Methods for the Analysis of High Precision Differential Hydrogen Deuterium Exchange Data.

Hydrogen/deuterium exchange (HDX) mass spectrometry has been widely applied to the characterization of protein dynamics. More recently, differential HDX has been shown to be effective for the characterization of ligand binding. Previously we have described a fully automated HDX system for use as a ligand screening platform.

A method for obtaining randomized block designs in preclinical studies with multiple quantitative blocking variables.

A method is proposed for block randomization of treatments to experimental units that can accommodate both multiple quantitative blocking variables and unbalanced designs. Hierarchical clustering in conjunction with leaf-order optimization is used to block experimental units in multivariate space. The method is illustrated in the context of a diabetic mouse assay.

A nonsecosteroidal vitamin D receptor ligand with improved therapeutic window of bone efficacy over hypercalcemia.

Vitamin D(3) analogues were shown to be beneficial for osteoporosis and other indications, but their narrow therapeutic window between efficacy and hypercalcemia has limited their clinical utility. A nonsecosteroidal, tissue-selective, orally bioavailable, vitamin D receptor (VDR) ligand was ascertained to be efficacious in bone while having modest calcemic effects in vivo. This compound (VDRM2) potently induced Retinoid X Receptor alpha (RXR)-VDR heterodimerization (EC(50) = 7.

Identification and characterization of noncalcemic, tissue-selective, nonsecosteroidal vitamin D receptor modulators.

Vitamin D receptor (VDR) ligands are therapeutic agents for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. VDR ligands also show immense potential as therapeutic agents for autoimmune diseases and cancers of skin, prostate, colon, and breast as well as leukemia. However, the major side effect of VDR ligands that limits their expanded use and clinical development is hypercalcemia that develops as a result of the action of these compounds mainly on intestine.

Statistical inference for relative potency in bivariate dose-response assays with correlated responses.

The analysis of dose-response assays measuring two correlated responses is considered. Attention is given to statistical inference for the potency ratio. Results from a simulation study suggest that a post hoc adjustment for the correlation in parameter estimates obtained from univariate fits provides nearly as much power to detect differences in potency as a bivariate response model fit.

Bilateral oophorectomy and breast cancer risk reduction among women with a family history.

Purpose: We investigated whether removal of the ovaries is an appropriate risk reduction option for women at elevated risk of breast cancer based on family history of breast cancer.

Patients And Methods: This question was investigated among a group of 851 women less than age 60 who underwent bilateral oophorectomy between 1970 and 1994 for various reasons. Questionnaire information was collected from 680 (80%) and women were grouped into family risk categories.

Genome-wide linkage analysis of systolic blood pressure: a comparison of two approaches to phenotype definition.

Problem 1 of the Genetic Analysis Workshop 13(GAW13) contains longitudinal data of cardiovascular measurements from 330 pedigrees. The longitudinal data complicates the phenotype definition because multiple measurements are taken on each individual. To address this complication, we propose an approach that uses generalized estimating equations to obtain residuals for each time point for each person.

Her-2/neu expression in ovarian cancer: pre- and postexposure to platinum chemotherapy.

Objective: Our objective was to determine if the level of Her-2/neu expression in advanced ovarian cancer changed after platinum-based chemotherapy.

Methods: Tissue samples from 43 patients who had surgery for ovarian cancer between 1991 and 2001 at the Mayo Clinic were stained for Her-2/neu expression using the DAKO kit and reviewed independently by two pathologists. Patient charts were reviewed for demographic data, clinical course, chemotherapy, and survival times.

Identification of a global gene expression signature of B-chronic lymphocytic leukemia.

B-chronic lymphocytic leukemia (B-CLL) is an adult-onset leukemia characterized by significant accumulation of apoptosis-resistant monoclonal B lymphocytes. In this study, we performed gene expression profiling on B cells obtained from 10 healthy age-matched individuals and CLL B cells from 38 B-CLL patients to identify key genetic differences between CLL and normal B cells. In addition, we leveraged recent independent studies to assess the reproducibility of our molecular B-CLL signature.

Differential gene expression of TGF-beta family members and osteopontin in breast tumor tissue: analysis by real-time quantitative PCR.

Several cytokines including members of the transforming growth factor-beta (TGF-beta) and tumor necrosis factor (TNF) families have been implicated in the homing mechanism of breast cancer metastasis. We hypothesize that primary breast tumor tissues differentially express modulators of bone cell function and that this expression pattern contributes to their aggressive and metastatic potential and to their capacity to establish and grow in bone. We, therefore, examined the gene expression pattern of the TGF-beta family members (inhibin/activin betaA subunit (activin betaA), inhibin alpha subunit, and bone morphogenetic protein-2 (BMP-2)), the TNF family members (receptor activator of NF-KB ligand (RANKL) and osteoprotegerin (OPG)), and osteopontin (OPN) in normal, non-invasive, invasive, and metastatic human breast cancer specimens.

Host genetic polymorphism analysis in cervical cancer.

Background: The natural history of cervical cancer comprises a latency period that probably involves long-term immunologic tolerance of human papillomavirus infection. Identifying host determinants of viral persistence may help to better understand the mechanisms of tolerance and may lead to the development of tests that can allow more focused follow-up of high-risk individuals.

Methods: Genotypic frequencies of 12 polymorphic loci in four candidate genes from 127 cervical cancer patients were compared with a control group of 108 female blood donors.