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PubMed1997

Molecular genetic pathways to Wilms tumor.

Wilms tumor remains a fascinating model for understanding how genes important in normal human embryogenesis can also contribute, in their mutant form, to cancer development in childhood. The cloning of the first Wilms tumor gene, WT1, in 1989, laid the framework for a model but also emphasized the underlying genetic complexity of this embryonal kidney cancer. Despite longstanding evidence for additional Wilms tumor gene loci, by 1997 very few of these have been cloned and none has yet been proven to be involved in Wilms tumorigenesis in man. However, the potential biological properties of these candidate genes suggest that disregulation of fetal mitogens, such as insulin-like growth factor 2, may be pivotal. Nephrogenesis is clearly sufficiently flexible to absorb many genetic errors. At present, it is unclear how often a simple two mutation model may account for Wilms tumor. Understanding how the various Wilms tumor genes interrelate, if indeed they do, awaits their identification. Piecing together these pathways may eventually lead to logical targets for therapeutic interventions.

Animals↗
PubMed2004

Molecular cues to implantation.

Successful implantation is the result of reciprocal interactions between the implantation-competent blastocyst and receptive uterus. Although various cellular aspects and molecular pathways of this dialogue have been identified, a comprehensive understanding of the implantation process is still missing. The receptive state of the uterus, which lasts for a limited period, is defined as the time when the uterine environment is conducive to blastocyst acceptance and implantation. A better understanding of the molecular signals that regulate uterine receptivity and implantation competency of the blastocyst is of clinical relevance because unraveling the nature of these signals may lead to strategies to correct implantation failure and improve pregnancy rates. Gene expression studies and genetically engineered mouse models have provided valuable clues to the implantation process with respect to specific growth factors, cytokines, lipid mediators, adhesion molecules, and transcription factors. However, a staggering amount of information from microarray experiments is also being generated at a rapid pace. If properly annotated and explored, this information will expand our knowledge regarding yet-to-be-identified unique, complementary, and/or redundant molecular pathways in implantation. It is hoped that the forthcoming information will generate new ideas and concepts for a process that is essential for maintaining procreation and solving major reproductive health issues in women.

Animals↗
PubMed2004

A review of multi-threat medical countermeasures against chemical warfare and terrorism.

The Multi-Threat Medical Countermeasure (MTMC) hypothesis has been proposed with the aim of developing a single countermeasure drug with efficacy against different pathologies caused by multiple classes of chemical warfare agents. Although sites and mechanisms of action and the pathologies caused by different chemical insults vary, common biochemical signaling pathways, molecular mediators, and cellular processes provide targets for MTMC drugs. This article will review the MTMC hypothesis for blister and nerve agents and will expand the scope of the concept to include other chemicals as well as briefly consider biological agents. The article will also consider how common biochemical signaling pathways, molecular mediators, and cellular processes that contribute to clinical pathologies and syndromes may relate to the toxicity of threat agents. Discovery of MTMC provides the opportunity for the integration of diverse researchers and clinicians, and for the exploitation of cutting-edge technologies and drug discovery. The broad-spectrum nature of MTMC can augment military and civil defense to combat chemical warfare and chemical terrorism.

Anti-Inflammatory Agents↗
PubMed2004

Identification of gene expression changes associated with the progression of retinal degeneration in the rd1 mouse.

