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PIK3CA -related overgrowth syndrome (PROS) is a genetic disorder caused by somatic mosaic gain-of-function mutations of PIK3CA . Clinical presentation of patients is diverse and associated with endocrine disruption. Adipose tissue is frequently involved, but its role in disease development and progression has not been elucidated. Here, we created a mouse model of PIK3CA -related adipose tissue overgrowth that recapitulates patient phenotype. We demonstrate that PIK3CA mutation leads to GLUT4 membrane accumulation with a negative feedback loop on insulin secretion, a burst of liver IGFBP1 synthesis with IGF-1 sequestration, and low circulating levels. Mouse phenotype was mainly driven through AKT2. We also observed that PIK3CA mutation induces metabolic reprogramming with Warburg-like effect and protein and lipid synthesis, hallmarks of cancer cells, in vitro, in vivo, and in patients. We lastly show that alpelisib is efficient at preventing and improving PIK3CA -adipose tissue overgrowth and reversing metabolomic anomalies in both animal models and patients.

Lymphatic cystic malformations are rare genetic disorders mainly due to somatic gain-of-function mutations in the PIK3CA gene. These anomalies are frequently associated with pain, inflammatory flar...

Objectives: Our aim is to compare the course of the disease between healthcare workers (HCWs) and non-HCWs suffering from covid-19 and eligible for outpatient management. Methods: Single-center prospective cohort of outpatients with covid-19, diagnosed between the 10th March and the 2nd April, 2020 with a daily collection of symptoms by an on-line auto-questionnaire. Results: A total of 186 patients were included (median age, 41 years [interquartile range, 19-78 years]; 74.2% female), of whom 132 (71 %) were HCWs. The median follow-up after symptom onset was 14 (min 4 - max 24) days. HCWs were significantly younger than non HCWs (median age 40.3 years vs. 47.2 years [p

Introduction Une grande partie des connaissances en cours concernant la COVID-19 est basée sur les données des patients hospitalisés. Notre objectif est de décrire l’évolution au jour le jour de la COVID-19 dans les cas admissibles à une prise en charge ambulatoire. Matériels et méthodes Cohorte prospective monocentrique de patients présentant une infection par le SARS-CoV-2 confirmée virologiquement et présentant des symptômes modérés, admissibles à une prise en charge ambulatoire, entre le 10 mars et le 2 avril 2020. Les symptômes quotidiens ont été recueillis au moyen d’un auto-questionnaire en ligne. Nous avons considéré qu’un patient était guéri lorsqu’aucun des trois symptômes principaux (fièvre, dyspnée et douleur thoracique) n’était signalé après les derniers symptômes connus via l’application en ligne. Résultats Un total de 186 patients ont été inclus (âge médian, 41 ans [intervalle interquartile, 19–78 ans] ; 74,2 % de femmes), dont 132 (71 %) étaient des professionnels de santé. Treize patients (7 %) souffraient d’hypertension artérielle (la comorbidité la plus courante) et le suivi médian après l’apparition des symptômes était de 14 jours (min 4–max 24). Les professionnels de santé étaient significativement plus jeunes que les autres (âge médian de 40,3 ans contre 47,2 ans [p

The cellular mechanisms governing the impact of the central circadian clock on neuronal networks are incompletely understood. We examine here the influence of the suprachiasmatic nucleus output neuropeptide arginine-vasopressin (AVP) on the activity of preoptic area kisspeptin neurons. These cells integrate circadian and hormonal signals within the neuronal network that regulates fertility in females. Electrophysiological recordings in brain slices from kisspeptin-GFP mice showed that AVP dose-dependently increased the firing rate of most kisspeptin neurons. These actions were mediated directly at the kisspeptin neuron. Experiments in mice expressing the calcium indicator GCaMP3 in kisspeptin neurons enabled simultaneous monitoring of intracellular calcium concentrations ([Ca2+]i) in multiple cells and revealed that AVP increased [Ca2+]iin >80% of diestrous kisspeptin neurons via a mechanism involving voltage-gated calcium channels. We next examined whether AVP signaling in kisspeptin neurons was time and ovarian cycle dependent. AVP exerted the same effects on diestrous and proestrous days of the ovarian cycle, whether hours before [zeitgeber time 4 (ZT4)–ZT6] or just before (ZT10) the expected time of the proestrous preovulatory luteinizing hormone surge. Remarkably, however, AVP signaling was critically dependent on circulating ovarian steroids as AVP no longer excited preoptic kisspeptin neurons in ovariectomized mice, an effect that was fully restored by estradiol treatment. Together, these studies show that AVP exerts a potent and direct stimulatory influence upon the electrical activity and [Ca2+]iof most preoptic kisspeptin neurons. Unexpectedly, estrogen is found to permit circadian AVP signaling at preoptic kisspeptin neurons rather than dynamically modulate its activity throughout the estrous cycle.

Metabolic and bone effects were investigated in growing (G, n = 45) and mature (M, n = 45) rats fed a high-fat/high-sucrose diet (HFS) isocaloric to the chow diet of controls (C, n = 30 per group). At week 19, a subset of 15 rats in each group (HFS or C, at both ages) was analyzed. Then one-half of the remaining 30 HFS rats in each groups continued HFS and one-half were shifted to C until week 27. Although no serum or bone marrow inflammation was seen, HFS increased visceral fat, serum leptin and insulin at week 19 and induced further alterations in lipid profile, serum adiponectin, and TGFβ1, TIMP1, MMP2, and MMP9, suggesting a prediabetic phenotype and cardiovascular dysfunction at week 27 more pronounced in M than G. These events were associated with dramatic reduction of osteoclastic and osteoid surfaces with accelerated mineralizing surfaces in both HFS age groups. Mineral metabolism and its major regulators were disturbed, leading to hyperphosphatemia and hypocalcemia. These changes were associated with bone alterations in the weight-bearing tibia, not in the non-weight-bearing vertebra. Indeed in fat rats, tibia trabecular bone accrual increased in G whereas loss of trabecular bone in M was alleviated. At diaphysis cortical porosity increased in G and even more in M at week 27. After the diet switch, metabolic and bone cellular disturbances fully reversed in G, but not in M. Trabecular benefit of the obese was preserved in both age groups and in M the age-related bone loss was even lighter after the diet switch than in prolonged HFS. At the diaphysis, cortical porosity normalized in G but not in M. Hypocalcemia in G and M was irreversible. Thus, the mild metabolic syndrome induced by isocaloric HFS is able to alter bone cellular activities and mineral metabolism, reinforce trabecular bone, and affect cortical bone porosity in an irreversible manner in older rats.

PIK3CA-related overgrowth spectrum (PROS) includes rare genetic conditions due to gain-of-function mutations in the PIK3CA gene. There is no approved medical therapy for patients with PROS, and alpelisib, an approved PIK3CA inhibitor in oncology, showed promising results in preclinical models and in patients. Here, we report for the first time the outcome of two infants with PROS having life-threatening conditions treated with alpelisib (25 mg) and monitored with pharmacokinetics. Patient 1 was an 8-mo-old girl with voluminous vascular malformation. Patient 2 was a 9-mo-old boy presenting with asymmetrical body overgrowth and right hemimegalencephaly with West syndrome. After 12 mo of follow-up, alpelisib treatment was associated with improvement in signs and symptoms, morphological lesions and vascular anomalies in the two patients. No adverse events were reported during the study. In this case series, pharmacological inhibition of PIK3CA with low-dose alpelisib was feasible and associated with clinical improvements, including a smaller size of associated complex tissue malformations and good tolerability.