Summary We report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCC/PGLs), a rare tumor type. Multi-platform integration revealed that PCC/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically-mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, NF1). We also discovered fusion genes in PCC/PGL, involving MAML3, BRAF, NGFR and NF1. Integrated analysis classified PCC/PGLs into four molecularly-defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCC/PGL included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine.

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SUMMARY Reduced expression of the Indy (= I am Not Dead, Yet) gene in D. melanogaster and C. elegans prolongs life span, and in D. melanogaster augments mitochondrial biogenesis in a manner akin to caloric restriction. However, the cellular mechanism by which Indy does this is unknown. Here, we report on the knockout-mouse model of the mammalian Indy (mIndy) homologue, SLC13A5. Deletion of mIndy in mice (mINDY−/− mice) reduces hepatocellular ATP/ADP ratio, activates hepatic AMPK, induces PGC-1α, inhibits ACC-2, and reduces SREBP-1c levels. This signaling network promotes hepatic mitochondrial biogenesis, lipid oxidation, and energy expenditure and attenuates hepatic de novo lipogenesis. Together, these traits protect mINDY−/− mice from the adiposity and insulin resistance that evolve with high-fat feeding and aging. Our studies demonstrate a profound effect of mIndy on mammalian energy metabolism and suggest that mINDY might be a therapeutic target for the treatment of obesity and type 2 diabetes.

Adrenocortical carcinoma (ACC) is a rare neoplasm with poor prognosis. Patients present with signs of steroid hormone excess (e.g. Cushing's syndrome, virilization) or an abdominal mass. Tumour size at presentation (mean diameter at diagnosis > 10 cm) is the most important indicator of malignancy. In addition, computed tomography (CT) typically demonstrates an inhomogeneous adrenal lesion with irregular margins and variable enhancement of solid components after intravenous contrast media. Magnetic resonance imaging (MRI) is equally effective as CT and is particularly helpful to visualize invasion into large vessels. Complete tumour removal (R0 resection) offers by far the best chance for long-term survival and therefore surgery is the treatment of choice in stage I-III ACC. Despite tumour resection for cure most patients will eventually develop local recurrence or distant metastases. Thus adjuvant treatment options need to be evaluated in high-risk patients (e.g. radiation therapy of the tumour bed and/or chemotherapy). In tumour recurrence re-operation should always be considered. In metastatic disease (stage IV ACC) not amenable to surgery mitotane (o,p'DDD) remains the first-line therapy. Drug monitoring is needed for effective treatment aiming at concentrations between 14 and 20 mg/l. Patients not responding to mitotane may benefit from cytotoxic chemotherapy (23% partial remissions, 4% complete remissions). Only large prospective multicentre trials comparing different treatment options will allow to make systematic progress in the management of ACC.

Patients with AI on current standard replacement suffer from significantly impaired health-related subjective health status, irrespective of origin of disease or concomitant disease. Future studies will have to assess whether more physiological glucocorticoid replacement strategies in AI will ameliorate these impairments.

Background-In patients with systolic heart failure, high levels of circulating aldosterone are associated with an adverse prognosis, and mineralocorticoid receptor blockade improves survival. The prognostic significance of cortisol that may also bind and activate the mineralocorticoid receptor in chronic heart failure is unknown. Methods and Results-Serum levels of cortisol and aldosterone were quantified in a prospective cohort study of 294 consecutive patients with chronic heart failure [48% were in New York Heart Association functional class III or IV; 58% had systolic heart failure]. During a median follow-up of 803 days (interquartile range, 314 to 1098), 79 patients died (27.3% mortality rate). Cortisol and aldosterone were independent predictors of increased mortality risk in Cox regression analyses adjusted for age, sex, New York Heart Association functional class, C-reactive protein, N-terminal pro-brain natriuretic peptide, sodium, and hypercholesterolemia. . Conclusions-In patients with chronic heart failure, higher serum levels of both cortisol and aldosterone were independent predictors of increased mortality risk that conferred complementary and incremental prognostic value. (Circulation.

Summary Peroxisome proliferator-activated receptor-gamma coactivator 1 beta (PGC-1β) is known to be a transcriptional coactivator for SREBP-1, the master regulator of hepatic lipogenesis. Here we evaluated the role of PGC-1β in the pathogenesis of fructose-induced insulin resistance by using an antisense oligonucletoide (ASO) to knockdown PGC-1 β in liver and adipose tissue. PGC-1 β ASO improved the metabolic phenotype induced by fructose feeding by reducing expression of SREBP-1 and downstream lipogenic genes in liver. PGC-1 β ASO also reversed hepatic insulin resistance induced by fructose in both basal and insulin stimulated states. Furthermore, PGC-1β ASO increased insulin-stimulated whole body glucose disposal due to a threefold increase in glucose uptake in white adipose tissue. These data support an important role for PGC-1 β in the pathogenesis of fructose-induced insulin resistance and suggest that PGC-1 β inhibition may be a novel therapeutic target for treatment of NAFLD, hypertriglyceridemia and insulin resistance associated with increased de novo lipogenesis.

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