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Untitled Document
CANCER GENOMICS & PROTEOMICS
Volume 3, Number
3-4, May-August 2006
| CONTENTS |
PAGE |
RNA Interference with siRNA. H. JOYCE, I. BRAY, M. CLYNES
(Dublin, Ireland) |
127 |
| Genomic Instability and Breast Cancer Progression. S. INGVARSSON (Reykjavik, Iceland) |
137 |
| Design of Nanoparticles as Drug Carriers for Cancer Therapy. J. ZHANG, C.Q. LAN, M. POST, B. SIMARD, Y. DESLANDES, T.H. HSIEH (Ottawa, ON, Canada) |
147 |
Molecular Replacement for Cancer Metabolic and Mitochondrial Dysfunction, Fatigue and the Adverse Effects of Cancer Therapy. G.L. NICOLSON,
K.A. CONKLIN (Huntington Beach; Los Angeles, CA, USA) |
159 |
Gene Expression Profiles of CD133-positive Fractions Predict the Survival of Individuals with Acute Myeloid Leukemia. Y. YAMASHITA, J. OHASHI,
Y. HIRAI, Y.L. CHOI, R. KANEDA, S.-I. FUJIWARA, Y. ARAI, M. AKUTSU, C. TSUTSUMI, Y. MIYAZAKI, K. USUKI, M. TERAMURA, K. MITANI,
Y. KANO, M.C. O’NEILL, A. URABE, M. TOMONAGA, K. OZAWA,
H. MANO (Tochigi; Tokyo; Nagasaki; Saitama, Japan; Baltimore, MD, USA) |
169 |
Effect of Vitamin E on Cytochrome P450 mRNA Levels in Cultured Hepatocytes (HepG2) and in Rat Liver. C. HUNDHAUSEN, J. FRANK,
G. RIMBACH, E. STOECKLIN, P.Y. MULLER, L. BARELLA (Kiel, Germany; Basel, Switzerland) |
183 |
Association of HLA-DRB1 and -DQB1 with Classic Kaposi’s Sarcoma in Mainland Italy. F.R. GUERINI, C. AGLIARDI, R. MANCUSO, L.BRAMBILLA, R. BIFFI, S. FERRUCCI, L. ZANETTA, M. ZANZOTTERA, M. BRAMBATI,
V. BONESCHI, P. FERRANTE (Milan, Italy) |
191 |
| Gene Expression Microarray Technology: Some Applications in Lung Cancer Research. L. BREEN, L. O’ DRISCOLL, M. CLYNES (Dublin, Ireland) |
197 |
| Metastasis Promoter S100A4 is a Potential Molecular Therapeutic Target. G.V. SHERBET (Newcastle upon Tyne, UK; Huntington Beach, CA, USA) |
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| Laser Microdissection: Application to Carcinogenesis. F.E. AHMED (Greenville, NC, USA) |
217 |
Considerations Regarding the Use of Blood Samples in the Proteomic Identification of Biomarkers for Cancer Diagnosis. C.V. SAPAN,
R.L. LUNDBLAD (Chapel Hill, NC, USA) |
227 |
| Methylation Inactivates Expression of CDP-diacylglycerol Synthase 1 (CDS1) in Hepatocellular Carcinoma. K.-T. YEH, K.-P. TANG, Y.-L. CHEN, W.-W. SU, Y.-F. WANG, J.-G. CHANG (Taichung; Changhua; Taipei; Taiwan, ROC) |
231 |
Reduced Expression of the Cell Cycle Regulator p27Kip1 within the Invasion Front of Renal Cell Carcinomas Proved to be a Significant Marker for Disease-specific Survival. A.S. MERSEBURGER, E. VON DER HEYDE,
A. KOBIERSKI, U. WEGENER, M. MENGEL, U. JONAS, J. SERTH,
M. KUCZYK (Tübingen; Hannover, Germany) |
239 |
Oligonucleotide Array Comparative Genomic Hybridization Profiling of Neuroblastoma Tumours. P. SCARUFFI, S. MORETTI, S. COCO,
K. MAZZOCCO, R. DEFFERRARI, D. ALBINO, S. BONASSI, G.P. TONINI (Genoa, Italy) |
245 |
Proteomics in Cancer Research and Diagnosis; An Update. V. IFANDI,
S.E. SLADE, M. KHAN (Coventry, UK) |
253 |
Relationship among Genetic Alterations, DNA Content, and Clinicopathological Features in Primary Lung Adenocarcinomas. K. UEDA,
Y. KANEDA, M. HAYASHI, M. JINBO, T.-S. LI, K. HAMANO (Yamaguchi, Japan) |
265 |
Correlative Analysis of DNA Methyltransferase Expression and Promoter Hypermethylation of Tumor Suppressor Genes in Hepatocellular Carcinoma. T.-W. LAM, J.H.-M. TONG, K.-F. TO, A. CHAN, C.-T. LIEW, P.B.-S. LAI,
N. WONG (Shatin, SAR Hong Kong, China) |
271 |
CANCER GENOMICS & PROTEOMICS 3: 147-158 (2006)
Design of Nanoparticles as Drug Carriers for Cancer Therapy
HJIN ZHANG1, CHRISTOPHER Q. LAN1, MICHAEL POST2,
BENOIT SIMARD3, YVES DESLANDES2 and TSUNG HAN HSIEH1
1Department of Chemical Engineering, University of Ottawa, Ottawa, Ontario, K1N 6N5;
2Institute for Chemical Process and Environmental Technology and
