Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis

Metastasis from primary tumors remains a major problem for tumor therapy. In the search for markers of metastasis and more effective therapies, the tumor metabolome is relevant because of its importance to the malignant phenotype and metastatic capacity of tumor cells. Altered choline metabolism is a hallmark of cancer. More specifically, a decreased glycerophosphocholine (GPC) to phosphocholine (PC) ratio was reported in breast, ovarian, and prostate cancers. Improved strategies to exploit this altered choline metabolism are therefore required. However, the critical enzyme cleaving GPC to produce choline, the initial step in the pathway controlling the GPC/PC ratio, remained unknown. In the present work, we have identified the enzyme, here named EDI3 (endometrial differential 3). Purified recombinant EDI3 protein cleaves GPC to form glycerol-3-phosphate and choline. Silencing EDI3 in MCF-7 cells decreased this enzymatic activity, increased the intracellular GPC/PC ratio, and decreased downstream lipid metabolites. Downregulating EDI3 activity inhibited cell migration via disruption of the PKCα signaling pathway, with stable overexpression of EDI3 showing the opposite effect. EDI3 was originally identified in our screening study comparing mRNA levels in metastasizing and nonmetastasizing endometrial carcinomas. Both Kaplan-Meier and multivariate analyses revealed a negative association between high EDI3 expression and relapse-free survival time in both endometrial (P < 0.001) and ovarian (P = 0.029) cancers. Overall, we have identified EDI3, a key enzyme controlling GPC and choline metabolism. Because inhibition of EDI3 activity corrects the GPC/PC ratio and decreases the migration capacity of tumor cells, it represents a possible target for therapeutic intervention.     

Dronedarone reduces arterial thrombus formation

Dronedarone has been associated with a reduced number of first hospitalisation due to acute coronary syndromes. Whether this is only due to the reduction in ventricular heart rate and blood pressure or whether other effects of dronedarone may be involved is currently elusive. This study was designed to investigate the role of dronedarone in arterial thrombus formation. C57Bl/6 mice were treated with dronedarone and arterial thrombosis was investigated using a mouse photochemical injury model. Dronedarone inhibited carotid artery thrombus formation in vivo (P?<?0.05). Thrombin- and collagen-induced platelet aggregation was impaired in dronedarone-treated mice (P?<?0.05), and expression of plasminogen activator inhibitor-1 (PAI1), an inhibitor of the fibrinolytic system, was reduced in the arterial wall (P?<?0.05). In contrast, the level of tissue factor (TF), the main trigger of the coagulation cascade, and that of its physiological inhibitor, TF pathway inhibitor, did not differ. Similarly, coagulation times as measured by prothrombin time and activated partial thromboplastin time were comparable between the two groups. Dronedarone inhibits thrombus formation in vivo through inhibition of platelet aggregation and PAI1 expression. This effect occurs within the range of dronedarone concentrations measured in patients, and may represent a beneficial pleiotropic effect of this drug.     

White-spot Lesions and Gingivitis Microbiotas in Orthodontic Patients

White-spot lesions (WSL) associated with orthodontic appliances are a cosmetic problem and increase risk for cavities. We characterized the microbiota of WSL, accounting for confounding due to gingivitis. Participants were 60 children with fixed appliances, aged between 10 and 19 yrs, half with WSL. Plaque samples were assayed by a 16S rRNA-based microarray (HOMIM) and by PCR. Mean gingival index was positively associated with WSL (p = 0.018). Taxa associated with WSL by microarray included Granulicatella elegans (p = 0.01), Veillonellaceae sp. HOT 155 (p < 0.01), and Bifidobacterium Cluster 1 (p = 0.11), and by qPCR, Streptococcus mutans (p = 0.008) and Scardovia wiggsiae (p = 0.04) Taxa associated with gingivitis by microarray included: Gemella sanguinis (p = 0.002), Actinomyces sp. HOT 448 (p = 0.003), Prevotella cluster IV (p = 0.021), and Streptococcus sp. HOT 071/070 (p = 0.023); and levels of S. mutans (p = 0.02) and Bifidobacteriaceae (p = 0.012) by qPCR. Species' associations with WSL were minimally changed with adjustment for gingivitis level. Partial least-squares discriminant analysis yielded good discrimination between children with and those without WSL. Granulicatella, Veillonellaceae and Bifidobacteriaceae, in addition to S. mutans and S. wiggsiae, were associated with the presence of WSL in adolescents undergoing orthodontic treatment. Many taxa showed a stronger association with gingivitis than with WSL.     

Breast Cancer and Non‐Hodgkin Lymphoma in a Young Male with Cowden Syndrome

Male breast cancer (MBC) is unusual, especially in young adults. Most cases of MBC as a secondary malignancy relate to the previous treatment with ionizing radiation. MBC can be associated with mutations in hereditary cancer predisposition syndrome genes (i.e., BRCA2); however, no such association has been reported in patients with Cowden syndrome (involving the phosphatase and tensin homolog [PTEN] gene). We describe a patient with Cowden syndrome who was initially diagnosed with B‐cell lymphoblastic lymphoma at the age of 7 years, then MBC at the age of 31 years, and never received radiation therapy.