PURPOSE: One approach to gaining insight into the biological pathways contributing to rod and cone photoreceptor death is to identify patterns of gene expression changes. In the present study, a custom retinal microarray was developed to analyze the rd1 mouse, a well-characterized animal model of human retinal degeneration. METHODS: A microarray was constructed containing cDNA fragments corresponding to genes known or postulated to be involved in normal retinal function, development, and disease. Gene expression in rd1 retina was compared with age-matched control retinas at three time points: the peak of rod degeneration (postnatal day [P]14), early in cone degeneration (P35), and during cone degeneration (P50). Selected microarray results were confirmed with real-time PCR. The cellular distribution of one of the differentially expressed genes, dickkopf 3 (Dkk3), was assessed by in situ hybridization. RESULTS: At each stage of degeneration, there was only limited overlap of the genes that showed increased expression, suggesting the involvement of temporally distinct molecular pathways. Genes active in transport mechanisms and in signaling pathways were differentially expressed during rod degeneration, whereas genes with functions in protein modification and cellular metabolism were differentially expressed during cone degeneration. Increased expression of genes involved in cell proliferation pathways and oxidative stress was observed at each time point. CONCLUSIONS: These microarray results provide clues to understanding the molecular pathways underlying photoreceptor degeneration and indicate directions for future studies. In addition, comparisons of normal and degenerated retina identified numerous genes and ESTs that are potentially enriched in rod photoreceptors.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Stem cells: cross-talk and developmental programs.

The thesis advanced in this essay is that stem cells-particularly those in the nervous system-are components in a series of inborn 'programs' that not only ensure normal development, but persist throughout life so as to maintain homeostasis in the face of perturbations-both small and great. These programs encode what has come to be called 'plasticity'. The stem cell is one of the repositories of this plasticity. This review examines the evidence that interaction between the neural stem cell (as a prototypical somatic stem cell) and the developing or injured brain is a dynamic, complex, ongoing reciprocal set of interactions where both entities are constantly in flux. We suggest that this interaction can be viewed almost from a 'systems biology' vantage point. We further advance the notion that clones of exogenous stem cells in transplantation paradigms may not only be viewed for their therapeutic potential, but also as biological tools for 'interrogating' the normal or abnormal central nervous system environment, indicating what salient cues (among the many present) are actually guiding the expression of these 'programs'; in other words, using the stem cell as a 'reporter cell'. Based on this type of analysis, we suggest some of the relevant molecular pathways responsible for this 'cross-talk' which, in turn, lead to proliferation, migration, cell genesis, trophic support, protection, guidance, detoxification, rescue, etc. This type of developmental insight, we propose, is required for the development of therapeutic strategies for neurodegenerative disease and other nervous system afflictions in humans. Understanding the relevant molecular pathways of stem cell repair phenotype should be a priority, in our view, for the entire stem cell field.

Brain↗
PubMed2005

The RAS/RAF/MEK/ERK and PI3K/AKT signaling pathways present molecular targets for the effective treatment of advanced melanoma.

Malignant melanoma is a highly aggressive tumor of the pigment-producing cells in the skin with a rapidly increasing incidence and a poor prognosis for patients with advanced disease that is resistant to current therapeutic concepts. Therefore, the development of novel strategies for treating melanoma are of utmost importance. In melanoma, both the Ras-Raf-MEK-ERK (MAPK) and the PI3K-AKT (AKT) signaling pathways are constitutively activated through multiple mechanisms, and thus exert several key functions in melanoma development and progression. Conversely, several molecules known to play key roles in melanoma development and progression such as the adhesion molecules E-/N-cadherin, MelCAM and alphavbeta3 integrin are regulated by these pathways and/or activate the same. The results of the research to date indicate that in melanoma both the MAPK and the AKT signaling pathways may represent promising therapeutic targets.

Apoptosis↗
PubMed2004

Sorting pathway and molecular targeting signals for the Arabidopsis peroxin 3.

Peroxin 3 (Pex3p) has been identified and characterized as a peroxisomal membrane protein in yeasts and mammals. We identified two putative homologs in Arabidopsis (AtPex3p, forms 1 and 2), both with an identical cluster of positively charged amino acid residues (RKHRRK) immediately preceding one of the two predicted transmembrane domains (TMD1). In transiently transformed Arabidopsis and tobacco BY-2 suspension-cultured cells, epitope-tagged AtPex3p (form 2) sorted post-translationally from the cytosol directly to peroxisomes, the first sorting pathway described for any peroxin in plants. TMD1 and RKHRRK were necessary for targeting form 2 to peroxisomes and sufficient for directing chloramphenicol acetyltransferase to peroxisomes in both cell types. The N and C termini of AtPex3p (form 2) extend into the peroxisomal matrix, different from mammal and yeast Pex3 proteins. Thus, two authentic peroxisomal membrane-bound Pex3p homologs possessing a membrane peroxisomal targeting signal, the first one defined for a plant peroxin and for any Pex3p homolog, exist in plant cells.

