Publications

High levels of arginine metabolizing enzymes, including inducible nitric oxide synthase (iNOS) and arginase (ARG), are typical in asthmatic airway epithelium; however, little is known about the metabolic effects of enhanced arginine flux in asthma. Here, we demonstrated that increased metabolism sustains arginine availability in asthmatic airway epithelium with consequences for bioenergetics and inflammation. Expression of iNOS, ARG2, arginine synthetic enzymes, and mitochondrial respiratory complexes III and IV was elevated in asthmatic lung samples compared with healthy controls. ARG2 overexpression in a human bronchial epithelial cell line accelerated oxidative bioenergetic pathways and suppressed hypoxia-inducible factors (HIFs) and phosphorylation of the signal transducer for atopic Th2 inflammation STAT6 (pSTAT6), both of which are implicated in asthma etiology. Arg2-deficient mice had lower mitochondrial membrane potential and greater HIF-2α than WT animals. In an allergen-induced asthma model, mice lacking Arg2 had greater Th2 inflammation than WT mice, as indicated by higher levels of pSTAT6, IL-13, IL-17, eotaxin, and eosinophils and more mucus metaplasia. Bone marrow transplants from Arg2-deficient mice did not affect airway inflammation in recipient mice, supporting resident lung cells as the drivers of elevated Th2 inflammation. These data demonstrate that arginine flux preserves cellular respiration and suppresses pathological signaling events that promote inflammation in asthma.

INTRODUCTION

Metastatic renal cell carcinoma (mRCC) has seen the introduction of numerous new treatments over the past decade. However, the efficacy of these therapies has plateaued, and new treatment options are needed for the majority of patients with mRCC whose disease inevitably progresses through one or more standard therapies ('refractory' mRCC). Recently approved agents in this space have shown great promise.

AREAS COVERED

This article reviews the evidence behind current management strategies for mRCC. After reviewing clinical trials that established current first-line therapies and agents used in the refractory setting, we address new ideas for the treatment of refractory disease including combination therapies and novel targeted agents. In particular, we focus on targeted immunotherapy in refractory mRCC. We conclude by considering future directions in combination treatments utilizing these novel agents.

EXPERT OPINION

Numerous approaches have produced tangible benefits for the treatment of patients with mRCC. These include development of next generation VEGFR/TKIs, targeted immunotherapy agents, and the development of combined regimens. In particular, immunotherapy agents targeting the PD1/PD-L1 pathway have shown great promise with a robust survival advantage seen in patients treated with nivolumab. A tolerable side effect profile of immunotherapy agents makes them amenable for use in combination therapies and ongoing trials are addressing this question.

The objective of this study was to conduct focus groups with youth (18-29 years old) living with HIV (YLWH) to better understand preferences for mobile applications in general and to inform the design of a mobile health application aimed at improving retention and engagement in healthcare and adherence to antiretroviral therapy. We conducted four focus groups with YLWH to elicit the names and characteristics of applications that they commonly used, reasons they deleted applications, and the features of an ideal mobile health application. A diverse sample of youth (N = 17) with a mean age of 25 years, 88.2% male, and 29.4% African American participated in four focus groups. Positive attributes of applications included informative, simple, allowing for networking, timely updates, little overlap with other applications, unlimited access to entertainment, and with ongoing advancement. Participants identified several reasons for deleting applications, including engaging in excessive behaviors (e.g., spending money), for hook ups only, too many notifications or restrictions, occupied too much space on device, or required wireless connectivity or frequent updates. Participants suggested that a mobile health application that they would find useful should have the ability to connect to a community of other YLWH, readily access healthcare providers, track personal data and information (such as laboratory data), and obtain health news and education. Privacy was a key factor in a mobile health application for all participants. Researchers can use the information provided by focus group participants in creating mobile health applications for YLWH.