A metabolic atlas of mouse aging.

Humans are living longer, but this is accompanied by an increased incidence of age-related chronic diseases. Many of these diseases are influenced by age-associated metabolic dysregulation, but how metabolism changes in multiple organs during aging in males and females is not known. Answering this could reveal new mechanisms of aging and age-targeted therapeutics. In this study, we describe how metabolism changes in 12 organs in male and female mice at 5 different ages. Organs show distinct patterns of metabolic aging that are affected by sex differently. Hydroxyproline shows the most consistent change across the dataset, decreasing with age in 11 out of 12 organs investigated. We also developed a metabolic aging clock that predicts biological age and identified alpha-ketoglutarate, previously shown to extend lifespan in mice, as a key predictor of age. Our results reveal fundamental insights into the aging process and identify new therapeutic targets to maintain organ health.

Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma.

In pancreatic ductal adenocarcinoma (PDAC), glutamine is a critical nutrient that drives a wide array of metabolic and biosynthetic processes that support tumor growth. Here, we elucidate how 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist that broadly inhibits glutamine metabolism, blocks PDAC tumor growth and metastasis. We find that DON significantly reduces asparagine production by inhibiting asparagine synthetase (ASNS), and that the effects of DON are rescued by asparagine. As a metabolic adaptation, PDAC cells upregulate ASNS expression in response to DON, and we show that ASNS levels are inversely correlated with DON efficacy. We also show that L-asparaginase (ASNase) synergizes with DON to affect the viability of PDAC cells, and that DON and ASNase combination therapy has a significant impact on metastasis. These results shed light on the mechanisms that drive the effects of glutamine mimicry and point to the utility of cotargeting adaptive responses to control PDAC progression.

The aging tumor metabolic microenvironment.

Despite the higher incidence of cancer with increasing age, few preclinical or clinical studies incorporate age. This, coupled with an aging world population, requires that we improve our understanding of how aging affects cancer development, progression, and treatment. One key area will be how the tumor microenvironment (TME) changes with age. Metabolite levels are an essential component of the TME, and they are affected by the metabolic requirements of the cells present and systemic metabolite availability. These factors are affected by aging, causing different TME metabolic states between young and older adults. In this review, we will summarize what is known about how aging impacts the TME metabolic state, and suggest how we can improve our understanding of it.

A super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy in need of new therapeutic options. Using unbiased analyses of super-enhancers (SEs) as sentinels of core genes involved in cell-specific function, here we uncover a druggable SE-mediated RNA-binding protein (RBP) cascade that supports PDAC growth through enhanced mRNA translation. This cascade is driven by a SE associated with the RBP heterogeneous nuclear ribonucleoprotein F, which stabilizes protein arginine methyltransferase 1 (PRMT1) to, in turn, control the translational mediator ubiquitin-associated protein 2-like. All three of these genes and the regulatory SE are essential for PDAC growth and coordinately regulated by the Myc oncogene. In line with this, modulation of the RBP network by PRMT1 inhibition reveals a unique vulnerability in Myc-high PDAC patient organoids and markedly reduces tumor growth in male mice. Our study highlights a functional link between epigenetic regulation and mRNA translation and identifies components that comprise unexpected therapeutic targets for PDAC.

Dual Inhibition of KRASG12D and Pan-ERBB Is Synergistic in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a low survival rate. Recently, new drugs that target KRASG12D, a common mutation in PDAC, have been developed. We studied one of these compounds, MRTX1133, and found it was specific and effective at low nanomolar concentrations in patient-derived organoid models and cell lines harboring KRASG12D mutations. Treatment with MRTX1133 upregulated the expression and phosphorylation of EGFR and HER2, indicating that inhibition of ERBB signaling may potentiate MRTX1133 antitumor activity. Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer. SIGNIFICANCE: KRAS-mutant pancreatic cancer models, including KRAS inhibitor-resistant models, show exquisite sensitivity to combined pan-ERBB and KRAS targeting, which provides the rationale for testing this drug combination in clinical trials.

The MST1R/RON Tyrosine Kinase in Cancer: Oncogenic Functions and Therapeutic Strategies.

The MST1R/RON receptor tyrosine kinase is a homologue of the more well-known MET receptor. Like MET, RON orchestrates cell signaling pathways that promote oncogenesis and enable cancer cell survival; however, it has a more unique role in the regulation of inflammation. RON was originally described as a transmembrane receptor expressed on tissue resident macrophages and various epithelial cells. RON is overexpressed in a variety of cancers and its activation modifies multiple signaling pathways with resultant changes in epithelial and immune cells which together modulate oncogenic phenotypes. While several RON isoforms have been identified with differences in structure, activation, and pathway regulation, increased RON expression and/or activation is consistently associated with worse outcomes. Tyrosine kinase inhibitors targeting RON have been developed, making RON an actionable therapeutic target.

A MET Targeting Antibody-Drug Conjugate Overcomes Gemcitabine Resistance in Pancreatic Cancer.

