Cushing's disease, also known as adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (PAs) that cause excess cortisol production, accounts for up to 85% of corticotrophin-dependent Cushing's syndrome cases. However, the genetic alterations in this disease are unclear. Here, we performed whole-exome sequencing of DNA derived from 12 ACTH-secreting PAs and matched blood samples, which revealed three types of somatic mutations in a candidate gene, USP8 (encoding ubiquitin-specific protease 8), exclusively in exon 14 in 8 of 12 ACTH-secreting PAs. We further evaluated somatic USP8 mutations in additional 258 PAs by Sanger sequencing. Targeted sequencing further identified a total of 17 types of USP8 variants in 67 of 108 ACTH-secreting PAs (62.04%). However, none of these mutations was detected in other types of PAs (n = 150). These mutations aggregate within the 14-3-3 binding motif of USP8 and disrupt the interaction between USP8 and 14-3-3 protein, resulting in an elevated capacity to protect EGFR from lysosomal degradation. Accordingly, PAs with mutated USP8 display a higher incidence of EGFR expression, elevated EGFR protein abundance and mRNA expression levels of POMC, which encodes the precursor of ACTH. PAs with mutated USP8 are significantly smaller in size and have higher ACTH production than wild-type PAs. In surgically resected primary USP8-mutated tumor cells, USP8 knockdown or blocking EGFR effectively attenuates ACTH secretion. Taken together, somatic gain-of-function USP8 mutations are common and contribute to ACTH overproduction in Cushing's disease. Inhibition of USP8 or EGFR is promising for treating USP8-mutated corticotrophin adenoma. Our study highlights the potentially functional mutated gene in Cushing's disease and provides insights into the therapeutics of this disease.

Significance: Hydrogen sulfide (H 2 S) has traditionally been considered a toxic environmental pollutant. In the late 1990s, the presumed solely harmful role of H 2 S has been challenged because H 2 S may also be involved in the maintenance and preservation of cardiovascular homeostasis. Recent Advances: The production of endogenous H 2 S has been attributed to three key enzymes, cystathionine c-lyase (CSE), cystathionine b-synthase, and 3-mercaptopyruvate sulfurtransferase. The recognition of H 2 S as the third gaseous signaling molecule has stimulated research on a multitude of pathophysiologic events in the cardiovascular system. In particular, important roles in cardiovascular disorder processes are ascribed to the CSE/H 2 S pathway, such as atherosclerosis, myocardial infarction, hypertension, and shock. Critical Issues: Many biological activities and molecular mechanisms of H 2 S in the cardiovascular system have been demonstrated in studies using different tools, such as the genetic overexpression of CSE, the direct administration of H 2 S donors, or the use of H 2 S-releasing prodrugs. Unfortunately, the role of the CSE/H 2 S pathway in cardiovascular disease remains controversial in numerous areas, and many questions regarding the gaseous molecule still remain unanswered. Future Directions: Advances in basic research indicate that the CSE/H 2 S pathway may provide potential therapeutic targets for treating cardiovascular disorders. But the molecular targets of H 2 S still need to be identified. Antioxid. Redox Signal. 17, 106-118.

BackgroundBevacizumab has been suggested as a new treatment modality for cerebral radiation necrosis due to its ability to block the effects of vascular endothelial growth factor (VEGF) in leakage-prone capillaries, though its use still remains controversial in clinical practice.MethodsThe use of bevacizumab in 17 patients with symptomatic cerebral radiation necrosis poorly controlled with dexamethasone steroid treatments was examined between March 2010 and January 2012. Bevacizumab therapy was administered for a minimum of two cycles (7.5 mg/kg, at two-week interval) with a median of four bevacizumab injections. Changes in bi-dimensional measurements of the largest radiation necrosis lesions were observed by gadolinium-enhanced and T2-weighted magnetic resonance imaging (MRI). Additionally, dexamethasone dosage, Karnofsky performance status (KPS), adverse event occurrence and associated clinical outcomes were recorded for each patient.ResultsMRI analysis revealed that the average reduction was 54.9% and 48.4% in post-gadolinium and T2-weighted sequence analysis, respectively. Significant clinical neurological improvements were expressed in 10 patients according to KPS values. Dexamethasone reduction was achieved four weeks after initiation of bevacizumab in all patients, with four patients successfully discontinuing dexamethasone treatment. Mild to moderate bevacizumab-related adverse events, such as fatigue, proteinuria and hypertension were observed in three patients. Upon follow-up at 4 to 12 months, 10 patients showed clinical improvement, and 7 patient deaths occurred from tumor progression (5 patients), recurrent necrosis (1 patient), and uncontrolled necrosis-induced edema (1 patient).ConclusionsThese findings suggest bevacizumab as a promising treatment for cerebral radiation necrosis induced by common radiation therapies, including external beam radiotherapy (EBRT), stereotactic radiosurgery (SRS), and fractionated stereotactic radiotherapy (FSRT).