Application of exposure bracketing to streamline the development of contraceptive products.

Developing new long-acting products of well-characterized contraceptive drugs is one way to address some of the reasons for unmet need for modern methods of family planning among women in low- and middle-income countries. Development and approval of such products traditionally follow a conventional paradigm that includes large Phase 3 clinical trials to evaluate efficacy (pregnancy prevention) and safety of the investigational product. Exposure-bracketing is a concept that applies known pharmacokinetics and pharmacodynamics of a drug substance to inform its safe and efficacious use in humans.

Overexpression of the calcium sensor visinin-like protein-1 leads to a cAMP-mediated decrease of in vivo and in vitro growth and invasiveness of squamous cell carcinoma cells.

Visinin-like protein-1 (VILIP-1) is a member of the neuronal EF-hand Ca(2+)-sensor protein family. VILIP-1 is expressed in the central nervous system where it plays a crucial role in regulating cAMP levels, cell signaling, and differentiation. Screening of mouse skin tumor cell lines for differentially expressed genes showed high-level VILIP-1 expression in less aggressive squamous cell carcinoma (SCC) and papilloma cell lines.

Ultraviolet B-induced squamous epithelial and melanocytic cell changes in a xenograft model of cancer development in human skin.

We previously demonstrated that precancers (actinic keratoses and dysplasias) and squamous cell carcinomas (SCCs) develop in one quarter of human neonatal foreskins grafted onto recombinase-activating gene-1-knockout mice treated once with 7,12-dimethylbenz[a]anthracene (DMBA) followed by chronic intermediate-range ultraviolet (UV) B light irradiation. The goals of this study were to determine if a longer UVB exposure followed by further observation would increase the number of precancers and invasive cancers and to evaluate whether this model results in changes in p53 expression and cell proliferation similar to those seen in sun-damaged normal skin, actinic keratoses, and SCCs. The treatment consisted of a single dose of DMBA followed by 500 J/m2 UVB radiation administered three times weekly for at least 5 mo.

Analysis of the FHIT gene and its product in squamous cell carcinomas of the head and neck.

The FHIT gene has been implicated as a tumor suppressor gene in human malignancies. To determine if FHIT alterations play a role in human squamous cell carcinogenesis of the head and neck (HNSCC), we examined the gene and its product by RT-PCR, SSCP, Northern, Southern, and Western blot analysis in primary HNSCC and/or HNSCC cell lines. Three of 32 tumor samples lacked detectable expression of FHIT by RT-PCR but showed amplification of a control gene of similar size.

The FHIT gene product is highly expressed in the cytoplasm of renal tubular epithelium and is down-regulated in kidney cancers.

Loss of heterozygosity and homozygous deletion of the 3p14.2 region in human cancers implies the existence of a tumor suppressor gene. One such candidate is the fragile histidine triad (FHIT) gene.