Adverse Events of Extracorporeal Ultrasound-Guided High Intensity Focused Ultrasound Therapy

High-intensity focused ultrasound (HIFU) is considered to be an alternative to surgery. Extracorporeal ultrasound-guided HIFU (USgFU) has been clinically used to treat solid tumors. Preliminary trials in a small sample of a Western population suggested that this modality was safe. Most trials are performed in China thereby providing comprehensive data for understanding the safety profile. The aim of this study was to evaluate adverse events of USgFU therapy.Clinical data were searched in 2 Chinese databases. Adverse events of USgFU were summarized and compared with those of magnetic resonance-guided HIFU (MRgFU; for uterine, bone or breast tumor) and transrectal ultrasound-guided HIFU (for prostate cancer or benign prostate hyperplasia). USgFU treatment was performed using 7 types of device. Side effects were evaluated in 13262 cases. There were fewer adverse events in benign lesions than in malignant lesions (11.81% vs. 21.65%, p<0.0001). Rates of adverse events greatly varied between the disease types (0-280%, p<0.0001) and between the applied HIFU devices in both malignant (10.58-44.38%, p<0.0001) and benign lesions (1.67-17.57%, p<0.0001). Chronological analysis did not demonstrate a decrease in the rate of adverse events. Based upon evaluable adverse events, incidences in USgFU were consistent with those in MRgFU or transrectal HIFU. Some side effects frequently occurred following transrectal HIFU were not reported in USgFU. Several events including intrahepatic metastasis, intraoperative high fever, and occlusions of the superior mesenteric artery should be of particular concern because they have not been previously noted. The types of adverse events suggested that they were ultrasonic lesions.The frequency of adverse events depended on the location of the lesion and the type of HIFU device; however, side effects of USgFU were not yet understood. USgFU did not decrease the incidence of adverse events compared with MRgFU

Functional Implications of Novel Human Acid Sphingomyelinase Splice Variants

BACKGROUND: Acid sphingomyelinase (ASM) hydrolyses sphingomyelin and generates the lipid messenger ceramide, which mediates a variety of stress-related cellular processes. The pathological effects of dysregulated ASM activity are evident in several human diseases and indicate an important functional role for ASM regulation. We investigated alternative splicing as a possible mechanism for regulating cellular ASM activity. METHODOLOGY/PRINCIPAL FINDINGS: We identified three novel ASM splice variants in human cells, termed ASM-5, -6 and -7, which lack portions of the catalytic- and/or carboxy-terminal domains in comparison to full-length ASM-1. Differential expression patterns in primary blood cells indicated that ASM splicing might be subject to regulatory processes. The newly identified ASM splice variants were catalytically inactive in biochemical in vitro assays, but they decreased the relative cellular ceramide content in overexpression studies and exerted a dominant-negative effect on ASM activity in physiological cell models. CONCLUSIONS/SIGNIFICANCE: These findings indicate that alternative splicing of ASM is of functional significance for the cellular stress response, possibly representing a mechanism for maintaining constant levels of cellular ASM enzyme activity

17β-Estradiol Enhances Breast Cancer Cell Motility and Invasion via Extra-Nuclear Activation of Actin-Binding Protein Ezrin

Estrogen promotes breast cancer metastasis. However, the detailed mechanism remains largely unknown. The actin binding protein ezrin is a key component in tumor metastasis and its over-expression is positively correlated to the poor outcome of breast cancer. In this study, we investigate the effects of 17β-estradiol (E2) on the activation of ezrin and its role in estrogen-dependent breast cancer cell movement. In T47-D breast cancer cells, E2 rapidly enhances ezrin phosphorylation at Thr567 in a time- and concentration-dependent manner. The signalling cascade implicated in this action involves estrogen receptor (ER) interaction with the non-receptor tyrosine kinase c-Src, which activates the phosphatidylinositol-3 kinase/Akt pathway and the small GTPase RhoA/Rho-associated kinase (ROCK-2) complex. E2 enhances the horizontal cell migration and invasion of T47-D breast cancer cells in three-dimensional matrices, which is reversed by transfection of cells with specific ezrin siRNAs. In conclusion, E2 promotes breast cancer cell movement and invasion by the activation of ezrin. These results provide novel insights into the effects of estrogen on breast cancer progression and highlight potential targets to treat endocrine-sensitive breast cancers