ATP-Binding Cassette Transporters↗
PubMed2006

Molecular aspects of insulin therapy in critically ill patients.

PURPOSE OF REVIEW: This review provides an overview of molecular mechanisms involved in beneficial effects of insulin in insulin resistant critically ill patients. RECENT FINDINGS: Intense insulin therapy reduced morbidity in critically ill patients. Insulin acts by two major molecular pathways: reduction of the inflammation process induced by free fatty acid excess in tissues and decrease of reactive oxygen species production induced by hyperglycemia. By these actions, insulin preserves mitochondrial function, enhances adiponectin secretion and probably modulates AMP-activated protein kinase activity, which in turn depletes lipid depots in tissues and restores glucose uptake and oxidation. Furthermore, it was recently established that insulin prevents microcirculation alteration and subsequent cellular hypoxia by reducing inducible nitric oxide synthase expression and activity in the endothelium. So, insulin beneficial effects in critically ill patients are dependent on metabolic and non-metabolic molecular pathways. SUMMARY: Critically ill patients requiring intensive care for more than a few days have a high risk of death. A tight control of glucose levels by intense insulin therapy reduced morbidity in critically ill patients. Unraveling the molecular mechanisms of insulin will provide new insights into the pathogenesis of multiple organ failure and will allow novel therapeutic strategies to manage patients needing intensive care.

Blood Glucose↗
PubMed2000

The molecular basis of acquired immunodeficiency syndrome-related lymphomagenesis.

Acquired immunodeficiency syndrome (AIDS)-related lymphomas consistently display a B-cell phenotype and are histogenetically related to germinal center (GC) or post-GC B cells in the overwhelming majority of cases. The pathogenesis of AIDS-related lymphoma is a multistep process involving factors provided by the host, as well as alterations intrinsic to the tumor one. Host factors involved in AIDS-related lymphomagenesis include reduced immunosurveillance particularly against Epstein-Barr virus (EBV)-infected B cells, human immunodeficiency virus (HIV)-induced alteration of endothelial functions, B-cell stimulation and selection by antigen, HIV-induced deregulation of several cytokine loops, and possibly the host's genetic background. The molecular pathways of viral infection and lesions of cancer related genes associated with AIDS-related lymphoma vary substantially in different clinicopathologic categories of the disease and highlight the marked degree of biological heterogeneity of these lymphomas. Although the reasons for the heterogeneity of AIDS-related lymphoma are not totally clear, it is generally believed that the host's background selects for which specific molecular pathway of AIDS-related lymphoma is activated in a given patient.

B-Lymphocytes↗
PubMed2005

The molecular biology of esophageal adenocarcinoma.

BACKGROUND: Barrett's esophagus is an acquired metaplastic change that occurs in the distal esophagus secondary to chronic gastroesophageal reflux. This premalignant condition forms the most important risk factor for developing esophageal adenocarcinoma, which is an extremely aggressive tumor with a 5-year survival rate of less than 25%. Carcinomas that arise in the setting of Barrett's esophagus are thought to develop as part of the metaplasia-dysplasia-carcinoma sequence. OBJECTIVE: To review the current knowledge on the genomic alterations involved in the development of Barrett's esophagus and its progression to dysplasia and/or cancer. RESULTS: Several changes in gene structure, gene expression, and protein structure are associated with the progression of Barrett's esophagus to adenocarcinoma. Accumulation of these changes seems to be essential, rather than the exact sequence of these changes. Multiple molecular pathways are involved and interact with each other. Alterations in tumor suppressor genes, amongst which p53 and p16, are early events in the metaplasia-dysplasia-adenocarcinoma sequence, followed by loss of cell cycle checkpoints. Ongoing genomic instability leads to cumulative genetic errors and thereby the generation of multiple clones of transformed cells. CONCLUSIONS: Within the multistep process of esophageal adenocarcinogenesis, to date no single molecular marker came forward able to predict who will and who will not develop cancer in the setting of Barrett's esophagus. Instead, panels of markers need to be developed in the future allowing to indicate disease progression. Identification of crucial molecular pathways involved in esophageal adenocarcinogenesis would ultimately improve therapy and facilitate development of new treatment strategies.

