Cutaneous melanoma: what if Laënnec was right? Search for a common malignancy marker in mammals

Cutaneousmelanomas are characterized by considerable inter and intraspecific heterogeneity. In 1806, René Laënnec used a single term to describe these malignant tumours believed to originate from melanocytes. Due to their highmetastatic potential, the prognosis ofmelanomas remains unfavourable. To improve it, early diagnosis is essential since metastasis-free stages can be treated. This is why we sought malignancy markers for melanomas. We identified the RACK1 protein as a marker of malignancy in humanmelanomas. A commonmalignancymarker for differentmammalianmelanomas would support the use of the single term “melanoma”. In the present article, we review current knowledge on the molecular basis of melanocyte tumorigenesis to explain our interest in the RACK1 protein.Les mélanomes cutanés se caractérisent par une considérable hétérogénéité intra et interspécifique. Ces tumeurs malignes censées dériver des mélanocytes ont été décrites sous un terme unique par René Laënnec en 1806. Par leur forte capacité métastatique, elles sont toujours de sombre pronostic. Pour améliorer celui-ci, leur diagnostic précoce est indispensable car les stades sans métastase peuvent être traités efficacement. Aussi, des marqueurs de malignité du mélanome sont recherchés. Nous avons identifié la protéine RACK1 comme marqueur de malignité des mélanomes chez l'homme. Un marqueur de malignité commun des mélanomes de mammifères conforterait l'utilisation du terme unique « mélanome ». Nous commentons les connaissances actuelles des bases moléculaires de la tumorigenèse des mélanocytes pour expliquer notre intérêt pour la protéine RACK1

Do Surgeons Anticipate Women’s Hopes and Fears Associated with Prolapse Repair? A Qualitative Analysis in the PROSPERE Trial

Women’s preoperative perceptions of pelvic-floor disorders may differ from those of their physicians. Our objective was to specify women’s hopes and fears before cystocele repair, and to compare them to those that surgeons anticipate. We performed a secondary qualitative analysis of data from the PROSPERE trial. Among the 265 women included, 98% reported at least one hope and 86% one fear before surgery. Sixteen surgeons also completed the free expectations-questionnaire as a typical patient would. Women’s hopes covered seven themes, and women’s fears eleven. Women’s hopes were concerning prolapse repair (60%), improvement of urinary function (39%), capacity for physical activities (28%), sexual function (27%), well-being (25%), and end of pain or heaviness (19%). Women’s fears were concerning prolapse relapse (38%), perioperative concerns (28%), urinary disorders (26%), pain (19%), sexual problems (10%), and physical impairment (6%). Surgeons anticipated typical hopes and fears which were very similar to those the majority of women reported. However, only 60% of the women reported prolapse repair as an expectation. Women’s expectations appear reasonable and consistent with the scientific literature on the improvement and the risk of relapse or complication related to cystocele repair. Our analysis encourages surgeons to consider individual woman’s expectations before pelvic-floor repair

Long-term cellular immunity of vaccines for Zaire Ebola Virus Diseases

Recent Ebola outbreaks underscore the importance of continuous prevention and disease control efforts. Authorized vaccines include Merck’s Ervebo (rVSV-ZEBOV) and Johnson & Johnson’s two-dose combination (Ad26.ZEBOV/MVA-BN-Filo). Here, in a five-year follow-up of the PREVAC randomized trial (NCT02876328), we report the results of the immunology ancillary study of the trial. The primary endpoint is to evaluate long-term memory T-cell responses induced by three vaccine regimens: Ad26–MVA, rVSV, and rVSV–booster. Polyfunctional EBOV-specific CD4+ T-cell responses increase after Ad26 priming and are further boosted by MVA, whereas minimal responses are observed in the rVSV groups, declining after one year. In-vitro expansion for eight days show sustained EBOV-specific T-cell responses for up to 60 months post-prime vaccination with both Ad26-MVA and rVSV, with no decline. Cytokine production analysis identify shared biomarkers between the Ad26-MVA and rVSV groups. In secondary endpoint, we observed an elevation of pro-inflammatory cytokines at Day 7 in the rVSV group. Finally, we establish a correlation between EBOV-specific T-cell responses and anti-EBOV IgG responses. Our findings can guide booster vaccination recommendations and help identify populations likely to benefit from revaccination

