A five-gene hedgehog signature developed as a patient preselection tool for hedgehog inhibitor therapy in medulloblastoma.

Purpose: Distinct molecular subgroups of medulloblastoma, including hedgehog (Hh) pathway-activated disease, have been reported. We identified and clinically validated a five-gene Hh signature assay that can be used to preselect patients with Hh pathway-activated medulloblastoma.

Experimental Design: Gene characteristics of the Hh medulloblastoma subgroup were identified through published bioinformatic analyses.

A single intradermal injection of IFN-γ induces an inflammatory state in both non-lesional psoriatic and healthy skin.

Psoriasis is a chronic, debilitating, immune-mediated inflammatory skin disease. As IFN-γ is involved in many cellular processes, including activation of dendritic cells (DCs), antigen processing and presentation, cell adhesion and trafficking, and cytokine and chemokine production, IFN-γ-producing Th1 cells were proposed to be integral to the pathogenesis of psoriasis. Recently, IFN-γ was shown to enhance IL-23 and IL-1 production by DCs and subsequently induce Th17 cells, which are important contributors to the inflammatory cascade in psoriatic lesions.

Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis.

Interleukin-17A (IL-17A) is elaborated by the T helper 17 (T(H)17) subset of T(H) cells and exhibits potent proinflammatory properties in animal models of autoimmunity, including collagen-induced arthritis, experimental autoimmune encephalomyelitis, and experimental autoimmune uveitis. To determine whether IL-17A mediates human inflammatory diseases, we investigated the efficacy and safety of AIN457, a human antibody to IL-17A, in patients with psoriasis, rheumatoid arthritis, and chronic noninfectious uveitis. Patients with chronic plaque-type psoriasis (n = 36), rheumatoid arthritis (n = 52), or chronic noninfectious uveitis (n = 16) were enrolled in clinical trials to evaluate the effects of neutralizing IL-17A by AIN457 at doses of 3 to 10 mg/kg, given intravenously.

Personalized medicine in psoriasis: developing a genomic classifier to predict histological response to Alefacept.

Background: Alefacept treatment is highly effective in a select group patients with moderate-to-severe psoriasis, and is an ideal candidate to develop systems to predict who will respond to therapy. A clinical trial of 22 patients with moderate to severe psoriasis treated with alefacept was conducted in 2002-2003, as a mechanism of action study. Patients were classified as responders or non-responders to alefacept based on histological criteria.

Identification of cellular pathways of "type 1," Th17 T cells, and TNF- and inducible nitric oxide synthase-producing dendritic cells in autoimmune inflammation through pharmacogenomic study of cyclosporine A in psoriasis.

Therapeutic modulation of psoriasis with targeted immunosuppressive agents defines inflammatory genes associated with disease activity and may be extrapolated to a wide range of autoimmune diseases. Cyclosporine A (CSA) is considered a "gold standard" therapy for moderate-to-severe psoriasis. We conducted a clinical trial with CSA and analyzed the treatment outcome in blood and skin of 11 responding patients.

Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells.

The importance of T helper 17 (Th17) cells in inflammation and autoimmunity is now being appreciated. We analyzed psoriasis skin lesions and peripheral blood for the presence of IL-17-producing T cells. We localized Th17 cells predominantly to the dermis of psoriasis skin lesions, confirmed that IL-17 mRNA increased with disease activity, and demonstrated that IL-17 mRNA expression normalized with cyclosporine therapy.

Bioinformatics tools enabling u-statistics for microarrays.

It is rare that a single gene is sufficient to represent all aspects of genomic activity. Similarly, most common diseases cannot be explained by a mutations at a single locus. Since complex systems tend to be neither linear nor hierarchical in nature, but to have correlated components of unknown relative importance, the assumptions of traditional (parametric) multivariate statistical methods can rarely be justified on theoretical grounds.

Insights into gene modulation by therapeutic TNF and IFNgamma antibodies: TNF regulates IFNgamma production by T cells and TNF-regulated genes linked to psoriasis transcriptome.

Therapeutic antibodies against tumor necrosis factor (TNF) (infliximab) and IFNgamma (fontolizumab) have been developed to treat autoimmune diseases. While the primary targets of these antibodies are clearly defined, the set of inflammatory molecules, which is altered by use of these inhibitors, is poorly understood. We elucidate the target genes of these antibodies in activated human peripheral blood mononuclear cells from healthy volunteers.

Cellular genomic maps help dissect pathology in human skin disease.

Genomic signature maps of different cell types can aid in the interpretation of genomic data of specimens collected during disease states. We have defined "lineage-specific" genes, as well as "activation" genes, for cellular components of the skin: keratinocytes, fibroblasts, macrophages, monocytes, T cells, immature, and mature dendritic cells (DCs). Re-analysis of a previously published gene set of psoriasis then provided a model for assessing the usefulness of these maps.

Novel insight into the agonistic mechanism of alefacept in vivo: differentially expressed genes may serve as biomarkers of response in psoriasis patients.