Adenocarcinoma↗
PubMed2006

Genetics of aging: implications for drug discovery and development.

Aging is not a passive activity, but an actively regulated metabolic process. Specific genes have been identified that regulate aging, although aging, and consequently longevity, is only partially under genetic influence. It is also possible to increase life span by environmental modification; for example, caloric restriction can increase life span. Because human life span is long, directly studying aging in humans is impractical. Fortunately, significant insights into aging can be achieved by studying short-lived organisms, such as yeast, worms, and fruit flies. Many of the molecular pathways regulating aging in these lower organisms are conserved in mammals and overlap with pathways regulating metabolism. For example, an insulin-growth hormone signaling system has been implicated in regulating aging and longevity in both worms and mammals. Furthermore, the dysregulation of glucose homeostasis is a hallmark of aging in humans. In fact, type 2 diabetes, a disease of glucose homeostasis, can be conceptualized as a form of accelerated aging. Consistent with this, aging and diabetes are both common risk factors for a wide range of diseases. Because aging and diabetes are intimately related at a molecular level, diabetes may be able to provide the link between disease treatment (eg, diabetes) and the prevention of age-related diseases. If specific molecular pathways controlling the rate of aging can be modulated genetically, then perhaps they can be modulated pharmacologically. These insights may ultimately have an important impact on the discovery and development of drugs to both treat and prevent a wide range of diseases.

Aging↗
PubMed2005

The molecular genetics of breast cancer: the contribution of comparative genomic hybridization.

Comparative genomic hybridization (CGH) has been the technique of choice over the last 10 years for mapping DNA copy number changes in human tumors. Here we review the literature to demonstrate how CGH has contributed to the comprehension of molecular aspects of breast tumorigenesis. At least two distinct molecular pathways of breast cancer have been characterized that show a strong correlation with histological grade. It seems that grade I invasive ductal carcinomas (IDCs) arise from well-differentiated ductal carcinoma in situ (DCIS), whereas grade III IDCs come from poorly differentiated DCIS. In addition, dedifferentiation from a low- to a high-grade breast cancer has proven an unlikely phenomenon. CGH has been instrumental in dissecting distinct molecular pathways toward breast malignancy and in establishing a direct relationship between genotype and clinical pathological features.

Breast↗
PubMed2000

No major difference in K-ras and p53 abnormalities in sporadic and hereditary nonpolyposis colorectal adenomas.

K-ras and p53 gene mutations are known to occur in high frequencies in sporadic colorectal cancers, but findings are inconsistent in hereditary nonpolyposis colorectal cancer (HNPCC). We compared K-ras codon 12 and 13 gene mutations and p53 protein overexpression in 48 HNPCC (positive for Amsterdam criteria) and 59 sporadic colorectal adenomas, to examine whether they may represent similar or different molecular pathways to cancer. In sporadic adenomas K-ras mutations were detected in 32% and p53 overexpression in 31% of the cases. Similarly, K-ras mutations and p53 overexpression were both found in 25% of HNPCC adenomas. The frequencies of these abnormalities were not significantly different between HNPCC and sporadic adenomas. When taking differences in adenoma size into account, the frequencies were even more similar. In conclusion, these results suggest a similar molecular pathway to adenomas in HNPCC and sporadic carcinogenesis, with respect to involvement of K-ras and p53.

