Breast cancer development is a complex pathobiological process involving sequential genetic alterations in normal epithelial cells that results in uncontrolled growth in a permissive microenvironment. Accordingly, physiologically relevant models of human breast cancer that recapitulate these events are needed to study cancer biology and evaluate therapeutic agents. Here, we report the generation and utilization of the human breast cancer in mouse (HIM) model, which is composed of genetically engineered primary human breast epithelial organoids and activated human breast stromal cells. By using this approach, we have defined key genetic events required to drive the development of human preneoplastic lesions as well as invasive adenocarcinomas that are histologically similar to those in patients. Tumor development in the HIM model proceeds through defined histological stages of hyperplasia, DCIS to invasive carcinoma. Moreover, HIM tumors display characteristic responses to targeted therapies, such as HER2 inhibitors, further validating the utility of these models in preclinical compound testing. The HIM model is an experimentally tractable human in vivo system that holds great potential for advancing our basic understanding of cancer biology and for the discovery and testing of targeted therapies.cancer model ͉ human in mouse ͉ tissue reconstitution

In order to elucidate the molecular mechanisms of CaP metastasis, it will be necessary to compare gene and protein expression patterns and biochemical analyses of clinical metastatic disease with data obtained from current models. We will also need to refine our ability to engineer and characterize genetic perturbation models. This type of integrative and iterative approach should facilitate better understanding of the molecular biology of CaP metastases.

A large scale process for the synthesis of HIV protease inhibitor candidate ABT-378 has been developed which utilizes an intermediate common to the synthesis of ritonavir, Abbott's first generation compound. The synthesis relies on the sequential acylation of this intermediate which is carried through as a mixture of diastereomers until the penultimate step. A synthesis of acid 5, derived from L-valine, is also reported.

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Caucasians with prevalence estimates of 2 to 8 cases per The prevalence of homozygous hereditary hemochro-1,000 population. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Approximately 70% of affected persons matosis (HHC) is estimated at 1:250 in Caucasian adults.possess HLA-A3 alloantigen. 5,[22][23][24][25][26][27][28] Simon et al. hypothesize Little is known about ethnic subpopulations that might that the genetic mutation leading to iron overload originally be at increased risk for this disease. HLA data have sugoccurred in the Celtic peoples and that the HLA marker for gested a Celtic origin for HHC. Screening for HHC was HHC might constitute a genetic tracer of the migratory patoffered to all employees of the Massachusetts Polaroid tern of these peoples. 29 More recently, a non-HLA-linked Corporation. Participants with a transferrin saturation form of iron overload has been described in South African of ú55% or ú45% and an elevated serum ferritin concenblacks. 30 tration on two screenings were referred for liver biopsy.Most studies have dealt with populations from ethnically The diagnosis of HHC was based on histological criteria, homogeneous areas (Table 1). [9][10][11][12][13][14][15][16][17][18][19][20][21]31 Detailed comparisons of quantitative hepatic iron determination, hepatic iron inethnic and racial backgrounds have not been reported. The dex, and the phlebotomy requirement for iron depletion.current study examines the prevalence of HHC in a healthy Participants completed a questionnaire regarding their working population of heterogeneous ethnic and racial backethnic background. Two thousand two hundred ninetyground. We sought to identify ethnic and racial subpopulafour employees were screened, and 5 cases of HHC were tions that might be at high risk for inheriting this disease. tion of HHC with Celtic background (P Å .012). The esti-Polaroid study of prostate-specific antigen values in male employees mated cost of screening per patient identified was over age 50 years, and an additional 1,331 nonduplicate serum sam-$18,041. Polaroid Corporation has a high representation ples were collected through a corporation-wide informational and of employees of British-Irish ancestry. Our data suggest promotional campaign offering free screening for HHC. This included that they are at high risk for developing HHC. A signifi-a telephone hotline outlining the signs and symptoms of HHC and cant association of HHC with Celtic ancestry was found the benefits of early detection. Demographic data for the total Polarin this subpopulation, supporting the concept of a Celtic oid population were made available for comparison ( HLA-A and -B phenotyping of T-lymphocytes was performed on TS, transferrin saturation; HII, hepatic iron index; SF, serum ferritin.probands in anticipation of family screening. 43,44 From the 1 Division of Gastroenterology, Faulkner Hospital, Tufts University School of Medicine, Boston, MA; 2 Medical Department, Polaroid Corporation, Cambridge, MA;Protocol. The initial sc...