Structural studies unravel the active conformation of apo RORγt nuclear receptor and a common inverse agonism of two diverse classes of RORγt inhibitors.

The nuclear receptor retinoid acid receptor-related orphan receptor γt (RORγt) is a master regulator of the Th17/IL-17 pathway that plays crucial roles in the pathogenesis of autoimmunity. RORγt has recently emerged as a highly promising target for treatment of a number of autoimmune diseases. Through high-throughput screening, we previously identified several classes of inverse agonists for RORγt. Here, we report the crystal structures for the ligand-binding domain of RORγt in both apo and ligand-bound states. We show that apo RORγt adopts an active conformation capable of recruiting coactivator peptides and present a detailed analysis of the structural determinants that stabilize helix 12 (H12) of RORγt in the active state in the absence of a ligand. The structures of ligand-bound RORγt reveal that binding of the inverse agonists disrupts critical interactions that stabilize H12. This destabilizing effect is supported by ab initio calculations and experimentally by a normalized crystallographic B-factor analysis. Of note, the H12 destabilization in the active state shifts the conformational equilibrium of RORγt toward an inactive state, which underlies the molecular mechanism of action for the inverse agonists reported here. Our findings highlight that nuclear receptor structure and function are dictated by a dynamic conformational equilibrium and that subtle changes in ligand structures can shift this equilibrium in opposite directions, leading to a functional switch from agonists to inverse agonists.

Pulmonary ablation: a primer.

Percutaneous image-guided thermal ablation is safe and efficacious in achieving local control and improving outcome in the treatment of both early stage non-small-cell lung cancer and pulmonary metastatic disease, in which surgical treatment is precluded by comorbidity, poor cardiorespiratory reserve, or unfavorable disease distribution. Radiofrequency ablation is the most established technology, but new thermal ablation technologies such as microwave ablation and cryoablation may offer some advantages. The use of advanced techniques, such as induced pneumothorax and the popsicle stick technique, or combining thermal ablation with radiotherapy, widens the treatment options available to the multidisciplinary team. The intent of this article is to provide the reader with a practical knowledge base of pulmonary ablation by concentrating on indications, techniques, and follow-up.

Syntheses and initial evaluation of a series of indolo-fused heterocyclic inhibitors of the polymerase enzyme (NS5B) of the hepatitis C virus.

Herein, we present initial SAR studies on a series of bridged 2-arylindole-based NS5B inhibitors. The introduction of bridging elements between the indole N1 and the ortho-position of the 2-aryl moiety resulted in conformationally constrained heterocycles that possess multiple additional vectors for further exploration. The binding mode and pharmacokinetic (PK) properties of select examples, including: 13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[2,1-d][1,4]benzodiazepine-10-carboxylic acid (7) (IC(50)=0.07 µM, %F=18), are reported.

CT of blunt pancreatic trauma: a pictorial essay.

Blunt trauma to pancreas is uncommon and clinical features are often non-specific and unreliable leading to possible delays in diagnosis and therefore increased morbidity. CT has been established as the imaging modality of choice for the diagnosis of abdominal solid-organ injury in the blunt trauma patient. The introduction of multidetector-row CT allows for high resolution scans and multiplanar reformations that improve diagnosis. Detection of pancreatic injuries on CT requires knowledge of the subtle changes produced by pancreatic injury. The CT appearance of pancreatic injury ranges from a normal initial appearance of the pancreas to active pancreatic bleeding. Knowledge of CT signs of pancreatic trauma and a high index of suspicion is required in diagnosing pancreatic injury.

Discovery and preclinical characterization of the cyclopropylindolobenzazepine BMS-791325, a potent allosteric inhibitor of the hepatitis C virus NS5B polymerase.

Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.

Mammographic and sonographic findings of steatocystoma multiplex presenting as breast lumps.

Steatocystoma multiplex (SM) is an uncommon cutaneous disorder characterised by multiple intradermal cysts distributed over the trunk and proximal extremities. This condition affects both genders and is often inherited as an autosomal dominant trait, although sporadic cases have been described. This report describes the mammographic and sonographic features of the cysts, which presented as breast lumps, for evaluation. The cysts appeared as numerous well-circumscribed, radiolucent nodules with thin radiodense rims on mammography. On sonography, the cysts could be hypoechoic, isoechoic or demonstrate mixed echoes containing debris-fluid levels, depending on the amount of clear oily liquid and keratinous material. SM can be diagnosed based on a clinical setting of multiple asymptomatic small intradermal nodules over the trunk and proximal extremities, positive family history and imaging findings.