Lane Medical Library

Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response.

Proc Natl Acad Sci U S A. 2013 May 20;

Authors: Tseng D, Volkmer JP, Willingham SB, Contreras-Trujillo H, Fathman JW, Fernhoff NB, Seita J, Inlay MA, Weiskopf K, Miyanishi M, Weissman IL

Abstract
Mobilization of the T-cell response against cancer has the potential to achieve long-lasting cures. However, it is not known how to harness antigen-presenting cells optimally to achieve an effective antitumor T-cell response. In this study, we show that anti-CD47 antibody-mediated phagocytosis of cancer by macrophages can initiate an antitumor T-cell immune response. Using the ovalbumin model antigen system, anti-CD47 antibody-mediated phagocytosis of cancer cells by macrophages resulted in increased priming of OT-I T cells [cluster of differentiation 8-positive (CD8(+))] but decreased priming of OT-II T cells (CD4(+)). The CD4(+) T-cell response was characterized by a reduction in forkhead box P3-positive (Foxp3(+)) regulatory T cells. Macrophages following anti-CD47-mediated phagocytosis primed CD8(+) T cells to exhibit cytotoxic function in vivo. This response protected animals from tumor challenge. We conclude that anti-CD47 antibody treatment not only enables macrophage phagocytosis of cancer but also can initiate an antitumor cytotoxic T-cell immune response.

PMID: 23690610 [PubMed - as supplied by publisher]

Systematic functional regulatory assessment of disease-associated variants.

Proc Natl Acad Sci U S A. 2013 May 20;

Authors: Karczewski KJ, Dudley JT, Kukurba KR, Chen R, Butte AJ, Montgomery SB, Snyder M

Abstract
Genome-wide association studies have discovered many genetic loci associated with disease traits, but the functional molecular basis of these associations is often unresolved. Genome-wide regulatory and gene expression profiles measured across individuals and diseases reflect downstream effects of genetic variation and may allow for functional assessment of disease-associated loci. Here, we present a unique approach for systematic integration of genetic disease associations, transcription factor binding among individuals, and gene expression data to assess the functional consequences of variants associated with hundreds of human diseases. In an analysis of genome-wide binding profiles of NFκB, we find that disease-associated SNPs are enriched in NFκB binding regions overall, and specifically for inflammatory-mediated diseases, such as asthma, rheumatoid arthritis, and coronary artery disease. Using genome-wide variation in transcription factor-binding data, we find that NFκB binding is often correlated with disease-associated variants in a genotype-specific and allele-specific manner. Furthermore, we show that this binding variation is often related to expression of nearby genes, which are also found to have altered expression in independent profiling of the variant-associated disease condition. Thus, using this integrative approach, we provide a unique means to assign putative function to many disease-associated SNPs.

PMID: 23690573 [PubMed - as supplied by publisher]

Christine Anne Cunegonde Wijman, MD, PhD (1965-2013).

Neurocrit Care. 2013 May 21;

Authors: Finley Caulfield A, Venkatasubramanian C

Abstract

PMID: 23690248 [PubMed - as supplied by publisher]

Pediatric Acute Myeloid Leukemia as Classified Using 2008 WHO Criteria: A Single-Center Experience.

Am J Clin Pathol. 2013 Jun;139(6):818-825

Authors: Davis KL, Marina N, Arber DA, Ma L, Cherry A, Dahl GV, Heerema-McKenney A

Abstract
The classification of acute myeloid leukemia (AML) has evolved to the most recent World Health Organization (WHO) schema, which integrates genetic, morphologic, and prognostic data into a single system. However, this system was devised using adult data and how this system applies to a pediatric cohort is unknown. Performing a retrospective chart review, we examined our single-center experience with AML in 115 children and classified their leukemia using the WHO 2008 schema. We examined patient samples for mutations of FLT3, NPM1, and CEBPA. Overall survival was calculated within categories. In our pediatric population, most cases of AML had recurrent genetic abnormalities of favorable prognosis. More than 10% of patients in our series were categorized as AML, with myelodysplasia-related changes, an entity not well-described in pediatric patients. In addition, a large proportion of patients were categorized with secondary, therapy-related AML. To our knowledge, this is the first application of the WHO 2008 classification to a pediatric cohort. In comparison to adult studies, AML in the pediatric population shows a distinct distribution within the WHO 2008 classification.

