[Dermatologic toxicities of immune checkpoint inhibitors]. / Toxicités dermatologiques des inhibiteurs de checkpoint immunologiques.

The development of immune checkpoint inhibitors (monoclonal antibodies targeting PD-1/PD-L1 or CTLA-4) represents a significant advance in the treatment of multiple cancers. Given their particular mechanism of action, which involves triggering CD4+/CD8+ T-cell activation and proliferation, they are associated with a specific safety profile. Their adverse events are primarily immune-related, and can affect practically all organs. In this context, dermatological toxicity is the most common, though it mostly remains mild to moderate and does not require discontinuation of treatment. More than a third of patients are faced with cutaneous adverse events, usually in the form of a maculopapular rash, pruritus or vitiligo (only in patients treated for melanoma). Much more specific dermatologic disorders, however, may occur such as lichenoid reactions, induced psoriasis, sarcoidosis, auto-immune diseases (bullous pemphigoid, dermatomyositis, alopecia areata), acne-like rash, xerostomia, etc. Rigorous dermatological evaluation is thus mandatory in the case of atypical, persistent/recurrent or severe lesions. In this article, we review the incidence and spectrum of dermatologic adverse events reported with immune checkpoint inhibitors. Finally, a management algorithm is proposed.

Coral calcifying fluid pH is modulated by seawater carbonate chemistry not solely seawater pH.

Reef coral calcification depends on regulation of pH in the internal calcifying fluid (CF) in which the coral skeleton forms. However, little is known about calcifying fluid pH (pHCF) regulation, despite its importance in determining the response of corals to ocean acidification. Here, we investigate pHCF in the coral Stylophora pistillata in seawater maintained at constant pH with manipulated carbonate chemistry to alter dissolved inorganic carbon (DIC) concentration, and therefore total alkalinity (AT). We also investigate the intracellular pH of calcifying cells, photosynthesis, respiration and calcification rates under the same conditions. Our results show that despite constant pH in the surrounding seawater, pHCF is sensitive to shifts in carbonate chemistry associated with changes in [DIC] and [AT], revealing that seawater pH is not the sole driver of pHCF Notably, when we synthesize our results with published data, we identify linear relationships of pHCF with the seawater [DIC]/[H+] ratio, [AT]/ [H+] ratio and [[Formula: see text]]. Our findings contribute new insights into the mechanisms determining the sensitivity of coral calcification to changes in seawater carbonate chemistry, which are needed for predicting effects of environmental change on coral reefs and for robust interpretations of isotopic palaeoenvironmental records in coral skeletons.

Photophysiology and daily primary production of a temperate symbiotic gorgonian.

Gorgonians are one of the most important benthic components of tropical and temperate areas, and play a fundamental role as ecosystem engineers. Although global warming and pollution increasingly threaten them, the acquisition of nutrients, which is a key process in fitness and stress resistance, has been poorly investigated in such species. This study has thus used an advanced in situ incubation chamber for the first time with gorgonians, to assess the daily acquisition of nutrients and the photophysiology of the Mediterranean symbiotic species, Eunicella singularis. The xanthophyll cycle was assessed in parallel. This work has revealed that E. singularis presents a different functioning than the Mediterranean symbiotic corals. This gorgonian indeed relies on both autotrophy and heterotrophy in summer to optimize its energetic budget, while corals mainly shift to autotrophy for their respiratory needs and tissue growth. In addition, although E. singularis lives in the same depths/locations, and harbours the same symbiont genotype than the corals, the photosynthetic performances of their respective symbionts are significantly different. Indeed, E. singularis acquired 2-3 times less autotrophic carbon from its symbionts than corals, but maintained a positive carbon budget by reducing respiration rates, and by presenting maximal photosynthetic rates throughout the day, suggesting a very efficient light utilization. Almost no photoinhibition was observed under very high light levels, because of the induction of a xanthophyll photoprotection process. These results help understanding why gorgonians often dominate many benthic ecosystems.

