Biomedical subjects

Fred Immermann

Publications and source records attributed to Fred Immermann.

4 recordsLinked to original sources

PubMed2006

Molecular classification of Crohn's disease and ulcerative colitis patients using transcriptional profiles in peripheral blood mononuclear cells.

Ulcerative colitis (UC) and Crohn's disease (CD) are common inflammatory bowel diseases producing intestinal inflammation and tissue damage. Although emerging evidence suggests these diseases are distinct, approximately 10% of patients remain classified as indeterminate inflammatory bowel disease even after invasive colonoscopy intended for diagnosis. A molecular diagnostic assay using a clinically accessible tissue would greatly assist in the classification of these diseases. In the present study we assessed transcriptional profiles in peripheral blood mononuclear cells from 42 healthy individuals, 59 CD patients, and 26 UC patients by hybridization to microarrays interrogating more than 22,000 sequences. Supervised analysis identified a set of 12 genes that distinguished UC and CD patient samples with high accuracy. The alterations in transcript levels observed by microarray were verified by real-time polymerase chain reaction. The results suggest that a peripheral blood mononuclear cell-based gene expression signature can provide a molecular biomarker that can complement the standard diagnosis of UC and CD.

Adult↗

PubMed2005

Transcriptional profiles in peripheral blood mononuclear cells prognostic of clinical outcomes in patients with advanced renal cell carcinoma.

PURPOSE: Given their accessibility, surrogate tissues, such as peripheral blood mononuclear cells (PBMC), may provide potential predictive biomarkers in clinical pharmacogenomic studies. In leukemias and lymphomas, the prognostic value of peripheral blast expression profiles is clear; however, it is unclear whether circulating mononuclear cells of patients with solid tumors might yield profiles with similar prognostic associations. EXPERIMENTAL DESIGN: In this study, we evaluated the association of expression profiles in PBMCs with clinical outcomes in patients with advanced renal cell cancer. Transcriptional patterns in PBMCs of 45 renal cell cancer patients were compared with clinical outcome data at the conclusion of a phase II study of the mTOR kinase inhibitor CCI-779 to determine whether pretreatment transcriptional patterns in PBMCs were correlated with eventual patient outcomes. RESULTS: Unsupervised hierarchical clustering of the PBMC profiles using all expressed genes identified clusters of patients with significant differences in survival. Cox proportional hazards modeling showed that the expression levels of many PBMC transcripts were predictors for the patient outcomes of time to progression and overall survival (time to death). Supervised class prediction approaches identified multivariate expression patterns in PBMCs capable of assigning favorable outcomes of time to death and time to progression in a test set of renal cancer patients, with overall performance accuracies of 72% and 85%, respectively. CONCLUSIONS: The present study provides the first example of gene expression profiling in peripheral blood, a clinically accessible surrogate tissue, for identifying patterns of gene expression associated with higher likelihoods of positive outcome in patients with a solid tumor.

Adolescent↗

PubMed2005

Population pharmacokinetics of CCI-779: correlations to safety and pharmacogenomic responses in patients with advanced renal cancer.

OBJECTIVE: Our objective was to estimate the pharmacokinetic parameters of CCI-779 and its metabolite, sirolimus, and evaluate associations of exposure parameters with safety and clinical activity. Exposure parameters were also correlated with pharmacogenomic responses in peripheral blood mononuclear cells (PBMCs). METHODS: In this randomized, double-blind, multicenter trial, once-weekly intravenous doses of 25, 75, or 250 mg CCI-779 were administered to patients with advanced renal cancer. Whole blood for CCI-779 and sirolimus concentrations was drawn. Population pharmacokinetic analyses yielded Bayesian-predicted exposure metrics that were correlated with severity and duration of adverse events and survival. PBMC samples taken before and after treatment were examined for pharmacogenomic responses. Ribonucleic acid samples were converted to labeled probes and hybridized to oligonucleotide arrays containing more than 12,600 human sequences. RESULTS: The final population pharmacokinetic models of CCI-779 and sirolimus included 235 and 305 observations, respectively, from 50 patients. For CCI-779, dose, single versus multiple dose, and body surface area were significant pharmacokinetic covariates. For sirolimus, dose and hematocrit were significant covariates. Age, sex, or race did not influence drug disposition. CCI-779 area under the curve correlated with adverse event severity for thrombocytopenia (P = .007), pruritus (P = .011), and hyperlipemia (P = .040). Exposure (CCI-779 cumulative area under the curve) correlated with a specific subset of gene transcripts in PBMCs following 16 weeks after therapy (P < .001, Spearman correlation). CONCLUSIONS: Concentrations of CCI-779 and sirolimus were adequately described with a population model incorporating factors for dose, attenuated exposure of multiple doses, body surface area, and hematocrit. Correlations with adverse event severity and duration profiles were provided to aid in the detection of treatment-emergent effects. Pharmacogenomic profiling of PBMCs identified altered ribonucleic acid transcript expression levels that correlate with exposure. These transcripts represent potential biomarkers of CCI-779 exposure in peripheral blood.

Adult↗

PubMed2002

A novel approach to combinatorial library design.

We address the problem of designing a general-purpose combinatorial library to screen for pharmaceutical leads. Conventional approaches focus on diversity as the primary factor in designing such libraries. We suggest making screening libraries out of a set of pharmaceutically relevant scaffolds, with multiple analogs per scaffold. The rationale for this rests on the fact that even though the hit-rate in active series is much higher than in the database as a whole, often a large fraction of the compounds in active series are inactive. This is especially true when the series has not been optimized for the target under study. We introduce the concept of hit-rate within a series and use historic screening data to arrive at a crude estimate for it. We then use simple probability arguments to show that 50-100 compounds are required in each series in order to be nearly certain of finding at least one active compound in each true active series for any given target.

Chemistry, Pharmaceutical↗