PMID: 23690127 [PubMed - as supplied by publisher]

Life stressors and resources and the 23-year course of depression.

J Affect Disord. 2013 May 17;

Authors: Cronkite RC, Woodhead EL, Finlay A, Timko C, Unger Hu K, Moos RH

Abstract
BACKGROUND: Life stressors and personal and social resources are associated with depression in the short-term, but little is known about their associations with the long-term course of depression. The current paper presents results of a 23-year study of community adults who were receiving treatment for depression at baseline (N=382). METHODS: Semi-parametric group-based modeling was used to identify depression trajectories and determine baseline predictors of belonging to each trajectory group. RESULTS: There were three distinct courses of depression: high severity at baseline with slow decline, moderate severity at baseline with rapid decline, and low severity at baseline with rapid decline. At baseline, individuals in the high-severity group had less education than those in the moderate-severity group, and more medical conditions than those in the moderate- and low-severity groups. Individuals in the high- and moderate-severity groups evidenced less psychological flexibility, and relied more on avoidance coping than individuals in the low-severity group. LIMITATIONS: Results are limited by use of self-report and lack of information about depression status and life events in the periods between follow-ups. CONCLUSIONS: These results assist in identifying groups at high risk for a long-term course of depression, and will help in selecting appropriate interventions that target depression severity, coping skills and management of stressors.

PMID: 23688913 [PubMed - as supplied by publisher]

Turning on the Lights: New Technologies in Optical Diagnostics and Therapeutics.

J Urol. 2013 May 17;

Authors: Liao JC, Leppert JT

PMID: 23688641 [PubMed - as supplied by publisher]

The roles of productivity and ecosystem size in determining food chain length in tropical terrestrial ecosystems.

Ecology. 2013 Mar;94(3):692-701

Authors: Young HS, McCauley DJ, Dunbar RB, Hutson MS, Ter-Kuile AM, Dirzo R

Abstract
Many different drivers, including productivity, ecosystem size, and disturbance, have been considered to explain natural variation in the length of food chains. Much remains unknown about the role of these various drivers in determining food chain length, and particularly about the mechanisms by which they may operate in terrestrial ecosystems, which have quite different ecological constraints than aquatic environments, where most food chain length studies have been thus far conducted. In this study, we tested the relative importance of ecosystem size and productivity in influencing food chain length in a terrestrial setting. We determined that (1) there is no effect of ecosystem size or productive space on food chain length; (2) rather, food chain length increases strongly and linearly with productivity; and (3) the observed changes in food chain length are likely achieved through a combination of changes in predator size, predator behavior, and consumer diversity along gradients in productivity. These results lend new insight into the mechanisms by which productivity can drive changes in food chain length, point to potential for systematic differences in the drivers of food web structure between terrestrial and aquatic systems, and challenge us to consider how ecological context may control the drivers that shape food chain length.

PMID: 23687895 [PubMed - in process]

The quality of systematic reviews in hand surgery: an analysis using AMSTAR.