3Steacie Institute for Molecular Sciences, National Research Council Canada, Ottawa,
Ontario, K1A 0R6, Canada.
Abstract: This review explores the recent chemotherapeutic work on drug delivery using nanoparticles as carriers for the targeted treatment of cancer. Compared to direct drug delivery, delivery through a carrier can increase the efficacy of a drug, but decrease the side-effects by utilizing the enhanced permeability and retention (EPR) effect and tumor-specific targeting. The search for efficient and safe transport vehicles (carriers) to achieve better drug availability at the target site has been a challenging yet exciting area of research. Current interest focuses on the colloidal nanoparticles (diameter <500 nm), including the biodegradable polymer- and liposome-systems, bioconjugating with antitumor drugs. These biocompatible nanoparticles, with an enlarged surface area-volume ratio can overcome non-cellular and cellular-based mechanisms of resistance and increase the selectivity of drugs towards cancer cells, while reducing their toxicity towards normal tissues. This review focuses on the evolution of nanoparticles as carriers for anticancer drug delivery, with emphasis on the biocompatible magnetic nanohybrids.
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CANCER GENOMICS & PROTEOMICS 3: 271-278 (2006)
Correlative Analysis of DNA Methyltransferase Expression and Promoter Hypermethylation of Tumor Suppressor Genes in Hepatocellular Carcinoma
TAI-WAI LAM1, JOANNA H.-M. TONG1, KA-FAI TO1, ANDREW CHAN2,
CHOONG-TSEK LIEW1, PAUL B.-S. LAI3 and NATHALIE WONG1
Departments of 1Anatomical and Cellular Pathology and 3Surgery,
The Chinese University of Hong Kong,
Prince of Wales Hospital, Shatin, N.T., SAR Hong Kong;
2Biotechnology and Development Versitech Ltd.,
The University of Hong Kong, Pokfulam Road, SAR Hong Kong, China.
Abstract: Background: Promoter hypermethylation of tumor suppressor genes (TSGs) is a common phenomenon in liver carcinogenesis, although the controlling mechanism remains unclear. Materials and Methods: The mRNA expression of DNA methyltransferases (DNMT1, 2, 3a, 3b and splice variants 3b3 and 3b4) and methyl-CpG binding protein (MBD2) were quantitated in 51 liver specimens (41 hepatocellular carcinoma (HCC), 1 cholangiocarcinoma, 1 macroregenerative nodule and 8 HCC cell lines) and the expression levels were correlated with the promoter methylation status of 14 TSG, including APC, RASSF1A, SOCS-1, GSTP1, E-cadherin, p14, p15, p16, DAP-kinase, HIC1, MGMT, TIMP-3, hMLH1 and HLTF. Results: Up-regulations of DNMT1, DNMT2, DNMT3a, DNMT3b4 and MBD2 were suggested in more than 40% of the cases. In particular, the overexpression of DNMT3b and the splice variant DNMT3b3 were identified in as many as 91% and 97.8% of cases, respectively. Using methylation-specific PCR, the most frequently methylated TSGs were APC (90.2%), RASSF1A (86.3%), SOC-1 (74.5%), GSTP1 (72.5%), E-cadherin (64.7%) and p16 (58%). Statistical correlations did not suggest the DNMTs and MBD2 expressions in association with cumulative methylated index in individual cases, but increased expression levels of DNMT2 and DNMT3a showed significant association with the hypermethylation of GSTP1 (p=0.014) and DAP-kinase (p=0.006), respectively. Furthermore, the analysis with clinicopathological data indicated aberrant DAP-kinase methylation was significantly associated with advanced stage T3/T4 HCC tumors (p=0.032) and that p16 hypermethylation was distinct more prevalent in tumors arising from a cirrhotic background (p=0.005). Conclusion: Our study indicated that DNMT deregulations are common in liver cancers and the existence of a relationship between DNMT2 and DNMT3a overexpression and promoter hypermethylation of candidate tumor suppressor genes in HCC.
