim/negative to bright HLA-DR expression to evaluate 1D09C3-induced cell death. Annexin V/propidium iodide (PI) staining showed that 1D09C3-induced cell death correlated with constitutive HLA-DR expression. Induction of HLA-DR by IFN-γ restored the sensitivity of HLA-DR dim cell lines to 1D09C3. In vivo, the combined IFN-γ/1D09C3 treatment significantly increased the median survival of nonobese diabetic/severe combined immunodeficient mice xenografted with KMS-11 cell line, compared with controls (147 versus 48 days, P ≤ 0.0001) or mice receiving 1D09C3 alone (147 versus 92 days, P ≤ 0.03). The better therapeutic activity of IFN-γ/1D09C3 treatment over 1D09C3 alone was further shown by a 2-fold increase of mice being disease-free at 150 days after xenograft (47% versus 25%). No mice experienced any apparent treatment-related toxicity. Our data show that (a) one fourth of MM patients express HLA-DR on CD138+ cells and (b) IFN-γ–induced up-regulation of HLA-DR results in a potent enhancement of the in vivo antimyeloma activity of 1D09C3. [Cancer Res 2007;67(7):3269–75]
Tumors Initiated by Constitutive Cdk2 Activation Exhibit Transforming Growth Factor β Resistance and Acquire Paracrine Mitogenic Stimulation during Progression
Authors: Corsino Patrick , Davis Bradley , Law Mary , Chytil Anna , Forrester Elizabeth , Nørgaard Peter , Teoh Nicole , Law Brian
Published: April 2007

Cyclin D1/cyclin-dependent kinase 2 (Cdk2) complexes are present at high frequency in human breast cancer cell lines, but the significance of this observation is unknown. This report shows that expression of a cyclin D1–Cdk2 fusion protein under the control of the mouse mammary tumor virus (MMTV) promoter results in mammary gland hyperplasia and fibrosis, and mammary tumors. Cell lines isolated from MMTV–cyclin D1–Cdk2 (MMTV-D1K2) tumors exhibit Rb and p130 hyperphosphorylation and up-regulation of the protein products of E2F-dependent genes. These results suggest that cyclin D1/Cdk2 complexes may mediate some of the transforming effects that result from cyclin D1 overexpression in human breast cancers. MMTV-D1K2 cancer cells express the hepatocyte growth factor (HGF) receptor, c-Met. MMTV-D1K2 cancer cells also secrete transforming growth factor β (TGFβ), but are relatively resistant to TGFβ antiproliferative effects. Fibroblasts derived from MMTV-D1K2 tumors secrete factors that stimulate the proliferation of MMTV-D1K2 cancer cells, stimulate c-Met tyrosine phosphorylation, and stimulate the phosphorylation of the downstream signaling intermediates p70s6k and Akt on activating sites. Together, these results suggest that deregulation of the Cdk/Rb/E2F axis reprograms mammary epithelial cells to initiate a paracrine loop with tumor-associated fibroblasts involving TGFβ and HGF, resulting in desmoplasia. The MMTV-D1K2 mice should provide a useful model system for the development of therapeutic approaches to block the stromal desmoplastic reaction that likely plays an important role in the progression of multiple types of human tumors. [Cancer Res 2007;67(7):3135–44]
Molecular Dissection of Hyperdiploid Multiple Myeloma by Gene Expression Profiling
Authors: Chng Wee J. , Kumar Shaji , VanWier Scott , Ahmann Greg , Price-Troska Tammy , Henderson Kim , Chung Tae-Hoon , Kim Seungchan , Mulligan George , Bryant Barbara , Carpten John , Gertz Morie , Rajkumar S. Vincent , Lacy Martha , Dispenzieri Angela , Kyle Robert , Greipp Philip , Bergsagel P. Leif , Fonseca Rafael
Published: April 2007

Hyperdiploid multiple myeloma (H-MM) is the most common form of myeloma. In this gene expression profiling study, we show that H-MM is defined by a protein biosynthesis signature that is primarily driven by a gene dosage mechanism as a result of trisomic chromosomes. Within H-MM, four independently validated patient clusters overexpressing nonoverlapping sets of genes that form cognate pathways/networks that have potential biological importance in multiple myeloma were identified. One prominent cluster, cluster 1, is characterized by high expression of cancer testis antigen and proliferation-associated genes. Tumors from these patients were more proliferative than tumors in other clusters (median plasma cell labeling index, 3.8; P < 0.05). Another cluster, cluster 3, is characterized by genes involved in tumor necrosis factor/nuclear factor-κB signaling and antiapoptosis. These patients have better response to bortezomib as compared with patients within other clusters (70% versus 29%; P = 0.02). Furthermore, for a group of patients generally thought to have better prognosis, a cluster of patients with short survival (cluster 1; median survival, 27 months) could be identified. This analysis illustrates the heterogeneity within H-MM and the importance of defining specific cytogenetic prognostic factors. Furthermore, the signatures that defined these clusters may provide a basis for tailoring treatment to individual patients. [Cancer Res 2007;67(7):2982–9]