EVALUATION OF HUMAN PROLACTIN, ITS ANTAGONIST, AND ANTAGONIST-BASED FUSION PROTEINS AS CHEMOPREVENTATIVE AND THERAPEUTIC AGENTS

Cancer is a collection of diseases with many different manifestations and is the second leading cause of death in the United States. Breast cancer accounts for nearly one third of cancer diagnosis in women. Prolactin (PRL) functions as a lactogen and as a mammary gland differentiation factor. PRL acts in an autocrine/paracrine manner within the mammary gland and in breast tumors which implies PRL may be involved in breast cancer progression. This is corroborated by the PRLR over-expression in breast cancer cells lines and the majority of patient biopsies. These reasons make PRL and PRLR attractive targets for breast cancer treatment and prevention. Transgenic mice expressing hPRL or G129R, under the regulation of the metallothionein (Mt) promoter, were fed a chemical carcinogen, 9,10-Dimethyl-1,2-benzanthracene (DMBA). G129R transgenic mice exhibited decreased growth rate of chemically-induced tumors, while hPRL transgenic mice had an increased cancer rate. Microarray analysis revealed that hPRL transgenic mammary gland showed an expression pattern similar to those of a pregnant mouse, while the G129R transgenic gland revealed an increase in various apoptotic markers. Previously, fusion proteins composed of a PRLR antagonist (G129R) and anti-tumor domains were developed; these included fusions with an angiogenesis inhibitor (Endostatin), an immune system modulator (interleukin-2), and a cytotoxin (PE38KDEL). The rationale was that each fusion protein would target the mammary gland via the G129R moiety and attack different hallmarks common to tumor cells via the second moiety. A novel clinically-relevant model was generated by surgically removing spontaneous mammary tumors from MMTV-neu transgenic mice and monitoring tumor recurrence while treating with the fusion protein cocktail. Tumor recurrence was significantly delayed in groups treated with the fusion proteins in comparison to the control group. In conclusion, targeting multiple hallmarks of cancer using a combination of dual function therapeutics was highly effective in the aggressive MMTV-neu mouse tumor model

A Radiographic Study of Patients Treated with the Reinforced Banded Herbst Appliance

Objectives: Orthopedic functional appliances have been shown to be effective in correcting Class II malocclusions with mandibular deficiency. However, most of the studies reported in the literature could not substantiate the effect of the appliance on mandibular growth because the appliance was worn for a short time and most of the studies were short term. In addition, there is also report on the breakage of the appliance with the use of the banded Herbst design. The objective of this study was to investigate the skeletal and dental changes of patients treated with the reinforced banded Herbst appliance during Herbst treatment and after completion of fixed appliance treatment. The results of this research should provide additional information on mode of action and the length of treatment when using the Herbst appliance. Methods: Thirty patients with Class II division 1 malocclusion (mean age = 12.34 years) treated by one of the investigator (M.R.) with Herbst followed by fixed appliance were compared to a matched control sample obtained from the Bolton-Brush study. Cephalometric radiographs were taken before treatment (T1), at the completion of Herbst treatment (T2), and following the removal of all fixed appliances (T3). Data was analyzed using a combination of ANOVA and Tukey-Kramer Test. Results: Treatment with the Herbst appliance (T2-T1) for an average of 1.5 years after growth is subtracted (t2-t1) resulted in a backward movement of the maxilla by 1.2 mm. The mandible moved forward 1.3 mm. The maxillary molars moved backward 4 mm and the maxillary incisors moved backward 4 mm. The mandibular molars moved forward 3.5 mm and the lower incisors moved forward 3.2 mm. The vertical changes were the maxilla moved downward 1.2 mm. The upper molars intruded 1 mm. The lower molar intruded 1mm and the lower incisors intruded 1.1 mm. The overbite decreased by 3.3 mm. The angular changes were SNB increased 3.6°. The SNA and ANB decreased 1° and 4.5°. The occlusal plane increased by about 5°. The upper incisor retracted 5.5° and the lower incisor proclined 8.6°. The Wits decreased by 4.2. The change in overjet was -7.2 mm. The skeletal contribution was -2.5 mm and the dental contribution was -4.7 mm. The change in molar relationship was -7.5 mm. The skeletal contribution was -2.5 mm and the dental contribution was -5 mm. The maxilla, maxillary molars, and maxillary incisors moved backwards. The mandible, mandibular molars, and mandibular incisors moved forward. The total treatment effect of the Herbst appliance and phase II treatment (T3-T1) after growth is subtracted (t3-t1) resulted in a backward movement of the maxilla by .4 mm. The mandible moved forward .9 mm. The maxillary molars moved backward 2.3 mm and the maxillary incisors moved backward 1.5 mm. The mandibular molars moved forward 2.7 mm and the lower incisors moved forward 2.9 mm. The vertical changes were the maxilla moved downward 1.2 mm. The upper molars extruded .3 mm and the lower molar extruded .8 mm. The overbite decreased by 4.2 mm. The angular changes were SNB increased 2.6°. The SNA and ANB decreased .2° and 3.3°. The occlusal plane increased by about 1.2°. The upper incisor retracted 5° and the lower incisor proclined 4.5 °. The Wits decreased by 3.2. The change in overjet was -4.4 mm. The skeletal contribution was -1.3 mm and the dental contribution was -3.1 mm. The change in molar relationship was -5 mm. The skeletal contribution was -1.3 mm and the dental contribution was -3.7 mm. The maxilla, maxillary molars, and maxillary incisors moved backwards. The mandible, mandibular molars, and mandibular incisors moved forward. Conclusions: The Herbst appliance when used for an average of 1.5 years was effective in correcting class II dental and skeletal malocclusions. The Herbst appliance when used for a longer period of time seems to allow for more over correction and less relapse