bluuebunny/crossref_metadata_2025 huggingface dataset:
A comparison study on multivariant and univariant finite elements for three‐dimensional incompressible viscous flows
Authors: Sheu Tony W. H. , Wang Morten M. T.
Published: August 2005

In this paper, four quadratic hexahedron elements are considered and assessed for analysis of an incompressible viscous flow underlying the mixed finite element method. We classify the investigated elements as multivariant and univariant finite elements. With the same number of pressure unknowns, multivariant elements are more constrained when the number of elements per side is larger than 10, as compared with that of continuous pressure elements. In multivariant eléments, the coding is complicated by the appearance of restricted degrees of freedom at mid‐face and mid‐edge nodes. The comparison consequently should be made via numerical example against the analytical problem.
Generalized differential and integral quadrature and their application to solve boundary layer equations
Authors: Shu C. , Chew Y. T. , Richards B. E.
Published: August 2005

Based on the work of generalized differential quadrature (GDQ), a global method of generalized integral quadrature (GIQ) is developed in this paper for approximating an integral of a function over a part of the closed domain. GIQ approximates the integral of a function over the part of the whole closed domain by a linear combination of all the functional values in the whole domain with higher order of accuracy. The weighting coefficients of GIQ can be easily determined from those of GDQ. Applications of GDQ and GIQ to solve boundary layer equations demonstrated that accurate numerical results can be obtained using just a few grid points.
Methylation of the O6‐methylguanine‐DNA methyltransferase promoter suppresses expression in mouse skin tumors and varies with the tumor induction protocol
Authors: Abdel‐Fattah Rana , Glick Adam , Rehman Ishtiaq , Maiberger Patrick , Hennings Henry
Published: August 2005

Hypermethylation of CpG sites within the promoter region of the O6‐methylguanine‐DNA methyltransferase (MGMT) gene occurs frequently in human cancer, preventing both MGMT expression and repair of alkylation damage. To assess the role of MGMT in the development of mouse skin tumors induced by initiation‐promotion protocols, methylation of the MGMT promoter was examined in tumor DNA using methylation‐specific PCR. To determine whether MGMT promoter methylation was affected by the tumor induction protocol, tumors were initiated by N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG) or 7,12‐dimethylbenz[a]anthracene (DMBA) and promoted by 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) or mezerein. Although the MGMT promoter was not methylated in normal skin, promoter methylation was found in 56 of 136 papillomas (41.2%) and in 19 of 37 squamous cell carcinomas (51.4%). When methylation of the MGMT promoter was compared in the 4 treatment groups, hypermethylation was found more frequently in tumors initiated by DMBA and promoted by mezerein, a protocol associated with a high frequency of malignant conversion. Methylation was found in some tumors as early as 5 weeks after initiation, but the methylation frequency increased with time. MGMT promoter methylation reduced MGMT expression as determined by immunohistochemistry. Although MGMT promoter methylation was not generally correlated with ras mutations, the frequency of MGMT methylation was higher in MNNG‐initiated, mezerein‐promoted papillomas with mutations in Ha‐ras compared to papillomas with Ki‐ras. Methylation of the MGMT promoter, associated with reduced MGMT expression, is found in nearly half of mouse skin tumors, but varies with both the tumor initiator and tumor promoter, and may be a key step in the progression from papillomas to carcinomas. © 2005 Wiley‐Liss, Inc.
Prospective study on the expression of cancer testis genes and antibody responses in 100 consecutive patients with primary breast cancer
Authors: Mischo Axel , Kubuschok Boris , Ertan Kubilay , Preuss Klaus‐Dieter , Romeike Bernd , Regitz Evi , Schormann Claudia , de Bruijn Diederik , Wadle Andreas , Neumann Frank , Schmidt Werner , Renner Christoph , Pfreundschuh Michael
Published: August 2005

To determine the expression of cancer testis (CT) genes and antibody responses in a nonselected population of patients with primary breast cancer, we investigated the composite expression of 11 CT genes by RT‐PCR in fresh biopsies of 100 consecutive cases of primary breast carcinoma and by immunohistology in selected RT‐PCR‐positive cases. Antibody responses against 7 CT antigens were analyzed using recombinant antigen expression on yeast surface. In 98 evaluable cases, SCP‐1 and SSX‐4 were expressed most frequently (both 65%), followed by HOM‐TES‐85/CT‐8 (47%), GAGE (26%), SSX‐1 (20%), NY‐ESO‐1 (13%), MAGE‐3 (11%), SSX‐2 (8%), CT‐10 (7%), MAGE‐4 (4%) and CT‐7 (1%). One CT gene was expressed by 90% of the cases; 79% expressed ≥2, 48% ≥3, 29% ≥4, 12% ≥5, 6% ≥6, 3% ≥7, 2% ≥8 and one case coexpressed 9 antigens. Of 100 serum samples screened for CT antigen‐specific antibodies, antibodies against NY‐ESO‐1 were detected in 4 patients, against SCP‐1 in 6 patients and against SSX‐2 in 1 patient, while no antibodies were detected against MAGE‐3, CT‐7 and CT‐10. Expression of CT genes or antibody responses was not correlated with clinical parameters (menopausal status, tumor size, nodal involvement, grading, histology and estrogen receptor status) or the demonstration of CT gene expression at the protein level, by immunohistology. Our results show that breast carcinomas are among the tumors with the most frequent expression of CT antigens, rendering many patients potential candidates for vaccine trials. © 2005 Wiley‐Liss, Inc.
Src family kinase members have a common response to histone deacetylase inhibitors in human colon cancer cells
Authors: Hirsch Calley L. , Smith‐Windsor Erin L. , Bonham Keith
Published: August 2005

