Laurent Meunier

High plasma proteasome levels are detected in patients with metastatic malignant melanoma

Background  Proteasomes, nonlysosomal proteolytic structures, are implicated in cell growth and differentiation. An abnormal expression has been described in haematopoietic malignancies and in some solid tumours.

Treatment with taxanes of refractory or life-threatening Kaposi sarcoma not associated with human immunodeficiency virus infection.

Kaposi sarcoma (KS) is an angioproliferative disease that may represent a difficult therapeutic challenge in disseminated stages. The efficacy of taxanes (paclitaxel and docetaxel), as agents with antiangiogenic properties, has been described previously in the treatment of patients with acquired immunodeficiency syndrome (AIDS)‐associated KS but remains unknown in the treatment of patients with refractory or life‐threatening KS without human immunodeficiency (HIV) infection.

MC1R expression in HaCaT keratinocytes inhibits UVA-induced ROS production via NADPH oxidase- and cAMP-dependent mechanisms.

Ultraviolet A (UVA) radiations are responsible for deleterious effects, mainly due to reactive oxygen species (ROS) production. Alpha‐melanocyte stimulating hormone (α‐MSH) binds to melanocortin‐1 receptor (MC1R) in melanocytes to stimulate pigmentation and modulate cutaneous inflammatory responses. MC1R may be induced in keratinocytes after UV exposure. To investigate the effect of MC1R signaling on UVA‐induced ROS (UVA‐ROS) production, we generated HaCaT cells that stably express human MC1R (HaCaT‐MC1R) or the Arg151Cys (R151C) non‐functional variant (HaCaT‐R151C). We then assessed ROS production immediately after UVA exposure and found that: (1) UVA‐ROS production was strongly reduced in HaCaT‐MC1R but not in HaCaT‐R151C cells compared to parental HaCaT cells; (2) this inhibitory effect was further amplified by incubation of HaCaT‐MC1R cells with α‐MSH before UVA exposure; (3) protein kinase A (PKA)‐dependent NoxA1 phosphorylation was increased in HaCaT‐MC1R compared to HaCaT and HaCaT‐R151C cells. Inhibition of PKA in HaCaT‐MC1R cells resulted in a marked increase of ROS production after UVA irradiation; (4) the ability of HaCaT‐MC1R cells to produce UVA‐ROS was restored by inhibiting epidermal growth factor receptor (EGFR) or extracellular signal‐regulated kinases (ERK) activity before UVA exposure. Our findings suggest that constitutive activity of MC1R in keratinocytes may reduce UVA‐induced oxidative stress via EGFR and cAMP‐dependent mechanisms. J. Cell. Physiol. 227: 2578–2585, 2012.

Nevus anemicus in neurofibromatosis type 1: a potential new diagnostic criterion.

BACKGROUND Children with multiple café-au-lait macules (CALMs) may be followed for years before a second National Institutes of Health clinical criterion of neurofibromatosis type 1 (NF1) develops to confirm the diagnosis. OBJECTIVE We sought to assess the prevalence of nevus anemicus (NA) in NF1 and its association with neuro-ophthalmologic complications. METHODS This was a prospective multicenter case-control study of 210 consecutive patients with multiple CALMs. Patients with NF1 were matched for age, sex, and center with control subjects. We documented the number, location, and morphologic appearance of NA; dermatologic features of NF1; magnetic resonance imaging results; and family history. RESULTS In all, 77 (51%) patients with NF1 had NA compared with 6 (2%) control subjects. NA was not detected in 26 patients with other genodermatoses associated with CALMs. Patients with NF1 and NA were younger than those without NA (median age: 17 years) (P = .002). NA was mostly localized to the upper anterior aspect of the chest. NA was not significantly linked with other clinical manifestations of NF1, including optic glioma and unidentified bright objects. LIMITATIONS A potential referral bias associated with tertiary care centers is a limitation. CONCLUSIONS NA appears to have a high prevalence and specificity in NF1 and might serve as a marker for NF1 in children with multiple CALMs.

Decreased human epidermal antigen‐presenting cell activity after ultraviolet A exposure: dose–response effects and protection by sunscreens

Background  Ultraviolet (UV) exposure of human skin causes immunosuppression that contributes to the growth of skin cancer. The contribution of UVA in these processes is still a matter of debate.