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CANCER GENOMICS & PROTEOMICS 3: 227-230 (2006)
Considerations Regarding the Use of Blood Samples in the Proteomic Identification of Biomarkers for Cancer Diagnosis
CHRISTINE V. SAPAN and ROGER L. LUNDBLAD
Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599-7525, U.S.A.
Abstract: Blood is the most common source of biomarkers for use in the diagnosis and prognosis of malignant disease. Utilizing proteomic technology for biomarker identification offers greatly increased sensitivity. Such an increase in sensitivity requires precise sample preparation to eliminate any bias in analysis. Here, issues concerning the use of blood, plasma and serum for proteomic analysis are summarized.
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CANCER GENOMICS & PROTEOMICS 3: 191-196 (2006)
Association of HLA-DRB1 and -DQB1 with Classic Kaposi's Sarcoma in Mainland Italy
FRANCA ROSA GUERINI1, CRISTINA AGLIARDI1, ROBERTA MANCUSO1,
LUCIA BRAMBILLA2, RENATO BIFFI1, SILVIA FERRUCCI2, LORENZO ZANETTA1, MILENA ZANZOTTERA1, MARINELLA BRAMBATI2, VINICIO BONESCHI2 AND PASQUALE FERRANTE3
1Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi Fond.
IRCCS, S. Maria Nascente, Via Capecelatro 66, 20148 Milan;
2Institute of Dermatology Sciences of the University of Milan and
IRCCS Ospedale Maggiore, Milan;
3Chair of Virology, Department of Biomedical Sciences and Technology,
University of Milan, Via F.lli Cervi 93, 20090 Segrate, Milan, Italy .
Abstract: Classic Kaposi's sarcoma (CKS) is a multifocal vascular mesenchymal tumour of unknown origin. Human herpesvirus 8 (HHV8) is now considered to be strongly involved, as a necessary co-factor, though insufficient for development of the disease. Additional identified risk factors include environmental factors, personal habits and genetic susceptibility, with different loci suspected of being risk factors for CKS. Since various human leukocyte antigen (HLA) patterns have been suggested as potential host-related co-factors, the distribution of these alleles was studied in 41 CKS patients, 285 geographically-matched healthy controls (HC) and 17 HHV8-positive controls. Molecular typing of HLA was performed using the polymerase chain reaction sequence-specific primer method (SSP-PCR). Frequency distribution was evaluated by the Chi-squared test with Yates' correction. Odds ratios (OR) and respective 95% confidence limits (CI) were calculated. A significantly higher frequency of HLA-DRB1*13 was observed among the CKS patients (20.7%) compared to the HC (9.8%) (p<0.01; OR: 2.32; 95%CI: 1.21-4.41). Overall, these results indicated that HLA-DRB1*13 may play a role in the development of CKS, while HLA-DQB1*0604 allele involvement occurs in linkage disequilibrium with HLA-DRB1*13. To our knowledge, this is the first study documenting an HLA-DRB1 and -DQB1 loci association with CKS development in the mainland Italian population.
