Intraoral Spitz naevus: a case report

Intraoral occurrences of Spitz naevus are very rare, there being only one previously documented case in the literature. Here is reported a case of a young male who presented with a pigmented lesion of the upper labial mucosa which had the clinical appearance of a simple naevus. Excision biopsy confirmed this to be a Spitz naevus. This lesion shares histopathological similarities with malignant melanoma. Spitz naevus is a benign lesion, but malignant transformation has been reported and close monitoring is recommended.     

A soluble activin type IIA receptor induces bone formation and improves skeletal integrity

Diseases that affect the regulation of bone turnover can lead to skeletal fragility and increased fracture risk. Members of the TGF-beta superfamily have been shown to be involved in the regulation of bone mass. Activin A, a TGF-beta signaling ligand, is present at high levels in bone and may play a role in the regulation of bone metabolism. Here we demonstrate that pharmacological blockade of ligand signaling through the high affinity receptor for activin, type II activin receptor (ActRIIA), by administration of the soluble extracellular domain of ActRIIA fused to a murine IgG2a-Fc, increases bone formation, bone mass, and bone strength in normal mice and in ovariectomized mice with established bone loss. These observations support the development of this pharmacological strategy for the treatment of diseases with skeletal fragility.     

A novel therapeutic approach to treating obesity through modulation of TGFβ signaling

Obesity results from disproportionately high energy intake relative to energy expenditure. Many therapeutic strategies have focused on the intake side of the equation, including pharmaceutical targeting of appetite and digestion. An alternative approach is to increase energy expenditure through physical activity or adaptive thermogenesis. A pharmacological way to increase muscle mass and hence exercise capacity is through inhibition of the activin receptor type IIB (ActRIIB). Muscle mass and strength is regulated, at least in part, by growth factors that signal via ActRIIB. Administration of a soluble ActRIIB protein comprised of a form of the extracellular domain of ActRIIB fused to a human Fc (ActRIIB-Fc) results in a substantial muscle mass increase in normal mice. However, ActRIIB is also present on and mediates the action of growth factors in adipose tissue, although the function of this system is poorly understood. In the current study, we report the effect of ActRIIB-Fc to suppress diet-induced obesity and linked metabolic dysfunctions in mice fed a high-fat diet. ActRIIB-Fc induced a brown fat-like thermogenic gene program in epididymal white fat, as shown by robustly increased expression of the thermogenic genes uncoupling protein 1 and peroxisomal proliferator-activated receptor-γ coactivator 1α. Finally, we identified multiple ligands capable of reducing thermogenesis that represent likely target ligands for the ActRIIB-Fc effects on the white fat depots. These data demonstrate that novel therapeutic ActRIIB-Fc improves obesity and obesity-linked metabolic disease by both increasing skeletal muscle mass and by inducing a gene program of thermogenesis in the white adipose tissues.     

Prevention of cachexia-like syndrome development and reduction of tumor progression in inhibin-deficient mice following administration of a chimeric activin receptor type II-murine Fc protein

Inhibin is a secreted tumor suppressor, and inhibin alpha null mice develop gonadal sex cord-stromal tumors with 100% penetrance at an early age. Inhibin-deficient mice die of a severe wasting syndrome due to increased activin signaling through activin receptor type II. The current study was designed to assess the in vivo effects of an activin antagonist, a chimeric activin receptor type II fused to the Fc region of a murine IgG2a (ActRII-mFc), administered transiently to the inhibin-deficient mice. Results showed that the severe weight loss was prevented in the ActRII-mFc-treated mice, FSH levels were reduced, and an extended life span was observed for these mice compared with phosphate-buffered saline-treated controls. Although ActRII-mFc treatment did not seem to prevent the formation of gonadal tumors, tumors were smaller in the majority of experimentally treated mice and were characterized by the presence of variable numbers and sizes of cysts in contrast to the solid hemorrhagic tumors that typically developed in the controls. Moreover, the ActRII-mFc-treated mice were less anemic, and their livers and stomachs were histologically normal. In summary, this study demonstrated that in vivo administration of the activin antagonist, ActRII-mFc, not only prevents the cachexia-like symptoms in the inhibin-deficient mouse model, but also reduces tumor progression. These results support an essential role of activins in the cachexia-like syndrome development and implicate activins as growth-promoting factors in gonadal tumor progression. The current findings have potential implications in the design of new drugs or strategies for the treatment of ovarian and testicular tumors and other conditions where ligands signal through ActRII.     

Single‐Dose,Randomized, Double‐Blind,Placebo‐Controlled Study of ACE‐011 (ActRIIA‐IgG1) in Postmenopausal Women

The effects of ACE‐011 on safety, pharmacokinetics, and bone biomarkers were evaluated in healthy, postmenopausal women. Our data indicate that ACE‐011 results in a sustained increase in biomarkers of bone formation and reduction in markers of bone resorption. The activin type IIA receptor (ActRIIA) is the high‐affinity receptor for activin. ACE‐011 is a dimeric fusion protein consisting of the extracellular domain of the human ActRIIA linked to the Fc portion of human IgG1. ACE‐011 binds to activin, preventing activin from binding endogenous receptors. A randomized, double‐blind, placebo‐controlled study was conducted to evaluate the safety and tolerability of ACE‐011. Forty‐eight healthy, postmenopausal women were randomized to receive either a single dose of ACE‐011 or placebo and were followed for 4 mo. Dose levels ranged from 0.01 to 3.0 mg/kg intravenously and from 0.03 to 0.1 mg/kg subcutaneously. Safety and pharmacokinetic (PK) analyses and the biological activity of ACE‐011, as assessed by markers of bone turnover, and follicle stimulating hormone (FSH) levels were measured. No serious adverse events (AEs) were reported. AEs were generally mild and transient. The PK of ACE‐011 was linear over the dose range studied, with a mean half‐life of 24–32 days. The absorption after subcutaneous dosing was essentially complete. ACE‐011 caused a rapid and sustained dose‐dependent increase in serum levels of bone‐specific alkaline phosphatase (BSALP) and a dose‐dependent decrease in C‐terminal type 1 collagen telopeptide (CTX) and TRACP‐5b levels. There was also a dose‐dependent decrease in serum FSH levels consistent with inhibition of activin. ACE‐011 is a novel agent with biological evidence of both an increase in bone formation and a decrease in bone resorption. ACE‐011 may be an effective therapy in a variety of diseases involving bone loss.