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    Squamous cell carcinoma (SCC) is the most common form of oral cancer. Destruction and invasion of mandibular and maxillary bone frequently occurs and contributes to morbidity and mortality. We hypothesized that the bisphosphonate drug zoledronic acid (ZOL) would inhibit tumor-induced osteolysis and reduce tumor growth and invasion in a murine xenograft model of bone-invasive oral SCC (OSCC) derived from an osteolytic feline OSCC. Luciferase-expressing OSCC cells (SCCF2Luc) were injected into the perimaxillary subgingiva of nude mice, which were then treated with 100 µg/kg ZOL or vehicle. ZOL treatment reduced tumor growth and prevented loss of bone volume and surface area but had no effect on tumor invasion. Effects on bone were associated with reduced osteolysis and increased periosteal new bone formation. ZOL-mediated inhibition of tumor-induced osteolysis was characterized by reduced numbers of tartrate-resistant acid phosphatase–positive osteoclasts at the tumor-bone interface, where it was associated with osteoclast vacuolar degeneration. The ratio of eroded to total bone surface was not affected by treatment, arguing that ZOL-mediated inhibition of osteolysis was independent of effects on osteoclast activation or initiation of bone resorption. In summary, our results establish that ZOL can reduce OSCC-induced osteolysis and may be valuable as an adjuvant therapy in OSCC to preserve mandibular and maxillary bone volume and function. Cancer Res; 70(21); 8607–16. ©2010 AACR.

    cancerres.aacrjournals.org


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    Current classification of breast cancers depends in great part on the expression of human epidermal growth factor receptor 2 (HER2), a cell surface tyrosine kinase receptor, and estrogen receptor (ER), the nuclear receptor for estrogen. In addition to reliable biomarkers, these receptors are targets of effective and widely used antitumor drugs. During malignant progression, HER2 and ER can establish an intricate cross-talk. In some cases, HER2 overexpression leads to the downregulation of ER and undermining of anti-ER therapies. A subgroup of HER2-positive breast cancer patients with poor prognosis expresses a heterogeneous collection of HER2 carboxy-terminal fragments (CTF) collectively known as p95HER2. One of these fragments, 611-CTF, is oncogenic in a variety of preclinical models. However, because of the lack of an appropriate tool to specifically analyze its levels in the clinical setting, the value of 611-CTF as a biomarker has not been established yet. Here, we show that 611-CTF induces resistance to antiestrogen therapy and a more pronounced down-modulation of ER than that induced by full-length HER2. To validate this effect in breast cancer samples, we developed specific anti–611-CTF antibodies. With these antibodies, we showed that, whereas the frequency of ER positivity in HER2-positive/611-CTF–negative tumors (72.6%) is similar to that reported for HER2-negative tumors (70–80%), the number of ER-positive tumors in the 611-CTF–positive subgroup is very low (31.2%). These results reveal a mechanism of ER regulation mediated by HER2, which suggests a new strategy to improve responses to endocrine therapy in breast cancer. Cancer Res; 70(21); 8537–46. ©2010 AACR.

    cancerres.aacrjournals.org


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    The p53 tumor suppressor plays a major protective role in tumor prevention by coordinating changes in gene expression that lead to the elimination of cancer cells. Mage-A proteins comprise a family of metastasis-associated transcriptional regulators that potently inhibit p53 function. Here, we show that Mage-A interacts with 3 distinct peptides each of which is located within the DNA binding surface of the core domain of p53 and encompasses amino acids that are critical for site-specific DNA binding. These data suggest that Mage-A may block the association of p53 with its cognate sites in chromatin. Consistent with this idea, silencing of Mage-A expression leads to upregulation of several p53-responsive genes in a p53-dependent manner and stimulates by several fold the interaction of p53 with the p21, MDM2, and PUMA promoters. Notably, these effects can occur in the absence of genotoxic stress, leading in a p53-dependent manner, to cell-cycle delay and increased cell death. These data reveal a novel mechanism by which Mage-A proteins may suppress the p53 transcriptional program during tumor development and highlight the p53/Mage-A interaction as a prospective therapeutic target. Cancer Res; 70(24); 10362–70. ©2010 AACR.

    cancerres.aacrjournals.org


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    You don’t have to give up eating chocolate just because you want to eat healthily. But you do need to choose the right chocolate this Easter, the type that brings positive health benefits and isn’t laden with disastrously unhealthy added fats and sugars. When you’re choosing chocolate Easter eggs this year, remember these facts: Healthy chocolate What does chocolate contain, that’s good for you? The cocoa bean, from which chocolate is made, contains antioxidants, as well as the minerals copper, magnesium and iron, and vitamins A, B1, B2, D and E. Research into chocolate shows that it can improve boost immunity, lower blood pressure and may even help to protect against cancer properties. Dark chocolate can lower cholesterol levels. And the chemical serotonin found in chocolate is a great natural anti-depressant. Choosing good chocolate Sad to say, a lot of mass-produced chocolate bars do not give you all these health benefits. Why? Because they contain very little cocoa solids, and way too much sugar, fats and other additives. Also, manufacturing processes have probably robbed them of what little nutritional value they had. To get the health benefits of chocolate, choose dark varieties, containing 65 per cent or more cocoa solids. These types of chocolate taste rich, with a complex flavour - and provide you with all the health benefits of the cocoa bean. Recognising good chocolate Look for a glossy surface, and dark colour with reddish-black undertones. The chocolate should break crisply when you snap it. Look for brands with no or low added sugar and a cocoa-solid content of 60% or more. Try to find trade brands, and also look out for organic chocolate such as Green & Blacks. How much chocolate to eat Top quality chocolate should be savoured, so don’t wolf those eggs down at a sitting. Make them last over 3-4 days. At other times of year, one or two squares of good chocolate, eaten twice or three times a week, can be part of a healthy diet, as long as you’re also getting plenty of fresh fruits and vegetables. This year, at Easter, remember these chocolate facts, and buy an egg that tastes great and does your health a good turn. Elizabeth Martyn is webmaster at http://healthy-eating-made-easy.com, where she provides information, tips and recipes on using seasonal, fresh ingredients to feed the family healthily and without hassle. Now you know how to choose chocolate, find out how to use it, in delicious chocolate recipes. There are also over 120 easy healthy recipes for family meals on the site. This article may be published electronically or in print in its entirety as long as the author by-lines in the resource box are included and urls kept live. Tweet This Post health.skreviews2.com


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    N-glycosylation is one of the most important forms of protein modification, serving key biological functions in multicellular organisms. N-glycans at the cell surface mediate the interaction between cells and the surrounding matrix and may act as pathogen receptors, making the genes responsible for their synthesis good candidates to show signatures of adaptation to different pathogen environments. Here, we study the forces that shaped the evolution of the genes involved in the synthesis of the N-glycans during the divergence of primates within the framework of their functional network. We have found that, despite their function of producing glycan repertoires capable of evading rapidly evolving pathogens, genes involved in the synthesis of the glycans are highly conserved, and no signals of positive selection have been detected within the time of divergence of primates. This suggests strong functional constraints as the main force driving their evolution. We studied the strength of the purifying selection acting on the genes in relation to the network structure considering the position of each gene along the pathway, its connectivity, and the rates of evolution in neighboring genes. We found a strong and highly significant negative correlation between the strength of purifying selection and the connectivity of each gene, indicating that genes encoding for highly connected enzymes evolve slower and thus are subject to stronger selective constraints. This result confirms that network topology does shape the evolution of the genes and that the connectivity within metabolic pathways and networks plays a major role in constraining evolutionary rates.
    mbe.oxfordjournals.org   ...Read On


    		   
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