Expression de la protéine adaptatrice RACK1 dans les tumeurs mélanocytaires du chien et du cheval

Le mélanome cutané est un problème de Santé Publique chez l'Homme. Ce cancer affecte les chiens et les chevaux. Une mise à jour des aspects épidémiologiques, cliniques, histopathologiques et génétiques des mélanomes canins et équins, ainsi que les avancées dans leur traitement est présentée. Les données animales sont comparées aux données obtenues chez l'Homme. Les concepts émergeants dans la compréhension de la biologie des mélanocytes et des mélanomes sont discutés. Le pronostic du mélanome est sombre de par sa forte capacité à métastaser. Une caractérisation histologique précoce des mélanomes constituerait un progrès indéniable pour le pronostic. La protéine RACK1 est un marqueur de malignité des mélanomes chez l'Homme. La comparaison avec les marqueurs actuels souligne l'intérêt de RACK1. Ses implications dans la tumorigenèse in vitro sont exposées. Notre travail expérimental a consisté à évaluer RACK1 comme marqueur de malignité des mélanomes canins et équins. Par immunofluorescence, nous avons recherché RACK1, MITF et CK5, sur des tissus fixés de proliférations tumorales mélanocytaires de chiens (N=24) et de chevaux (N=22). Nos résultats montrent que la différence de distribution du marquage RACK1 permet une distinction des tumeurs mélanocytaires bénignes et malignes dans ces deux espèces. De façon intéressante, le marquage RACK1 n'est pas identique dans les tumeurs mélanocytaires bénignes animales et humaines. Enfin, la surexpression de RACK1 dans les mélanomes de plusieurs Mammifères suggère un rôle de cette protéine dans la progression des mélanomes.MAISONS-ALFORT-Ecole Vétérin (940462302) / SudocSudocFranceF

Implication de la protéine RACK1 dans le développement du mélanome cutané in vivo

Le mélanome cutané est une tumeur maligne, dérivée des mélanocytes, de mauvais pronostic de par sa forte capacité à métastaser. Pour améliorer le pronostic, un diagnostic précoce est indispensable. La protéine échafaudage RACK1 a été proposée comme marqueur de malignité du mélanome cutané. La structure de RACK1 lui permet d interagir avec de nombreux partenaires et de coordonner des interactions entre différentes voies de signalisation. Ce travail propose l étude du rôle fonctionnel de RACK1 dans la progression du mélanome cutané métastatique in vivo. Nos résultats ont confirmé la détection de RACK1 comme marqueur de malignité du mélanome des mammifères. De plus, la détection de RACK1 associée à phospho-ERK marque la prédisposition au mélanome cutané in vivo. La surexpression de RACK1 ne semble pas causale dans le développement du mélanome cutané. Néanmoins, dans un contexte de prédisposition, nous avons établi RACK1 comme co-facteur oncogénique dans l initiation et le développement du mélanome cutané. Dans ce cadre, nous avons proposé phospho-STAT3 et phospho-JNK comme partenaires de RACK1. Enfin, nous avons présenté la preuve de principe de l intérêt thérapeutique du ciblage de RACK1 dans le traitement du mélanome cutanéCutaneous melanoma is a malignant tumor, derived from melanocytes, with severe prognosis resulting from high metastatic capacity. To improve prognosis, early diagnosis is essential. RACK1 scaffold protein was proposed as a malignancy marker of cutaneous melanoma. RACK1 peculiar structure allows it to interact with many partners and to coordinate crosstalks between signaling pathways. This work presents the study of RACK1 role in cutaneous metastatic melanoma progression in vivo. Our results confirmed RACK1 detection as a malignancy marker of cutaneous melanoma in mammals. Moreover, RACK1 detection in association with phospho-ERK marked cutaneous melanoma predisposition in vivo. RACK1 overexpression did not seem causative in cutaneous melanoma development. Nonetheless, in a predisposition context, we established RACK1 as an oncogenic co-factor in cutaneous melanoma initiation and development. Within this framework, we proposed phospho-STAT3 and phospho-JNK as RACK1 partners. Finally, we presented a proof positive of the therapeutic interest of RACK1 targeting in cutaneous melanoma treatmentPARIS-BIUSJ-Biologie recherche (751052107) / SudocPARIS-Académie Médecine (751065201) / SudocSudocFranceF