Diagnostic value and prognostic significance of plasmatic proteasome level in patients with melanoma

Abstract:  Plasmatic proteasome (p‐proteasome) also called circulating proteasome has recently been described as a tumor marker. We investigated the diagnostic and prognostic accuracies of p‐proteasome levels in a melanoma population classified according to the American Joint Committee on Cancer staging system. Using an ELISA test, we measured p‐proteasome levels in 90 patients and 40 controls between March 2003 and March 2008. The subunit composition of p‐proteasomes was determined in metastatic melanoma by proteomic analysis. The mean p‐proteasome levels were correlated with stages (P < 0.0001; rS = 0.664). They were significantly higher in patients with stage IV and stage III with lymph node metastasis (9187 ± 1294 and 5091 ± 454 ng/ml, respectively) compared to controls (2535 ± 187 ng/ml; P < 0.001), to stage I/II (2864 ± 166 ng/ml; P < 0.001) and to stage III after curative lymphadenectomy (2859 ± 271 ng/ml; P < 0.001). The diagnostic accuracy of p‐proteasome was evaluated by receiver operating characteristic analysis. With a cut‐off of 4300 ng/ml, diagnostic specificity and sensitivity of p‐proteasome for regional or visceral metastases were respectively 96.3% and 72.2%. In univariate analysis, high p‐proteasome levels (>4300 ng/ml) were significantly correlated with an increased risk of progression [hazard ratio (HR) = 7.34; 95% CI 3.54–15.21, P < 0.0001] and a risk of death (HR = 5.92; 95% CI 2.84–12.33, P < 0.0001). In multivariate analysis, high p‐proteasome levels were correlated with a poorer clinical outcome in the subgroup analysis limited to patients with disease stages I, II and III. Proteomic analysis confirmed the presence of all proteasome and immunoproteasome subunits. Taken together, these results indicate that p‐proteasomes are a new marker for metastatic dissemination in patients with melanoma.

The nuclear export signal-dependent localization of oligonucleopeptides enhances the inhibition of the protein expression from a gene transcribed in cytosol

Upon endocytosis, most oligodeoxynucleotides (ODNs) accumulate in vesicular compartments; a tiny number of them cross the vesicle membrane, reach the cytosol and by passive diffusion enter the nucleus where they are entrapped. So far, the compartment in which an antisense ODN interacts with its mRNA target has not been precisely characterized. In an attempt to answer this question, ODN-peptides were designed with the aim of maintaining them in the cytosol. This has been achieved by a short peptide sequence called the nuclear export signal (NES). Upon microinjection, ODN-NES peptide conjugates were efficiently and rapidly exported from the nucleus to the cytosol whereas ODN-peptides containing an inactive NES were found to be located in the nucleus. The inhibitory activity of antisense ODN was tested in a system allowing the specific transcription of a luciferase reporter gene in the cytosol. Antisense propynylated ODN-NES peptide conjugates, directed against the luciferase gene, efficiently inhibited (75%) the cytosolic expression of luciferase whereas at the same concentration the peptide-free propynylated ODN or the propynylated ODN-peptides containing an inactive NES were nearly inactive.

Familial Eruptive Pseudoangiomatosis

In 1969, Cherry et al. [1] first described 4 children with an acute echovirus infection who had hemangioma-like skin lesions. Later Prose et al. [2] reported 3 additional cases of such vascular lesions and proposed the name of ‘eruptive pseudoangiomatosis’ (EPA) to design this entity. Similar cases have been described in adulthood indicating that EPA is not restricted to children [3]. We describe a case of EPA arising concomitantly in a mother and her daughter. This observation strongly suggests that a transmissible vector such as a virus is involved in the pathogenesis of EPA. A 6-month-old girl had asymptomatic bright red papules surrounded by a 2to 3-mm halo of blanching on the face, the trunk and the extremities that developed within 3 days (fig. 1). The lesions blanched completely with pressure and rapidly refilled from the center after release. The onset of lesions coincided with the resolution of an upper respiratory tract infection. All the lesions completely resolved within 3 weeks. At the same time, her mother, a 27-yearold woman, had identical lesions strictly localized to the legs and the arms (fig. 1). This exanthema appeared without any associated symptom and resolved spontaneously within 2 weeks. Routine laboratory results of the mother were normal, and serological testing was negative or highlighted an old infection by echovirus, enterovirus, cytomegalovirus, parvovirus B19, hepatitis B and hepatitis C virus. Histological examination showed slightly dilated capillaries in the papillary dermis and a sparse perivascular lymphocytic infiltrate. The vessels were not increased in number, and the epidermis was normal. EPA is a rare, benign, spontaneously regressing exanthema that occurrs preferentially in children. Clinically, this asymptomatic eruption is characterized by the occurrence of bright red angiomatous papules surrounded by a 2to 6-mm halo of blanching. Histological findings show dilated dermal blood vessels with plump endothelial cells but no evidence of an increased number of vessels [2]. The differential diagnosis includes multiple eruptive capillary hemangiomas, multiple pyogenic granuloma, bacillary angiomatosis, bartonellosis, insect bites, telangiectases and spider angiomas [4]. The etiology of EPA is still unknown. However, most pediatric cases appeared after prodromal symptoms such as fever, diarrhea or respiratory infections indicating that this eruption may be due to a viral infection [1]. The occurrence of 2 cases of pediatric EPA within a family could confirm this hypothesis [5]. Recently, some adulthood cases of EPA have also been reported [3]. In these observations, the eruption occurred more commonly in females, did not systematically follow an episode of fever and was longer than in childhood [3]. In some patients, the existence of an immune deficiency or a life in collectivity (hospital, retirement home) may favor the development of a Fig. 1. EPA: bright red papules in the mother and child.