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CANCER GENOMICS & PROTEOMICS 3: 183-190 (2006)
Effect of Vitamin E on Cytochrome P450 mRNA Levels in Cultured Hepatocytes (HepG2) and in Rat Liver
CHRISTOPH HUNDHAUSEN1, JAN FRANK1, GERALD RIMBACH1,
ELISABETH STOECKLIN2, PATRICK Y. MULLER2 and LUCA BARELLA2
1Institute of Human Nutrition and Food Science, Christian-Albrechts-University,
Hermann-Rodewald-Strasse 6, D-24118 Kiel, Germany;
2DSM Nutritional Products, Research and Development, P.O. Box 3255,
CH-4002 Basel, Switzerland.
Abstract: Vitamin E has been described in the literature as a regulator of gene expression. The gene-regulatory activity of vitamin E with regard to genes encoding cytochrome P450 (CYP) enzymes, which play a pivotal role both in the metabolism of xenobiotics and vitamin E, has not been conclusively characterised. The objective of the current study was, therefore, to elucidate the short- and long-term effects of natural and synthetic vitamin E on CYP gene expression using Affymetrix GeneChip® technology. To this end, HepG2 cells were incubated with 0, 10, 30, 80 and 300 ìM RRR-á-tocopheryl acetate (natural vitamin E) or all rac-á-tocopheryl acetate (synthetic vitamin E) for 7 days and the mRNA of CYP genes was quantified. The expression of only one (CYP20A1) of 14 CYP genes with detectable mRNA levels was dose-dependently up-regulated. No differences in gene-regulatory activity were observed between RRR- and all rac-á-tocopheryl acetate. To study the role of vitamin E in CYP gene expression in vivo, Fisher 344 rats were randomly assigned to either a vitamin E-enriched (60 mg/kg RRR-á-tocopheryl acetate) or -deficient (1.7 mg/kg RRR-á-tocopheryl acetate) diet for 290 days. Neither in the vitamin E-enriched, nor in the vitamin E-deficient rats, were significant changes in the liver CYP, mRNA levels observed. In conclusion, our data indicated that vitamin E does not appear to modulate cytochrome P450 mRNA expression in HepG2 cells or in rats.
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CANCER GENOMICS & PROTEOMICS 3: 197-202 (2006)
Gene Expression Microarray Technology: Some Applications in Lung Cancer Research
LAURA BREEN, LORRAINE O'DRISCOLL AND MARTIN CLYNES
National Institute for Cellular Biotechnology, Dublin City University, Glasnevin,
Dublin 9, Ireland.
Abstract: Gene expression microarray technology has the unique advantage of allowing the study of the expression of thousands of genes simultaneously in cancer cells and tissues. This review provides an overview of how microarrays have been applied to many areas of cancer research, such as biomarker identification, improved diagnostics and targeted therapy, focusing in particular on lung cancer studies. Advances made in the field of microarrays, especially in interpretation of microarray data, have the potential to significantly increase our understanding of the causes and progression of different types of cancer and, hence, to enhance the treatment of patients suffering from these diseases.
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CANCER GENOMICS & PROTEOMICS 3: 169-182 (2006)
Gene Expression Profiles of CD133-positive Fractions Predict the Survival of Individuals with Acute Myeloid Leukemia
YOSHIHIRO YAMASHITA1, JUN OHASHI2, YUJI HIRAI3, YOUNG LIM CHOI1,
RURI KANEDA1, SHIN-ICHIRO FUJIWARA1,4, YUKIHIRO ARAI5,
MIYUKI AKUTSU6, CHIZUKO TSUTSUMI7, YASUSHI MIYAZAKI7,
KENSUKE USUKI8, MASANAO TERAMURA3, KINUKO MITANI5,
YASUHIKO KANO6, MICHAEL C. O'NEILL9, AKIO URABE8,
MASAO TOMONAGA7, KEIYA OZAWA4 and HIROYUKI MANO1,10
Divisions of 1Functional Genomics and 4Hematology, Jichi Medical University,
Tochigi 329-0498;
2Department of Human Genetics, Graduate School of Medicine, University of Tokyo,
Tokyo 113-0033;
3Department of Hematology, Tokyo Women's Medical University, Tokyo 162-8666;
5Department of Hematology, Dokkyo University School of Medicine, Tochigi 321-0293;
6Tochigi Cancer Center, Tochigi 320-0834; 7Department of Hematology and Molecular Medicine Unit, Nagasaki University, Nagasaki 852-8523;
8Department of Hematology, Kanto Medical Center NTT EC, Tokyo 141-8625, Japan; 9Department of Biological Sciences, University of Maryland, Baltimore,
Maryland 21250, U.S.A.;
10CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan.