Histone deacetylase inhibitors (HDIs) induce cell cycle arrest, differentiation and/or apoptosis in numerous cancer cell types and have shown promise in clinical trials. These agents are particularly novel, given their ability to selectively influence gene expression. Previously, we demonstrated that the HDIs butyrate and trichostatin A (TSA) directly repress c‐Src proto‐oncogene expression in many cancer cell lines. Activation and/or overexpression of c‐Src have been frequently observed in numerous malignancies, especially of the colon. Therefore, our observation was particularly interesting since butyrate is a naturally abundant component of the large intestine and has been suggested to be a cancer‐preventive agent. However, c‐Src is not the only Src family kinase (SFK) member to be implicated in the development of human cancers, including those of the colon. Therefore, the relative expression levels of known SFKs were examined in a panel of human colon cancer cell lines. We found a surprisingly diverse expression pattern but noted that most cell lines expressed relatively high levels of at least 2 SFKs. When the effects of butyrate and TSA were examined in representative cell lines, the expression of all SFKs was repressed in a dose‐ and time‐dependent manner. Further, detailed examination of Lck, Yes and Lyn demonstrated that this repression had a direct effect on transcription and was independent of new protein synthesis. These results mirror our earlier data obtained with c‐Src and suggest that SFKs are a major target of HDIs and likely account in part for the anticancer effects of these promising new drugs. © 2005 Wiley‐Liss, Inc.
Parental lung cancer as predictor of cancer risks in offspring: Clues about multiple routes of harmful influence?
Authors: Hemminki Kari , Chen Bowang
Published: August 2005

The carcinogenic effects of active smoking have been demonstrated for many sites, but the effects of passive smoking and exposures during pregnancy and breastfeeding are less well documented. We examined whether 0–70‐year‐old offspring of parents with lung cancer are at a risk of cancer that cannot be explained by their smoking or familial risk. It was assumed that known target sites for tobacco carcinogenesis would be affected, if any. The nationwide Swedish Family‐Cancer Database with cancers recorded from 1958 to 2002 was used to calculate age‐specific standardized incidence ratios (SIRs). Among offspring of affected mothers, increased risks were observed for upper aerodigestive (SIR 1.45), nasal (2.93), lung (1.71) and bladder (1.52) cancers and for kidney cancer (6.41) in one age group. The risk of bladder cancer was found in younger age groups than that of lung cancer. Cancers at many of these sites, but not the kidney or the bladder, were in excess in offspring of affected fathers. Nasal cancer was even increased when either parent was diagnosed with lung cancer; the highest risk was for nasal adenoid cystic carcinoma (7.73). The data suggest that passive smoking during childhood is associated with an increase risk of nasal cancer. For bladder and kidney cancers, a contribution by tobacco carcinogens is implicated through breastfeeding and in utero exposure. © 2005 Wiley‐Liss, Inc.
Inhibitory effect of linoleic acid on transformation of IEC6 intestinal cells by in vitro azoxymethane treatment
Authors: Sasaki Takamitsu , Yoshida Kazuhiro , Shimura Hideo , Ichiba Masayosi , Sasahira Tomonori , Shimomoto Takasumi , Denda Ayumi , Kuniyasu Hiroki
Published: August 2005

The effect of linoleic acid (LA) on growth and transformation of IEC6 intestinal cells was examined. IEC6 cells expressed mRNAs of 15‐lipooxygenase (LOX15) and peroxisome proliferator–activated receptor (PPAR)γ but not COX‐2. Cell growth was suppressed by LA in a dose‐dependent manner in IEC6 cells. Three‐week treatment with LA provided IEC6 cells a quiescent state. LA‐induced growth inhibition was abrogated by exposure to antisense S‐oligodeoxynucleotides (S‐ODNs) for LOX15 and/or PPARγ. In an in vitro carcinogenesis model, IEC6 cells, which had confirmed CYP2E1 expression and activity, were continuously treated with AOM and/or LA for 40 weeks. DNA injury in AOM‐treated cells was suppressed to the control level by concurrent LA treatment. Colony formation of AOM‐treated cells in soft agar was suppressed by treatment with LA, which was reversed by exposure to antisense S‐ODNs for LOX15 and/or PPARγ. AOM‐treated IEC6 cells formed s.c. tumors in 9 of 12 mice, whereas AOM+LA‐treated cells formed no tumor. IEC6 cells showed no remarkable alteration of protein production by AOM treatment, whereas cells treated with AOM+LA showed decreased epidermal growth factor receptor (EGFR) and phospho‐EGFR and increased BAX. These findings suggest that LA inhibited AOM‐induced transformation of COX‐2‐negative IEC6 cells, which was possibly mediated with PPARγ ligands generated by LOX15 from LA. © 2005 Wiley‐Liss, Inc.
Comparison of implantation and cytotoxicity testing for initially toxic biomaterials
Authors: Rosengren Agneta , Faxius Linda , Tanaka Noriho , Watanabe Mika , Bjursten Lars M.
Published: August 2005