Plast Reconstr Surg. 2013 Apr;131(4):831-7

Authors: Momeni A, Lee GK, Talley JR

Abstract
BACKGROUND: Systematic reviews constitute the top of the "level-of-evidence pyramid." Despite their strengths, they have been found to be of varying quality, thus raising concerns about their validity and role in influencing clinical practice. In the present study, a quality analysis of systematic reviews with a focus on hand surgery was performed.
METHODS: A PubMed search was performed to identify all systematic reviews published up to and including December of 2011 in eight surgical journals. Two authors independently reviewed the literature and extracted data from included reviews. Discrepancies were resolved by consensus. Quality assessment was performed using AMSTAR.
RESULTS: The initial search retrieved 687 articles. After screening titles and abstracts, 635 articles were excluded. Full-text review of the remaining 52 articles resulted in further exclusion of 10 articles, leaving 42 systematic reviews for final analysis. A significant increase in the number of published systematic reviews over time was noted (p = 0.04), with the majority of systematic reviews being published in The Journal of Hand Surgery (n = 19) and Plastic and Reconstructive Surgery (n = 12). Although a significant improvement in the quality of systematic reviews was noted over time (p = 0.01), a median AMSTAR score of 7 indicated the bulk of reviews to be of fair to good quality.
CONCLUSIONS: The trend to publish more systematic reviews in hand surgery is paralleled by an increase in the quality of systematic reviews. Nonetheless, increased efforts are indicated to further improve the quality of systematic reviews in hand surgery.

PMID: 23542254 [PubMed - indexed for MEDLINE]

Cardiac testing to manage cardiovascular risk in cancer patients.

Semin Oncol. 2013 Apr;40(2):147-55

Authors: Davis M, Witteles RM

Abstract
Cardiovascular toxicity is one of the most feared complications of cancer treatment. Recent advances in oncologic therapies have resulted in improved cancer outcomes but also a new set of cardiovascular adverse effects. Common toxicities include left ventricular dysfunction/heart failure, hypertension, and myocardial ischemia. Accurate risk stratification allows avoidance of potentially harmful treatments in those patients at greatest risk while maintaining the ability to deliver high doses of effective therapies to the lower-risk population. Cardiac investigations, including echocardiography, nuclear imaging, magnetic resonance imaging, biomarker measurement, blood pressure monitoring, electrocardiography, stress testing, and invasive angiography, can help to risk-stratify selected patients. In this review, common complications are discussed in terms of the factors used to identify patients with elevated risk, the monitoring strategies available, and selected interventions that have been used to modify outcomes in patients identified as being at high risk for cardiac complications of cancer treatment.

PMID: 23540740 [PubMed - indexed for MEDLINE]

Asthma discordance in twins is linked to epigenetic modifications of T cells.

PLoS One. 2012;7(11):e48796

Authors: Runyon RS, Cachola LM, Rajeshuni N, Hunter T, Garcia M, Ahn R, Lurmann F, Krasnow R, Jack LM, Miller RL, Swan GE, Kohli A, Jacobson AC, Nadeau KC

Abstract
T cells mediate the inflammatory responses observed in asthma among genetically susceptible individuals and have been suspected to be prone to epigenetic regulation. However, these relationships are not well established from past clinical studies that have had limited capacity to control for the effects of variable genetic predisposition and early environmental exposures. Relying on a cohort of monozygotic twins discordant for asthma we sought to determine if epigenetic modifications in T cells were associated with current asthma and explored whether such modifications were associated with second hand smoke exposures. Our study was conducted in a monozygotic twin cohort of adult twin pairs (n = 21) all discordant for asthma. Regulatory T cell (Treg) and effector T cell (Teff) subsets were assessed for levels of cellular function, protein expression, gene expression and CpG methylation within Forkhead box P3 (FOXP3) and interferon gamma-γ (IFNγ) loci. Comparisons by asthma and current report of exposure to second hand smoke were made. Treg from asthmatic discordant twins demonstrated decreased FOXP3 protein expression and impaired Treg function that was associated with increased levels of CpG methylation within the FOXP3 locus when compared to their non-asthmatic twin partner. In parallel, Teff from discordant asthmatic twins demonstrated increased methylation of the IFNγ locus, decreased IFNγ expression and reduced Teff function when compared to Teff from the non-asthmatic twin. Finally, report of current exposure to second hand smoke was associated with modifications in both Treg and Teff at the transcriptional level among asthmatics. The results of the current study provide evidence for differential function of T cell subsets in monozygotic twins discordant for asthma that are regulated by changes in DNA methylation. Our preliminary data suggest exposure to second hand smoke may augment the modified T cell responses associated with asthma.

