Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been shown to be increased in liver fibrosis development both in murine experimental models and human samples. However, the direct role of TIMP-1 during liver fibrosis development has not been defined. To address this issue, we developed transgenic mice overexpressing human TIMP-1 (hTIMP-1) in the liver under control of the albumin promoter/ enhancer. A model of CCl(4)-induced hepatic fibrosis was used to assess the extent of fibrosis development in TIMP-1 transgenic (TIMP-Tg) mice and control hybrid (Cont) mice. Without any treatment, overexpression of TIMP-1 itself did not induce liver fibrosis. There were no significant differences of pro-(alpha1)-collagen-I, (alpha2)-collagen-IV, and alpha-smooth muscle actin (alpha-SMA) mRNA expression in the liver between TIMP-Tg and Cont-mice, suggesting that overexpression of TIMP-1 itself did not cause hepatic stellate cell (HSC) activation. After 4-week treatment with CCl(4), however, densitometric analysis revealed that TIMP-Tg-mice had a seven-fold increase in liver fibrosis compared with the Cont-mice. The hepatic hydroxyproline content and serum hyaluronic acid were also significantly increased in TIMP-Tg-mice, whereas CCl(4)-induced liver dysfunction was not altered. An active form of matrix metalloproteinases-2 (MMP-2) level in the liver of TIMP-Tg-mice was decreased relative to that in Cont-mice because of the transgenic TIMP-1. Immunohistochemical analysis revealed that collagen-I and collagen-IV accumulation was markedly increased in the liver of CCl(4)-treated TIMP-Tg-mice with a pattern similar to that of alpha-SMA positive cells. These results suggest that TIMP-1 does not by itself result in liver fibrosis, but strongly promotes liver fibrosis development.

Tumor invasion, angiogenesis and metastasis involve secretion of proteolytic enzymes and cell migration into blood vessels. Tumor cells are capable of degrading the extracellular matrix via a proteolytic cascade that includes urokinase-type plasminogen activator (uPA) and matrix metalloproteases (MMPs). We have investigated the antitumor and antiangiogenic properties of soy isoflavone genistein in B16 melanoma and F3II mammary carcinoma mouse models. At non-cytotoxic concentrations (0.1-50 μM) genistein induced dosedependent spindle-cell morphology and significantly reduced motility in both cell lines. Genistein inhibited uPA secreted by F3II cell monolayers, while inducing an increase in the proteolytic activity of B16 cells. On the contrary, the compound did not modify the MMP-9 and-2 produced by tumor cells. In vivo, i.p. administration of genistein at a dose of 10 mg/kg/ day reduced tumor-induced angiogenesis in syngeneic mice implanted with B16 or F3II cells. Similar antiangiogenic effects were obtained with a soybean-based diet. This data suggest that tumor cell migration and proteolysis may be associated with the antitumor and antiangiogenic activity of soy isoflavone genistein.

Protein Kinase CK2 is a serine-threonine kinase frequently deregulated in many human tumors. Here, we hypothesized that a peptide binder to the CK2 phosphoacceptor site could exhibit anticancer properties in vitro, in tumor animal models, and in cancer patients. By screening a random cyclic peptide phage display library, we identified the CIGB-300 (formerly P15-Tat), a cyclic peptide which abrogates the CK2 phosphorylation by blocking recombinant substrates in vitro. Interestingly, synthetic CIGB-300 led to a dose-dependent antiproliferative effect in a variety of tumor cell lines and induced apoptosis as evidenced by rapid caspase activation. Importantly, CIGB-300 elicited significant antitumor effect both by local and systemic administration in murine syngenic tumors and human tumors xenografted in nude mice. Finally, we performed a First-in-Man trial with CIGB 300 in patients with cervical malignancies. The peptide was found to be safe and well tolerated in the dose range studied. Likewise, signs of clinical benefit were clearly identified after the CIGB-300 treatment as evidenced by significant decrease of the tumor lesion area and histological examination. Our results provide an early proof-of-principle of clinical benefit by using an anti-CK2 approach in cancer. Furthermore, this is the first clinical trial where an investigational drug has been used to target the CK2 phosphorylation domain.

<p>Many potential applications of quantum dots (QDs) can only be realized once the luminescence from single nanocrystals is understood. These applications include the development of quantum logic devices, single photon sources, long-life LEDs, and single molecule biolabels. At the singlenanocrystal level, random fluctuations in the QD photo-luminescence (PL) occur, a phenomenon termed blinking. There are two competing models to explain this blinking: Auger recombination and surface trap induced recombination. Here we use lifetime scaling on core-shell NCs with close to unity quantum yield to demonstrate that both types of blinking occur in the same QDs.</p> <p><br></p><p>We prove that Auger-blinking can yield exponential on/off times in contrast to earlier work. The surface passivation strategy determines which blinking mechanism dominates. This study unifies earlier studies on blinking mechanisms and provides direct evidence that stable single QDs can be engineered for optoelectronic applications.</p>

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