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PubMedDate not supplied

Differential expression of progression-related genes in the evolution of superficial to invasive transitional cell carcinoma of the bladder.

It is generally accepted that there are dichotomous biologic pathways that lead to the development of either: i) superficial papillary (Ta) transitional cell carcinoma (TCC) or ii) precursor lesions to muscle-invasive (CIS, T1) TCC and muscle-invasive (> or =T2) TCC. We investigated the expression of several progression-related genes to characterize the phenotype of these tumors within these divergent developmental pathways. Using a colorimetric in situ hybridization technique, we examined the expression of mRNAs of several progression-related genes in archival, pathologic specimens from 77 patients with bladder TCC. These genes included basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), interleukin (IL)-8, matrix metalloproteinase (MMP)-9, and epidermal growth factor receptor (EGFR). Relative gene expression was quantified using image analysis. Gene expression was normalized using poly (dT) and the expression of each factor in a panel of specimens of normal urothelium. Patients were stratified according to disease stage, and the level of gene expression among the stratified groups was compared. VEGF, bFGF, IL-8, and MMP-9 expression was increased in muscle-invasive compared with superficial papillary tumors, (p<0.05) and VEGF expression was increased in muscle-invasive tumors compared with CIS specimens (p<0. 05). bFGF, IL-8, and EGFR expression was increased in CIS specimens compared with superficial papillary tumors (p<0.05). The pattern of expression of bFGF, VEGF, IL-8, MMP-9, and EGFR represent the divergent developmental pathways in the pathogenesis of bladder TCC, which characterizes superficial or invasive bladder cancer. bFGF, IL-8, and EGFR appear to be upregulated in early precursor lesions (CIS), whereas VEGF appears to be upregulated at later stages in the development of muscle-invasive TCC.

Carcinoma in Situ↗
PubMed2003

Novel quantitative trait loci controlling development of experimental autoimmune encephalomyelitis and proportion of lymphocyte subpopulations.

The B10.RIII mouse strain (H-2(r)) develops chronic experimental autoimmune encephalomyelitis (EAE) upon immunization with the myelin basic protein 89-101 peptide. EAE was induced and studied in a backcross between B10.RIII and the EAE-resistant RIIIS/J strain (H-2(r)), and a complete genome scan with microsatellite markers was performed. Five loci were significantly linked to different traits and clinical subtypes of EAE on chromosomes 1, 5, 11, 15, and 16, three of the loci having sex specificity. The quantitative trait locus on chromosome 15 partly overlapped with the Eae2 locus, previously identified in crosses between the B10.RIII and RIIIS/J mouse strains. The loci on chromosomes 11 and 16 overlapped with Eae loci identified in other mouse crosses. By analyzing the backcross animals for lymphocyte phenotypes, the proportion of B and T cells in addition to the levels of CD4(+)CD8(-) and CD4(-)CD8(+) T cells and the CD4(+)/CD8(+) ratio in spleen were linked to different loci on chromosomes 1, 2, 3, 5, 6, 11, and 15. On chromosome 16, we found significant linkage to spleen cell proliferation. Several linkages overlapped with the quantitative trait loci for disease phenotypes. The identification of subphenotypes that are linked to the same loci as disease traits could be most useful in the search for candidate genes and biological pathways involved in the pathological process.

Animals↗
PubMed2007

Metastatic cancer cells from c-erbB-2 negative primary breast cancer maintain the original c-erbB-2/HIF1alpha phenotype.

The expression of c-erbB-2 and HIF1alpha proteins is linked with an aggressive tumor phenotype and poor survival in breast cancer. In the present study we investigated whether this ominous effect is a result of c-erbB-2/HIF1alpha expressing clone appearance within the primary tumor, by examining the c-erbB-2/HIF1alpha expression status in the primary tumor, node metastasis and cancer cells invading into the lymphovascular spaces. The metastasizing cancer cell clones, whether migrating to the lymph nodes or entering into the systemic circulation maintained the original c-erbB-2/HIF1alphaphenotype of the primary tumor. Migrating c-erbB-2/HIF1alpha negative tumors do so through activation of alternative biologic pathways and not through positive clone appearance. These results strongly support the concept that targeted therapies against c-erbB-2 or against HIF1alpha can be guided with precision by the primary tumor c-erbB-2/HIF1alpha status without demanding the detection of the metastatic tumor phenotype.

