Morbidity of total thyroidectomy for substernal goiter: A series of 70 patients.

Total thyroidectomy for substernal goiter occasionally requires a sternotomy associated with a cervical incision. We sought to analyze the postoperative complications of thyroidectomy for substernal goiters in our center and more precisely the complications related to the sternotomy. All patients who underwent total thyroidectomy for substernal goiter in our center between 2007 and 2016 were reviewed retrospectively. Patients with combined cervical incision and sternotomy (ST group, n=16) were compared to those with cervical incision alone (CT group, n=54), with regard to postoperative complications. Risk factors for the occurrence of postoperative complications were investigated in this population. A total of 24 patients (34.2%) had one or more postoperative complications. The incidence of transient hypoparathyroidism and recurrent laryngeal nerve injury were higher in the ST group (P=0.001 and P=0.052, respectively). The median duration of hospitalization was longer in the ST group (P<0.001). Eighteen patients (25.8%) had a malignant tumor on final pathology. In univariate analysis, the following risk factors for transient postoperative hypoparathyroidism were identified: sternotomy, preoperative symptomatic character and thyroid height (P=0.001, P=0.009 and P=0.013, respectively). In multivariable analysis, only sternotomy was an independent risk factor for postoperative transient hypoparathyroidism (OR=4.48 [1.1; 18], P=0.035). Sternotomy is associated with added morbidity that is not negligible. This surgical approach should be reserved for substernal goiters that descend into the posterior mediastinum, below the level of the aortic arch, when there is suspicion of carcinoma with loco-regional invasion, or when the thyroid tissue is located mainly intrathoracically (conical shaped thyroid, asymptomatic goiter, ectopic thyroid).

In Vitro Characterization of VPS34 Lipid Kinase Inhibition by Small Molecules.

VPS34 is a class III phosphoinositide 3-kinase that acts on vesicle trafficking. This kinase has recently attracted significant attention because of the function it plays in the machinery involved in the early steps of autophagy. Moreover, because significant progress had been made in the optimization of specific kinase inhibitors, its potential to be targeted by catalytic inhibitors has been investigated by different groups. The aim of this review is to present the key in vitro assays necessary for characterizing inhibitors of the catalytic activity of VPS34. The review covers catalytic (IC50 on purified recombinant protein) and binding assays (KD, ka, kd on purified recombinant protein), and a cell-based assay (IC50 in GFP-FYVE expressing cell line). The methodology for crystallization of VPS34 protein is also presented as it can provide guidance for the design by medicinal chemistry of small molecular mass kinase inhibitor.

Structural basis for human monoglyceride lipase inhibition.

Monoglyceride lipase (MGL) is a serine hydrolase that hydrolyses 2-arachidonoylglycerol (2-AG) into arachidonic acid and glycerol. 2-AG is an endogenous ligand of cannabinoid receptors, involved in various physiological processes in the brain. We present here the first crystal structure of human MGL in its apo form and in complex with the covalent inhibitor SAR629. MGL shares the classic fold of the alpha/beta hydrolase family but depicts an unusually large hydrophobic occluded tunnel with a highly flexible lid at its entry and the catalytic triad buried at its end. Structures reveal the configuration of the catalytic triad and the shape and nature of the binding site of 2-AG. The bound structure of SAR629 highlights the key interactions for productive binding with MGL. The shape of the tunnel suggests a high druggability of the protein and provides an attractive template for drug discovery.