Gene electrotransfer of plasmid AMEP, an integrin-targeted therapy, has antitumor and antiangiogenic action in murine B16 melanoma.

Gene therapy with Plasmid AMEP (antiangiogenic metargidin peptide) has recently been studied as a potential targeted therapy for melanoma. This plasmid is designed to downregulate α5ß1 and αvß3 integrins. In our study, electroporation was used as a nonviral delivery system. We investigated the antiangiogenic and direct antitumor effectiveness of this gene therapy on low and highly metastatic B16 melanoma variants. In vitro, the antiangiogenic effectiveness as determined by tube formation assay on endothelial cells was predominantly dependent on AMEP expression levels. In vivo, antitumor effectiveness was mediated by the inhibition of proliferation, migration and invasion of melanoma cells and correlated with the expression of integrins on tumor cells after intratumor delivery. In addition, reduced metastatic potential was shown. Intramuscular gene electrotransfer of Plasmid AMEP, for AMEP systemic distribution, had no antitumor effect with this specific preventive treatment protocol, confirming that direct tumor delivery was more effective. This study confirms our previous in vitro data that the expression levels of integrins on melanoma cells could be used as a biomarker for antitumor effectiveness in integrin-targeted therapies, whereas the expression levels of AMEP peptide could be a predictive factor for antiangiogenic effectiveness of Plasmid AMEP in the treatment of melanoma.

Tumor radiosensitization by gene therapy against endoglin.

Gene electrotransfer of plasmid encoding shRNA against endoglin exerts antitumor efficacy, predominantly by vascular targeted effect. As vascular targeting therapies can promote radiosensitization, the aim of this study was to explore this gene therapy approach with single and split dose of irradiation in an endoglin non-expressing TS/A mammary adenocarcinoma tumor model to specifically study the vascular effects. Intratumoral gene electrotransfer of plasmids encoding shRNA against endoglin, under the control of a constitutive or tissue-specific promoter for endothelial cells, combined with a single or three split doses of irradiations was evaluated for the antitumor efficacy and histologically. Both plasmids proved to be equally effective in tumor radiosensitization with 40-47% of tumor cures. The combined treatment induced a significant decrease in the number of blood vessels and proliferating cells, and an increase in levels of necrosis, apoptosis and hypoxia; therefore, the antitumor efficacy was ascribed to the interaction of vascular targeted effect of gene therapy with irradiation. Endoglin silencing by the shRNA technology, combined with electrotransfer and the use of a tissue-specific promoter for endothelial cells, proved to be a feasible and effective therapeutic approach that can be used in combined treatment with tumor irradiation.

Epidemiology of holoprosencephaly and phenotypic characteristics of affected children: New York State, 1984-1989.

Holoprosencephaly is a congenital defect of the median structures of the brain and face. The epidemiology is poorly known due to the paucity of population-based studies. This study describes the epidemiology of holoprosencephaly in a large population, using cases identified through the New York State Congenital Malformations Registry, and born in 1984-1989. We describe the craniofacial abnormalities present, their frequency, and their cooccurrence, and we examine the correspondence between the severity of craniofacial abnormalities, chromosomal abnormalities, and severity of the brain defect. Liveborn cases totaled 78, yielding a prevalence of 4.8 per 100,000 live births. Prevalence among girls was nearly double that in boys, and was 4.2 times higher among infants of mothers under age 18 compared to infants of older mothers. Only 9.8% of all cases had no craniofacial abnormalities other than the brain defect. Eye malformations were present in 76.8%, nose malformations in 69.5%, ear malformations in 50%, and oral clefts in 41.5%. These malformations arise at different times during gestation. The variability in patterns of cooccurrence suggests variability in the developmental pathways and/or timing of developmental derangements which result in holoprosencephaly. This, in turn, is consistent with a model of multiple causes. Children with alobar holoprosencephaly tended to have the most severe craniofacial anomalies, but the correspondence was not 100%. Craniofacial phenotype does not consistently discriminate between cytogenetically normal and abnormal cases.

Strategies for resolving conflict: their functional and dysfunctional sides.

Conflict in the workplace can have a beneficial effect. That is if appropriately resolved, it plays an important part in effective problem solving, according to author Michele Stimac, associate dean, curriculum and instruction, and professor at Pepperdine University Graduate School of Education and Psychology. She advocates confrontation--by way of negotiation rather than brute force--as the best way to resolve conflict, heal wounds, reconcile the parties involved, and give the resolution long life. But she adds that if a person who has though through when, where, and how to confront someone foresees only disaster, avoidance is the best path to take. The emphasis here is on strategy. Avoiding confrontation, for example, is not a strategic move unless it is backed by considered judgment. Stimac lays out these basic tenets for engaging in sound negotiation: (1) The confrontation should take place in neutral territory. (2) The parties should actively listen to each other. (3) Each should assert his or her right to fair treatment. (4) Each must allow the other to retain his or her dignity. (5) The parties should seek a consensus on the issues inconflict, their resolution, and the means of reducing any tension that results from the resolution. (6) The parties should exhibit a spirit of give and take--that is, of compromise. (7) They should seek satisfaction for all involved.

Process of and problems in changing a birth defects registry reporting system.

BACKGROUND: The New York State (NYS) Department of Health (DOH) Congenital Malformations Registry (CMR), which began operations in 1982, was developed after the Love Canal crisis. New York hospitals are mandated to report children under age 2 years in whom a congenital anomaly is diagnosed. The CMR has tried to maintain a quality birth defects registry by using identifiers; narrative for defects; and completeness and accuracy, balanced with timeliness. In recent years, the existence of the registry has been questioned, and the NYS DOH evaluated the CMR to streamline it and to reduce the reporting burden on the hospitals. METHODS: Because NYS hospitals were already required to submit hospital discharge data through the Statewide Planning and Research Cooperative System (SPARCS), the CMR used this system as an alternative method for reporting. RESULTS: The evaluation indicated that the CMR, SPARCS, and hospital systems needed to be modified. Modifications needed to maintain registry quality were the most difficult. CMR staff worked closely with hospital personnel on all modifications so they would understand the reasons for the modifications. The changes were more global than originally anticipated, involving large national software vendors. CONCLUSIONS: The transition is ongoing. Additional work will be needed to verify data quality. Some of the modification will affect national software vendors and may be useful for other birth defects registries.