Breast Neoplasms↗
PubMed2006

Ubiquitin transfer from the E2 perspective: why is UbcH5 so promiscuous?

Protein ubiquitination is a regulatory process that influences nearly every aspect of eukaryotic cell biology. Pathways that range from cell-cycle progression and differentiation to DNA repair to vesicle budding all rely on regulated modification of target proteins by ubiquitin. Target proteins can be tagged by a single molecule of ubiquitin or modified by ubiquitin polymers that can vary in length and linkage specificity, and these variations influence how ubiquitination signals are interpreted. Surprisingly, little is understood regarding mechanisms of protein ubiquitination and how poly-ubiquitin chains are synthesized. Simple models to explain ubiquitin transfer have dominated the literature, but recent work suggests basic assumptions as to how proteins assemble to facilitate protein ubiquitination and poly-ubiquitin chain synthesis should be reexamined. This is particularly necessary for understanding the roles played by E2 ubiquitin-conjugating enzymes, a central protein component in all ubiquitin transfer reactions. In particular, UbcH5, a canonical E2 protein that is active in a broad number of in vitro ubiquitin transfer reactions, is capable of binding ubiquitin noncovalently on a surface distinct from its active site. This unique property allows activated UbcH5 approximately Ub complexes to self-assemble and has a profound influence on poly-ubiquitin chain synthesis.

Amino Acid Sequence↗
PubMed2006

Post-transcription meets post-genomic: the saga of RNA binding proteins in a new era.

Gene expression is regulated by a complex series of events that take place both at the transcriptional and post-transcriptional levels. The mechanisms and factors involved in transcriptional regulation are relatively well understood, whereas post-transcriptional regulation, in comparison, is still a poorly appreciated process. RNA binding proteins (RBPs) are the key regulators of all post-transcriptional events (RNA splicing, stability, transport and translation). Essentially, in order to improve our knowledge in post-transcriptional regulation, we need to elucidate the mechanisms employed by RBPs to control gene expression. The combination of genomic tools with traditional biochemical approaches generated novel technologies, like ribonomics. The application of these novel technologies not only had a profound impact in the study of RBPs but also created the ground work necessary for the identification of post-transcriptional gene networks; a selected group of mRNAs associated with a particular function or biological pathway/ process that is regulated by the same RBP. In this review article, we explore the latest achievements and discuss future challenges that lie ahead in the RBP world.

Gene Expression Regulation↗
PubMed1999

Isolation and characterization of a rat homologue of the human tuberous sclerosis 1 gene (Tsc1) and analysis of its mutations in rat renal carcinomas.

In the Eker rat, a germ-line mutation in the homologue of the human tuberous sclerosis gene (Tsc2) causes renal cell carcinomas (RCs) with a complete penetrance in all heterozygotes. Tsc2 mutations have also been found in a subset of chemically induced non-Eker rat RCs. Because tuberous sclerosis patients with alteration of either of the two predisposing genes (TSC1 and TSC2) show identical symptoms, the products of these two genes are thought to be involved in a common biological pathway. In this study, to analyze the possible overlap between the functions of Tsc2 and Tscl gene products, we isolated and characterized a rat homologue of the TSC1 gene (Tsc1). The rat Tsc1 gene, which has an identical exon-intron structure to that of human TSC1 and is localized on rat chromosome 3, has been shown to encode a protein (hamartin) that is highly homologous to the human counterpart with an approximately 86% amino acid sequence identity. Using PCR-single-strand conformational polymorphism analysis, we identified two splicing donor site mutations in one chemically induced rat RC (1 of 15). This suggests that alterations of the Tsc1 gene may be involved in the development of a subset of rat RCs.

Adult↗
PubMed1999

Surgery, pain, and immune function.

Research findings have demonstrated that surgery negatively affects immune function. Pain also has deleterious effects on immune function. Most research in this area has been conducted on animals. Psychoneuroimmunology provides the framework for this article. Psychoneurological phenomena, such as stress, depression, and pain, can influence immune system functioning through neuroendocrine pathways. Biological and behavioral processes appear to be closely related and need to be jointly considered when planning and providing anesthesia care. The anesthesia planning process increasingly involves aggressive assessment and treatment of postoperative pain, which may benefit immune function.

