Laminin, as a key component of the basement membrane extracellular matrix (ECM), regulates tissue morphogenesis. Here, we show that multiple laminin isoforms promiscuously bind to growth factors (GFs) with high affinity, through their heparin-binding domains (HBDs) located in the α chain laminin-type G (LG) domains. These domains also bind to syndecan cell-surface receptors, promoting attachment of fibroblasts and endothelial cells. We explore the application of these multifunctional laminin HBDs in wound healing in the type-2 diabetic mouse. We demonstrate that covalent incorporation of laminin HBDs into fibrin matrices improves retention of GFs and significantly enhances the efficacy of vascular endothelial cell growth factor (VEGF-A165) and platelet-derived growth factor (PDGF-BB) in promoting wound healing in vivo, under conditions where the GFs alone in fibrin are inefficacious. This laminin HBD peptide may be clinically useful by improving biomaterial matrices as both GF reservoirs and cell scaffolds, leading to effective tissue regeneration.

Integrin ligation activates both cell adhesion and signal transduction, in part through reorganization of the actin cytoskeleton. Plastins (also known as fimbrins) are actin-crosslinking proteins of the cortical cytoskeleton present in all cells and conserved from yeast to mammals. Here we show that plastin-deficient polymorphonuclear neutrophils (PMN) are deficient in killing the bacterial pathogen Staphylococcus aureus in vivo and in vitro, despite normal phagocytosis. Like integrin beta2-deficient PMN, plastin-deficient PMN cannot generate an adhesion-dependent respiratory burst, because of markedly diminished integrin-dependent syk activation. Unlike beta2(-/-) PMN, plastin-deficient PMN adhere and spread normally. Deficiency of plastin thus separates the classical integrin receptor functions of adhesion and spreading from intracellular signal transduction.

Purpose: To evaluate prophylactic salpingo-oophorectomy uptake and timing among BRCA1/2 mutation carriers in a cancer risk assessment program. Methods: Clinical records of female BRCA1/2 mutation carriers who received cancer genetic counseling between 1996 and 2003 were reviewed to determine the completion and the timing of prophylactic salpingo-oophorectomy. Logistic regression models evaluated associations between subject characteristics and surgery. Survival analysis methods were used to estimate the distribution of time to surgery. Results:Among 88 women, 70% underwent prophylactic salpingo-oophorectomy. Prophylactic salpingo-oophorectomy was associated with older age, white race, having children, and a family history of ovarian cancer. Many women waited more than 12 months to undergo surgery and some delayed by several years. Younger age and not having children were associated with delays to surgery. Conclusion: Prophylactic salpingo-ooporectomy is an acceptable risk reduction measure for many BRCA1/2 mutation carriers. Some women make this decision many years after genetic testing. Continued discussion of the risks and benefits of risk reduction options may facilitate the uptake of recommended risk reduction interventions among BRCA mutation carriers. Genet Med 2008:10(3):161-166. Key Words: BRCA1, BRCA2, prophylactic salpingo-oophorectomyWomen who carry a BRCA1 or BRCA2 mutation have a 31-87% risk of developing breast cancer and a 15-40% risk of developing ovarian cancer 1-4 compared with the risk in the general population of 12.5% and 1.5%, respectively. 5 In light of these risks, BRCA mutation carriers are counseled regarding available risk reduction methods, including prophylactic surgery, increased surveillance, and chemoprevention. One of these options, bilateral prophylactic salpingo-oophorectomy (BSO), has been shown to decrease the risk of ovarian cancer in BRCA mutation carriers by 85-96% and the risk of breast cancer by 50%. 6 -8 In addition, surgical morbidity and mortality has decreased with the advent of laparoscopic surgical techniques. 9 Thus, BSO is currently recommended to BRCA mutation carriers between 35 and 40 years of age or at completion of childbearing. 5,10 Despite this, many women and clinicians are concerned about the effects of premature menopause after surgical prophylaxis. 11,12 Although there is some evidence suggesting that short-term hormone replacement therapy (HRT) does not increase breast cancer risks in BRCA mutation carriers, long-term prospective data are not available and many physicians are reluctant to provide, and many women are reluctant to consider postsurgical HRT. 13 Thus, some women elect not to undergo BSO and receive ovarian cancer surveillance with transvaginal ultrasound, serum CA-125, and clinical pelvic examination, although studies have suggested that the ability to detect early cancers with such screening is poor. 14,15 Despite these recommendations and considering the controversy surrounding postsurgical HRT, the acceptability of BSO as a risk reduc...

Epidermal regeneration following middermal injuries to skin requires both proliferation and migration of keratinocytes. Epidermal growth factor (EGF) stimulates the proliferation of keratinocytes in culture, and topical administration of EGF accelerates epidermal regeneration of partial thickness burns or split-thickness incisions in vivo. Transforming growth factor-alpha (TGF-alpha) and vaccinia growth factor (VGF) have substantial sequence homology with EGF, and all appear to bind to the same receptor protein. Whether TGF-alpha or VGF can affect epidermal wound healing in vivo is not known. The present studies show that topical administration of TGF-alpha or VGF in antibiotic cream to partial thickness burns (second degree) accelerated epidermal regeneration in comparison with untreated or vehicle-treated burns. Low levels of both TGF-alpha and VGF (0.1 microgram per milliliter) appeared to be more effective than EGF in stimulating epidermal regeneration. Regenerated epithelium from burns treated with TGF-alpha or VGF appeared normal histologically. This finding suggests that topical application of selected growth factors may be useful in accelerating healing of partial thickness injuries.