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Important Modifier (important + modifier)

Distribution by Scientific Domains

Medical Sciences	80%

Selected Abstracts

INSULIN-LIKE GROWTH FACTOR-I RECEPTOR AS A CANDIDATE FOR A NOVEL MOLECULAR TARGET IN GASTROINTESTINAL CANCERS

DIGESTIVE ENDOSCOPY, Issue 4 2006
Yasushi Adachi
Abnormal activation of growth factor receptors and their signal pathways are required for neoplastic transformation and tumor progression. The concept of targeting specific tumorigenic receptors has been validated by successful clinical application of multiple new drugs, such as those acting against HER2/neu, epidermal growth factor receptor 1, and c-Kit. In this review, we focus on the next promising therapeutic molecular target of insulin-like growth factor (IGF)-I receptor (IGF-Ir). The IGF/IGF-Ir system is an important modifier of cancer cell proliferation, survival, growth, and treatment sensitivity in a number of neoplastic diseases, including human gastrointestinal carcinomas. Preclinical studies demonstrated that downregulation of IGF-Ir signals reversed the neoplastic phenotype and sensitized cells to antitumor treatments. We summarize a variety of ways to disrupt IGF-Ir function. Then, we introduce our strategy of adenoviruses expressing dominant negative of IGF-Ir (IGF-Ir/dn) against gastrointestinal cancers, including stomach, colon, and pancreas. IGF-Ir/dn suppresses tumorigenicity both in vitro and in vivo and increases stressor-induced apoptosis. IGF-Ir/dn expression upregulates chemotherapy-induced apoptosis and these combination therapies with chemotherapy are very effective against tumors in mice. Some drugs blocking IGF-Ir function are now entering clinical trial, thus IGF-Ir might be a candidate for a therapeutic target in several gastrointestinal malignancies. [source]

Rad51 overexpression rescues radiation resistance in BRCA2-defective cancer cells

MOLECULAR CARCINOGENESIS, Issue 2 2009
Erika T. Brown
Abstract Breast cancers with BRCA2 mutations exhibit DNA repair defects and are particularly sensitive to radiation. BRCA2 interacts with Rad51 in a complex manner involving internal BRC and C-terminal TR2 domains which play a key role in homologous recombination. BRCA2 expression also modulates Rad51 protein levels such that Rad51 protein is relatively decreased in BRCA2-defective cancer cells. This is mediated in part through BRCA2's capacity to protect Rad51 from caspase-3 proteolytic degradation. In order to distinguish between functional and expression related roles for BRCA2 we studied the results of Rad51 overexpression in mouse and human cells with inactivating BRCA2 mutations. The results show that overexpression of wild-type Rad51 partially rescues BRCA2 deficiency but that overexpression of a caspase-3 resistant Rad51 completely complements the BRCA2 defect in radiation responsiveness. These results indicate that Rad51 can compensate for some aspects of a BRCA2 gene defect and suggest that Rad51 expression levels may be an important modifier of the BRCA2 defective genotype. © 2008 Wiley-Liss, Inc. [source]

Transforming growth factor-, signaling at the tumor,bone interface promotes mammary tumor growth and osteoclast activation

CANCER SCIENCE, Issue 1 2009
Mitsuru Futakuchi
Understanding the cellular and molecular changes in the bone microenvironment is important for developing novel therapeutics to control breast cancer bone metastasis. Although the underlying mechanism(s) of bone metastasis has been the focus of intense investigation, relatively little is known about complex molecular interactions between malignant cells and bone stroma. Using a murine syngeneic model that mimics osteolytic changes associated with human breast cancer, we examined the role of tumor,bone interaction in tumor-induced osteolysis and malignant growth in the bone microenvironment. We identified transforming growth factor-, receptor 1 (TGF-,RI) as a commonly upregulated gene at the tumor-bone (TB) interface. Moreover, TGF-,RI expression and activation, analyzed by nuclear localization of phospho-Smad2, was higher in tumor cells and osteoclasts at the TB interface as compared to the tumor-alone area. Furthermore, attenuation of TGF-, activity by neutralizing antibody to TGF-, or TGF-,RI kinase inhibitor reduced mammary tumor-induced osteolysis, TGF-,RI expression and its activation. In addition, we demonstrate a potential role of TGF-, as an important modifier of receptor activator of NF-,B ligand (RANKL)-dependent osteoclast activation and osteolysis. Together, these studies demonstrate that inhibition of TGF-,RI signaling at the TB interface will be a therapeutic target in the treatment of breast cancer-induced osteolysis. (Cancer Sci 2009; 100: 71,81) [source]

Effects of predator-induced visual and olfactory cues on 0+ perch (Perca fluviatilis L.) foraging behaviour

ECOLOGY OF FRESHWATER FISH, Issue 2 2006
V. N. Mikheev
Abstract,,, Foraging juvenile fish with relatively high food demands are usually vulnerable to various aquatic and avian predators. To compromise between foraging and antipredator activity, they need exact and reliable information about current predation risk. Among direct predator-induced cues, visual and olfactory signals are considered to be most important. Food intake rates and prey-size selectivity of laboratory-reared, naive young-of-the-year (YOY) perch, Perca fluviatilis, were studied in experiments with Daphnia magna of two size classes: 2.8 and 1.3 mm as prey and northern pike, Esox lucius, as predator. Neither total intake rate nor prey-size selectivity was modified by predator kairomones alone (water from an aquarium with a pike was pumped into the test aquaria) under daylight conditions. Visual presentation of pike reduced total food intake by perch. This effect was significantly more pronounced (synergistic) when visual and olfactory cues were presented simultaneously to foraging perch. Moreover, the combination of cues caused a significant shift in prey-size selection, expressed as a reduced proportion of large prey in the diet. Our observations demonstrate that predator-induced olfactory cues alone are less important modifiers of the feeding behaviour of naive YOY perch than visual cues under daylight conditions. However, pike odour acts as a modulatory stimulus enhancing the effects of visual cues, which trigger an innate response in perch. [source]

Teratogenicity of antiepileptic drugs: role of drug metabolism and pharmacogenomics

ACTA NEUROLOGICA SCANDINAVICA, Issue 1 2007
R. Sankar
The approach to clinical decision-making pertaining to the use of antiepileptic drugs (AEDs) during pregnancy has relied on previous accumulated experience and, since the 1990s, on data from pregnancy registries. The limitations of this process are that no information regarding the chemical attributes of the AED under consideration, nor the role of a number of enzyme systems that are known to interact with foreign compounds to modify their potential for harm, are included. The role of the hepatic mixed function oxidase system may be especially important in conferring teratogenic risk. However, systems such as epoxide hydrolase, glutathione reductase, superoxide dismutase and other toxin-scavenging systems may be important modifiers that lower the risk. Knowledge is also accumulating on the interactions of AEDs with molecular targets such as histone deacetylase and peroxisome proliferator-activated receptors that may play important roles in teratogenesis. While our knowledge of these factors are incomplete, progress can be achieved by beginning to include these concepts in our discussion on the topic and by promoting research that may improve our ability to individualize the analysis of risk for a specific patient with regards to specific AEDs. [source]