Anesthesia↗
PubMed2000

PLAG1 fusion oncogenes in lipoblastoma.

Lipoblastomas are pediatric neoplasms resulting from transformation of adipocytes. These benign tumors are typically composed of adipose cells in different stages of maturation within a variably myxoid matrix, and they contain clonal rearrangements of chromosome band 8q12. Because lipoblastomas resemble embryonic adipose tissue, characterization of their transforming mechanisms might reveal biological pathways in physiological adipogenesis. Herein, we demonstrate that lipoblastoma chromosome 8q12 rearrangements bring about promoter-swapping events in the PLAG1 oncqgene. We show that the hyaluronic acid synthase 2 (HAS2) or collagen 1 alpha 2 (COL1A2) gene promoter regions are fused to the entire PLAG1 coding sequence in each of four lipoblastomas. PLAG1 is a developmentally regulated zinc finger gene whose tumorigenic function has been shown previously only in epithelial salivary gland cells. Our findings reveal that PLAG1 activation, presumably resulting from transcriptional up-regulation, is a central oncogenic event in lipoblastoma.

Adipose Tissue↗
PubMed1975

Toxicological and clinical aspects of cyanide metabolism.

This contribution deals with the occurrence of cyanide and its biological pathways in the body. Especially possibilities of detoxification are pointed out. Intoxications are caused by acute and chronical cyanide uptake. Tobacco amblyopia, retrobulbar neuritis in pernicious anaemia, Leber's optic atrophy, Nigerian nutritional neuropathy, and sterility in female heavy smokers are attributed to cyanide intoxication. Various methods for treating acute and chronic cyanide intoxication are discussed.

Acute Disease↗
PubMedDate not supplied

Cellular therapy: an introduction.

Cellular therapy is defined as the transfer, to the intact host, of living cells with the intent of introducing new host functions or correcting defective functions. The appeal and the promise of cellular therapy derive from the ability to manipulate, ex vivo, cellular and molecular biologic pathways in a way that is not possible in the intact organism.

Cell Transplantation↗
PubMed2001

[From the physiopathology of thrombosis to therapeutic targets].

Structural changes in blood vessels associated with atherosclerosis are at the onset of arterial thrombosis. Thrombi form at the sites of plaque rupture. Plateletrich masses accumulate in the vessel lumen perturb blood flow, thereby aggravating ischemic syndromes. Other local modifications include the recruitment of cells with inflammatory and immunologic potential, showing how complicated this process is. The demonstration that aspirin lowered the number of thrombotic events was an important step in proving the value of anti-platelet therapy. Since then, newer strategies involving drugs acting on the fibrinogen receptor (the GPIIb-IIIa complex) or on ADP receptors have evolved largely as a result of the increased knowledge of the biological pathways of platelet aggregation. These drugs have given superior results in many international trials and their usefulness in interventional cardiology has been proven. Such encouraging progress also incites efforts to find new and improved targets for anti-platelet therapy as well as testing new associations of existing anti-platelet drugs which may also be used with anticoagulant therapies, and in the future, be combined with drugs directly preventing restenosis.

Arteriosclerosis↗
PubMed2002

BAFF: a novel therapeutic target for autoimmunity.

Autoimmunity results from a break in self-tolerance involving humoral and/or cell-mediated immune mechanisms. One pathological consequence of a failure in central and/or peripheral tolerance is the generation of autoantibodies and subsequent formation of complement-fixing immune complexes that contribute to tissue damage. Prevailing pharmacological strategies for treating autoimmune diseases involve the use of broad-acting immunosuppressants that with long term use have associated toxicities. The current drive in drug development is towards therapies that target a specific biological pathway or pathogenic cell population. Recent discovery of the BAFF-mediated B-cell survival pathway provides a unique opportunity for developing focused intervention for autoreactive B-cell function.

Animals↗
PubMed1999

Coping with Stress: Neuroendocrine Reactions and Implications for Health.

