HIBISCUS: Hydroxychloroquine for the secondary prevention of thrombotic and obstetrical events in primary antiphospholipid syndrome

The relapse rate in antiphospholipid syndrome (APS) remains high, i.e. around 20%-21% at 5 years in thrombotic APS and 20-28% in obstetrical APS [2, 3]. Hydroxychloroquine (HCQ) appears as an additional therapy, as it possesses immunomodulatory and anti-thrombotic various effects [4-16]. Our group recently obtained the orphan designation of HCQ in antiphospholipid syndrome by the European Medicine Agency. Furthermore, the leaders of the project made the proposal of an international project, HIBISCUS, about the use of Hydroxychloroquine in secondary prevention of obstetrical and thrombotic events in primary APS. This study has been launched in several countries and at now, 53 centers from 16 countries participate to this international trial. This trial consists in two parts: a retrospective and a prospective study. The French part of the trial in thrombosis has been granted by the French Minister of Health in December 2015 (the academic trial independent of the pharmaceutical industry PHRC N PAPIRUS) and is coordinated by one of the members of the leading consortium of HIBISCUS

Unbalancing p53/Mdm2/IGF-1R axis by Mdm2 activation restrains the IGF-1-dependent invasive phenotype of skin melanoma

Melanoma tumors usually retain wild-type p53; however, its tumor-suppressor activity is functionally disabled, most commonly through an inactivating interaction with mouse double-minute 2 homolog (Mdm2), indicating p53 release from this complex as a potential therapeutic approach. P53 and the tumor-promoter insulin-like growth factor type 1 receptor (IGF-1R) compete as substrates for the E3 ubiquitin ligase Mdm2, making their relative abundance intricately linked. Hence we investigated the effects of pharmacological Mdm2 release from the Mdm2/p53 complex on the expression and function of the IGF-1R. Nutlin-3 treatment increased IGF-1R/Mdm2 association with enhanced IGF-1R ubiquitination and a dual functional outcome: Receptor downregulation and selective downstream signaling activation confined to the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. This Nutlin-3 functional selectivity translated into IGF-1-mediated bioactivities with biphasic effects on the proliferative and metastatic phenotype: An early increase and late decrease in the number of proliferative and migratory cells, while the invasiveness was completely inhibited following Nutlin-3 treatment through an impaired IGF-1-mediated matrix metalloproteinases type 2 activation mechanism. Taken together, these experiments reveal the biased agonistic properties of Nutlin-3 for the mitogen-activated protein kinase pathway, mediated by Mdm2 through IGF-1R ubiquitination and provide fundamental insights into destabilizing p53/Mdm2/IGF-1R circuitry that could be developed for therapeutic gain

The oral and gut microbiota: beyond a short communication

Introduction. The current treatment and prevention of oral disorders, dental caries, periodontal and gum diseases, follow a very non-specific control of plaque as the main causative factor. The main therapeutically approach is carried out on the sole perspective to keep the levels of oral bacteria in an acceptable range compatible with one-way vision of oral-mouth health, as something completely separated from a systemic microbial homeostasis (dysbiosis) concomitant present in the gut. A sealed compartmental view which sees separate and incommunicable responses to a specific condition without considering the presence of interacting confounding factors can negatively influence the diagnosis a diseases and of course its progression. A general non-specific antimicrobial with more general antiplaque therapy based mainly on oral care products together with surgery interventions represent at the moment the only mechanical responses in treating oral diseases. Material and method. The present paper is a narrative review concening interractions between oral and gut microbiota, with a focus on the interdisciplinary approach in antimicrobial treatment. Pubmed, Cochrane Library database were used for searching engines. Key words used were as follows: “inflammatory bowel syndrome (IBS)”, “ulcerative colitis”, “oral dysbiosis”, “gut dysbiosis”, “probiotics”, “periodontitis”. Results and discussions. Literature research showed that there are few issues to be discussed the ever increasing resistance to antibiotics, the high consumption of industrial food and sugars and their negatively effect on gut and oral microbiota. There is a need to highlight and develop a novel philosophical approach in the treatments for oral diseases that will necessarily involve non-conventional antimicrobial solutions. Such approaches should preferably reduce the consumption of both intestinal and oral microbiota, that are intimately connected and host approximately well over 1000 different species of bacteria at 108–109 bacteria per mL of mucous and saliva. Preventive approaches based upon the restoration of the microbial ecological balance, rather than elimination of the disease associated species, have been proposed. Conclusions. Having both oral-gut microbiota screened is an essential moment that influence the healthy immune modulatory and regenerative capacity of the body and, the new proposed formula integrates a wider screen on the patients where oral condition is strictly evaluated together with gut screen; therefore any proposed treatment will be inevitably sustained by the use of prebiotics and probiotics to promote health-associated bacterial growth