Abstract: Background: The current classification of acute myeloid leukemia (AML) is based predominantly on the cytogenetic abnormalities and morphology of the malignant blasts and is not always helpful for optimization of the treatment strategy. Gene expression profiles of AML blasts were obtained and a gene expression-based means of predicting the outcome of AML patients was developed. Materials and Methods: CD133-positive hematopoietic stem cell-like fractions were purified from the bone marrow of 99 individuals with AML-related disorders and the expression profiles of ~33,000 human transcripts in these cells were characterized with the use of DNA microarray analysis. Results: The comparison of the expression data between individuals with short- or long-term survival by application of Cox's proportional hazard model led to the identification of four genes, whose expression patterns discriminated between the two groups. The gene expression-based stratification (GES) system, based on a combination of the karyotype approach and the risk index calculated from the expression levels of the four outcome predictor genes, was developed to separate the patients into subgroups with distinct prognoses. Conclusion: DNA microarray analysis of purified fractions provides novel stratification schemes for AML based on the expression profiles of a handful of genes.
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CANCER GENOMICS & PROTEOMICS 3: 137-146 (2006)
Genomic Instability and Breast Cancer Progression
SIGURDUR INGVARSSON
Institute for Experimental Pathology, University of Iceland at Keldur,
112 Reykjavik, Iceland.
Abstract: The genome of breast tumour cells is considered to be unstable, as reflected by multiple chromosomal and gene abnormalities. The molecular mechanism of genomic instability progression in breast cancer is poorly understood, but recent data suggest that mutated or overexpressed proteins affect the genome in several ways, including an abnormal number of centrosomes, inefficient DNA repair and unwanted telomere maintenance. Among these proteins are p53, Brca1, Brca2, Aurora kinase A, Myc and telomerase. The involved molecular networks include co-regulation with cell cycle checkpoints. p53 has been relatively well studied and is considered to be a guardian of the genome integrity. Myc seems to affect tumour pathogenesis in several ways, including increased proliferation and immortalisation of the cancer cells and induction of genomic instability. Aurora kinase A has been shown to control the centrosome number of cells and the segregation of the correct chromosomes to the daughter cells during mitosis. Genomic instability is high in some hereditary breast cancer, particularly in tumours of Brca1- and Brca2- mutation carriers, a finding that is in line with their role in DNA repair.
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CANCER GENOMICS & PROTEOMICS 3: 217-226 (2006)
Laser Microdissection: Application to Carcinogenesis
FARID E. AHMED
Department of Radiation Oncology, Leo W. Jenkins Cancer Center, The Brody School of Medicine (BSOM) at East Carolina University (ECU), Greenville, NC, U.S.A.
Abstract: Although several microscopic techniques are available for separation of small groups of cells from surrounding tissue, the high energy concentrated into a small area, the easy control of beam position and the lack of direct contact with the material to be dissected make lasers the best option for a large scale microdissection. Laser microdissection technology provides samples of homogenous cells, or even a single cell, isolated from whole tissue or cytological materials to ensure that biological molecules such as DNA, RNA or protein are undamaged during sampling in order to define the molecular and cellular biology of diseases, including cancer. This article reviews the various techniques of laser microdissection including capture, catapulting and gravity-assisted, in addition to a cheaper alternative (ultrasound). Methods of sample preparation, including contamination eradication, enrichment, fixation, staining and extraction of biological molecules are also reviewed. Application of genomic and proteomic technology to laser microdissected cells has revolutionized the classification of solid cancer and enhanced its diagnosis, prognosis and drug discovery.
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CANCER GENOMICS & PROTEOMICS 3: 203-216 (2006)
Metastasis Promoter S100A4 is a Potential Molecular Therapeutic Target
G.V. SHERBET
School of Electrical, Electronic and Computer Engineering,
University of Newcastle upon Tyne, U.K.;
The Institute for Molecular Medicine, Huntington Beach CA, U.S.A.
