Citations

Abstract Obesity is a multifactorial disease with a variable and underwhelming weight loss response to current treatment approaches. Precision medicine proposes a new paradigm to improve disease classification based on the premise of human heterogeneity, with the ultimate goal of maximizing treatment effectiveness, tolerability, and safety. Recent advances in high-throughput biochemical assays have contributed to the partial characterization of obesity's pathophysiology, as well as to the understanding of the role that intrinsic and environmental factors, and their interaction, play in its development and progression. These data have led to the development of biological markers that either are being or will be incorporated into strategies to develop personalized lines of treatment for obesity. There are currently many ongoing initiatives aimed at this; however, much needs to be resolved before precision obesity medicine becomes common practice. This review aims to provide a perspective on the currently available data of high-throughput technologies to treat obesity.

No effective systemic treatment is available for patients with unresectable, recurrent, or metastatic mucoepidermoid carcinoma (MEC), the most common salivary gland malignancy. MEC is frequently associated with a t(11;19)(q14-21;p12-13) translocation that creates a CRTC1-MAML2 fusion gene. The CRTC1-MAML2 fusion exhibited transforming activity in vitro; however, whether it serves as an oncogenic driver for MEC establishment and maintenance in vivo remains unknown. Here, we show that doxycycline-induced CRTC1-MAML2 knockdown blocked the growth of established MEC xenografts, validating CRTC1-MAML2 as a therapeutic target. We further generated a conditional transgenic mouse model and observed that Cre-induced CRTC1-MAML2 expression caused 100% penetrant formation of salivary gland tumors resembling histological and molecular characteristics of human MEC. Molecular analysis of MEC tumors revealed altered p16-CDK4/6-RB pathway activity as a potential cooperating event in promoting CRTC1-MAML2–induced tumorigenesis. Cotargeting of aberrant p16-CDK4/6-RB signaling and CRTC1-MAML2 fusion–activated AREG/EGFR signaling with the respective CDK4/6 inhibitor Palbociclib and EGFR inhibitor Erlotinib produced enhanced antitumor responses in vitro and in vivo. Collectively, this study provides direct evidence for CRTC1-MAML2 as a key driver for MEC development and maintenance and identifies a potentially novel combination therapy with FDA-approved EGFR and CDK4/6 inhibitors as a potential viable strategy for patients with MEC.

AbstractBackgroundThe fasting proinsulin to insulin ratio is elevated in people with type 2 diabetes and has been suggested as a marker of β‐cell health. However, its utility in discriminating between individuals with varying degrees of β‐cell dysfunction is unclear. Proinsulin has a very different half‐life to insulin and unlike insulin does not undergo hepatic extraction prior to reaching the systemic circulation. Given these limitations, we sought to examine the relationship between fasting and postprandial concentrations of β‐cell polypeptides (proinsulin, insulin and C‐peptide) in people with normal and impaired glucose tolerance in differing metabolic environments.DesignSubjects were studied on two occasions in random order while undergoing an oral challenge. During one study day, free fatty acids were elevated (to induce insulin resistance) by infusion of Intralipid with heparin. Proinsulin to insulin and proinsulin to C‐peptide ratios were calculated for the 0‐, 30‐, 60‐ and 240‐minute time points. Insulin action (Si) and β‐cell responsivity (Φ) indices were calculated using the oral minimal model.ResultsThe fasting proinsulin to c‐peptide or fasting proinsulin to insulin ratios did not differ between groups and did not predict subsequent β‐cell responsivity to glucose during the glycerol or Intralipid study days in either group.ConclusionsAmong nondiabetic individuals, the fasting proinsulin to insulin ratio is not a useful marker of β‐cell function.

AbstractObjectivesLong-term follow-up is important for determining performance characteristics of thyroid fine-needle aspiration (FNA).MethodsHistologic or 3 or more years of clinical follow-up was used to calculate performance characteristics of thyroid FNA before and after implementation of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). The impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) classification was also investigated.ResultsFollow-up was obtained for 1,277/1,134 and 1,616/1,393 aspirates/patients (median clinical follow-up, 9.9 and 4.4 years, pre- and post-TBSRTC, respectively). Nondiagnostic, suspicious for follicular neoplasm, and suspicious for malignancy (SFM) diagnoses decreased and benign diagnoses increased post-TBSRTC, while atypical rate remained less than 1%. Negative predictive value for benign nodules and positive predictive value (PPV) for SFM increased significantly. Eleven nodules were reclassified as NIFTP, slightly decreasing PPV/risk of malignancy (ROM).ConclusionsAppropriate ROM for thyroid FNA can be achieved through application of TBSRTC terminology with minimal use of atypical category.

Summary Objective To identify predictors of hypothalamic‐pituitary‐adrenal ( HPA ) axis recovery interval and severity of glucocorticoid withdrawal symptoms ( GWS ) in patients undergoing adrenalectomy for corticotropin‐independent cortisol excess. Design This is a retrospective study of patients with mild autonomous cortisol excess ( MACE ), moderate and severe Cushing syndrome ( CS ) who developed adrenal insufficiency after unilateral adrenalectomy between 1998 and 2017. Results Adrenalectomy was performed in 81 patients (79% women, median age 52 years [ IQR 42‐62]). HPA axis recovery occurred at a median of 4.3 months ( IQR 1.6‐11.4) after adrenalectomy (severe CS vs moderate CS vs MACE : median 11.4 vs 2.8 vs 2.1 months, P < 0.01). Main predictors of HPA axis recovery interval included: preoperative serum cortisol concentration after 1‐mg overnight dexamethasone suppression test >10 μg/ dL or >276 nmol/L (9.7 vs 1.3 months if cortisol ≤10 μg/ dL or ≤276 nmol/L, P < 0.01); body mass index (for every 3 kg/m 2 decrease, glucocorticoid taper increased by 1 month, P < 0.05); age <45 (11.4 vs 2.3 months if ≥45 years, P < 0.05); duration of symptoms prior to diagnosis >1 year (11.4 vs 2.8 months if ≤1 year); moon facies (11.4 vs 2.2 months if no rounding of the face); and myopathy (13.1 vs 2.7 months if no myopathy, P < 0.05). Patients with severe CS had a higher incidence of GWS compared to patients with MACE (66.7% vs 40.0%, P < 0.05) with a median of 1 and 0 events/patient, respectively. Conclusions The HPA axis recovery interval was the longest for patients with severe CS . Surprisingly, patients with moderate CS recovered their HPA axis as quickly as those with MACE . Glucocorticoid withdrawal symptoms were observed in all groups, with more events in patients with severe CS . This study emphasizes the need to counsel patients on expectations for HPA axis recovery and address intervention for GWS based on individual preoperative parameters.