To evaluate the predictive value of cytotoxicity testing, the present study compares the in vivo tissue responses to in vitro cytotoxicity before and after implantation. Material toxicity was caused by addition of the toxic substance Zincdiethyldithiocarbamate (ZDEC) that is used as a standard for in vitro cytotoxicity testing. Polyurethane discs with the addition of 0.5% or 1% ZDEC as well as nontoxic discs were inserted in the abdominal wall of rats for 1 day up to 6 weeks. After explantation the foreign body response was analyzed immunohistochemically. An in vitro reanalysis of the explanted reference materials (RMs) revealed remaining high concentrations of toxic compounds after 1‐week implantation, whereas no toxicity was seen after 6 weeks implantation. This was reflected in the foreign body response where a significantly thicker capsule and more inflammatory cells were seen at 1 week for the toxic implants. Over time, with decreasing toxicity, these differences disappeared. Test samples that only were subjected to in vitro extraction with water did not elute toxic compounds to the same extent as the in vivo conditions. It is concluded that many clinically useful implant materials may be unnecessarily rejected due to the results of in vitro tests. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res, 2005
Permeable guidance channels containing microfilament scaffolds enhance axon growth and maturation
Authors: Cai Jie , Peng Xuejun , Nelson Kevin D. , Eberhart Robert , Smith George M.
Published: August 2005

Successful peripheral nerve regeneration is still limited in artificial conduits, especially for long lesion gaps. In this study, porous poly(L‐lactide‐co‐DL‐lactide, 75:25) (PLA) conduits were manufactured with 16 poly(L‐lactide) (PLLA) microfilaments aligned inside the lumen. Fourteen and 18 mm lesion gaps were created in a rat sciatic nerve lesion model. To evaluate the combined effect of permeable PLA conduits and microfilament bundles on axon growth, four types of implants were tested for each lesion gap: PLA conduits with 16 filaments; PLA conduits without filaments; silicone conduits with 16 filaments; and silicone conduits without filaments. Ten weeks following implantation, regeneration within the distal nerve was compared between corresponding groups. Antibodies against the markers S100, calcitonin gene related peptide (CGRP), RMDO95, and P0 were used to identify Schwann cells, unmyelinated axons, myelinated axons, and myelin, respectively. Results demonstrated that the filament scaffold enhanced tissue cable formation and Schwann cell migration in all groups. The filament scaffold enhanced axonal regeneration toward the distal stump, especially across long lesion gaps, but significance was only achieved with PLA conduits. When compared to corresponding silicone conduits, permeable PLA conduits enhanced myelinated axon regeneration across both lesion gaps and achieved significance only in combination with filament scaffolds. Myelin staining indicated PLA conduits supported axon myelination with better myelin quantity and quality when compared to silicone conduits. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res, 2005
Prefabrication of vascularized bone graft using a combination of fibroblast growth factor‐2 and vascular bundle implantation into a novel interconnected porous calcium hydroxyapatite ceramic
Authors: Nakasa Tomoyuki , Ishida Osamu , Sunagawa Toru , Nakamae Atsuo , Yasunaga Yuji , Agung Muhammad , Ochi Mitsuo
Published: August 2005

The aim of this study was to create a prefabricated vascularized bone graft using a novel interconnected porous calcium hydroxyapatite ceramic (IP‐CHA) by combining vascular bundle implantation and basic fibroblast growth factor (FGF)‐2 administration in a rabbit model. Twenty‐four Japanese white rabbits were used. The saphenous artery and vein were passed through the hole of the IP‐CHA. In an experimental group, 100 μg of FGF‐2 was administered into the IP‐CHA before implanting the vascular bundle. In the control group, the saline was administered into the IP‐CHA before implanting the vascular bundle. Finally, the IP‐CHA was placed subcutaneously in the medial thigh. Neovascularization from the vascular bundle was evaluated at 2 weeks after surgery, and osteogenesis was evaluated at 4 weeks. At 2 weeks, the length and density of newly formed vessels were significantly greater in the experimental group than in the control group. Histological evaluation showed osteoid deposition in the pores of the IP‐CHA at 4 weeks in the experimental group, whereas no evidence of osteoid deposition was noted in the control group. This study showed the potential of creating a vascularized bone graft of a predetermined size and shape using a combination of FGF‐2 and vascular bundle implantation in the IP‐CHA. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res, 2005
In vitro induction of polyploidy and chromatid exchanges by culture medium extracts of natural rubbers compounded with 2‐mercaptobenzothiazole as a positive control candidate for genotoxicity tests
Authors: Matsuoka Atsuko , Isama Kazuo , Tsuchiya Toshie
Published: August 2005

We tested extracts of custom‐made natural rubber samples for cytotoxicity using V79 cells and for chromosome aberration (CA) induction using CHL cells in compliance with the Japanese guidelines for basic biological tests of medical materials and devices. The samples were formulated with a high level of 2‐mercaptobenzothiazole (MBT) (A); a low level of MBT (B); or zinc dibutyldithiocarbamate (ZDBC) (C). In the CA test, MBT induced mainly polyploidy, including endoreduplication, and ZDBC induced structural CAs. In the cytotoxicity test, culture medium extracts of A, B, and C suppressed colony formation to 50% of the control value at 53.1%, 94.3%, and >100%, respectively. Culture medium extracts of sample A induced polyploidy and structural CAs in the absence of an exogenous metabolic activation system (S9 mix), but at lower concentrations in its presence, indicating the existence of other leachable promutagens. The extracts of sample B induced structural CAs at the highest concentration and only with S9 mix. Sample C was negative. The facts suggest that sample A may be a candidate for a positive control for genotoxicity tests. The high frequency of polyploidy induced by sample A was not predicted by MBT, suggesting the usefulness of the test for safety evaluation of medical devices. Numerical CAs induced by MBT and sample A are discussed. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res, 2005
In vivo evaluation of a porous hydroxyapatite/poly‐DL‐lactide composite for use as a bone substitute
Authors: Hasegawa Shin , Tamura Jiro , Neo Masashi , Goto Koji , Shikinami Yasuo , Saito Makoto , Kita Masakazu , Nakamura Takashi
Published: August 2005

