Fibulin-5 functions as an endogenous angiogenesis inhibitor.

Ablation of the fibulin-5 gene (fbln5) in mice results in loose skin, emphysematous lungs and tortuous vessels. Additionally, fbln5(-/-) animals display an apparent increase in vascular sprouting from systemic and cutaneous vessels. From these observations, we hypothesized that a de-regulation of vascular sprouting occurs in the absence of endogenous fibulin-5.

XP-828l in the treatment of mild to moderate psoriasis: randomized, double-blind, placebo-controlled study.

Background: XP-828L, a protein extract obtained from sweet whey, has demonstrated potential benefit for the treatment of mild to moderate psoriasis in an open-label study.

Objective: To study in a randomized, double-blind, placebo-controlled study the safety and efficacy of XP-828L in the treatment of mild to moderate psoriasis.

Design: XP-828L 5 g/d (group A, n = 42) or placebo (group B, n = 42) was given orally for 56 days followed by XP-828L 5 g/d in group A and by XP-828L 10 g/d in group B for an additional 56 days.

Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. International Society for Photodynamic Therapy in Dermatology, 2005.

Topical photodynamic therapy (PDT) is used to treat nonmelanoma skin cancers, such as actinic keratoses, Bowen's disease, and basal cell carcinoma (superficial and nodular). This article presents up-to-date, practical, evidence-based recommendations on the use of topical PDT using 5-aminolevulinic acid or methyl aminolevulinate for the treatment (and prevention) of nonmelanoma skin cancers. A systematic literature review was conducted (using MEDLINE), and recommendations were made on the basis of the quality of evidence for efficacy, safety/tolerability, cosmetic outcome, and patient satisfaction/preference.

Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays.

Retinoids have been found to be promising chemopreventive agents that play an important role in regulating cell growth, differentiation, and apoptosis. The action of retinoids is mediated by retinoid receptors (retinoic acid receptors and retinoid X receptors), which are nuclear transcription factors that, when bound to retinoids, regulate gene expression. LGD1069 is a highly selective RXR agonist that has reduced toxicity compared with retinoids.

Chemopreventative thoughts for photodynamic therapy.

The concept of skin cancer prevention with photodynamic therapy has evolved over the past few years to include large surface application of aminolevulinic acid or methyl aminolevulinate followed by light exposure to prevent the development of new lesions. Pre-clinical studies using various mouse models have shown that large surface photodynamic therapy can prevent the appearance of actinic keratoses, squamous cell carcinomas, and basal cell carcinomas. Recent clinical studies also suggest that large surface photodynamic therapy can prevent the development of actinic keratoses and possibly skin cancer.

Multiple large surface photodynamic therapy sessions with topical methylaminolaevulinate in PTCH heterozygous mice.

Background: Photodynamic therapy (PDT) combines the administration of a photosensitizer with its subsequent activation by light of the appropriate wavelength. Methylaminolaevulinate (MAL) is a photosensitizer precursor, transformed by cells into protoporphyrin IX. The PTCH gene plays a central role in the genesis of basal cell carcinoma (BCC).

A randomized, multicenter, double-blind, placebo-controlled phase 2 trial of ISA247 in patients with chronic plaque psoriasis.

Background: Use of current oral calcineurin inhibitors for the treatment of psoriasis is limited by toxicity.

Objective: Evaluate the safety and efficacy of ISA247, a new oral calcineurin inhibitor, in plaque psoriasis patients.

Methods: This 12-week, randomized, double-blind, placebo-controlled, parallel-group study included 201 plaque psoriasis patients with > or = 10% body surface area involvement.

Etanercept for the treatment of psoriasis.

Etanercept has recently been approved for the treatment of moderate-to-severe plaque psoriasis at a dose of 50mg twice per week for 12 weeks followed by a maintenance dose of 50mg once weekly thereafter. Clinical studies have shown excellent efficacy and a good safety profile in patients with psoriasis. Extensive information on etanercept safety is available as this biological agent has been used for many years for other indications such as rheumatoid arthritis, and psoriatic arthritis.

Receptor-selective retinoids inhibit the growth of normal and malignant breast cells by inducing G1 cell cycle blockade.

