We recently developed a novel approach to the creation of a fully synthetic, covalently crosslinked extracellular matrix (sECM). This material may be crosslinked in situ in the presence of cells to provide an injectable cell‐seeded hydrogel for tissue repair, or with drugs in a controlled‐release format. Chemical modification of hyaluronan (HA), other glycosaminoglycans (GAGs), proteins, or other carboxylate‐containing polymers with thiol residues creates macromonomers that can be crosslinked with biocompatible electrophiles. First, we show in vitro and in vivo growth of healthy cellularized tissues using films, sponges, and hydrogels based on the sECM technology. Second, we extend the use of the in situ crosslinkable sECM to the growth for the in vivo repair of cartilage and bone defects and for the healing of tympanic membrane perforations. Third, we describe the use of biointeractive, crosslinked heparin‐containing GAG dressings for controlled release of bFGF and re‐epithelializaion of full‐thickness wounds in a diabetic mouse model of chronic wound healing. Finally, we illustrate the use of in situ crosslinkable HA‐derived hydrogels, with and without covalently linked antiproliferatives, for prevention of abdominal surgical adhesions for scar‐free healing following sinus surgery.

WW domain-containing oxidoreductase (WWOX) is a tumor suppressor that has been reported to lose function due to genetic alterations in several cancers. WWOX maps to the common chromosomal fragile site FRA16D and several copy number variations (CNVs) were found within this gene. In this study, we investigated the association between the CNVs of WWOX and lung cancer risk in four independent case-control studies, which are on 2942 lung cancer cases and 3074 cancer-free controls of southern, eastern and northern Chinese. A common CNV-67048 was genotyped by the Taqman real-time PCR, and its biological effect was accessed with protein expression and sequencing assays. We found that in comparison with the common 2-copy genotype, the carriers of loss variant genotypes (1-copy or 0-copy) had a significantly increased risk of lung cancer (adjusted OR = 1.39, 95% CI = 1.24-1.55, P = 9.01×10(-9)) in a dose-response manner (Ptrend = 1.12 × 10(-10)), and the WWOX protein expressions in lung cancer tissues were significantly lower (P = 0.036), accompanying a higher rate of exons absence (P = 0.021) in subjects with loss genotypes of CNV-67048. Our data suggest that the loss genotypes of CNV-67048 in WWOX predispose their carriers to lung cancer; this might be related with altered WWOX gene expression and exons absence in them.

The benzothiophene selective estrogen receptor modulators (SERM) raloxifene and arzoxifene are in clinical use and clinical trials for chemoprevention of breast cancer and other indications. These SERMs are ''oxidatively labile'' and therefore have potential to activate antioxidant responsive element (ARE) transcription of genes for cytoprotective phase II enzymes such as NAD(P)Hdependent quinone oxidoreductase 1 (NQO1). To study this possible mechanism of cancer chemoprevention, a family of benzothiophene SERMs was developed with modulated redox activity, including arzoxifene and its metabolite desmethylarzoxifene (DMA). The relative antioxidant activity of these SERMs was assayed and correlated with induction of NQO1 in murine and human liver cells. DMA was found to induce NQO1 and to activate ARE more strongly than other SERMs, including raloxifene and 4-hydroxytamoxifen. Livers from female, juvenile rats treated for 3 days with estradiol and/or with the benzothiophene SERMs arzoxifene, DMA, and F-DMA showed substantial induction of NQO1 by the benzothiophene SERMs. No persuasive evidence in this assay or in MCF-7 breast cancer cells was obtained of a major role for the estrogen receptor in induction of NQO1 by the benzothiophene SERMs. These results suggest that arzoxifene might provide chemopreventive benefits over raloxifene and other SERMs via metabolism to DMA and stimulation of ARE-mediated induction of phase II enzymes. The correlation of SERM structure with antioxidant activity and NQO1 induction also suggests that oxidative bioactivation of SERMs may be modulated to enhance chemopreventive activity. [Mol Cancer Ther 2007;6(9):2418 -28]

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Antioxidant genes and enzymes play important roles in human spermatogenesis. Although low levels of antioxidant enzyme expression are associated with poor sperm quality, it is not clear whether mRNA expression of antioxidant genes is lower in these men than in normozoospermic men. In this study, 55 asthenozoospermic and oligoasthenozoospermic patients and 65 controls were recruited. Quantitative real-time reverse transcription PCR was performed and the abundance of mRNA of four antioxidant genes known to be important to spermatogenesis were evaluated. These genes were nuclear factor erythroid 2-related factor 2 (NRF2), catalase (CAT), glutathione S-transferase Mu 1 (GSTM1), and superoxide dismutase isoenzyme 2 (SOD2). Results showed the level of NRF2 mRNA expression to be significantly lower in patients than in controls (P < 0.001), but no statistically significant difference in the level of SOD2, CAT, or GSTM1 gene expression was observed between the two groups. A significant correlation was observed between the level of NRF2 mRNA expression and specific sperm function parameters, including concentration, progressive motility, immotility, vitality, and morphology (all P < 0.01). NRF2 expression was also found to be associated with seminal SOD activity and mRNA levels of the CAT and SOD2 genes (all P < 0.05). Therefore, our data demonstrated that the level of NRF2 mRNA expression is significantly lower in human males with low sperm motility and correlated with specific sperm function parameters. This suggests that NRF2 is important to spermatogenesis and may serve as a useful biomarker in the prediction of male infertility.