Benjamin A. Olenchock

Environment Impacts the Metabolic Dependencies of Ras-Driven Non-Small Cell Lung Cancer

Cultured cells convert glucose to lactate, and glutamine is the major source of tricarboxylic acid (TCA)-cycle carbon, but whether the same metabolic phenotype is found in tumors is less studied. We infused mice with lung cancers with isotope-labeled glucose or glutamine and compared the fate of these nutrients in tumor and normal tissue. As expected, lung tumors exhibit increased lactate production from glucose. However, glutamine utilization by both lung tumors and normal lung was minimal, with lung tumors showing increased glucose contribution to the TCA cycle relative to normal lung tissue. Deletion of enzymes involved in glucose oxidation demonstrates that glucose carbon contribution to the TCA cycle is required for tumor formation. These data suggest that understanding nutrient utilization by tumors can predict metabolic dependencies of cancers in vivo. Furthermore, these data argue that the in vivo environment is an important determinant of the metabolic phenotype of cancer cells.

Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells

Reductively metabolized glutamine is a major cellular carbon source for fatty acid synthesis during hypoxia or when mitochondrial respiration is impaired. Yet, a mechanistic understanding of what determines reductive metabolism is missing. Here we identify several cellular conditions where the α-ketoglutarate/citrate ratio is changed due to an altered acetyl-CoA to citrate conversion, and demonstrate that reductive glutamine metabolism is initiated in response to perturbations that result in an increase in the α-ketoglutarate/citrate ratio. Thus, targeting reductive glutamine conversion for a therapeutic benefit might require distinct modulations of metabolite concentrations rather than targeting the upstream signalling, which only indirectly affects the process.

A genetic mechanism for Tibetan high-altitude adaptation

Tibetans do not exhibit increased hemoglobin concentration at high altitude. We describe a high-frequency missense mutation in the EGLN1 gene, which encodes prolyl hydroxylase 2 (PHD2), that contributes to this adaptive response. We show that a variant in EGLN1, c.[12C>G; 380G>C], contributes functionally to the Tibetan high-altitude phenotype. PHD2 triggers the degradation of hypoxia-inducible factors (HIFs), which mediate many physiological responses to hypoxia, including erythropoiesis. The PHD2 p.[Asp4Glu; Cys127Ser] variant exhibits a lower Km value for oxygen, suggesting that it promotes increased HIF degradation under hypoxic conditions. Whereas hypoxia stimulates the proliferation of wild-type erythroid progenitors, the proliferation of progenitors with the c.[12C>G; 380G>C] mutation in EGLN1 is significantly impaired under hypoxic culture conditions. We show that the c.[12C>G; 380G>C] mutation originated ∼8,000 years ago on the same haplotype previously associated with adaptation to high altitude. The c.[12C>G; 380G>C] mutation abrogates hypoxia-induced and HIF-mediated augmentation of erythropoiesis, which provides a molecular mechanism for the observed protection of Tibetans from polycythemia at high altitude.

Current Use of Beta Blockers in Patients With Reactive Airway Disease Who Are Hospitalized With Acute Coronary Syndromes

Beta blockers have a proven benefit in the management of patients with acute coronary syndromes (ACS) and for secondary prevention of coronary events. Current guidelines list such reactive airway diseases (RADs) such as asthma and chronic obstructive pulmonary disease as relative contraindications to beta-blocker use. However, the co-morbid burden of RAD and coronary heart disease is substantial, and data suggest that the treatment benefit of beta blockers is shared by patients with RAD. The Get with the Guidelines (GWTG) database was used to evaluate use of beta blockers within 24 hours of admission and at discharge in patients with ACS with (n = 12,967) and without (n = 81,140) a history of RAD. Data were collected in 435 hospitals between January 2000 and September 2006. A multivariable logistic regression model was used to determine predictors of beta-blocker treatment. In patients with no RAD history, beta-blocker prescription rates were 78.3% at admission and 88.7% at discharge; in patients with a RAD history, rates were 65.6% at admission and 77.2% at discharge. Compared with patients with no history of RAD, patients with a history of RAD were 42% less likely (odds ratio 0.58, confidence interval 0.54 to 0.62, p <0.0001) to receive a beta blocker upon admission and 55% less likely (odds ratio 0.45, confidence interval 0.41 to 0.48, p <0.0001) to receive a beta blocker at discharge in multivariable analysis. Among all other clinical factors, RAD history was the most significant predictor of likelihood of not receiving a beta blocker at admission or discharge. Receipt of beta blockers within 24 hours after admission was associated with a lower in-hospital mortality rate for patients with RAD (odds ratio = 0.52, p <0.001) and for patients without RAD (odds ratio = 0.38, p <0.001). Careful assessment of beta-blocker safety and RAD severity by physicians is needed to improve beta-blocker prescription rates in this large group of patients with ACS.

EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection

Ischemic preconditioning is the phenomenon whereby brief periods of sublethal ischemia protect against a subsequent, more prolonged, ischemic insult. In remote ischemic preconditioning (RIPC), ischemia to one organ protects others organs at a distance. We created mouse models to ask if inhibition of the alpha-ketoglutarate (αKG)-dependent dioxygenase Egln1, which senses oxygen and regulates the hypoxia-inducible factor (HIF) transcription factor, could suffice to mediate local and remote ischemic preconditioning. Using somatic gene deletion and a pharmacological inhibitor, we found that inhibiting Egln1 systemically or in skeletal muscles protects mice against myocardial ischemia-reperfusion (I/R) injury. Parabiosis experiments confirmed that RIPC in this latter model was mediated by a secreted factor. Egln1 loss causes accumulation of circulating αKG, which drives hepatic production and secretion of kynurenic acid (KYNA) that is necessary and sufficient to mediate cardiac ischemic protection in this setting.

Organization and staffing practices in US cardiac intensive care units: a survey on behalf of the American Heart Association Writing Group on the Evolution of Critical Care Cardiology:

Background: The cardiac intensive care unit (CICU) has evolved into a complex patient-care environment with escalating acuity and increasing utilization of advanced technologies. These changing demographics of care may require greater clinical expertise among physician providers. Despite these changes, little is known about present-day staffing practices in US CICUs. Methods and Results: We conducted a survey of 178 medical directors of ICUs caring for cardiac patients to assess unit structure and physician staffing practices. Data were obtained from 123 CICUs (69% response rate) that were mostly from academic medical centres. A majority of hospitals utilized a dedicated CICU (68%) and approximately half of those hospitals employed a ‘closed’ unit model. In 46% of CICUs, an intensivist consult was available, but not routinely involved in care of critically ill cardiovascular patients, while 11% did not have a board-certified intensivist available for consultation. Most CICU directors (87%) surveyed agreed that a closed ICU structure provided better care than an open ICU and 81% of respondents identified an unmet need for cardiologists with critical care training. Conclusions: We report contemporary structural models and staffing practices in a sample of US ICUs caring for critically ill cardiovascular patients. Although most hospitals surveyed had dedicated CICUs, a minority of CICUs employed a ‘closed’ CICU model and few had routine intensivist staffing. Most CICU directors agree that there is a need for cardiologists with intensivist training and expertise. These survey data reveal potential areas for continued improvement in US CICU organizational structure and physician staffing.

Biochemical Underpinnings of Immune Cell Metabolic Phenotypes

&NA; The metabolism of immune cells affects their function and influences host immunity. This review explores how immune cell metabolic phenotypes reflect biochemical dependencies and highlights evidence that both the metabolic state of immune cells and nutrient availability can alter immune responses. The central importance of oxygen, energetics, and redox homeostasis in immune cell metabolism, and how these factors are reflected in different metabolic phenotypes, is also discussed. Linking immune cell metabolic phenotype to effector functions is important to understand how altering metabolism can impact the way in which immune cells meet their metabolic demands and affect the immune response in various disease contexts. &NA; The metabolic phenotype of immune cells reflects the biochemical adaptations these cells use to support function. This review summarizes how metabolism is adapted to meet the energetic and redox demands of immune cell populations.