PMID: 23226205 [PubMed - indexed for MEDLINE]

Pulmonary circulation imaging: embryology and normal anatomy.

Semin Ultrasound CT MR. 2012 Dec;33(6):473-84

Authors: Murillo H, Cutalo MJ, Jones RP, Lane MJ, Fleischmann D, Restrepo CS

Abstract
This review focuses on the embryology and normal imaging anatomy of the pulmonary circulation, with emphasis on the major arterial and venous vasculature. The pulmonary circulation and parenchyma have a complex intertwined embryologic origin. Understanding the embryologic basis of normal pulmonary vasculature aids recognition of anomalies and visceral situs in the chest. Adaptive changes to congenital anomalies of the pulmonary arterial vasculature are used to contrast from normal and review associated temporal adaptive vascular and parenchymal changes.

PMID: 23168059 [PubMed - indexed for MEDLINE]

Structural basis for progression toward the carbapenemase activity in the GES family of β-lactamases.

J Am Chem Soc. 2012 Dec 5;134(48):19512-5

Authors: Smith CA, Frase H, Toth M, Kumarasiri M, Wiafe K, Munoz J, Mobashery S, Vakulenko SB

Abstract
Carbapenem antibiotics have become therapeutics of last resort for the treatment of difficult infections. The emergence of class-A β-lactamases that have the ability to inactivate carbapenems in the past few years is a disconcerting clinical development in light of the diminished options for treatment of infections. A member of the GES-type β-lactamase family, GES-1, turns over imipenem poorly, but the GES-5 β-lactamase is an avid catalyst for turnover of this antibiotic. We report herein high-resolution X-ray structures of the apo GES-5 β-lactamase and the GES-1 and GES-5 β-lactamases in complex with imipenem. The latter are the first structures of native class-A carbapenemases with a clinically used carbapenem antibiotic in the active site. The structural information is supplemented by information from molecular dynamics simulations, which collectively for the first time discloses how the second step of catalysis by these enzymes, namely, hydrolytic deacylation of the acyl-enzyme species, takes place effectively in the case of the GES-5 β-lactamase and significantly less so in GES-1. This information illuminates one evolutionary path that nature has taken in the direction of the inexorable emergence of resistance to carbapenem antibiotics.

PMID: 23148776 [PubMed - indexed for MEDLINE]

Determining host metabolic limitations on viral replication via integrated modeling and experimental perturbation.

PLoS Comput Biol. 2012;8(10):e1002746

Authors: Birch EW, Ruggero NA, Covert MW

Abstract
Viral replication relies on host metabolic machinery and precursors to produce large numbers of progeny - often very rapidly. A fundamental example is the infection of Escherichia coli by bacteriophage T7. The resource draw imposed by viral replication represents a significant and complex perturbation to the extensive and interconnected network of host metabolic pathways. To better understand this system, we have integrated a set of structured ordinary differential equations quantifying T7 replication and an E. coli flux balance analysis metabolic model. Further, we present here an integrated simulation algorithm enforcing mutual constraint by the models across the entire duration of phage replication. This method enables quantitative dynamic prediction of virion production given only specification of host nutritional environment, and predictions compare favorably to experimental measurements of phage replication in multiple environments. The level of detail of our computational predictions facilitates exploration of the dynamic changes in host metabolic fluxes that result from viral resource consumption, as well as analysis of the limiting processes dictating maximum viral progeny production. For example, although it is commonly assumed that viral infection dynamics are predominantly limited by the amount of protein synthesis machinery in the host, our results suggest that in many cases metabolic limitation is at least as strict. Taken together, these results emphasize the importance of considering viral infections in the context of host metabolism.