Abstract: S100A4, a member of the S100 family of proteins involved in calcium signalling, has come into the fore in recent years on account of its close relationship with tumour development and progression; therefore, S100A4 commends itself as a prime therapeutic target. The phenotypic effects of S100A4 are generated via diverse signalling pathways encompassing and incorporating the functions of cell cycle regulators, growth factor receptors, extracellular matrix components, and the inducers of angiogenesis and lymphangiogenesis. By virtue of this, S100A4 signalling can be specifically targeted to down-regulate the phenotypic activities that contribute to the growth, invasion and metastasis of cancer. Here, the discussion has focused on the signalling pathways that S100A4 uses, with a view to identifying the most effective targets to which drugs can be designed and specifically directed. Some approaches to the problem of inhibiting or deregulating the functions of S100A4, to control invasion and metastasis have been identified. S100A4 could provide a wide channel to control the growth, invasion and secondary spread of cancer and, thus, amply rationalise and validate it as an important therapeutic target.
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CANCER GENOMICS & PROTEOMICS 3: 231-238 (2006)
Methylation Inactivates Expression of CDP-diacylglycerol Synthase 1 (CDS1) in Hepatocellular Carcinomay
KUN-TU YEH1,2, KAI-PING TANG1, YAO-LI CHEN3, WEI-WEN SU4,
YU-FEN WANG2 AND JAN-GOWTH CHANG1,5,6
1Department of Molecular Medicine, China Medical University, Taichung, Taiwan;
2Department of Pathology, 3Division of General Surgery and Department of Surgery and
4Division of Gastroenterology and Hepatology, Department of Internal Medicine,
Changhua Christian Hospital, Changhua, Taiwan;
5Taipei Institute of Pathology, Taipei, Taiwan;
6Department of Biological Science and Technology, Asia University,
Taichung, Taiwan, R.O.C.
Abstract: Background: CDS1 is an enzyme required for the regeneration of the signaling molecule phosphatidylinositol-4,5-bisphosphate (PIP2) from phosphatidic acid. These phosphoinositides and their cleavage products are a class of second messengers, which are involved in cell growth and oncogenesis. The role of CDS1 in the development of hepatocellular carcinoma (HCC) was explored. Materials and Methods: The expression of CDS1 in 52 HCC and paired non-cancer tissues was examined by real-time quantitative reverse transcription-polymerase chain reaction analysis. Results: The results showed that the expression levels of CDS1 significantly decreased in HCC. However, no mutation was found within the coding region. Interestingly, in the promoter area of the CDS1 gene, most of the CpG sites were methylated in 73% of the cancer tissues; in contrast, only a partial methylation of CpG was found in 50% of the non-cancer tissues. Conclusion: Our results suggested that the down-regulated CDS1 expression in HCC was due to the inactivation of the CDS1 gene by methylation and that the differential expression correlated to the ratio of CpG sites being methylated.
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CANCER GENOMICS & PROTEOMICS 3: 159-168 (2006)
Molecular Replacement for Cancer Metabolic and Mitochondrial Dysfunction, Fatigue and the Adverse Effects of Cancer Therapy
GARTH L. NICOLSON1 and KENNETH A. CONKLIN2
1Department of Molecular Pathology, The Institute for Molecular Medicine,
Huntington Beach, CA 92647;
2Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA,
Los Angeles, CA 90095, U.S.A.
Abstract: During cancer treatment drug-induced oxidative stress can limit the effectiveness of therapy and cause a number of side effects such as fatigue, nausea, vomiting and diarrhea, as well as more serious adverse effects including cardiomyopathy, peripheral neuropathy, hepatotoxicity and pulmonary fibrosis. Many of these adverse effects are due to oxidative stress-mediated damage to normal tissues. Antioxidant administration and molecular replacement can mitigate the damage to normal tissues and reduce the adverse effects of cancer therapy without loss of therapeutic potential. For example, loss of efficiency in the electron transport chain caused by membrane peroxidation and reduction in coenzyme Q10 can occur during cytotoxic therapy. Molecular replacement of membrane lipids and enzymatic cofactors administered as nutritional supplements with antioxidants can prevent oxidative membrane damage and reduction of cofactors in normal tissues, restore mitochondrial and other cellular functions and reduce the adverse effects of cancer therapy. Recent clinical trials using cancer and non-cancer patients with chronic fatigue have shown the benefit of Molecular Replacement Therapy plus antioxidants in restoring mitochondrial electron transport function, reducing moderate to severe chronic fatigue and protecting mitochondrial and other cellular structures and enzymes from oxidative or other damage due to cytotoxic therapy
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CANCER GENOMICS & PROTEOMICS 3: 245-252 (2006)
Oligonucleotide Array Comparative Genomic Hybridization Profiling of Neuroblastoma Tumours
PAOLA SCARUFFI1, STEFANO MORETTI2, SIMONA COCO1,
KATIA MAZZOCCO3, RAFFAELLA DEFFERRARI3,
DOMENICO ALBINO3, STEFANO BONASSI2
and GIAN PAOLO TONINI1
1Unit of Translational Paediatric Oncology and 2Molecular Epidemiology,
National Institute for Cancer Research (IST), Genoa;
3Laboratory of Italian Neuroblastoma Foundation,
Advanced Biotechnology Centre, Genoa, Italy .