Co-activation of VTA DA and GABA neurons mediates nicotine reinforcement.

Smoking is the most important preventable cause of mortality and morbidity worldwide. This nicotine addiction is mediated through the nicotinic acetylcholine receptor (nAChR), expressed on most neurons, and also many other organs in the body. Even within the ventral tegmental area (VTA), the key brain area responsible for the reinforcing properties of all drugs of abuse, nicotine acts on several different cell types and afferents. Identifying the precise action of nicotine on this microcircuit, in vivo, is important to understand reinforcement, and finally to develop efficient smoking cessation treatments. We used a novel lentiviral system to re-express exclusively high-affinity nAChRs on either dopaminergic (DAergic) or γ-aminobutyric acid-releasing (GABAergic) neurons, or both, in the VTA. Using in vivo electrophysiology, we show that, contrary to widely accepted models, the activation of GABA neurons in the VTA plays a crucial role in the control of nicotine-elicited DAergic activity. Our results demonstrate that both positive and negative motivational values are transmitted through the dopamine (DA) neuron, but that the concerted activity of DA and GABA systems is necessary for the reinforcing actions of nicotine through burst firing of DA neurons. This work identifies the GABAergic interneuron as a potential target for smoking cessation drug development.

Psoriasis associated with idiopathic CD4+ T-cell lymphopenia: a regulatory T-cell defect?

Idiopathic CD4(+) lymphocytopenia (ICL) is a rare immunodeficiency syndrome of unknown origin for which the increased risks of opportunistic infections and of malignancies have been well established; however, skin dysimmune diseases, including psoriasis, have been scarcely reported up to now. We report herein the severe course of psoriasis in four patients with ICL, and show evidence for a defect in the skin recruitment of regulatory CD4(+) FoxP3(+) T cells. These data raise the apparent paradigm of the occurrence of a severe immunomediated disease together with a profound T-cell defect, a model that might also apply to other immune deficiencies associated with psoriasis.

Identification of a new HLA-C allele, HLA-C*08:75 in a Caucasian individual.

HLA-C*08:75 differs from C*08:02:01 by a non-synonymous mutation at codon 229 (GAG to AAG) in exon 4.

Identification of a new HLA-C allele, HLA-C*08:76 in a Caucasian individual.

HLA-C*08:76 differs from HLA-C*08:02:01 by one nonsynonymous nucleotide change at the codon 144 (CAG to AAG) in exon 3.

Kaposi's sarcoma and pregnancy: case report and literature review.

We report the observation of cutaneous Kaposi's sarcoma (KS) worsening during the second trimester of pregnancy in 2 African women. Both patients were tested seronegative for HIV. They had no complication during their pregnancy, and no evidence of extracutaneous disease was found, allowing therapeutic abstention. They gave birth to healthy children showing no clinical evidence of human herpesvirus 8 (HHV-8) infection. Based on these observations and on the review of the literature, we discuss the risk of vertical transmission of HHV-8 as well as the impact of pregnancy on KS.

[Primary pigmented breast adenocarcinoma in a male patient]. / Adénocarcinome mammaire pigmenté primitif chez un homme.

BACKGROUND: Pigmented mammary tumours are rare. Herein, we report the third case of primary pigmented breast adenocarcinoma in a male patient with clinical mimicking of nodular melanoma of the nipple. PATIENTS AND METHODS: A male patient presented with a pigmented nodule of the right nipple. Histological examination of the lesion showed dermal and subcutaneous adenocarcinomatous proliferation. The perilesional stroma contained melanin both inside and outside macrophages, leading us to conclude on primary pigmented breast adenocarcinoma clinically mimicking nodular melanoma of the nipple. DISCUSSION: Local production of melanin by neoplastic cells in the mammary carcinoma was postulated as the cause of hyperpigmentation of the tumour. Other possible causes are transfer of melanin from overlying melanocytes of the pigmented areolar epidermis to the underlying neoplastic cells, or melanin synthesis by intratumoral melanocytes migrating from the epidermis (which strikes us as the most convincing interpretation for the reported case). CONCLUSION: Breast adenocarcinoma is a rare tumour in men and may present clinically as a pigmented lesion of the nipple, resulting in the problem of differential diagnosis with primary or metastasised nodular melanoma.

