Network measures for chemical library design.

In this overview, we examine recent developments in network approaches to drug design. A brief overview of networks is followed by a discussion of how chemical similarity networks and their properties address challenges in drug design. Multiple methods used to assess or enhance chemical diversity for early-stage drug discovery are discussed, as well as methods that can be used for drug repositioning and ligand polypharmacology.

Outcome of antegrade continent enema (ACE) procedures in children and young adults.

OBJECTIVE: Intractable incontinence affects a large number of children and young adults in the US. The goal of this study is to evaluate the long-term outcomes of surgical access for administration of antegrade continence enemas (ACE) in affected children and young adults. METHODS: Patients who underwent surgical procedure to enable administration of ACE from 1994 to 2011 were retrospectively reviewed. Data collected included patient demographics, primary diagnosis, surgical technique, conduit used, complications, follow-up duration, and social continence. RESULTS: Sixty eighty patients underwent surgery to enable ACE; mean follow up was 61 months. Enteral conduit (EC) was performed in 19 patients, tube cecostomy catheters (CC) in 49. Meningomyelocele was diagnosed in 60% of patients. Mean age was 11 (1.67-53) years. Complications included tube dislodgement (43%), granulation tissue (46%), site infection (13%), leakage (32%), break in the tube (6%) and tract stenosis (6%). Complete social continence was achieved in 68%, partial continence was achieved in 29%, and no benefit was achieved in 3% of patients. The rate of complications and incontinence resolution following CC was 78% and 66%, and following EC 89% and 74%. The differences were not statistically significant. CC patients developed granulation tissue more frequently (53%) and leaks of fecal material less frequently (20%) compared to EC patients (26% and 53%) (p < 0.05 and < 0.01). Although children 7 years or younger developed more overall complications (94%) than older patients (69%; p < 0.05), there was not a significant difference in the frequency of any one complication or in the rate of continence, between the two groups. Multivariate analysis showed that EC is three times more likely to be complicated by fecal leakage. CC patients are at greater risk to develop granulation tissue (p < 0.05). CONCLUSIONS: Most patients achieved social continence and improved hygiene with the aid of ACE. Younger children also benefited greatly from institution of ACE. CC was associated with fewer major complications such as leak of fecal contents than EC but required regular tube changes.

Annexin-V promotes anti-tumor immunity and inhibits neuroblastoma growth in vivo.

The goal of the current study is to determine the effects of blocking phosphatidylserine (PS) on the growth of neuroblastoma in mice. PS, an anionic phospholipid restricted to the cytoplasmic surface of plasma membranes in most cells, is externalized to the surface of apoptotic cells. PS has been shown to induce immune tolerance to self-antigens. PS can also be found on the surface of live cells and in particular tumor cells. Annexin-V (AnV) is a protein that specifically binds and blocks PS. To determine the effects of blocking PS with AnV on tumor growth and immunogenicity, mice were inoculated with AGN2a, a poorly immunogenic murine neuroblastoma that expresses high level of PS on the cell surface. Survival and anti-tumor T cell response were determined. AGN2a were engineered to secrete AnV. Secreted protein effectively blocked tumor PS. 40 % of mice inoculated with AnV-expressing AGN2a cells survived free of tumor, whereas none of the mice inoculated with control cells survived (p = 0.0062). The benefits of AnV were lost when mice were depleted of T cells. The findings suggest that AnV could protect mice from tumor challenge through an immune mediated mechanism. Mice were then immunized with irradiated AnV-secreting or control cells, and challenged with wild-type AGN2a cells. AnV-secreting cell vaccine protected 80 % of mice from AGN2a challenge, while control cell vaccine prevented tumor growth in only 30 % of animals (p = 0.012). ELISPOT analysis demonstrated that AnV-secreting cell vaccine induced a greater frequency of interferon-gamma producing splenic T cells. T cells isolated from mice immunized with AnV-secreting but not control vaccine lysed AGN2a. In summary, AnV blocked PS, enhanced T cell mediated tumor immunity, and inhibited tumor growth.

Outcomes of plastic closure in gastroschisis.

BACKGROUND: Gastroschisis is a congenital abdominal wall defect in which the intestines develop outside the abdomen and are exposed to amniotic fluid. When the defect is small, lymphatic, venous, and intestinal obstruction may occur and contribute to the formation of intestinal edema, atresia, ischemia, and a thick inflammatory peel. Treatment requires early coverage of abdominal contents either by primary closure or by the placement of temporary Silastic silo followed by abdominal wall closure. Currently, both traditional suture closure and the sutureless plastic closure are being employed to repair the gastroschisis defect. The goal of the current study is to evaluate plastic closure. We predict no difference will be found in clinical outcomes between plastic closure and traditional suture closure. METHODS: A retrospective review of 80 patients treated between 2000 and 2009 was performed. Plastic closure was used in 52 (65%) and traditional suture closure in 28 (35%) babies. The surgical procedure was determined by surgeon preference. Of the 31(39%) babies who required silos, 15 (19%) were treated with plastic closure and 16 (20%) underwent traditional closure. We collected the following demographic data and clinical progression data. Using SAS 9.2 (SAS Institute Inc, Cary, NC), we conducted linear regression, logistic regression, and time to event models to compare the following outcomes: days on ventilator, days to start enteral feeds, days to reach goal enteral feeds, days on total parenteral nutrition, hospital charges, duration of stay, mortality, and complications. RESULTS: The mean duration of follow-up was 11.4 months. Patients spent an average of 6 days on the ventilator. There were 2 mortalities. A multivariate analysis demonstrated that no differences were found between the 2 closures with most of the outcomes; however, when compared with traditional suture closure, those babies treated with plastic closure spent 4 days fewer days on the ventilator (P < .01). Those babies who underwent suture closure were more likely to have an infection or sepsis (odds ratio, 5.15; P < .001). When the entire cohort was considered, no significant difference was found between plastic and suture closure in time to start feeds, time to reach goal feeds, time on parenteral nutrition, hospital charges, duration of stay, or complications. Ventral hernias were noted in 46 (58%) patients, 32 (62%) after plastic closure and 14 (50%) after suture closure (P = .32). Hernia repair was required in 16 (20%) patients, 11 (21%) after plastic closure, and 5 (18%) after traditional repair (P = .32). In the silo cohort, children treated with plastic closure required 7.5(P < .01) fewer days to start enteral feeds than those treated with suture closure. CONCLUSION: Plastic closure of abdominal wall defects in gastroschisis is effective both as a primary procedure and after silo placement. A multivariate analysis shows plastic closure to be associated with fewer days of mechanical ventilation and less likelihood of developing infection or sepsis.