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William L Trepicchio

Publications and source records attributed to William L Trepicchio.

10 recordsLinked to original sources
PubMed2005

Exploiting genotypic differences to identify genes important for EAE development.

Experimental autoimmune encephalomyelitis (EAE) is an animal model of the human autoimmune disease multiple sclerosis (MS) and is primarily driven by T helper type 1 (Th1) cells. Interleukin (IL)-12 and interferon (IFN)-gamma are important cytokines involved in the differentiation and amplification of Th1 cells, however mice deficient in either IFN-gamma or IL-12 still develop EAE. We have used microarray analysis of EAE-affected CNS tissues in wild-type, IFN-gamma -/- and IL-12 -/- animals to identify genes critical for development of EAE. Over 500 genes were regulated in at least one genotype and over 94 genes were regulated in all three. Of those, 17 were also upregulated in spleen during the disease. We show that a majority of the genes regulated in EAE are also regulated in diseased regions of human MS tissues. The genes in the pool of 94 are more likely to be found regulated in MS patients than the genes regulated in only one or two of the mouse strains suggesting that analyzing gene expression under these multiple genetic conditions may lead to better identification of the genes critical for disease development.

Animals↗
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

A single administration of recombinant human interleukin-12 is associated with increased expression levels of interferon-gamma and signal transducer and activator of transcription in healthy subjects.

The objectives of this study were to assess the safety and tolerability of single doses of 1, 4, and 8 mug of recombinant human interleukin-12 (rhIL-12) administered subcutaneously to healthy subjects. The pharmacokinetics, pharmacodynamics, and pharmacogenomics of rhIL-12 were evaluated. Recombinant human IL-12 was well tolerated in these healthy male and female subjects. The most frequently reported adverse events were flu-like symptoms, which exhibited a dose-response relationship. Pharmacokinetic analysis suggested that serum IL-12 levels increased with dose. Analysis of serum levels indicated that interferon-gamma increased with the dose of rhIL-12, whereas IL-6 levels showed no changes with rhIL-12 treatment. The messenger ribonucleic acid expression of signal transducer and activator of transcription was significantly increased 24 hours after the administration of rhIL-12 for all dose groups versus placebo, and results indicated that the magnitude of increase may be dose dependent. This study suggests that interferon-gamma and signal transducer and activator of transcription are biomarkers of rhIL-12 activity.

Adult↗
PubMed2005

Clinical pharmacogenomics and transcriptional profiling in early phase oncology clinical trials.

Microarray-based expression profiling studies in the field of oncology have demonstrated encouraging correlations between tumor transcriptional profiles and eventual patient outcomes. These findings have fueled great interest in the application of transcriptional profiling to samples available from real-time clinical trials, and clinical pharmacogenomic objectives utilizing transcriptional profiling strategies are becoming increasingly incorporated into clinical trial study designs. Over the last few years several retrospective studies based on the profiling of archival tumor tissues suggest that transcriptional analysis of oncology samples may provide general prognosis measures, and in some cases may even predict response to specific therapies. Recently the FDA released a voluntary genomic data guidance meant to assist both regulatory agencies and pharmaceutical companies alike in evaluating the potential benefit of implementing expression profiling studies during the preclinical and clinical phases of drug development. Despite the great promise afforded by this technology, the ultimate benefit of applying transcriptional profiling in prospective clinical trials has yet to be realized because a number of practical impediments to this process exist. The multi-fold purpose of the current review is to highlight the increasing evidence from studies that have identified transcriptional signatures in archived tumors prognostic of patient outcome, to describe some of the drivers for the implementation of transcriptional profiling strategies in real-time drug development, to discuss the use of transcriptional profiling in the context of increasingly complex translational medicine strategies, and to highlight the practical issues and potential approaches involved in the successful application of clinical pharmacogenomic objectives during real-time clinical trials. Strategic implementation of transcriptional profiling in early oncology clinical trials can provide an opportunity to identify predictive markers of clinical response and eventually provide a substantial step forward towards the era of personalized medicine.

Antineoplastic Agents↗
PubMed2004

Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris.

Psoriasis is a type I-deviated disease characterized by the presence of interferon (IFN)-gamma and multiple IFN-related inflammatory genes in lesions. Because interleukin (IL)-23 is now recognized to play a role in the recruitment of inflammatory cells in a T helper cell (Th)1-mediated disease, we examined psoriasis skin lesions for production of this newly described cytokine. IL-23 is composed of two subunits: a unique p19 subunit and a p40 subunit shared with IL-12. We found a reliable increase in p19 mRNA by quantitative reverse transcription polymerase chain reaction in lesional skin compared with nonlesional skin (22.3-fold increase; P = 0.001). The p40 subunit, shared by IL-12 and IL-23, increased by 11.6-fold compared with nonlesional skin (P = 0.003), but the IL-12 p35 subunit was not increased in lesional skin. IL-23 was expressed mainly by dermal cells and increased p40 immunoreactivity was visualized in large dermal cells in the lesions. Cell isolation experiments from psoriatic tissue showed strong expression of p19 mRNA in cells expressing monocyte (CD14+ CD11c+ CD83-) and mature dendritic cell (DC) markers (CD14- CD11c+ CD83+), whereas in culture, the mRNAs for p40 and p19 were strongly up-regulated in stimulated monocytes and monocyte-derived DCs, persisting in the latter for much longer periods than IL-12. Our data suggest that IL-23 is playing a more dominant role than IL-12 in psoriasis, a Th1 type of human inflammatory disease.

Adult↗
PubMed2004

Interleukin-11 inhibits NF-kappaB and AP-1 activation in islets and prevents diabetes induced with streptozotocin in mice.