Efficacy and safety of biologics in erythrodermic psoriasis: a multicentre, retrospective study.

BACKGROUND: Even though efficacy of biologics has been extensively studied in psoriasis vulgaris, studies in erythrodermic psoriasis, the most severe form of the disease, have been scarcely reported. OBJECTIVES: To address the efficacy and safety of biologics in patients with erythrodermic psoriasis. METHODS: A multicentre national retrospective study was performed using the French Psoriasis Group network. Patients showing psoriasis involving at least 90% of body surface area (BSA), and in whom severity of the disease had been evaluated before and after 3 and/or 6 months of treatment with biologics, were enrolled in the study. Results were expressed using intention-to-treat analysis. RESULTS: We included 28 patients, representing 42 flares of erythrodermic psoriasis treated with infliximab (n=24), adalimumab (n=7), etanercept (n=6), ustekinumab (n=3) or efalizumab (n=2). A 75% improvement of BSA or Psoriais Area and Severity Index 12-14 weeks after treatment onset was reached in 48% of flares treated with infliximab, in 50% of those treated with adalimumab and in 40% of those treated with etanercept. Twelve serious adverse events, consisting of bacterial infection in seven of them, were observed. Biological treatment was discontinued for safety concern in 19% of cases. A given biologic was administered for up to 48 weeks in 34% of flares. CONCLUSIONS: Biologics show overall good short-term efficacy, but treatment switch due to lack of efficacy or side-effects is frequently observed on a longer term, with only one-third of patients still receiving the same drug after 1 year. The most significant safety concern consists of severe infections.

Acute exposure to perfluorooctane sulfonate exacerbates heat-induced oxidative stress in a tropical coral species.

Perfluorooctane sulfonate (PFOS) is among the most commonly per- and poly-fluoroalkyl substances (PFAS) found in environmental samples. Nevertheless, the effect of this legacy persistent organic contaminant has never been investigated on corals to date. Corals are the keystone organisms of coral reef ecosystems and sensitive to rising ocean temperatures, but it is not understood how the combination of elevated temperature and PFOS exposure will affect them. Therefore, the aims of the present study were (1) to evaluate the time-dependent bioconcentration and depuration of PFOS in the scleractinian coral Stylophora pistillata using a range of PFOS exposure concentrations, and (2) to assess the individual and combined effects of PFOS exposure and elevated seawater temperature on key physiological parameters of the corals. Our results show that the coral S. pistillata rapidly bioconcentrates PFOS from the seawater and eliminates it 14 days after ceasing the exposure. We also observed an antagonistic effect between elevated temperature and PFOS exposure. Indeed, a significantly reduced PFOS bioconcentration was observed at high temperature, likely due to a loss of symbionts and a higher removal of mucus compared to ambient temperature. Finally, concentrations of PFOS consistent with ranges observed in surface waters were non-lethal to corals, in the absence of other stressors. However, PFOS increased lipid peroxidation in coral tissue, which is an indicator of oxidative stress and enhanced the thermal stress-induced impairment of coral physiology. This study provides valuable insights into the combined effects of PFOS exposure and ocean warming for coral's physiology. PFOS is usually the most prevalent but not the only PFAS defected in reef waters, and thus it will be also important to monitor PFAS mixture concentrations in the oceans and to study their combined effects on aquatic wildlife.

Management and outcome of metastatic melanoma during pregnancy.