Alefacept is an LFA3-Ig fusion protein that binds to CD2 and is thought to inhibit T cell activation by antagonism of CD2 signaling or by lysis of CD2(+) cells. Alefacept is potential future therapeutic for organ transplant recipients or graft-vs-host disease and is an approved therapeutic for psoriasis vulgaris, which is a T cell-mediated inflammatory disease. However, alefacept improves psoriasis in only approximately 50% of patients treated for 12 wk.

Human basal cell carcinoma is associated with Foxp3+ T cells in a Th2 dominant microenvironment.

Basal cell carcinoma (BCC), the most common human cancer, undergoes spontaneous regression in certain circumstances, which is potentially immune-mediated. To understand the immune response surrounding BCCs, we characterized the genomic, protein, and cellular microenvironment associated with BCC in comparison to normal skin. Our results demonstrated the following: (1) CD4+ CD25+ Foxp3+ surround epithelial tumor aggregates; (2) Immature dendritic cells (DCs) were abundant in the tumor microenvironment; (3) BCC showed increased expression of IL-4, IL-10, and CCL22 and increased expression of interferon-associated genes (IFI27, IRF1, IRF7, and G1P2) and IL-12/23, gene indicating a Th2 dominant microenvironment.

Effects of etanercept are distinct from infliximab in modulating proinflammatory genes in activated human leukocytes.

Proinflammatory diseases like rheumatoid arthritis, Crohn's disease, and psoriasis have been treated by the tumor necrosis factor (TNF) antagonists infliximab and etanercept with different degrees of success. Although these agents are widely used in humans, little is known about their mechanisms of action or why etanercept and infliximab have differences in clinical activity. In this study, we define leukocyte genes that are suppressed by etanercept within 24 hours of exposure.

Major differences in inflammatory dendritic cells and their products distinguish atopic dermatitis from psoriasis.

Background: Atopic dermatitis (AD) and psoriasis represent contrasting poles of the T(H)1 versus T(H)2 paradigm. Both diseases have been associated with increased numbers of dendritic cells (DCs) in the skin, but the similarities and differences in DC populations need to be established.

Objective: We aimed to characterize the specific DC subsets, as well as chemokine and cytokine environment in chronic AD compared with psoriasis.

Prominent production of IL-20 by CD68+/CD11c+ myeloid-derived cells in psoriasis: Gene regulation and cellular effects.

We assessed expression of IL-20 and its receptors in psoriasis, given the recent implication of IL-20 in epidermal hyperplasia. Psoriatic lesional (LS) skin consistently expressed more IL-20 mRNA than nonlesional (NL) skin. Immunoreactivity to IL-20 protein was greater in LS tissue and mainly localized to infiltrating CD68+/CD11c+ (myeloid-derived) dermal leukocytes.

Genomic analysis defines a cancer-specific gene expression signature for human squamous cell carcinoma and distinguishes malignant hyperproliferation from benign hyperplasia.

Using high-density oligonucleotide arrays, we measured expression of >12,000 genes in surgical excisions of invasive human squamous cell carcinomas (SCCs) versus site-matched control skin. This analysis defined >1,900 genes with altered expression in SCCs that were statistically different from controls. As SCCs are composed of epithelial cells, which are both hyperplastic and invasive, we sought to define gene sets associated with these biologic processes by comparing gene expression to psoriasis vulgaris, which is a condition of benign keratinocyte hyperplasia without invasiveness or pre-malignant potential.

"Harshlighting" small blemishes on microarrays.

Background: Microscopists are familiar with many blemishes that fluorescence images can have due to dust and debris, glass flaws, uneven distribution of fluids or surface coatings, etc. Microarray scans show similar artefacts, which affect the analysis, particularly when one tries to detect subtle changes. However, most blemishes are hard to find by the unaided eye, particularly in high-density oligonucleotide arrays (HDONAs).

Dual functionality of cyclooxygenase-2 as a regulator of tumor necrosis factor-mediated G1 shortening and nitric oxide-mediated inhibition of vascular smooth muscle cell proliferation.

Background: Cyclooxygenase (COX)-2 contributes to vascular smooth muscle cell (VSMC) proliferation induced by tumor necrosis factor (TNF) and angiotensin II. The present study demonstrates, however, that depending on prevailing conditions, COX-2-derived prostanoids may also inhibit VSMC proliferation.

Methods And Results: TNF-alpha stimulated proliferation of VSMCs by shortening the G1 phase of the cell cycle.

In vitro model of "wound healing" analyzed by laser scanning cytometry: accelerated healing of epithelial cell monolayers in the presence of hyaluronate.

Background: In vitro models of "wound healing" rely on analysis of confluent cell cultures that are mechanically wounded, e.g., by scratching the cell monolayer.

Regulation of cyclooxygenase by the heme-heme oxygenase system in microvessel endothelial cells.

Heme oxygenase (HO) is a microsomal enzyme that oxidatively cleaves heme to form biliverdin, with the release of iron and carbon monoxide (CO). HO not only controls the availability of heme for the synthesis of heme proteins but also is responsible for the generation of CO, which binds to the heme moiety of heme proteins thus affecting their enzymatic activity. Cyclooxygenase (COX) is a heme protein that catalyzes the conversion of arachidonic acid to prostaglandin H(2), the precursor of prostanoids that participate in the regulation of vascular function.