Adenomatous Polyps↗
PubMed2002

Anatomical pathways and molecular mechanisms for plasticity in the barrel cortex.

The barrel cortex has yielded a wealth of information about cortical plasticity in recent years. Barrel cortex is one of the few cortical areas studied so far where plasticity can be examined from birth through to adulthood. This review looks at plasticity mechanisms in three periods of life: early post-natal development, adolescence and adulthood. Separate consideration is given to depression and potentiation mechanisms. Plasticity can be induced in barrel cortex by whisker deprivation. Single whisker experience leads to expansion of the area of cortex responding to the spared whisker. In early post-natal life, plasticity occurs in thalamocortical pathways, while later in adolescence, intracortical pathways become more important. Ablation of the spared whisker's barrel prevents expression of plasticity in the cortex. A row of lesions between the spared and an adjacent barrel prevents expression of plasticity in the adjacent barrel. This evidence, together with latency of response data and an analysis of pathways capable of inducing long-term potentiation (LTP) within barrel cortex, leads to the view that horizontal and/or diagonal pathways between barrels are responsible for plasticity expression. The mouse has become the most commonly mutated mammalian species and has a well-developed barrel cortex. Therefore, mutations can be used to study the role of particular molecules in experience-dependent plasticity of barrel cortex. Through this work, it has become clear that the major post-synaptic density protein, alpha-CaMKII, and its T286 autophosphorylation site are essential for experience-dependent plasticity. This points to a major role for excitatory transmission in cortical plasticity and raises the possibility that LTP like mechanisms are involved. Furthermore, transgenic mice carrying a reporter gene for CRE have provided evidence that CRE-mediated gene expression is also involved in barrel cortex plasticity. This view is supported by studies on alpha/delta CREB knockouts, and provides a starting point for studying the role of gene expression in experience-dependent cortical plasticity.

Age Factors↗
PubMed2003

Induction of apoptosis in human bladder cancer cells in vitro and in vivo caused by FTY720 treatment.

PURPOSE: FTY720 is a unique immunosuppressant that induces apoptosis in activated lymphocytes but not in other hematopoietic cells. We examined whether FTY720 has anticancer effects on human bladder cancer cells by inducing apoptosis and we investigated its molecular pathway. MATERIALS AND METHODS: We used the 3 human bladder cancer cell lines T24, UMUC3 and HT1197, and the human fibroblast derived cell line CRL-2096 (American Type Tissue Collection, Rockville, Maryland) in this study. The difference in drug susceptibility to FTY720 in cancer cells and fibroblasts was examined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and cell growth assays. FTY720 induced apoptosis was determined by morphological analysis under light and electron microscopy, and DNA electrophoresis, and its molecular pathway was evaluated by Western blot analysis focusing on the p42/p44 mitogen activated protein kinase pathway. We then tested the in vivo effect of this agent using 2 mouse models of human bladder cancer xenograft. RESULTS: FTY720 treatment in vitro induced selective apoptosis in cancer cells at a concentration of less than 10 microM. Morphological analysis revealed features characteristic of apoptosis, including small cytoplasm with fragmented nuclei and condensed chromatin. DNA electrophoresis confirmed apoptosis, as evidenced by a distinct oligosomal ladder. Western blot analysis revealed that the agent significantly inhibited hepatocyte growth factor induced p42/p44 mitogen activated protein kinase activity. The in vivo anticancer effect was clearly confirmed by significantly decreased tumor growth without notable side effects in the 2 xenograft models. CONCLUSIONS: FTY720 treatment may induce selective apoptosis in vitro as well as in vivo in cancer cells. We suggest that FTY720 is a potent and clinically applicable anticancer agent for bladder cancer.

Animals↗
PubMed2005

Small animal positron emission tomography in food sciences.