PMID: 23093930 [PubMed - indexed for MEDLINE]

Concurrent laparoscopic morgagni hernia repair and sleeve gastrectomy.

J Laparoendosc Adv Surg Tech A. 2012 Dec;22(10):999-1002

Authors: Chiou G, Tedesco M, Eisenberg D

Abstract
The Morgagni-type anterior diaphragmatic hernia is a congenital defect that is a very uncommon hernia presenting in an adult. Surgical repair is usually recommended upon diagnosis and often requires synthetic mesh for a durable, tension-free repair. The use of synthetic mesh concurrently with several of bariatric operations is controversial owing to the potential for mesh infection. In this report we describe a laparoscopic repair of a symptomatic Morgagni hernia with synthetic mesh, concurrently with sleeve gastrectomy, in a morbidly obese man. The patient was a 58-year-old man with a body mass index of 48 kg/m(2) and associated co-morbid conditions that included obstructive sleep apnea, hypertension, hyperlipidemia, impaired fasting glucose, and osteoarthritis. He was diagnosed with Morgagni hernia with exertional dyspnia. He underwent concurrent laparoscopic Morgagni hernia repair with mesh and sleeve gastrectomy. At 2 months after surgery the patient was doing well and tolerating solid foods, and his percentage excess weight loss was 35%. He was exercising regularly and had no exertional dyspnea. Laparoscopy is an attractive approach to performing multiple intra-abdominal procedures concurrently. The Morgagni hernia repair with mesh can be performed safely and effectively using a laparoscopic approach. This can be performed concurrently with bariatric surgery in the morbidly obese.

PMID: 23067069 [PubMed - indexed for MEDLINE]

The mineralocorticoid receptor agonist, fludrocortisone, differentially inhibits pituitary-adrenal activity in humans with psychotic major depression.

Psychoneuroendocrinology. 2013 Jan;38(1):115-21

Authors: Lembke A, Gomez R, Tenakoon L, Keller J, Cohen G, Williams GH, Kraemer FB, Schatzberg AF

Abstract
INTRODUCTION: Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been linked with major depression, particularly psychotic major depression (PMD), with mineralocorticoid receptors (MRs) playing a role in HPA-axis regulation and the pathophysiology of depression. Herein we hypothesize that the MR agonist fludrocortisone differentially inhibits the HPA axis of psychotic major depression subjects (PMDs), non-psychotic major depression subjects (NPMDs), and healthy control subjects (HCs).
METHODS: Fourteen PMDs, 16 NPMDs, and 19 HCs were admitted to the Stanford University Hospital General Clinical Research Center. Serum cortisol levels were sampled at baseline and every hour from 18:00 to 23:00h, when greatest MR activity is expected, on two consecutive nights. On the second afternoon at 16:00h all subjects were given 0.5mg fludrocortisone. Mean cortisol levels pre- and post-fludrocortisone and percent change in cortisol levels were computed.
RESULTS: There were no significant group differences for cortisol at baseline: F(2,47)=.19, p=.83. There were significant group differences for post-fludrocortisone cortisol: F(2,47)=5.13, p=.01, which were significantly higher in PMDs compared to HCs (p=.007), but not compared to NPMDs (p=.18). There were no differences between NPMD's and HC's (p=.61). Also, PMDs had a lower percent change from baseline in cortisol levels at 2200h than NPMDs (p=.01) or HCs (p=.009).
CONCLUSIONS: Individuals with psychotic major depression compared to healthy control subjects have diminished feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis in response to the mineralocorticoid receptor agonist fludrocortisone. To our knowledge, this is the first study to examine HPA axis response to MR stimulation in major depression (with and without psychosis), and only the third study to demonstrate that exogenously administered fludrocortisone can down-regulate the HPA axis in humans.

PMID: 22727477 [PubMed - indexed for MEDLINE]