We investigated the biocompatibility, osteoconductivity, and biodegradability of a porous composite of hydroxyapatite (HA) and poly‐DL‐lactide (PDLLA) implanted into rabbit femoral condyles and compared it with porous HA. Six weeks after implantation, the HA/PDLLA was covered with bone and contacted the bone directly. The amount of newly formed bone in the pores was similar in both materials during the examined period. The newly formed bone in the HA/PDLLA tended to increase over 26 weeks, but that in the HA did not show a significant increase after 12 weeks. By 26 weeks, remodeling of the newly formed bone in the pores was seen and bone marrow tissue was found in the pores of the HA/PDLLA. The porous HA/PDLLA was resorbed much faster than the porous HA. Porous HA/PDLLA was resorbed continuously through bone formation and remodeling. Conversely, porous HA was scarcely resorbed throughout the period. HA/PDLLA is thought to be degraded almost completely after about 1 year, and in this study, porous HA/PDLLA showed excellent osteoconductivity and faster resorption than HA. Therefore, HA/PDLLA might be a desirable material for bone substitutes. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res, 2005
Fatigue of kidney stones with heterogeneous microstructure subjected to shock‐wave lithotripsy
Authors: Zohdi T. I. , Szeri A. J.
Published: August 2005

In this article a theoretical framework is developed for the mechanics of kidney stones with an isotropic, random microstructure—such as those comprised of cystine or struvite. The approach is based on a micromechanical description of kidney stones comprised of crystals in a binding matrix. Stress concentration functions are developed to determine load sharing of the particle phase and the binding matrix phase. Measurements have shown the inclusions to be considerably harder than the binder; consequently, loading of a stone leads to higher stresses in the inclusions than in the binder. As an illustration of the theory, the fatigue of kidney stones subject to shock‐wave lithotripsy is considered. Stress concentration functions are used to construct fatigue‐life estimates for each phase, as a function of the volume fraction and of the mechanical properties of the constituents, as well as the loading from SWL. The failure of the binding matrix, or of the particulate phase, is determined explicitly in a model for the accumulation of distributed damage. The theory can be used to assess the importance of microscale heterogeneity on the comminution of renal calculi, and to estimate the number of cycles to failure in terms of measurable material properties. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2005
Prospects: Histone deacetylase inhibitors
Authors: Dokmanovic Milos , Marks Paul A.
Published: August 2005

Histone deacetylase (HDAC), inhibitors represent a new class of targeted anti‐cancer agents. Several of these compounds are in clinical trials with significant activity against a spectrum of both hematologic and solid tumors at doses that are well tolerated by the patients. The HDAC inhibitors are a structurally diverse group of molecules that can induce growth arrest, differentiation, apoptosis, and autophagocytic cell death of cancer cells. While the base sequence of DNA provides the genetic code for proteins, the expression of genes is regulated, in large part, by the structure of the chromatin proteins around which the DNA is wrapped (epigenetic gene regulation). The acetylation and deacetylation of the lysines in the tails of the core histones, among the most extensively studied aspects of chromatin structure, is controlled by the action of two families of enzymes, histone deacetylases (HDACs) and histone acetyltransferases (HATs). Protein components of transcription factor complexes and many other non‐histone proteins are also substrates for HDACs and HATs. The structure and activity of these non‐histone proteins may be altered by acetylation/deacetylation with consequent effects on various cell functions including gene expression, cell cycle progression, and cell death pathways. This review focuses on several key questions with respect to the mechanism of action of HDACi, including, what are the different cell phenotypes induced by HDACi, why are normal cells compared to transformed cells relatively resistant to HDACi induced cell death, why are certain tumors more responsive to HDACi than others, and what is the basis of the selectivity of HDACi in altering gene expression. The answers to these questions will have therapeutic importance since we will identify targets for enhancing the efficacy and safety of HDACi. © 2005 Wiley‐Liss, Inc.
Upregulation of Daxx mediates apoptosis in response to oxidative stress
Authors: Kim Kyung Soon , Hwang Hyun‐Ah , Chae Suhn‐Kee , Ha Hyunjung , Kwon Ki‐Sun
Published: August 2005

Oxidative stress induces apoptosis in a variety of cell types by as yet unclear signaling mechanisms. The Daxx protein is reportedly involved in apoptosis through its interactions with Fas, transforming growth factor‐β receptor, and promyelocytic leukemia protein (PML). Here, we explored the possible roles of Daxx in oxidative stress‐induced apoptosis. We found that both the mRNA and protein levels of Daxx markedly increased when cells underwent apoptosis after H2O2 treatment. Pretreatment with the cell‐permeable antioxidant, N‐acetyl cysteine, prevented cells from H2O2‐induced Daxx upregulation and subsequent apoptosis, indicating that the endogenous oxidant regulated Daxx expression. Furthermore, suppression of endogenous Daxx expression by antisense oligonucleotide technology inhibited oxidative stress‐induced apoptosis in HeLa cells. Taken together, these results suggest that Daxx acts as an intermediary messenger of pro‐apoptotic signals triggered by oxidative stress. © 2005 Wiley‐Liss, Inc.
PIKE/nuclear PI 3‐kinase signaling in preventing programmed cell death
Authors: Ye Keqiang
Published: August 2005