This laboratory has reported that multiple low doses of streptozotocin (MLD-STZ) similarly upregulate the T helper (Th)1-type proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in islets of both the diabetes-susceptible male and the diabetes-resistant female C57BL/6 mice and that MLD-STZ downregulates the anti-inflammatory Th2-type cytokines interleukin (IL)-4 and IL-10, as well as the anti-inflammatory Th3-type cytokine-transforming growth factor (TGF)-ss1 in islets of male, but not female, mice. Thus, diabetes is associated with a relative preponderance of local proinflammatory cytokines. Here, we investigated the effects of MLD-STZ on the anti-inflammatory cytokine IL-11 and the transcription factors nuclear factor (NF)-kappaB and activator protein (AP)-1, which are involved in gene activation of proinflammatory cytokines, and on the cytosolic kinase (IKK-alpha) of NF-kappaB inhibitor (IkappaB). Furthermore, the effect of recombinant human (rh)IL-11 on MLD-STZ diabetes, insulitis, cytokines, IKK-alpha, NF-kappaB, and AP-1 was analyzed in islets. Interleukin-11 prevented diabetes without affecting insulitis; attenuated TNF-alpha and IFN-gamma response; and stimulated IL-4 production and inhibited activation of IKK-alpha, NF-kappaB, and AP-1. The results demonstrated the potential of rhIL-11 in preventing MLD-STZ diabetes through enhancement of anti-inflammatory responses in islets. In this process, the transcription factors NF-kappaB and AP-1 might play a key role.

Animals↗
PubMed2003

Disease-associated expression profiles in peripheral blood mononuclear cells from patients with advanced renal cell carcinoma.

Expression profiling has demonstrated that transcriptomes of primary malignancies differ from those in normal tissue. It is unknown, however, whether there exist "surrogate" transcriptional markers in peripheral blood mononuclear cells (PBMCs) of patients with solid tumors. We identified transcripts expressed differentially between PBMCs from renal cell carcinoma patients and normal subjects, some of which appear to reflect specific immune responses of circulating cells. We also identified small sets of predictor genes distinguishing PBMCs from renal cell carcinoma patients and normal volunteers with high accuracy. The present findings have important implications for diagnosis and future clinical pharmacogenomic studies of antitumor therapies.

Adult↗
PubMed2003

Narrowband (312-nm) UV-B suppresses interferon gamma and interleukin (IL) 12 and increases IL-4 transcripts: differential regulation of cytokines at the single-cell level.

OBJECTIVE: To determine whether 312-nm UV-B alters production of effector and regulatory cytokines by viable T cells that remain in psoriatic lesions during UV-B phototherapy. DESIGN: Prospective study. SETTING: General clinical research center of The Rockefeller University Hospital. PATIENTS: Ten adult patients with moderate to severe psoriasis vulgaris that was difficult to manage were sequentially enrolled in our protocols, and biopsies were taken at various time points from resolving lesions. INTERVENTION: Narrowband (312-nm) UV-B was given starting at 50% of a minimum erythema dose, then increased daily 10% to 15% if no apparent erythema was induced. Patients continued with treatment until maximal benefit was noted. In some experiments, T cells were irradiated ex vivo with standard TL-01 fluorescent bulbs (Philips Lighting Co, Somerset, NJ). MAIN OUTCOME MEASURES: Intracellular cytokine staining was done using flow cytometry to quantify numbers of cytokine-producing cells from epidermal and peripheral T cells. The production of messenger RNA for interleukin (IL) 12, interferon (IFN) gamma, tumor necrosis factor alpha, IL-4, and IL-10 was measured by quantitative reverse transcription-polymerase chain reaction. RESULTS: Ultraviolet-B treatment eliminated production of IL-12 messenger RNA and decreased production of IFN-gamma messenger RNA by more than 60% in irradiated psoriasis lesions (P<.03 for both). Within 1 to 2 weeks of starting UV-B treatment, the frequency of viable T cells producing IFN-gamma decreased 40% to 65%. In contrast, mRNA for IL-4 increased by 82% (P =.05) during UV-B treatment, and the number of IL-4-producing cells increased by 228% after 1 week of treatment. In vitro experiments established that, on the single-cell level, survival and cytokine production by type 1 T cells were differentially regulated by UV-B. CONCLUSIONS: Therapeutic UV-B suppresses the type 1 (proinflammatory) axis as defined by IL-12, IFN-gamma, and IL-8, and can selectively reduce proinflammatory cytokine production by individual T cells. Knowledge of the immunomodulatory effects of UV-B will help to integrate this modality in future therapeutics for psoriasis based on deliberate blockade of inflammatory molecular pathways in the type 1 T-cell pathway.

Adult↗
PubMed1998

Interleukin-11. A gp130 cytokine.

Interleukin (IL)-11 is a member of the gp130 family of cytokines. Comparison of IL-11 with another gp130 family member, IL-6, indicates that these two cytokines share many overlapping signal transduction mechanisms. However, unlike IL-6, treatment of patients with a recombinant human form of IL-11 (rhIL-11) does not increase body temperature, suggesting significant differences in the in vivo function of these two molecules. Recent studies demonstrate that IL-11 has potent anti-inflammatory activity in a variety of preclinical animal models of disease. rhIL-11 reduces production of proinflammatory mediators such as tumor necrosis factor-alpha and IL-12 from activated macrophages. This effect on proinflammatory cytokine production is mediated at the transcriptional level by inhibition of the transcription factor, NF- kappa B. To further understand the anti-inflammatory mechanisms of action of rhIL-11 and to elucidate differences between IL-11 and IL-6 signal transduction pathways, the effects of these two cytokines on in vitro macrophage function were compared.

Animals↗