CDK4/6 Dependence of Cyclin D1-Driven Parathyroid Neoplasia in Transgenic Mice.

The protein product of the cyclin D1 oncogene functions by activating partner cyclin-dependent kinases (cdk)4 or cdk6 to phosphorylate, thereby inactivating, the retinoblastoma protein pRB. Nonclassical, cdk-independent, functions of cyclin D1 have been described but their role in cyclin D1-driven neoplasia, with attendant implications for recently approved cdk4/6 chemotherapeutic inhibitors, requires further examination. We investigated whether cyclin D1's role in parathyroid tumorigenesis in vivo is effected primarily through kinase-dependent or kinase-independent mechanisms. Using a mouse model of cyclin D1-driven parathyroid tumorigenesis (PTH-D1), we generated new transgenic lines harboring a mutant cyclin D1 (KE) that is unable to activate its partner kinases. While this kinase-dead KE mutant effectively drove mammary tumorigenesis in an analogous model, parathyroid-overexpressed cyclin D1 KE mice did not develop the characteristic biochemical hyperparathyroidism or parathyroid hypercellularity of PTH-D1 mice. These results strongly suggest that in parathyroid cells, cyclin D1 drives tumorigenesis predominantly through cdk-dependent mechanisms, in marked contrast with the cdk-independence of cyclin D1-driven mouse mammary cancer. These findings highlight crucial tissue-specific mechanistic differences in cyclin D1-driven tumorigenesis, suggest that parathyroid/endocrine cells may be more tumorigenically vulnerable to acquired genetic perturbations in cdk-mediated proliferative control than other tissues, and carry important considerations for therapeutic intervention.

Formulation development and investigation of domperidone transdermal patches.

AIM AND BACKGROUND: Domperidone is a dopamine antagonist with antiemetic properties having a plasma half life of 7-9 h with 15% oral bioavailability. In the present work transdermal patches of domperidone were prepared with the objective to improve its therapeutic efficacy, patient compliance and to reduce the frequency of dosing and side effects, as well as to avoid its extensive first pass metabolism of the drug. MATERIALS AND METHODS: THE PATCHES WERE PREPARED USING ETHYL CELLULOSE (EC): Poly vinyl pyrrolidone (PVP), poly vinyl alcohol (PVA): Poly vinyl pyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC): Sodium (carboxy methyl cellulose) CMC as polymers in combination. The physicochemical parameters like thickness, drug content, weight variation, moisture absorption and drug permeation studies were evaluated for the prepared patches. No significant difference in thickness, average weight and in the drug content among the patches. RESULTS: It was observed that from hydrophilic polymers the drug release was found to be faster compared to (F5 and F6 & F3 and F4) combination of hydrophilic and lipophilic polymers used in the study. Patches containing HPMC and Sodium CMC (F5 and F6) showed faster release as the patches showed maximum percentage amount moisture absorption. The in vitro release data was treated with kinetic equations and it followed Higuchi's diffusion mechanism. The in vivo bioavailability study was performed in rats and observed that, drug reached to the peak in approximately 60 min (16%) after oral route of administration. However, approximately same amount of drug was found in the serum from transdermal formulation in 6 h and further increase in the amount of drug in the serum, indicated that the drug 5 bioavailability could be better and hence the hepatic metabolism can be avoided, as it is evident from the data. Further, the decrease in the amount of drug present in the serum 45 min after oral administration also indicated that major amount of drug might have got metabolized and the bioavailability is reduced. However, the transdermal patch released further amount of drug (33%) at the end of 24 h. CONCLUSION: The present study can be concluded that transdermal patch can extend the release of drug for many hours with better bioavailability and also can avoid the first pass effect.

Electrical properties of retinal-electrode interface.

A critical element of a retinal prosthesis is the stimulating electrode array, which is placed in close proximity to the retina. It is via this retinal-electrode interface that a retinal prosthesis electrically stimulates nerve cells to produce the perception of light. The impedance load seen by the current driver consists of the tissue resistance and the complex electrode impedance. The results in this paper show that the tissue resistance of the retina is significantly greater than that of the vitreous humor in the eye. Circuit models of the electrode-retina interface are used to parameterize the different contributors to the overall impedance.

Intraocular impedance as a function of the position in the eye, electrode material and electrode size.

A critical element of a retinal prosthesis is the electrode assembly, which is placed on the retina. It is via this interface that the nerve cells are stimulated to produce the perception of light. The electrode impedance is an integral part in determining the design of the stimulating electrode and the attached circuit. The impedances involved are not only the tissue impedance but the electrode itself contributes to the impedance. Further on the electrode impedance depends not only the material of the electrode but also the size of the electrode. This paper discusses the results obtained by the intraocular impedance measurements with varying electrode size, electrode material and position of the electrode within the eye.