A new stress model, the Allostatic Load Model, refers to the ability to achieve stability through change. The various biological functions activated during stress serve an important role in the organism's adaptation to the environment by protecting and restoring the body but may, under certain conditions, also have health damaging consequences. Two different psychoneuroendocrine stress systems are of particular interest: (1) the sympathetic adrenal medullary (SAM) and (2) the hypothalamic pituitary adrenocortical (HPA) systems. Sustained activation of the SAM system with overexposure to epinephrine (adrenaline) and norepinephrine (noradrenaline) is considered to contribute to the development of cardiovascular disease (CVD). Chronic stress exposure influencing the HPA-axis is associated with metabolic changes which also increase the risk of CVD but, in addition, also contribute to impaired immune function, diabetes, depressive symptoms and cognitive disturbances. The present paper is focused on the possible biological pathways between environmental stress and somatic illness, including the role of environmental stress for the development of musculoskeletal disorders. It is concluded that the SAM and the HPA systems play an important role in linking environmental stress to various negative health outcomes and that knowledge about these psychobiological pathways is of considerable importance for the possibilities to prevent and treat environmentally induced ill health.

Journal Article↗
PubMed2003

Chemotherapy for non-small-cell lung cancer. Part 2: Advanced disease.

The prognosis of patients with advanced non-small-cell lung cancer (NSCLC) remains poor. Systemic chemotherapy prolongs survival in this group of patients and palliates symptoms compared to best supportive care alone but more effective therapeutic strategies are needed. Novel agents that selectively target biological pathways of tumor growth offer hope of improving response and survival rates beyond what has been achieved with standard cytotoxic chemotherapy. Part 2 of this two-part article addresses the role of chemotherapy in locally advanced and advanced NSCLC, including the use of novel agents, considerations in elderly patients, and studies of second-line treatment.

Antineoplastic Agents↗
PubMed2003

Profiling of genes differentially expressed between fetal liver and postnatal liver using high-density oligonucleotide DNA array.

The liver is an essential organ in humans not only for the production and storage of energy but also for detoxification of chemical compounds, but knowledge about changes in the gene expression profile in the human liver during the prenatal and postnatal periods is limited. Profiling of genes differentially expressed between the fetal liver (FL) and the postnatal liver (PNL) is one of the methods to investigate candidates affecting the difference in biological characteristics between FL and PNL. To identify genes differentially expressed between FL and PNL (childhood and adult liver), we analyzed the gene expression profiles across 9 FL and 14 PNL samples using a high-density oligonucleotide DNA array. Using Mann-Whitney U test followed by k-nearest-neighbors (supervised learning method) and hierarchical clustering (unsupervised learning method) algorithms, we found 33 genes clearly discriminating between the FL group and PNL group. The functional classification of the 33 genes identified was related to several kinds of biological pathways, regulating the cell cycle (PCNA, CDC7L1, CCND3, YWHA1, PKMYT1), DNA replication and repair (RFC4, RECQ2, PCNA, NAP1L1), cell growth (IGF2, IGFBP2, PRSS11), hormonal signals (AR, SRD5A1, NR1I3), and cellular metabolism (E2-EPF, WWP1, CYP2C9, CYP2E1, CYP2A6, CYP2A7, CYP2A13, CYP4F2, CYP3A4, DDT). The results presented herein provide evidence of a differential expression profile of genes regulating the cell cycle, DNA replication and repair, cell growth, regulation of hormonal signals, and cellular metabolism, between FL and PNL in humans. The 33 genes identified in this study are suggested to be useful markers clearly discriminating between FL and PNL using the gene expression profile.

Adult↗
PubMed2003

Genome-wide analysis of gene expression associated with MYCN in human neuroblastoma.

Molecular mechanisms through which MYCN expression contributes to the malignant phenotype of neuroblastoma are unknown. We performed a genome-widegene expression analysis of 40 well-characterized neuroblastic tumors and 12 cell lines to identify genes and biological pathways associated with MYCN expression. Gene expression was validated by reverse transcription-PCR and immunohistochemistry using tissue arrays. Two hundred twenty-two of 62,839 oligonucleotide probe sets detected expression of genes that were strongly associated with MYCN expression. Differentially expressed genes included examples of known oncogenes, genes associated with neural differentiation, and genes related to cell proliferation. Expression of a subset of these genes was altered after transfection of a neuroblastoma cell line, SK-N-ER, with a MYCN expressing gene construct when protein synthesis was inhibited and have consensus MYCN binding E-box sequences in their promotor regions, suggesting they represent direct targets. Several novel genes/expressed sequences were identified as overexpressed and most likely coamplified with MYCN in a subset of cases. A classification model to identify neuroblastomas with high levels of MYCN expression was developed based on expression profiles. The identification of coexpressed and coamplified genes associated with MYCN overexpression in neuroblastoma suggests biochemical pathways that contribute to the malignant behavior of these tumors and forms a basis for molecular classification.