A single sub-erythematous exposure of solar-simulated radiation on the elicitation phase of contact hypersensitivity induces IL-10-producing T-regulatory cells in human skin

Abstract:  Solar ultraviolet (UV) radiation has hazardous effects on human health that are, in part, associated with its immunosuppressive effects via the induction of interleukin (IL)‐10 production. Although IL‐10 is produced by both T helper type 2 (Th2) cells and T‐regulatory type 1 (Tr1) cells, the relative contribution of either subset in UV radiation‐induced immunosuppression has not been established. Here, we show that T cells isolated from non‐treated allergic contact dermatitis (ACD) reactions, 48 h following nickel challenge and propagated for 7–10 days in the presence of IL‐2, were mainly CD4+ and produced IL‐10, but little interferon‐γ. A single sub‐erythematous solar‐simulated radiation (SSR) prior to antigen challenge exposure resulted in a clinical attenuation of the intensity of ACD reactions which was associated with a significant increase in both the magnitude of IL‐10 production by skin‐infiltrating T cells and the frequency of IL‐10‐producing Tr1 cells. Skin‐infiltrating T cells in SSR‐exposed, as well as non‐exposed, ACD reactions showed a perturbed T‐cell receptor (TCR)‐Vβ repertoire, without overexpression of a particular TCR‐Vβ gene product, indicating the presence of high frequencies of nickel non‐specific T cells in ACD reactions. These results show that a single sub‐erythematous SSR induces immunosuppression via the cutaneous infiltration of IL‐10‐producing Tr1, and to a lesser extent, Th2 cells.

Photothérapie à spectre étroit dans le traitement du lichen plan cutané disséminé

Resume Introduction La PUVAtherapie, l’acitretine et la corticotherapie generale sont actuellement les traitements de premiere ligne du lichen plan cutane dissemine. Nous avons etudie, l’efficacite des UVB a spectre etroit dans cette indication. Malades et methode Il s’agissait d’une etude retrospective sur dossiers etudiant les malades atteints d’un lichen plan cutane dissemine et traites par phototherapie a spectre etroit dans l’unite de phototherapie du CHU de Montpellier pendant la periode de mai 1994 a novembre 2001. Le lichen plan cutane dissemine etait defini comme un lichen affectant au moins 20 p. 100 de la surface cutanee. Vingt malades ont ete inclus. Les UVB etaient delivres 3 fois par semaine par une cabine Philips TL01 (311-313 nm). Le protocole etait celui utilise pour le traitement du psoriasis. Nous avons defini 4 types de reponse : reponse complete (disparition de plus de 90 p. 100 des lesions), reponse partielle (disparition d’au moins 50 p. 100 des lesions), reponse mediocre (amelioration comprise entre 20 et 50 p. 100 des lesions), echec (diminution de moins de 20 p. 100 des lesions). L’evaluation de la recidive a long terme a ete realisee par une enquete telephonique aupres des malades ou de leur medecin traitant. Resultats Une reponse complete a ete obtenue chez 11 malades sur 20 (55 p. 100), une reponse partielle a ete observee chez 4 malades (20 p. 100), ce qui correspond a 75 p. 100 de repondeurs. La reponse a ete obtenue avec un delai median de 3 mois avec des extremes allant de 2 a 6 mois, apres une mediane de 30 seances (12 a 50) et une dose cumulee d’UVB de 36 ± 4,8 joules/cm2. Le phototype, le sexe, l’âge et la duree d’evolution avant traitement n’ont pas eu d’influence sur la reponse. La recidive a ete estimee a 18 p. 100 (2/11) apres 42 mois d’interruption du traitement. Discussion Ces resultats nous paraissent en faveur de l’efficacite des UVB a spectre etroit dans le traitement du lichen plan cutane dissemine. Ils confirment ceux des etudes precedentes et sont superposables a ceux de la PUVAtherapie orale.