Abstract: Neuroblastoma (NB) is one of the most common paediatric solid tumours and displays a broad variety of genomic alterations. Recently, array comparative genomic hybridization (aCGH) has emerged as a novel technology enabling high-resolution detection of DNA copy number aberrations. We have previously optimized a custom cDNA-array to detect MYCN gain and chromosome 1p36 loss, two molecular markers of tumour aggressiveness in NB. In spite of the power of this technique, the production of cDNA arrays is time-consuming and expensive. In the present study, we report a printed 55-mer oligonucleotide aCGH with the aim of increasing the resolution and the sensitivity of our platform. The oligonucleotide probes, designed and validated for expression profiling, reproducibly assessed amplifications, even when using whole genomes as targets. On the contrary, this microarray platform seems to offer little accuracy in measuring genomic single-copy deletions. Therefore, an oligo library specifically designed for aCGH should improve the performance of oligonucleotide aCGH in accurately mapping unbalanced chromosomal abnormalities.
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CANCER GENOMICS & PROTEOMICS 3: 253-264 (2006)
Proteomics in Cancer Research and Diagnosis; An Update
VASILIKI IFANDI1,2, SUSAN E. SLADE3 AND MICHAEL KHAN1,2
1Biomedical Research Institute and 3Biological Mass Spectrometry and Proteomics Facility,
Department of Biological Sciences, University of Warwick, Coventry, CV4 7AL;
2Clinical Sciences Research Institute, Warwick Medical School, Walsgrave Hospital,
Coventry, CV2 2DX, U.K.
Abstract: The availability of reference genomes for, amongst others, man and mouse, coupled with the ability to manipulate the expression of single genes/proteins in model organisms, has fuelled a revolution in biomedical research. Non-invasive diagnosis and treatment, disease prediction and personalised medicine are all expected developments to result from the genomics revolution. Building on this resource, we are now able to employ high-throughput techniques for profiling the expression of thousands of genes/proteins in tissues, body fluids and even individual cells and have evolved a whole new science-systems biology that seeks to reveal the biological information in such data-rich studies. Given that proteins are the ultimate biological effectors within the cell and, due to various post-translational regulatory steps, are more varied and numerous than the protein-encoding genes, researchers are increasingly progressing from genome and gene transcript analyses to powerful proteomics techniques that offer a more complete picture of cell behaviour. Cancer research and clinical oncology, in particular, have been at the forefront in adapting and exploiting the new biology. The road map to cancer is being described for many individual cancers, tumours are profiled for prognostic and therapeutic purposes and biomarkers are sought to help with early diagnosis and disease monitoring. This review will focus on proteomics and its application to cancer research and diagnosis.
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CANCER GENOMICS & PROTEOMICS 3: 239-244 (2006)
Reduced Expression of the Cell Cycle Regulator p27Kip1 within the Invasion Front of Renal Cell Carcinomas Proved to be a Significant Marker for Disease-specific Survival
A.S. MERSEBURGER1, E. VON DER HEYDE2, A. KOBIERSKI2, U. WEGENER3,
M. MENGEL4, U. JONAS2, J. SERTH2 AND M. KUCZYK1
1Department of Urology, Eberhard - Karls - University Tubingen, Tubingen;
Departments of 2Urology, 4Pathology and 3Clinical Cancer Registry,
Hannover University Medical School, Hannover, Germany.