PI 3‐kinase enhancer (PIKE) is a nuclear GTPase that enhances PI 3‐kinase (PI3K) activity. Nerve growth factor (NGF) treatment leads to PIKE activation by triggering the nuclear translocation of PLC‐γ1, which acts as a physiological guanine nucleotide exchange factor (GEF) for PIKE. PI3K occurs in the nuclei of a broad range of cell types, and various stimuli elicit PI3K nuclear translocation. While cytoplasmic PI3K has been well characterized, little is known about the biological function of nuclear PI3K. Surprisingly, nuclei from 30 min NGF‐treated PC12 cells are resistant to DNA fragmentation initiated by the activated cell‐free apoptosome, and both PIKE and nuclear PI3K are sufficient and necessary for this effect. Moreover, pretreatment of the control nucleus with PI(3,4,5)P3 alone mimics the anti‐apoptotic activity of NGF by selectively preventing apoptosis, for which nuclear Akt is required but not sufficient. Recently, a nuclear PI(3,4,5)P3 receptor, nucleophosmin/B23, has been identified from NGF‐treated PC12 nuclear extract. PI(3,4,5)P3/B23 complex mediates the anti‐apoptotic effects of NGF by inhibiting DNA fragmentation activity of caspase‐activated DNase (CAD). Thus, PI(3,4,5)P3/B23 complex and nuclear Akt effectors might coordinately mediate PIKE/nuclear PI3K signaling in promoting cell survival by NGF. © 2005 Wiley‐Liss, Inc.
Stimulation of amphiregulin expression in osteoblastic cells by parathyroid hormone requires the protein kinase A and cAMP response element‐binding protein signaling pathway
Authors: Qin Ling , Partridge Nicola C.
Published: August 2005

Parathyroid hormone (PTH), an anabolic agent for bone metabolism, has profound effects on gene expression in the osteoblast. Recently, we identified that amphiregulin (AR), an EGF‐like ligand, is an immediate early gene for PTH treatment and has an important role in bone metabolism. In the present report, by using different PTH peptide fragments, protein kinase activators, and inhibitors, we have demonstrated that PTH regulates amphiregulin in a cAMP‐protein kinase A (PKA)‐dependent manner both in vitro and in vivo. We found that the phosphorylation of cAMP‐response element (CRE)‐binding protein (CREB) preceded AR transcription after PTH treatment. Moreover, luciferase reporter assays revealed that the binding of phosphorylated CREB to a conserved CRE site in the AR promoter plays an important role in basal, PTH‐induced, and prostaglandin E2 (PGE2)‐induced AR expression in osteoblastic cells. In summary, our data suggest that PTH‐induced AR mRNA expression is mediated primarily through cAMP‐PKA‐CREB signaling. © 2005 Wiley‐Liss, Inc.
Molecular markers in malignant cutaneous melanoma: Gift horse or one‐trick pony?
Authors: Martinez Steve R. , Hoon Dave S.B.
Published: August 2005

The management of malignant cutaneous melanoma is problematic. Current clinical prognostic factors do not adequately predict disease recurrence and overall survival in a significant subset of patients. Adjuvant therapies for melanoma are notoriously toxic and associated with significant morbidity. Furthermore, it has been difficult to predict which patients will respond best to these treatments, if at all. DNA and RNA biomarkers have been developed to help overcome these problems. Biomarkers have been shown to upstage patients with melanoma, but are the assays sensitive and specific enough for clinical use as predictors of disease outcome or treatment response? We review our experience with DNA and RNA biomarkers in terms of their prognostic and predictive capabilities in malignant melanoma and outline their likely role in the future of melanoma staging, surveillance, and treatment. © 2005 Wiley‐Liss, Inc.
TGF‐β control of cell proliferation
Authors: Huang Shuan S. , Huang Jung S.
Published: August 2005

This article focuses on recent findings that the type V TGF‐β receptor (TβR‐V), which co‐expresses with other TGF‐β receptors (TβR‐I, TβR‐II, and TβR‐III) in all normal cell types studied, is involved in growth inhibition by IGFBP‐3 and TGF‐β and that TGF‐β activity is regulated by two distinct endocytic pathways (clathrin‐ and caveolar/lipid‐raft‐mediated). TGF‐β is a potent growth inhibitor for most cell types, including epithelial and endothelial cells. The signaling by which TGF‐β controls cell proliferation is not well understood. Many lines of evidence indicate that other signaling pathways, in addition to the prominent TβR‐I/TβR‐II/Smad2/3/4 signaling cascade, are required for mediating TGF‐β‐induced growth inhibition. Recent studies revealed that TβR‐V, which is identical to LRP‐1, mediates IGF‐independent growth inhibition by IGFBP‐3 and mediates TGF‐β‐induced growth inhibition in concert with TβR‐I and TβR‐II. In addition, IRS proteins and a Ser/Thr‐specific protein phosphatase(s) are involved in the TβR‐V‐mediated growth inhibitory signaling cascade. The TβR‐V signaling cascade appears to cross‐talk with the TβR‐I/TβR‐II, insulin receptor (IR), IGF‐I receptor (IGF‐IR), integrin and c‐Met signaling cascades. Attenuation or loss of the TβR‐V signaling cascade may enable carcinoma cells to escape from TGF‐β growth control and may contribute to the aggressiveness and invasiveness of these cells via promoting epithelial‐to‐mesenchymal transdifferentiation (EMT). Finally, the ratio of TGF‐β binding to TβR‐II and TβR‐I is a signal controlling TGF‐β partitioning between two distinct endocytosis pathways and resultant TGF‐β responsiveness. These recent studies have provided new insights into the molecular mechanisms underlying TGF‐β‐induced cellular growth inhibition, cross‐talk between the TβR‐V and other signaling cascades, the signal that controls TGF‐β responsiveness and the role of TβR‐V in tumorigenesis. © 2005 Wiley‐Liss, Inc.
Differential regulation of cyclooxygenase 2 expression by small GTPases Ras, Rac1, and RhoA
Authors: Chang Yu‐Wen E. , Putzer Kevin , Ren Ling , Kaboord Barbara , Chance Terry W. , Qoronfleh M. Walid , Jakobi Rolf
Published: August 2005

