ABSTRACT
Cervical cancer affects millions of Americans, but the rate for cervical cancer in the Mexican American is approximately twice that for non-Mexican Americans. The etiologies of cervical cancer are still not fully understood. A number of somatic mutations, including several copy number alterations (CNAs), have been identified in the pathogenesis of cervical carcinomas in non-Mexican Americans. Thus, the purpose of this study was to investigate CNAs in association with cervical cancer in the Mexican American population. We conducted a pilot study of genome-wide CNA analysis using 2.5 million markers in four diagnostic groups: reference (n = 125), low grade dysplasia (cervical intraepithelial neoplasia (CIN)-I, n = 4), high grade dysplasia (CIN-II and -III, n = 5) and invasive carcinoma (squamous cell carcinoma (SCC), n = 5) followed by data analyses using Partek. We observed a statistically-significant difference of CNA burden between case and reference groups of different sizes (>100 kb, 10-100 kb and 1-10 kb) of CNAs that included deletions and amplifications, e.g., a statistically-significant difference of >100 kb deletions was observed between the reference (6.6%) and pre-cancer and cancer (91.3%) groups. Recurrent aberrations of 98 CNA regions were also identified in cases only. However, none of the CNAs have an impact on cancer progression. A total of 32 CNA regions identified contained tumor suppressor genes and oncogenes. Moreover, the pathway analysis revealed endometrial cancer and estrogen signaling pathways associated with this cancer (p < 0.05) using Kyoto Encyclopedia of Genes and Genomes (KEGG). This is the first report of CNAs identified for cervical cancer in the U.S. Latino population using high density markers. We are aware of the small sample size in the study. Thus, additional studies with a larger sample are needed to confirm the current findings.
ABSTRACT
A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. Furthermore, this compound displayed good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. Oral administration of compound 28 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity.
Subject(s)
Adenosine Triphosphate/metabolism , Binding, Competitive , Drug Discovery , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Administration, Oral , Animals , Benzoxazines/chemistry , Benzoxazines/metabolism , Benzoxazines/pharmacokinetics , Benzoxazines/pharmacology , Biological Availability , Cell Line, Tumor , Dogs , Female , Humans , Male , Mice , Models, Molecular , Protein Conformation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Rats , Substrate Specificity , TOR Serine-Threonine Kinases/chemistryABSTRACT
With structural guidance, tropane-derived HTS hits were modified to optimize for HSP90 inhibition and a desirable in vivo profile. Through an iterative SAR development process 12i (XL888) was discovered and shown to reduce HSP90 client protein content in PD studies. Furthermore, efficacy experiments performed in a NCI-N87 mouse xenograft model demonstrated tumor regression in some dosing regimens.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Azabicyclo Compounds/chemistry , Azabicyclo Compounds/therapeutic use , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Phthalic Acids/chemistry , Phthalic Acids/therapeutic use , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Azabicyclo Compounds/pharmacokinetics , Azabicyclo Compounds/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Discovery , HSP90 Heat-Shock Proteins/metabolism , Humans , Mice , Models, Molecular , Neoplasms/metabolism , Neoplasms/pathology , Phthalic Acids/pharmacokinetics , Phthalic Acids/pharmacologyABSTRACT
El propósito de este trabajo fue caracterizar las fases fenológicas florales y determinar los visitantes florales en una población natural de Drimys granadensis (nombre común: canelo; Winteraceae) ubicada en Altos de Yerbabuena ( 2.850 m ), cerros orientales de la Sabana de Bogotá, (Colombia). El desarrollo fenológico floral duró 9,5 días cuando la floración ocurrió en época soleada, 12,5 días en época lluviosa y 16 días cuando se excluyeron a los visitantes florales mediante embolsado. Se realizaron observaciones del recurso utilizado, fase fenólogica de la flor visitada y cargas polínicas en los visitante florales, los cuales correspondieron a seis órdenes, 21 familias y 29 morfoespecies de insectos. Cuatro especies de coleópteros y dos de dípteros fueron considerados posibles polinizadores por su abundancia y carga de polen. Los resultados obtenidos se discuten en relación con aquellos reportados en otras especies del género Drimys y de la familia Winteraceae.
The purpose of this research was to characterize the flowering phenological phases and to determine the flower visitors in a natural population of Drimys granadensis (common name: canelo; Winteraceae) in Altos de Yerbabuena, eastern mountains of Sabana de Bogotá ( Colombia ). Floral phenology development lasted 9.5 days when flowering occurred under sunny conditions, 12.5 days under rainy conditions and 16 days when flower visitors were excluded using cloth bags. It was done observations related with the resources used, the phenological phases of visited flowers and the pollen load on the flower visitors. Visitors corresponded with 29 morphospecies, 6 orders y 21 families of insects. Four species of coleoptera and two species of diptera were considered as possible pollinators taking in account abundance and pollen load. The results are analyzed in relation with those reported for other species in the genus Drimys and in the family Winteraceae.
