A Report on the Safety of Acitretin Use in Renal Failure Patients on Hemodialysis.

Acitretin, commonly used for severe psoriasis and keratinocyte carcinoma chemoprevention in high-risk patients, is contraindicated in patients with end stage renal disease on hemodialysis. However, these patients often lack medication choices and in certain clinical scenarios, the benefits of acitretin may outweigh the potential risks. We identified 24 end stage renal disease patients on HD taking acitretin from Duke and Vanderbilt University Medical Centers. While adverse effects were common, patients did not frequently discontinue the medication due to them. We also found no association between acitretin with hospital admissions or mortality. We lastly found statistically significant increases in ALP and total bilirubin when on acitretin and dialysis compared to baseline. However, there was no dose-dependency or temporal association with acitretin or hemodialysis initiation. Based off these preliminary findings, we find that acitretin may safely be used in patients receiving HD with close monitoring of ALP and bilirubin.

Signal transduction at GPCRs: Allosteric activation of the ERK MAPK by ß-arrestin.

ß-arrestins are multivalent adaptor proteins that bind active phosphorylated G protein-coupled receptors (GPCRs) to inhibit G protein signaling, mediate receptor internalization, and initiate alternative signaling events. ß-arrestins link agonist-stimulated GPCRs to downstream signaling partners, such as the c-Raf-MEK1-ERK1/2 cascade leading to ERK1/2 activation. ß-arrestins have been thought to transduce signals solely via passive scaffolding by facilitating the assembly of multiprotein signaling complexes. Recently, however, ß-arrestin 1 and 2 were shown to activate two downstream signaling effectors, c-Src and c-Raf, allosterically. Over the last two decades, ERK1/2 have been the most intensely studied signaling proteins scaffolded by ß-arrestins. Here, we demonstrate that ß-arrestins play an active role in allosterically modulating ERK kinase activity in vitro and within intact cells. Specifically, we show that ß-arrestins and their GPCR-mediated active states allosterically enhance ERK2 autophosphorylation and phosphorylation of a downstream ERK2 substrate, and we elucidate the mechanism by which ß-arrestins do so. Furthermore, we find that allosteric stimulation of dually phosphorylated ERK2 by active-state ß-arrestin 2 is more robust than by active-state ß-arrestin 1, highlighting differential capacities of ß-arrestin isoforms to regulate effector signaling pathways downstream of GPCRs. In summary, our study provides strong evidence for a new paradigm in which ß-arrestins function as active "catalytic" scaffolds to allosterically unlock the enzymatic activity of signaling components downstream of GPCR activation.

Long-term follow up of ALA 10% gel and red-light photodynamic therapy for the treatment of squamous cell carcinoma in situ.

Photodynamic Therapy (PDT) with 10% aminolevulinic acid (ALA) gel and narrow-band red light has been previously shown to be safe and effective for the treatment of squamous cell carcinoma in situ (SCCis) on the trunk and extremities. However, there is a paucity of data in the literature evaluating long-term disease recurrence after PDT. Hence, we performed a follow-up study in which nine of the original twelve patients from our pilot study returned 29-40 months after their last PDT treatment. All patients were clinically clear of disease and only one of seven patients biopsied had residual disease, indicating a long-term clearance rate of 88%. Cosmetic outcomes and patient satisfaction were favorable. Our data supports that red-light PDT with 10% ALA gel can achieve long-term clinical and histopathologic disease clearance and is a viable alternative to surgery for select SCCis.

Photodynamic therapy for extramammary Paget's disease: A systematic review of the literature.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare intraepithelial adenocarcinoma that arises in areas rich in apocrine sweat glands. Photodynamic therapy (PDT) is a non-invasive technique demonstrating clinical efficacy in various case reports and case series for the treatment of EMPD. METHODS: A review of the current literature of patients with EMPD treated with PDT. RESULTS: 177 patients with 211 lesions were included in this review with an overall complete response rate of 59.7 %. Lesion size was correlated with the efficacy of 5-aminolevulinic acid (ALA) PDT. Topical methyl-ALA had lower complete response rates compared to ALA. Systemic PDT with intravenous sodium porfimer had high response rates but can be associated with more adverse reactions. The efficacy of PDT was enhanced with the combination of other treatments such as surgery, imiquimod, or laser ablation. PDT was also shown to be effective for previously treated lesions, recurrent lesions, and select invasive lesions. CONCLUSION: PDT can be a therapeutic option for EMPD patients. Given the lack of PDT guidelines, general recommendations for treatment are offered.

Mechanism of ß2AR regulation by an intracellular positive allosteric modulator.

Drugs targeting the orthosteric, primary binding site of G protein-coupled receptors are the most common therapeutics. Allosteric binding sites, elsewhere on the receptors, are less well-defined, and so less exploited clinically. We report the crystal structure of the prototypic ß2-adrenergic receptor in complex with an orthosteric agonist and compound-6FA, a positive allosteric modulator of this receptor. It binds on the receptor's inner surface in a pocket created by intracellular loop 2 and transmembrane segments 3 and 4, stabilizing the loop in an α-helical conformation required to engage the G protein. Structural comparison explains the selectivity of the compound for ß2- over the ß1-adrenergic receptor. Diversity in location, mechanism, and selectivity of allosteric ligands provides potential to expand the range of receptor drugs.