Cyclooxygenase 2 (COX‐2) is an immediate early gene induced by a variety of stimuli and its expression is stimulated by individual activation of Ras or Rho GTPases. Here we investigate the role of coordinate activation of Ras and Rho GTPases in the induction of COX‐2. Individual expression of constitutively active Ras, RhoA, or Rac1 was capable of stimulating COX‐2 expression in NIH3T3 cells, but co‐expression of constitutively active RhoA with either constitutively active Ras or Rac1 was required for full stimulation of COX‐2 expression. Serum growth factors differentially activated Ras, RhoA, and Rac1, which correlated with the activation of Raf‐1, ERK, and c‐Jun as well as with induction of COX‐2. Inhibition of Ras significantly blocked the activation of Raf‐1, ERK, and c‐Jun and the stimulation of COX‐2 expression in response to serum. In contrast, inhibition of Rho family GTPases partially blocked serum induction of ERK activation but had little effects on COX‐2 expression. Both inhibitors of MEK (PD098059) and JNK (SP600125) inhibited serum induction of COX‐2. PD98059 only inhibited constitutively active Ras‐induced COX‐2 expression, while SP600125 significantly inhibited both constitutively active Ras‐ and RhoA‐induced COX‐2 expression. Together, our data suggest that constitutively active oncogenic Ras and Rho coordinately stimulate COX‐2 expression whereas transient activation of Ras but not RhoA or Rac1 mediates the induction of COX‐2 in response to serum. Furthermore, ERK and JNK activation are both required for serum‐ and oncogenic Ras‐mediated COX‐2 expression whereas only JNK activation is required for oncogenic RhoA‐mediated stimulation of COX‐2 expression. © 2005 Wiley‐Liss, Inc.
E2F1 induces cell death, calpain activation, and MDMX degradation in a transcription independent manner implicating a novel role for E2F1 in neuronal loss in SIV encephalitis
Authors: Strachan Gordon D. , Koike Maya A. , Siman Robert , Hall David J. , Jordan‐Sciutto Kelly L.
Published: August 2005

The E2F1 transcription factor can initiate proliferation or apoptosis, the latter by both transcription‐dependent and ‐independent mechanisms. Recently, an E2F1 mutant lacking the DNA binding domain, E2F1(180–437), has been implicated in degradation of MDMX and MDM2 proteins via lysosomal proteases. MDM proteins block p53 dependent apoptosis by directly inhibiting p53 stability and function. Here we demonstrate E2F1(180–437) induces death in HEK293 cells independent of E2F1 transcriptional activation and p53 stabilization. E2F1(180–437) elevates the activity of the calcium‐activated protease, calpain, which is required for E2F1 induced proteolysis of MDMX and E2F1 induced cell loss. To determine if E2F1 could be activating proteolysis via calpains in neurodegeneration, we examined MDMX immunofluorescence in simian immunodeficiency virus encephalitis (SIVE). We found a reciprocal relationship between E2F1 and MDMX staining: in SIVE where E2F1 immunostaining is increased, MDMX is decreased, while in controls where E2F1 immunostaining is low, MDMX is high. Together these experiments support a new function for E2F1 in the activation of calpain proteases and suggest a role for this pathway in SIVE. © 2005 Wiley‐Liss, Inc.
CH/π interactions involving aromatic amino acids: Refinement of the CHARMM tryptophan force field
Authors: Macias Alba T. , MacKerell Alexander D.
Published: August 2005

High‐level ab initio calculations have been carried out to study weak CH/π interactions and as a check of the CHARMM force field for aromatic amino acids. Comparisons with published data indicate that the MP2/cc‐pVTZ level of theory is suitable for calculations of CH/π interaction, including the T‐shape benzene dimer. This level of theory was, therefore, applied to investigate CH/π interactions between ethene or cis‐2‐butene and benzene in a variety of orientations. In addition, complexes between ethene and a series of model compounds (toluene, methylindole and p‐cresol) representing the aromatic amino acids were studied motivated by the presence of CH/π interactions in biological systems. Ab initio binding energies were compared to the binding energies obtained with the CHARMM22 force field. In the majority of orientations, CHARMM22 reproduces the preferred binding modes, with excellent agreement for the benzene dimer. Small discrepancies found in the calculations involving methylindole along with a survey of published thermodynamic data for the aromatic amino acids prompted additional optimization of the tryptophan force field. Partial atomic charges, Lennard–Jones parameters, and force constants were improved to obtain better intra‐ and intermolecular properties, with significant improvements obtained in the reproduction of experimental heats of sublimation for indole and free energies of aqueous solvation for methylindole. © 2005 Wiley Periodicals, Inc. J Comput Chem 26: 1452–1463, 2005
Poverty reduction strategy papers and the fisheries sector: an opportunity forgone?
Authors: Thorpe Andy , Reid Chris , Anrooy Raymon Van , Brugere Cecile , Becker Denis
Published: August 2005