Identification of Novel Functional Inhibitors of Acid Sphingomyelinase

We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimer's disease, major depression, radiation- and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 µM drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate Lipinski's Rule-of-Five than compounds without effect on ASM. Inhibition of ASM appears to be associated with good permeability across the blood-brain barrier. In the present investigation, we developed a novel structure-property-activity relationship by using a random forest-based binary classification learner. Virtual screening revealed that only six out of 768 (0.78%) compounds of natural products functionally inhibit ASM, whereas this inhibitory activity occurs in 135 out of 2028 (6.66%) drugs licensed for medical use in humans

Place de la néphrectomie partielle assistée par robot : revue de la littérature à l’heure d’une demande de nomenclature spécifique

International audienceRobot-assisted surgery is practiced more and more frequently in urology. Besides its place in prostatectomy for cancer, it also concerns partial nephrectomy (NP), in the treatment of renal tumors. The objective of this review is to compare the robot-assisted approach with laparoscopic or open approaches in partial nephrectomy in terms of functional or oncological outcomes and per- and postoperative complications.MATERIAL AND METHODS:A systematic review of the literature published from 2009 was carried out on PubMed. Clinical studies or meta-analyzes comparing robot-assisted surgery versus laparoscopic or open surgery in the NP domain were used.RESULTS:The clinical data presented in this review of the literature are based mainly on meta-analyzes of comparative studies. Patients operated with robotic assistance (NPAR) had significantly fewer postoperative complications than patients operated by open (RR 0.61; P=0.0002) or laparoscopic surgery (RR 0.84; P=0.007). Positive margins, at equivalent pathological stages, are comparable to the open and appear to be lower than the laparoscopic surgery (RR 0.53; P<0.001). After NP, the change in postoperative glomerular filtration rate (GFR) appears to be identical between the 3 pathways. Hot ischemia time is significantly shorter for NPAR compared to NPL. Finally, the estimated blood loss and length of stay are less severe in patients operated by NPAR compared to those operated by open surgery.CONCLUSION:Robot-assisted surgery offers the same oncological results (in the short and medium term) and appears to improve functional outcomes and morbidity. However, these findings need to be carefully analyzed, due to the low level of evidence from the studies presented and included in the meta-analyzes, and the lack of randomized clinical studies

Role for NHE1 in chemically-induced apoptosis

International audienc

Role for NHE1 in chemically-induced apoptosis

International audienc

[Postoperative C-reactive protein is a reliable marker to detect complications after radical cystectomy]

International audiencePURPOSE: Postoperative serum C-reactive protein (CRP) can be measured after major abdominal surgery to predict of complications at postoperative day (POD) 4. However, in urology, no studies have been conduced to analyze the role of CRP after radical cystectomy. The present study aims to analyze the relationship between a high postoperative level of CRP and the presence of complications after radical cystectomy for cancer. MATERIALS AND METHODS: This multicenter retrospective study included 313 patients treated with radical cystectomy for cancer between January 2013 and July 2016. Among the patients, 57.5% of patients received urinary diversion using a Bricker ileal conduit, 30.5% an orthotropic ileal neobladder, and 11.5% had an ureterocutaneostomy. RESULTS: Three hundred and thirteen patients were included (mean age 68.1\textpm9.2 years). Among the patients, 26.5% had grade>=2 complications, according to the Clavien-Dindo classification. In multivariate analysis, only CRP level at POD 4 predicted the risk of a complication (P\textless0.001). CRP\textgreater150mg/L at POD 4 was strongly associated with a risk of a postoperative complication after a cystectomy (OR=81.42, 95% CI [25.6-258.3], P\textless0.001). CRP assessed on POD4 was reliable at ruling out the existence of an infectious complications with a negative predictive value of 0.94. The main limitation of our study was it observational design. CONCLUSIONS: CRP at POD4 with a threshold of 150mg/L would reliably predict the risk of postoperative complications after cystectomy. Monitoring postoperative CRP could help adapt rehabilitation protocols after radical cystectomy and also the early management of complications