Positron emission tomography (PET) is a 3-dimensional imaging technique that has undergone tremendous developments during the last decade. Non-invasive tracing of molecular pathways in vivo is the key capability of PET. It has become an important tool in the diagnosis of human diseases as well as in biomedical and pharmaceutical research. In contrast to other imaging modalities, radiotracer concentrations can be determined quantitatively. By application of appropriate tracer kinetic models, the rate constants of numerous different biological processes can be determined. Rapid progress in PET radiochemistry has significantly increased the number of biologically important molecules labelled with PET nuclides to target a broader range of physiologic, metabolic, and molecular pathways. Progress in PET physics and technology strongly contributed to better scanners and image processing. In this context, dedicated high resolution scanners for dynamic PET studies in small laboratory animals are now available. These developments represent the driving force for the expansion of PET methodology into new areas of life sciences including food sciences. Small animal PET has a high potential to depict physiologic processes like absorption, distribution, metabolism, elimination and interactions of biologically significant substances, including nutrients, 'nutriceuticals', functional food ingredients, and foodborne toxicants. Based on present data, potential applications of small animal PET in food sciences are discussed.

Animal Nutritional Physiological Phenomena↗
PubMed2002

Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers.

BACKGROUND: Germline mutations in BRCA1 and BRCA2 are responsible for 5%-10% of epithelial ovarian cancers, but the molecular pathways affected by these mutations are unknown. We used complementary DNA (cDNA) microarrays to compare gene expression patterns in ovarian cancers associated with BRCA1 or BRCA2 mutations with gene expression patterns in sporadic epithelial ovarian cancers and to identify patterns common to both hereditary and sporadic tumors. METHODS: Tumor samples from 61 patients with pathologically confirmed epithelial ovarian adenocarcinoma with matched clinicopathologic features were studied, including 18 with BRCA1 founder mutations, 16 with BRCA2 founder mutations, and 27 without either founder mutation (termed sporadic cancers). The cDNA microarrays contained 7651 sequence-verified features. Gene expression data were analyzed with a modified two-sided F test, with P<.0001 considered statistically significant. The expression level of six genes was also studied with reverse transcription-polymerase chain reaction. RESULTS: The greatest contrast in gene expression was observed between tumors with BRCA1 mutations and those with BRCA2 mutations; 110 genes showed statistically significantly different expression levels (P<.0001). This group of genes could segregate sporadic tumors into two subgroups, "BRCA1-like" and "BRCA2-like," suggesting that BRCA1-related and BRCA2-related pathways are also involved in sporadic ovarian cancers. Fifty-three genes were differentially expressed between tumors with BRCA1 mutations and sporadic tumors; six of the 53 mapped to Xp11.23 and were expressed at higher levels in tumors with BRCA1 mutations than in sporadic tumors. Compared with the immortalized ovarian surface epithelial cells used as reference, several interferon-inducible genes were overexpressed in the majority of tumors with a BRCA mutation and in sporadic tumors. CONCLUSIONS: Mutations in BRCA1 and BRCA2 may lead to carcinogenesis through distinct molecular pathways that also appear to be involved in sporadic cancers. Sporadic carcinogenic pathways may result from epigenetic aberrations of BRCA1 and BRCA2 or their downstream effectors.

Adenocarcinoma, Clear Cell↗
PubMed2000

The TGF-beta family member derrière is involved in regulation of the establishment of left-right asymmetry.

Although a number of genes that are involved in the establishment of left-right asymmetry have been identified, earlier events in the molecular pathway developing left-right asymmetry remain to be elucidated. Here we present evidence suggesting that the transforming growth factor-beta family member derrière is involved in the development of left-right asymmetry in Xenopus embryos. Ectopic expression of derrière on the right side can fully invert cardiac and visceral left-right orientation and nodal expression, and expression of a dominant-negative form of derrière on the left side can partially randomize the left-right orientation and nodal expression. Moreover, while expression of the dominant-negative derrière does not inhibit the activity of Vg1 directly, it can rescue the altered left-right orientation induced by Vg1. Vg1 can induce derrière in animal cap explants. These results suggest that derrière is involved in earlier molecular pathways developing the left-right asymmetry.

Animals↗