The Genesis, Maturation, and Future of Critical Care Cardiology

The cardiac intensive care unit (CICU) has changed considerably over time and now serves a unique patient population with a high burden of cardiovascular and noncardiovascular critical illness. Patient complexity and technological evolutions in the CICU have catalyzed the development of critical care cardiology, a fledgling discipline that combines specialization in cardiovascular diseases with knowledge and experience in critical care medicine. Numerous uncertainties and challenges threaten to stymie the growth of this field. A multidisciplinary dialogue focused on the best care design for the CICU patient is needed as we consider alternative approaches to clinical training, staffing, and investigation in this rapidly evolving arena.

Providing Initial Transthoracic Echocardiography Training for Anesthesiologists: Simulator Training Is Not Inferior to Live Training

OBJECTIVE Transthoracic echocardiography (TTE) is finding increased use in anesthesia and critical care. Efficient options for training anesthesiologists should be explored. Simulator mannequins allow for training of manual acquisition and image recognition skills and may be suitable due to ease of scheduling. The authors tested the hypothesis that training with a simulator would not be inferior to training using a live volunteer. DESIGN Prospective, randomized trial. SETTING University hospital. PARTICIPANTS Forty-six anesthesia residents, fellows, and faculty. INTERVENTIONS After preparation with a written and video tutorial, study subjects received 80 minutes of TTE training using either a simulator or live volunteer. Practical and written tests were completed before and after training to assess improvement in manual image acquisition skills and theoretic knowledge. The written test was repeated 4 weeks later. MEASUREMENTS AND MAIN RESULTS Performance in the practical image-acquisition test improved significantly after training using both the live volunteer and the simulator, improving by 4.0 and 4.3 points out of 15, respectively. Simulator training was found not to be inferior to live training, with a mean difference of -0.30 points and 95% confidence intervals that did not cross the predefined non-inferiority margin. Performance in the written retention test also improved significantly immediately after training for both groups but declined similarly upon repeat testing 4 weeks later. CONCLUSIONS When providing initial TTE training to anesthesiologists, training using a simulator was not inferior to using live volunteers.

Outcomes in patients undergoing percutaneous ventricular assist device implantation for cardiogenic shock

Background: Percutaneous ventricular assist devices (PVADs) offer an important but resource-intensive option for management of severe cardiogenic shock (CS). Optimal selection of patients for PVAD support remains undefined. We investigated outcomes, including characteristics associated with in-hospital survival, during PVAD support for CS. Methods: We established a prospective quality improvement program among patients undergoing TandemHeart PVAD implantation for CS at Brigham and Women’s Hospital (Boston, MA). We evaluated 65 consecutive patients between 2006 and 2014, analyzing demographic, clinical, laboratory, hemodynamic, and survival data. Results: Thirty-two patients (49.2%) survived to hospital discharge, of which 12 received destination surgical therapy. Baseline characteristics associated with survival included younger age (47 ± 15 years vs 61 ± 11 years; p<0.001), non-ischemic cardiomyopathy (NICMP) vs ischemic CMP (survival 70.4% vs 34.2%, p=0.004), and, paradoxically, lower presenting left ventricular ejection fraction (LVEF) (survival 66.7% for LVEF ⩽15%, 41.2% for LVEF 16–25%, 25.0% for LVEF >25%; p=0.010). Younger age (p=0.026) and NICMP (p=0.034) remained independent predictors of survival. Twenty-four hours after PVAD placement, a more modest increase in cardiac index (⩽0.75 L/min/m2) was associated with higher in-hospital mortality (OR 6.3, 95% CI 1.8–22.1), as was lack of improvement in serum anion gap (⩽2 mEq/L; OR 5.1, 95% CI 1.6–16.6). Conclusions: Despite intensive care and provision of circulatory support, survival is poor in severe CS. Patients in CS with younger age and NICMP were more likely to survive to hospital discharge. Less robust hemodynamic improvement and persistent acidosis after 24 hours of PVAD support also identified patients less likely to survive.