Data from: Distinguishing migration from isolation using genes with intragenic recombination: detecting introgression in the Drosophila simulans species complex

Background: Determining the presence or absence of gene flow between populations is the target of some statistical methods in population genetics. Until recently, these methods either avoided the use of recombining genes, or treated recombination as a nuisance parameter. However, genes with recombination contribute additional information for the detection of gene flow (i.e. through linkage disequilibrium). Methods: We present three summary statistics based on the spatial arrangement of fixed differences, and shared and exclusive polymorphisms that are sensitive to the presence and direction of gene flow. Power and false positive rate for tests based on these statistics are studied by simulation. Results: The application of these tests to populations from the Drosophila simulans species complex yielded results consistent with migration between D. simulans and its two endemic sister species D. mauritiana and D. sechellia, and between populations D. mauritiana on the islands of the Mauritius and Rodrigues. Conclusions: We demonstrate the sensitivity of the developed statistics to the presence and direction of gene flow, and characterize their power as a function of differentiation level and recombination rate. The properties of these statistics make them especially suitable for analyzing high-throughput sequencing data or for their integration within the approximate Bayesian computation framework

AP-1/KIF13A Blocking Peptides Impair Melanosome Maturation and Melanin Synthesis

Melanocytes are specialized cells that generate unique organelles called melanosomes in which melanin is synthesized and stored. Melanosome biogenesis and melanocyte pigmentation require the transport and delivery of melanin synthesizing enzymes, such as tyrosinase and related proteins (e.g., TYRP1), from endosomes to maturing melanosomes. Among the proteins controlling endosome-melanosome transport, AP-1 together with KIF13A coordinates the endosomal sorting and trafficking of TYRP1 to melanosomes. We identify here β1-adaptin AP-1 subunit-derived peptides of 5 amino acids that block the interaction of KIF13A with AP-1 in cells. Incubating these peptides with human MNT-1 cells or 3D-reconstructed pigmented epidermis decreases pigmentation by impacting the maturation of melanosomes in fully pigmented organelles. This study highlights that peptides targeting the intracellular trafficking of melanocytes are candidate molecules to tune pigmentation in health and disease

Data from: Inter-island divergence within Drosophila mauritiana, a species of the D. simulans complex: past history and/or speciation in progress?

Speciation with gene flow may be more common than generally thought making detailed understanding of the extent and pattern of genetic divergence between geographically isolated populations useful. Species of the Drosophila simulans complex provide a good model for speciation and evolutionary studies; understanding their population genetic structure will increase our understanding of the context in which speciation has occurred. Here we describe the genetic diversity and the genetic differentiation, at mitochondrial and nuclear loci, of two distant populations of D. mauritiana (Mauritius and Rodrigues Islands). We surveyed the two populations for their mitochondrial types, eight nuclear genes and 18 microsatellite loci. A new mitochondrial type is fixed in the Rodrigues population of D. mauritiana. The two populations are highly differentiated, their divergence appears relatively ancient (100,000 years) compared to the origin of the species, around 0.25 MYA, and they exhibit very limited gene flow. However, they have similar levels of divergence from their sibling, D. simulans. Both nuclear genes and microsatellites revealed contrasting demographic histories between the two populations; expansion for the Mauritius population and stable population size for the Rodrigues Island population. The pronounced geographic structure discovered within D. mauritiana in addition to the low amount of genetic exchange between those two island populations is significant for understanding how the genetic structuring of the species contributes to its evolutionary history, and clearly merits further attention in the broad context of speciation