Despite advances in treatment, breast cancer continues to be the second leading cause of cancer mortality in women. Statistics suggest that while focus on treatment should continue, chemopreventive approaches should also be pursued. Previous studies have demonstrated that naturally occurring retinoids such as 9-cis retinoic acid (9cRA) can prevent breast cancer in animal models.

Differentiation and growth inhibition mediated via the RXR:PPARgamma heterodimer in colon cancer.

This study evaluated the anti-tumor efficacy of combining the RXR agonist, bexarotene, with the PPARgamma agonist, rosiglitazone, in colon cancer. Moser, a human colon cancer cell line, was treated with bexarotene and rosiglitazone alone or in combination and the effect on growth and differentiation were examined. The data demonstrated that the bexarotene/rosiglitazone combination produced greater efficacy in growth inhibition than either single agent.

Retinoid-induced mu opioid receptor expression by phytohemagglutinin-stimulated U937 cells.

Opioid use may be associated with an increased risk of neurological disease in human immunodeficiency virus (HIV) infection through effects on immune cell function. Studies were performed to examine the effects of specific retinoid receptor activation on mu opioid receptor (MOR) production by phytohemagglutinin (PHA)-stimulated U937 cells, a mononuclear cell line. PHA stimulation increased activation of the MOR promoter as well as levels of MOR mRNA, total receptor protein in cell lysates, and surface and cytoplasmic receptor expression.

The retinoid X receptor agonist bexarotene (Targretin) synergistically enhances the growth inhibitory activity of cytotoxic drugs in non-small cell lung cancer cells.

This study was designed to evaluate, using preclinical models of non-small cell lung cancer (NSCLC), the growth inhibitory effects of the retinoid X receptor (RXR) agonist bexarotene (LGD1069, Targretin) in combination with cytotoxic agents currently used as standard first-line therapy in advanced disease. Although single-agent bexarotene had modest growth inhibitory effects in several cell lines, efficacy was observed only in the micromolar range (>1muM), which approximates the plasma C(max) measured in pharmacokinetic studies in patients. However, when combined with paclitaxel or vinorelbine, bexarotene produced a concentration-dependent enhancement of the growth inhibitory activities of paclitaxel and vinorelbine.

Integrating biologic agents into management of moderate-to-severe psoriasis: a consensus of the Canadian Psoriasis Expert Panel. February 27, 2004.

Background: Approximately 2% of people worldwide have psoriasis, with as many as 1 million people with psoriasis in Canada alone.1,2 The severity of psoriasis ranges from mild to severe. It can lead to substantial morbidity and psychological stress and have a profound negative impact on patient quality of life.

The retinoid X receptor-selective retinoid, LGD1069, down-regulates cyclooxygenase-2 expression in human breast cells through transcription factor crosstalk: implications for molecular-based chemoprevention.

Retinoids and their derivatives can suppress the development of cancer in animals and in humans. We and others have shown that retinoid X receptor (RXR)-selective retinoids or "rexinoids" suppress the development of breast cancer in several animal models with minimal toxicity. LGD1069 (Bexarotene) is a potent RXR-selective retinoid with reduced toxicity compared with naturally occurring retinoids.

Multiple large-surface photodynamic therapy sessions with topical or systemic aminolevulinic acid and blue light in UV-exposed hairless mice.

Background: The use of photodynamic therapy (PDT) with topical aminolevulinic acid (ALA) on large skin surfaces has recently been reported for patients with multiple actinic keratoses.

Objective: The current study compared the ability of topical and systemic ALA-PDT as well as topical ALA-PDT with blue light to delay the appearance of UV-induced skin cancer using the hairless mouse as a model.

Methods: Groups of hairless mice were exposed daily to UV radiation and weekly to ALA-PDT.

A selective retinoid X receptor agonist bexarotene (Targretin) prevents and overcomes acquired paclitaxel (Taxol) resistance in human non-small cell lung cancer.

Purpose: Paclitaxel is an important anticancer agent for the treatment of non-small cell lung cancer (NSCLC). However, its use in cancer therapy is limited by development of acquired drug resistance. The goal of this study was to determine the effect of bexarotene on development of acquired paclitaxel resistance in NSCLC.

Nuclear receptor activation and interaction with morphine.