This article examines the extent to which the fisheries sector has been mainstreamed into the Poverty Reduction Strategy Papers (PRSPs) published by fifty nations by the end of 2003. Applying content analysis techniques we find that there is little overt relationship between the extent of such mainstreaming and the significance of the sector (as either a contributor to food security, a generator of foreign exchange, a provider of employment or as a refuge of the poor). Copyright © 2005 John Wiley & Sons, Ltd.
Simulation of capacitive array sensors using finite and infinite elements
Authors: Heyliger P. R. , Moulder J. C. , Nakagawa N.
Published: August 2005

The response of capacitive array sensors in the presence of flawed solid materials is simulated using finite elements and infinite elements with exponential decay. Conventional finite elements are used to model the critical regions near the probe and the surface of the solid. Infinite elements are used to represent the farfield conditions of the space surrounding the probe and the solid. The method is first applied to problems with analytic solutions to determine the accuracy of the results obtained using the infinite elements. The response of a capacitive array sensor is then simulated using a line integral which measures the relative change in admittance between flawed and unflawed solids. Examples of capacitive probe responses are given for several parametric variations of the flaw size and dielectric constant of the solid.
A new time‐domain transverse resonance method in solving guided wave problems
Authors: Kuo Chih‐Wen , Itoh Tatsuo
Published: August 2005

A new time‐domain approach based on the frequency‐domain transverse resonance method is proposed to solve guided wave problems. This new method is capable of solving both the two‐dimensional and the three‐dimensional propagation problems. The structure under investigation is cut into individual substructures. Time‐domain Green's functions of each substructure are computed via the analytical inverse Laplace transform of the frequency‐domain Green's functions. The original problem is reconstructed by connecting the cut‐out substructures together through the interface boundary conditions. In order to verify the present approach, the empty rectangular waveguide is used as a comparison. With accurately calculated time‐domain Green's functions, the data obtained are in good agreement with the analytical results.
Analysis of passive microwave devices by using three‐dimensional tangential vector finite elements
Authors: Lee Jin‐Fa
Published: August 2005

There are two major difficulties in applying the finite element method to the analysis of microwave devices in three dimensions. One is to obtain a stable vector finite element which does not generate spurious modes, or non‐physical solutions, in the numerical analysis. The other is to model efficiently the coupling of port regions and the discontinuity region. In this paper, we describe the application of two new finite element techniques, the tangential vector finite element method and the transfinite element method, for modelling three‐dimensional microwave devices. The tangential vector finite element method, unlike the conventional nodal finite element methods, imposes only the tangential continuity of the vector unknown across elements' boundaries. As a result, there would be no spurious modes, and reliable solutions are obtained. The transfinite element method, which combines the modal basis functions and the finite element basis functions through the variational technique, provides an efficient way to model the open boundary nature of the device. To validate the current analysis, a low VSWR waveguide connector and two microstrip low‐pass filters are analysed. Numerical results agree very well with the measurements or those obtained by other methods.
Multiple multipole (MMP) computations of guided waves and waveguide discontinuities
Authors: Hafner Ch.
Published: August 2005

The MMP (multiple multipole) code, that is based on the generalized multipole technique (GMT), offers several features to overcome problems occurring in computations of guided waves and waveguide discontinuities. The most important problems and the corresponding MMP solutions are outlined. The procedure is illustrated with different examples which demonstrate the wide range of applications of the code.
Full‐wave analysis of multiport microstrip discontinuities using a superposition principle and mode‐matching technique
Authors: Bögelsack Frank , Wolff Ingo
Published: August 2005

Accurate full‐wave analysis of shielded microstrip discontinuities, based on a mode‐matching technique and employing Kühn's method is presented. Finite thickness of the strip metallization is taken into account. Examples include bends, T‐junctions, and crossings.
Noise analysis of linear microwave circuits
Authors: Russer Peter , Müller Stefan
Published: August 2005

The fundamentals of computer‐aided noise analysis of linear noisy microwave circuits are presented. The method is based on the description of noisy networks by correlation matrices, and allows the noise analysis of linear circuits of general topology exhibiting arbitrary correlations between the noise sources. The description of linear noisy networks by correlation matrices in different representations, the interconnection of noisy networks and the nodal analysis of noisy networks are treated. The correlation matrices of circuits or subcircuits exhibiting thermal noise may be calculated directly from its admittance matrix. The application of the method for the noise analysis of linear microwave amplifiers is discussed.
Concurrent processing applied to the Exodus Monte Carlo technique
Authors: Fusco V. F.
Published: August 2005

This paper illustrates how problems based on the Probabilistic Potential Method can be solved using a parallelized form of the Exodus Monte Carlo technique. The Exodus technique which does not use random number generation is shown to be more efficient for moderately large problems than the conventional fixed random walk method when programmed in both sequential and concurrent forms.