Abstract: Background: The expression of the negative cell cycle regulator p27Kip1 is frequently found to be deregulated in various human cancer types. Whether the expression of p27Kip1 can be used as a prognostic marker for renal cell cancer patients still remains to be clarified. Therefore, in the present investigation the expression of protein within different tissue areas obtained from renal cell carcinomas, their invasion front and corresponding histologically benign renal parenchyma was determined and statistically correlated with several tumor and patient characteristics including the disease-specific long-term survival following surgical treatment. Patients and Methods: For analysis of p27Kip1 expression in 420 tumor nephrectomy specimens obtained from 420 consecutively included patients, tissue microarrays were used comprising 1260 tissue samples each obtained from the tumor itself, the invasive front as well as the non-malignant surrounding parenchyma. A sufficient follow-up after surgical therapy was available in 251 cases In total, 88 out of 251 patients (35%) had died from tumor progression after a median follow-up of 138 (36-240) months. Results: In univariate survival analysis, decreased expression of p27Kip1 within tissue cores obtained from the invasion front was significantly correlated with the patients' disease-specific long-term survival (p=0.02, log rank test). In contrast, expression of p27Kip1 within the primary tumors was not identified to reveal any prognostically important information. In Cox regression analysis, histological stage and grade (p<0.01), the presence of regional lymph node (p<0.01) or distant metastases at the time of surgery (p<0.01) as well as decreased expression of p27Kip1 (p=0.04) within the invasion front tissue samples independently predicted the disease-specific long-term survival following surgery. Conclusion: Our analysis demonstrated that p27Kip1 is heterogeneously expressed in renal cell carcinomas. Moreover, the results of the present study supports the prognostic value of p27Kip1 protein expression for patients diagnosed with renal cell carcinoma.
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CANCER GENOMICS & PROTEOMICS 3: 265-270 (2006)
Relationship among Genetic Alterations, DNA Content, and Clinicopathological Features in Primary Lung Adenocarcinomas
KAZUHIRO UEDA, YOSHIKAZU KANEDA, MASATARO HAYASHI,
MITSUTAKA JINBO, TAO-SHENG LI AND KIMIKAZU HAMANO
Division of Thoracic Surgery, Department of Medical Bioregulation,
Yamaguchi University School of Medicine, Yamaguchi, Japan.
Abstract: Background: Only fragmentary information is available about the genomic imbalances affecting the malignant potential of lung cancers. Patients and Methods: Chromosomal DNA sequence copy number aberrations (DSCNAs) and DNA content (ploidy status) were examined in 34 resected tumor specimens, using comparative genomic hybridization and laser scanning cytometry, respectively. Results: Twenty-seven tumors showed DNA aneuploidy. Gains of 9q22-33 and 10q26-qter and loss of 15q14-qter were the significant indicators of lymph node metastasis. These DSCNAs were identified only in aneuploid tumors. Aneuploid tumors with any of these DSCNAs were associated with a worse prognosis than those not associated with any of these DSCNAs. The DNA index was a significant prognosticator in aneuploid tumors, although it was not dependent on the level of genetic alterations. Conclusion: Clinically-relevant genetic alterations were identified predominantly in aneuploid tumors. The DNA content also affected the prognosis of patients with aneuploid tumors. Thus, a comprehensive genomic study of aneuploid lung adenocarcinomas should be of great clinical value.
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CANCER GENOMICS & PROTEOMICS 3: 127-136 (2006)
RNA Interference with siRNA
HELENA JOYCE, ISABELLA BRAY and MARTIN CLYNES
National Institute for Cellular Biotechnology, Dublin City University, Glasnevin,
Dublin, Ireland.
Abstract: Over the last decade, RNA interference has emerged as an effective mechanism for silencing gene expression. This ancient cellular antiviral response can be used to allow specific inhibition of the function of any chosen target gene, including those involved in diseases such as cancer, AIDS and hepatitis. It has become an invaluable research tool to aid in the identification of novel genes involved in disease processes. It has advanced from the use of synthetic RNA for the endogenous production of small hairpin RNA by plasmid and viral vectors, and from transient inhibition in vitro to longer-lasting effects in vivo. However, as with antisense and ribozymes, the efficient delivery of siRNA into cells is currently the limiting factor to successful gene expression inhibition in vivo. This review gives an overview of the mechanism of action of siRNA and its use in cancer research. It also discusses the successes and shortcomings of this new gene knockdown tool.
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