Nervous system disease in HIV infection is associated with toxic damage induced by effects from proinflammatory responses and oxidative stress, and such effects may be more prominent among opioid abusers. In these studies, the effects of activating retinoid receptor (retinoic acid receptor (RAR) and retinoid X receptor (RXR)) and peroxisome proliferator activated receptor (PPAR) gamma, which belong to the steroid-lipid nuclear receptor family, on tumor necrosis factor (TNF)-alpha production and inducible nitric oxide synthase (iNOS) gene expression by stimulated U937 and SVG cells, respectively, were examined. Also studied were the effects of morphine on these responses.

Irradiance and light dose influence histological localization of photodamage induced by photodynamic therapy with aminolaevulinic acid.

Background: Photodynamic therapy (PDT) with aminolaevulinic acid (ALA) is used in many countries for the treatment of actinic keratoses.

Objectives: The objectives of the current study were to evaluate the influence of irradiance and light dose on the localization and extent of photodamage to mouse skin following ALA-PDT.

Methods: In this study we evaluated the influence of irradiance and light dose on epidermal photodamage following ALA-PDT.

RXR-induced TNF-alpha suppression is reversed by morphine in activated U937 cells.

Deficiency in vitamin A has been associated with adverse clinical outcomes in drug users with HIV-1 infection. Retinoids have been demonstrated to suppress proinflammatory cytokine production by immune cells in vitro. These effects are induced by ligand-mediated activation of the retinoid receptors--retinoic acid receptor (RAR) and retinoid X receptor (RXR).

Photodynamic therapy of multiple nonmelanoma skin cancers with verteporfin and red light-emitting diodes: two-year results evaluating tumor response and cosmetic outcomes.

Background: Efficient treatment of patients with multiple synchronous nonmelanoma skin cancers represents a therapeutic challenge.

Objective: To study the safety and efficacy of photodynamic therapy (PDT) with verteporfin and red light in the treatment of multiple nonmelanoma skin cancers.

Design: Open-label, randomized, multicenter, dose-ranging phase 2 study conducted at 4 North American university-based dermatology clinics.

Restoration of hair growth with topical diphencyprone in mouse and rat models of alopecia areata.

Background: The contact sensitizer, diphencyprone (DPCP), is one of the most effective therapies for the more severe forms of alopecia areata (AA).

Objective: The purpose of this study was to determine the efficacy of topical DPCP on the 2 available rodent models for AA, and to determine the underlying therapeutic mechanisms.

Methods: AA-affected mice and rats were treated unilaterally with topical DPCP on the ventral and dorsal surface, respectively.

Repeated exposure to blue light does not improve psoriasis.

Background: Increased endogenous levels of protoporphyrin IX (PpIX) have been reported in the skin of patients with psoriasis. Activation of PpIX with blue light after exogenous topical application of its precursor, aminolevulinic acid, can improve psoriasis. Light activation of endogenous PpIX for the treatment of psoriasis has never been studied.

Expression, regulation, and activity of ABCA1 in human cell lines.

Mutations in the ATP-binding cassette transporter A1 (ABCA1) gene cause familial high-density lipoprotein deficiency and Tangier disease. ABCA1 plays a crucial role in active apolipoprotein A-I (apoA-I) lipidation, a key step in reverse cholesterol transport. We compared ABCA1 transcriptional regulation and cholesterol efflux in human skin fibroblasts, monocyte-derived macrophages and hepatocytes (HepG2).

Photodynamic therapy with toluidine blue in Jurkat cells: cytotoxicity, subcellular localization and apoptosis induction.

Toluidine blue (TBO) is a cationic thiazine dye with an affinity for neoplastic tissues in vivo. The objective of this study was to explore the in vitro photosensitizing potential of TBO and its capacity to induce apoptosis in human leukaemic T cells. Jurkat cells were incubated with TBO for one hour followed by exposure to 11 J cm(-2) of visible light from a slide projector.

Cellular phospholipid and cholesterol efflux in high-density lipoprotein deficiency.

Background: Prospective studies have examined the relationship between coronary artery disease and low plasma levels of high-density lipoprotein cholesterol (HDL-C).

Methods And Results: We investigated the causes of hypoalphalipoproteinemia (HypoA; HDL-C <5th percentile) in 64 subjects (12 women and 52 men). Apolipoprotein AI-mediated cellular cholesterol and phospholipid efflux were measured in fibroblasts from HypoA subjects, 9 controls, 2 patients with Tangier disease, and 5 patients with hyperalphalipoproteinemia.