Cell Nucleus↗
PubMed2003

Identification and functional clustering of global gene expression differences between human age-related cataract and clear lenses.

PURPOSE: Age-related cataract is a multi-factorial disease with a poorly understood etiology. Numerous studies provide evidence that the human eye lens has evolved specific regulatory and protective systems to ameliorate lens damage associated with cataract. Other studies suggest that the presence of cataract is associated with the altered expression of specific genes including metallothionein IIa, osteonectin, transglutaminase 2, betaig-h3, multiple ribosomal proteins, ADAM9, and protein phosphatase 2A. Here, we sought to identify further gene expression changes that are associated with cataract and to cluster the identified genes into specific biological pathways. METHODS: Oligonucleotide microarray hybridization was used to analyze the full complement of gene expression differences between lens epithelia isolated from human age-related cataract relative to clear lenses. The expression levels of a subset of the identified genes were further evaluated by semi-quantitative RT-PCR. The identified genes were functionally clustered into specific categories and the probability of over-representation of each category was determined using the computer program EASE. RESULTS: 412 transcripts were observed to be increased and 919 transcripts were observed to be decreased by 2 fold or more in lens epithelia isolated from age-related cataract relative to clear lenses. Of these, 74 were increased and 241 were decreased at the 5 fold level or greater. Seventeen genes selected for further confirmation exhibited similar trends in expression when examined by RT-PCR using both the original and separately prepared clear and cataract RNA populations. Functional clustering of the identified genes using the EASE bioinformatics software package revealed that, among others, transcripts increased in cataract are associated with transcriptional control, chromosomal organization, ionic and cytoplasmic transport, and extracellular matrix components while transcripts decreased in cataract are associated with protein synthesis, defense against oxidative stress, heat-shock/chaperone activity, structural components of the lens, and cell cycle control. CONCLUSIONS: These data suggest that cataract is associated with multiple previously identified and novel changes in lens epithelial gene expression and they point to numerous pathways likely to play important roles in lens protection, maintenance, and age-related cataract.

Aged↗
PubMed2003

Novel bone-targeted Src tyrosine kinase inhibitor drug discovery.

Bone-targeted Src tyrosine kinase (STK) inhibitors have recently been developed for the treatment of osteoporosis and cancer-related bone diseases. The concept of bone targeting derives from bisphosphonates, and from the evolution of such molecules in terms of therapeutic efficacy for the treatment of bone disorders. Interestingly, some of the earliest bisphosphonates were recognized for their ability to inhibit calcium carbonate precipitation (scaling) by virtue of their affinity to chelate calcium. This chelating property was subsequently exploited in the development of bisphosphonate analogs as inhibitors of the bone-resorbing cells known as osteoclasts, giving rise to breakthrough medicines, such as Fosamax (for the treatment of osteoporosis) and Zometa (for the treatment of osteoporosis and bone metastases). Relative to these milestone achievements, there is a tremendous opportunity to explore beyond the limited chemical space (functional group diversity) of such bisphosphonates to design novel bone-targeting moieties, which may be used to develop other classes of promising small-molecule drugs affecting different biological pathways. Here, we review studies focused on bone-targeted inhibitors of STK, a key enzyme in osteoclast-dependent bone resorption. Two strategies are described relative to bone-targeted STK inhibitor drug discovery: (i) the development of novel Src homology (SH)-2 inhibitors incorporating non-hydrolyzable phosphotyrosine mimics and exhibiting molecular recognition and bone-targeting properties, leading to the in vivo-effective lead compound AP-22408; and (ii) the development of novel ATP-based Src kinase inhibitors incorporating bone-targeting moieties, leading to the in vivo-effective lead compound AP-23236. In summary, AP-22408 and AP-23236, which differ mechanistically by virtue of blocking Src-dependent non-catalytic or catalytic activities in osteoclasts, exemplify ARIAD Pharmaceuticals' structure-based design of novel bone-targeted lead compounds, successfully achieving in vivo proof-of-concept and providing the framework for the next-generation molecules that have further advanced, in terms of preclinical studies, for the treatment of osteoporosis and related bone diseases, including osteolytic bone metastases.

Animals↗