PURPOSE: Pancreatic cancer is an aggressive disease associated with a poor 5-year overall survival. Most patients are ineligible for surgery due to late diagnosis and are treated primarily with chemotherapy with very limited success. Pancreatic cancer is relatively insensitive to chemotherapy due to multiple factors, including reduced bioavailability of drugs to tumor cells. One strategy to improve drug efficacy with reduced toxicity is the development of antibody-drug conjugates (ADC), which have now been used successfully to treat both solid and liquid tumors. Here, we evaluate the efficacy of TR1801-ADC, a newly developed ADC composed of a MET antibody conjugated to the highly potent pyrrolobenzodiazepine toxin-linker, tesirine. EXPERIMENTAL DESIGN: We first evaluated MET expression and subcellular localization in pancreatic cancer cell lines, human tumors, and patient-derived xenografts (PDX). We then tested TR1801-ADC efficacy in vitro in pancreatic cancer cell lines. Preclinical evaluation of TR1801-ADC efficacy was conducted on PDXs selected on the basis of their MET expression level. RESULTS: We show that MET is highly expressed and located at the plasma membrane of pancreatic cancer cells. We found that TR1801-ADC induces a specific cytotoxicity in pancreatic cancer cell lines and a profound tumor growth inhibition, even in a gemcitabine-resistant tumor. We also noted synergism between TR1801-ADC and gemcitabine in vitro and an improved response to the combination in vivo. CONCLUSIONS: Together, these results suggest the promise of agents such as TR1801-ADC as a novel approach to the treatment of pancreatic cancer.

Impact of psychiatric illness on decreased survival in elderly patients with bladder cancer in the United States.

BACKGROUND: Treatments for muscle-invasive bladder cancer are multimodal, complex, and often carry significant risks of physical and psychological morbidity. The objectives of this study were to define the incidence and types of psychiatric illnesses diagnosed after treatment and to determine their impact on survival outcomes. METHODS: In total, 3709 patients who were diagnosed with clinical stage T2 through T4a bladder cancer from January 1, 2002, to December 31, 2011, from the Surveillance, Epidemiology, and End Results-Medicare were analyzed. Multivariable analysis and Cox proportional-hazards models were used to determine the predictors associated with psychiatric diagnosis and impact on survival outcomes. RESULTS: Of 3709 patients, 1870 (50.4%) were diagnosed with posttreatment psychiatric disorders. Patients who underwent radical cystectomy were identified as being at significantly greater risk of having a posttreatment psychiatric illness compared with those who received radiotherapy and/or chemotherapy (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.07-1.31; P = .001). In adjusted analyses, diagnosis of a psychiatric disorder resulted in significantly worse overall survival (HR, 2.80; 95% CI, 2.47-3.17; P < .001) and cancer-specific survival (HR, 2.39; 95% CI, 2.05-2.78; P < .001). CONCLUSIONS: One-half of patients with muscle-invasive bladder cancer who underwent treatment were diagnosed with a psychiatric disorder, which resulted in worse survival outcomes compared with patients who did not have a posttreatment psychiatric diagnosis. This information can be used to inform interventions to educate patients with muscle-invasive bladder cancer regarding the impact of different treatments on mental health. Cancer 2018. © 2018 American Cancer Society.

Accessory bronchus in a patient with chronic cough.

The accessory bronchus involving the trachea or main bronchi is very rare. In this report, we present images of an accessory bronchus, detected by computed tomography scan and flexible bronchoscopy. Our patient was suffering from persistent productive cough and had normal chest x-ray. We review the literature to establish relationship between our patient's symptoms and this congenital anomaly.

Non-erosive reflux disease manifested exclusively by protracted hiccups.

Hiccups are a benign physiological feature affecting almost everyone at one time or another. They tend to be short-lived and do not affect quality of life; however, there are various pathologies that may present with long-lasting hiccups. These are grouped into 3 categories according to their duration: acute, persistent and intractable or protracted hiccups. Intractable hiccups last longer than 2 months and are usually associated with more severe conditions. The association between intractable hiccups and reflux disease has not been previously documented by objective methods. This report describes the case of a 23-year-old female who presented with protracted hiccups; all other organic pathologies were ruled out, and endoscopy and conventional pH-metry confirmed a diagnosis of non-erosive reflux disease as the unique cause.

Technical problems produced by the Bravo pH test in nonerosive reflux disease patients.

AIM: To evaluate the technical failures of the Bravo pH test in a population with nonerosive gastroesophageal reflux disease. METHODS: Over the course of a year, we prospectively studied a population of 66 nonerosive reflux disease patients who received a Bravo pH test. The number and frequency of all technical failures were documented, quantified and analyzed. RESULTS: A total of 66 patients, with a mean age of 41.7 years, were studied. Technical failures occurred in 15.15% of the sample. The most frequent failures were due to poor data reception (4.5%), early dislodgement (4.5%) and capsule removal (6.1%). CONCLUSION: The Bravo capsule pH test involves a low but non-negligible rate of technical problems, a fact that must always be considered by physicians.

Cold and hot snare endoscopic techniques for removal of the Bravo pH monitoring capsule.

BACKGROUND: Currently, use of the Bravo capsule is a very common method for evaluating the gastroesophageal reflux because it has the advantage of being an intraesophageal catheter-free system. However, endoscopic removal of the capsule is necessary when technical problems or severe discomfort are present. Most frequently, endoscopists solve this problem by nudging the device with the tip of the endoscope to dislodge it; others have used a cold snare to produce traction on the capsule, and then tear the probe off. These techniques however are not free of complications. We report here the cold and hot snare techniques used in 4 of our patients, which resulted in the successful removal of the capsule without complications. METHODS: The polypectomy cold snare procedure is a typical polypectomy method. The cold snare loops the mucosal pedicle and tightly closes it until sectioning is achieved. In the hot snare technique, a monopolar coagulating current is added to the previous procedure, making the resection more feasible when the cold snare is not sufficient. Finally, in both situations, the probe is removed from the esophagus with the same snare. CONCLUSIONS: The cold and hot snare techniques are safe and simple endoscopic procedures when the removal of the Bravo capsule is required. We recommend the cold snare method as a first option and the hot snare method in case the former fails.