Small-Molecule Positive Allosteric Modulators of the ß2-Adrenoceptor Isolated from DNA-Encoded Libraries.

Conventional drug discovery efforts at the ß2-adrenoceptor (ß2AR) have led to the development of ligands that bind almost exclusively to the receptor's hormone-binding orthosteric site. However, targeting the largely unexplored and evolutionarily unique allosteric sites has potential for developing more specific drugs with fewer side effects than orthosteric ligands. Using our recently developed approach for screening G protein-coupled receptors (GPCRs) with DNA-encoded small-molecule libraries, we have discovered and characterized the first ß2AR small-molecule positive allosteric modulators (PAMs)-compound (Cmpd)-6 [(R)-N-(4-amino-1-(4-(tert-butyl)phenyl)-4-oxobutan-2-yl)-5-(N-isopropyl-N-methylsulfamoyl)-2-((4-methoxyphenyl)thio)benzamide] and its analogs. We used purified human ß2ARs, occupied by a high-affinity agonist, for the affinity-based screening of over 500 million distinct library compounds, which yielded Cmpd-6. It exhibits a low micro-molar affinity for the agonist-occupied ß2AR and displays positive cooperativity with orthosteric agonists, thereby enhancing their binding to the receptor and ability to stabilize its active state. Cmpd-6 is cooperative with G protein and ß-arrestin1 (a.k.a. arrestin2) to stabilize high-affinity, agonist-bound active states of the ß2AR and potentiates downstream cAMP production and receptor recruitment of ß-arrestin2 (a.k.a. arrestin3). Cmpd-6 is specific for the ß2AR compared with the closely related ß1AR. Structure-activity studies of select Cmpd-6 analogs defined the chemical groups that are critical for its biologic activity. We thus introduce the first small-molecule PAMs for the ß2AR, which may serve as a lead molecule for the development of novel therapeutics. The approach described in this work establishes a broadly applicable proof-of-concept strategy for affinity-based discovery of small-molecule allosteric compounds targeting unique conformational states of GPCRs.

Design, synthesis, and functional assessment of Cmpd-15 derivatives as negative allosteric modulators for the ß2-adrenergic receptor.

The ß2-adrenergic receptor (ß2AR), a G protein-coupled receptor, is an important therapeutic target. We recently described Cmpd-15, the first small molecule negative allosteric modulator (NAM) for the ß2AR. Herein we report in details the design, synthesis and structure-activity relationships (SAR) of seven Cmpd-15 derivatives. Furthermore, we provide in a dose-response paradigm, the details of the effects of these derivatives in modulating agonist-induced ß2AR activities (G-protein-mediated cAMP production and ß-arrestin recruitment to the receptor) as well as the binding affinity of an orthosteric agonist in radio-ligand competition binding assay. Our results show that some modifications, including removal of the formamide group in the para-formamido phenylalanine region and bromine in the meta-bromobenzyl methylbenzamide region caused dramatic reduction in the functional activity of Cmpd-15. These SAR results provide valuable insights into the mechanism of action of the NAM Cmpd-15 as well as the basis for future development of more potent and selective modulators for the ß2AR based on the chemical scaffold of Cmpd-15.

Clinical experience of Ganz surgical dislocation approach for metal-on-metal hip resurfacing.

Although the posterior approach is the most commonly used for hip resurfacing, concerns remain in terms of risk of femoral neck fracture secondary to an osteonecrotic event. The purpose of this study was to look at the short-term results of metal-on-metal hip resurfacing done by the vascular-preserving surgical approach as developed by Ganz in 116 hip resurfacing arthroplasties performed in 106 patients (86 men, 20 women; mean age, 46.5 years; range, 19-62). At a mean follow-up of 38.3 months (range, 12-84), Harris Hip Scores improved significantly from 53.1 to 90.16 (P < .001). There were 10 nonunions (8.7%) and 21 hips (18.3%) requiring screw removal for painful bursitis. Two hips underwent conversion to total hip arthroplasty: one at 18 months for femoral loosening and one at 7 years for acetabular loosening. Although the trochanteric slide approach as developed by Ganz provides excellent exposure to the hip joint and preserves femoral head vascularity, it does carry some inherent morbidity in regard to the greater trochanter.

Femoral head blood flow during hip resurfacing.

Preserving femoral head vascularity during hip resurfacing may avoid femoral neck fractures and late femoral loosening. The posterior approach and notching of the femoral neck influence femoral head perfusion. However, it is not known if standard preparation of the femoral head during hip resurfacing can disrupt blood flow. Ten patients (10 hips) with advanced osteoarthritis having metal-on-metal hip resurfacing by means of a vascular-preserving surgical approach had femoral head blood flow measurements using laser Doppler flowmetry. Nine hips had a mean decrease of 70% in femoral head blood flow after standard reaming and preparation. The data suggest femoral head reaming during hip resurfacing substantially impacts blood flow to the femoral head and infers the extra osseous blood supply is still important in the arthritic femoral head. To avoid damaging the retinacular vessels, surgeons should direct the cylindrical reamer superolaterally staying as close as possible to the inferomedial neck.