BACKGROUND: Although metastatic melanoma occurrence during pregnancy challenges the physician in several ways, only a few studies have been published. OBJECTIVES: Our aim was to investigate therapeutic management together with maternal and fetal outcomes in pregnant women with advanced melanoma. METHODS: A French national retrospective study was conducted in 34 departments of Dermatology or Oncology. All patients with American Joint Committee on Cancer (AJCC) stage III/IV melanoma diagnosed during pregnancy were included. Data regarding melanoma history, pregnancy, treatment, delivery, maternal and infant outcomes were collected. RESULTS: Twenty-two women were included: 10 AJCC stage III and 12 stage IV. Abortion was performed in three patients. Therapeutic abstention during pregnancy was observed in three cases, 14 patients underwent surgery, four patients received chemotherapy and one patient was treated with brain radiotherapy alone. The median gestational age was 36 weeks amenorrhoea. Neither neonatal metastases nor deformities were observed. Placenta metastases were found in one case. Among 18 newborns, 17 are currently alive (median follow up, 17 months); one died of sudden infant death. The 2-year maternal survival rates were 56% (stage III) and 17% (stage IV). CONCLUSIONS: Faced with metastatic melanoma, a majority of women chose to continue with pregnancy, giving birth, based on our samples, to healthy, frequently premature infants. Except during the first trimester of pregnancy, conventional melanoma treatment was applied. No serious side effect was reported, except one case of miscarriage after surgery. Mortality rates do not suggest a worsened prognosis due to pregnancy but larger prospective controlled studies are necessary to assess this specific point.

Isolation of microsatellite markers in the Calliptamus genus (Orthoptera, Acrididae).

The Calliptamus genus (Orthoptera: Acrididae) includes locust and grasshopper species, some of which have a high economic impact. Using an enriched methodology, 10 microsatellite markers have been developed from two species, Calliptamus italicus and Calliptamus barbarus. These polymorphic markers were tested on different populations of three Calliptamus species: C. italicus, C. barbarus, C. wattenwylianus. Two markers were amplified on the three species, as well as four on C. barbarus and two on C. italicus. In each species, 9 to 23 alleles per locus were observed. These molecular markers might prove to be a new and interesting tool for Calliptamus population genetics and dispersion studies.

[Treatment of patients with brain metastases from a melanoma]. / Prise en charge des patients atteints de métastases cérébrales de mélanome.

Whereas immune checkpoint inhibitors of serine/threonine protein kinase B-raf therapy dramatically changed metastatic outcomes of patients with melanoma, they remain at high risk of brain extension. Additional local treatment can be offered in this situation such as surgery and or stereotactic radiotherapy. In this review article, we describe the different options with published data and their optimal timing.

Enhancement of coral calcification via the interplay of nickel and urease.

Corals are the main reef builders through the formation of calcium carbonate skeletons. In recent decades, coral calcification has however been impacted by many global (climate change) and local stressors (such as destructive fishing practices and changes in water quality). In this particular context, it is crucial to identify and characterize the various factors that promote coral calcification. We thus performed the first investigation of the effect of nickel and urea enrichment on the calcification rates of three coral species. These two factors may indeed interact with calcification through the activity of urease, which catalyzes the hydrolysis of urea to produce inorganic carbon and ammonia that are involved in the calcification process. Experiments were performed with the asymbiotic coral Dendrophyllia arbuscula and, to further assess if urea and/or nickel has an indirect link with calcification through photosynthesis, results were compared with those obtained with two symbiotic corals, Acropora muricata and Pocillopora damicornis, for which we also measured photosynthetic rates. Ambient and enriched nickel (0.12 and 3.50 µg L-1) combined with ambient and enriched urea concentrations (0.26 and 5.52 µmol L-1) were tested during 4 weeks in aquaria. We demonstrate in the study that a nickel enrichment alone or combined with a urea enrichment strongly stimulated urea uptake rates of the three tested species. In addition, this enhancement of urea uptake and hydrolysis significantly increased the long-term calcification rates (i.e. growth) of the three coral species investigated, inducing a 1.49-fold to 1.64-fold increase, respectively for D. arbuscula and P. damicornis. Since calcification was greatly enhanced by nickel in the asymbiotic coral species - i.e. in absence of photosynthesis - we concluded that the effect of increased urease activity on calcification was mainly direct. According to our results, it can be assumed that corals in some fringing reefs, benefiting from seawater enriched in nickel may have advantages and might be able to use urea more effectively as a carbon and nitrogen source. It can also be suggested that urea, for which hotspots are regularly measured in reef waters may alleviate the negative consequences of thermal stress on corals.