The technique is illustrated for an electrostatic field problem by using as an example internal potential evaluation for a rectangular coaxial line. The problem geometry is torn into subsections which are then analysed independently using concurrent programming methods. The resulting algorithm is compared with the same problem executed using a conventional sequential algorithm. Computation is achieved by use of an array of transputers. The design of the concurrent algorithm is described in detail and typical results are compared with the fixed random walk Monte Carlo method and also with the finite difference relaxation method. Parallel Fortran is used throughout as the programming language.
Solving the helmholtz equation using multiply propagated fields
Authors: Miller E. K. , Gilbert M. A.
Published: August 2005

Computer models in electromagnetics are based primarily either on integral or on differential equations. The former arise from source integrals using some appropriate Green's function whereas the latter originate from the Maxwell curl equations. Although requiring volume rather than surface sampling even for spatially homogeneous problems, in contrast to integral‐equation (IE) models, differential‐equation (DE) models are geneally a better choice for problems involving spatial inhomogeneities. This is because such problems require volumetric sampling using either approach, but the DE model produces a sparse matrix rather than the full matrix of the IE formulation.

In this paper we describe a new approach based on using multiply propagated fields for numerically solving the banded matrix that results from discretizing the Helmholtz equation. A computer‐time savings of N1/2 and N2/3 for two‐dimensional (2‐D) and three‐dimensional (3‐D) problems, respectively, is made possible, where N is the total number of field samples or unknowns. For even moderate‐size problems where 100 samples per linear dimension are used (N2 = 10,000 and N3 = 1,000,000), the time savings can be of the order of 100 and 10,000 respectively. Another advantage of this procedure, which we call Helmholtz equation multiple propagator (HEMP), is that the radiation or closure condition needed to terminate the spatial solution mesh for exterior problems can be enforced rigorously with essentially no additional computational cost.

The method is illustrated for a 2‐D problem by application to plane‐wave scattering from an infinite, metal, circular cylinder. Results are presented for the mode amplitudes of the scattered field, the induced surface current, and the bistatic far field as obtained from HEMP, and shown to be in good agreement with the analytical results. Although limited here to the simplest possible application in order to establish its feasibility, the approach's advantage would be its applicability to 2‐D and 3‐D problems involving inhomogeneous, penetrable objects.
Transmission‐line modelling in electromagnetic compatibility studies
Authors: Herring J. L. , Naylor P. , Christopoulos C.
Published: August 2005

The transmission‐line modelling (TLM) method is applied to problems in electromagnetic compatibility (EMC). Simulated results for a field‐to‐wire coupling problem are presented, together with comparisons with experimental results. The comparisons confirm the validity of the model and its accuracy. The effects on resonances and field profiles, of placing a measurement dipole antenna inside a screened room are investigated. The resonant structure inside an unlined screened room and the same room when lined with radiation‐absorbing material are investigated using a TLM model. The results confirm that the model developed can be used for the characterization of the entire EMC test environment.
Time‐domain integral equations for EMP analysis
Authors: Gomez R. , Salinas A. , Bretones A. Rubio , Fornieles J. , Martin M.
Published: August 2005

Two computer programs DOTIG1 and DOTIG2 were developed to calculate, in the time‐domain, the interaction of transient electromagnetic pulses (EMP) with perfect electric conductor structures modelled by thin wires (DOTIG1) or patches (DOTIG2). DOTIG1 uses the electric field integral equation and DOTIG2 the magnetic field integral equation. Briefly described below are the numerical procedures used to develop both programs and some results that show their characteristics.
A companion macromodelling approach for the transient analysis of MOS large‐scale integrated circuits
Authors: Turchetti C. , Conti M. , Masetti G.
Published: August 2005

Purpose of this work is to present a new macromodelling approach for the simulation at the device level of large MOS integrated circuits, requiring only marginal modifications to be implemented in the widely used circuit simulator SPICE. This method results in a substantial saving in computing time and guarantees the same accuracy of SPICE. A prototype simulator based on this method has been developed and used to analyse several significant circuits. In addition, since the method is particularly suitable to be implemented in parallel computers, some results obtained with the CRAY‐YMP/432 computer are provided.
Numerical analysis of waveguide apertures radiating into lossy media
Authors: Sibbald C. L. , Stuchly S. S. , Costache G. I.
Published: August 2005

Three numerical methods are applied to the analysis of a rectangular waveguide‐fed aperture radiating into a lossy media. A novel approach, the finite element method with an impedance boundary condition, and two established methods, the moment method and the mode‐matching method, are presented. The methods are compared with respect to accuracy, execution time, memory requirement, and versatility. Four aperture geometries are chosen for detailed study: the full aperture of the rectangular waveguide, and three reduced apertures. The reflection coefficient of the aperture in contact with five known dielectrics is calculated in the frequency range 8·5–11·5 GHz. The theoretical results are validated by measurements performed on an HP8510 network analyser.
Simulation of a class of multiprocessor machines
Authors: Diab Hassan B. , Tabbara Hassan S.
Published: August 2005

This paper presents the simulation of a class of MIMD systems using discrete‐event simulation enhanced by graphics‐oriented reporting. MIMD systems can be specified, modelled and simulated using the package and in turn provide estimates of certain performance indices. A multiserver queueing model is constructed to describe the flow of data and instructions through the various elements of the system. The model is composed of P processors sharing M memory modules through a user‐defined interconnection network. Graphical outputs allow the user to view the state of every processor/memory module over the simulation time with performance estimates such as the relative speedup, throughput, and utilization factor. Moreover, system performance graphs as a function of various system parameters are obtained to indicate the expected system behaviour for various loads and system configurations. The results section shows a case study of the influence of the memory modules' access time on the system performance. The purpose of the results is to aid in the analysis, understanding, design, and performance prediction of a class of MIMD systems in a user‐friendly environment.