Alpha2-adrenergic receptor-mediated release of lysophosphatidic acid by adipocytes. A paracrine signal for preadipocyte growth.

In the search for the existence of adrenergic regulation of the autocrine/paracrine function of the white adipose tissue, it was observed that conditioned media from isolated adipocytes or dialysates obtained by in situ microdialysis of human subcutaneous adipose tissue increased spreading and proliferation of 3T3F442A preadipocytes. These effects were amplified when an alpha2-adrenergic agonist was present during the obtention of conditioned media and microdialysates. This alpha2-adrenergic-dependent trophic activity was completely abolished by pretreatment of the conditioned media or microdialysates with the lysophospholipase, phospholipase B. Among the different lysophospholipids tested only lysophosphatidic acid (LPA) was able to induce spreading and proliferation of 3T3F442A preadipocytes. Moreover, previous chronic treatment of 3T3F442A preadipocytes with LPA which led to a specific desensitization of LPA responsiveness, abolished the alpha2-adrenergic-dependent trophic activities of the conditioned media and microdialysates. Finally, alpha2-adrenergic stimulation led to a rapid, sustained, and pertussis toxin-dependent release of [32P]LPA from [32P]-labeled adipocytes. Based upon these results it was proposed that in vitro and in situ stimulation of adipocyte alpha2-adrenergic receptors provokes the extracellular release of LPA leading, in turn, to regulation of preadipocyte growth.

Glutamate induces phosphorylation of Elk-1 and CREB, along with c-fos activation, via an extracellular signal-regulated kinase-dependent pathway in brain slices.

In cell culture systems, the TCF Elk-1 represents a convergence point for extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) subclasses of mitogen-activated protein kinase (MAPK) cascades. Its phosphorylation strongly potentiates its ability to activate transcription of the c-fos promoter through a ternary complex assembled on the c-fos serum response element. In rat brain postmitotic neurons, Elk-1 is strongly expressed (V. Sgambato, P. Vanhoutte, C. Pagès, M. Rogard, R. A. Hipskind, M. J. Besson, and J. Caboche, J. Neurosci. 18:214-226, 1998). However, its physiological role in these postmitotic neurons remains to be established. To investigate biochemically the signaling pathways targeting Elk-1 and c-fos in mature neurons, we used a semi-in vivo system composed of brain slices stimulated with the excitatory neurotransmitter glutamate. Glutamate treatment leads to a robust, progressive activation of the ERK and JNK/SAPK MAPK cascades. This corresponds kinetically to a significant increase in Ser383-phosphorylated Elk-1 and the appearance of c-fos mRNA. Glutamate also causes increased levels of Ser133-phosphorylated cyclic AMP-responsive element-binding protein (CREB) but only transiently relative to Elk-1 and c-fos. ERK and Elk-1 phosphorylation are blocked by the MAPK kinase inhibitor PD98059, indicating the primary role of the ERK cascade in mediating glutamate signaling to Elk-1 in the rat striatum in vivo. Glutamate-mediated CREB phosphorylation is also inhibited by PD98059 treatment. Interestingly, KN62, which interferes with calcium-calmodulin kinase (CaM-K) activity, leads to a reduction of glutamate-induced ERK activation and of CREB phosphorylation. These data indicate that ERK functions as a common component in two signaling pathways (ERK/Elk-1 and ERK/?/CREB) converging on the c-fos promoter in postmitotic neuronal cells and that CaM-Ks act as positive regulators of these pathways.