Lane Medical Library

Improving macrophage responses to therapeutic antibodies by molecular engineering of SIRPα variants.

Oncoimmunology. 2013 Sep 1;2(9):e25773

Authors: Weiskopf K, Ring AM, Schnorr PJ, Volkmer JP, Volkmer AK, Weissman IL, Garcia KC

Abstract
CD47 transduces inhibitory signals through signal-regulatory protein α (SIRPα), a plasma membrane receptor expressed by macrophages. Many cancers upregulate CD47 to evade immunosurveillance. We have recently engineered SIRPα variants that potently antagonize CD47 for use as anticancer immunotherapeutics. These high-affinity SIRPα variants synergize with antineoplastic antibodies by lowering the threshold for macrophage-mediated destruction of malignant cells.

PMID: 24319639 [PubMed - as supplied by publisher]

Science Communication to the General Public: Why We Need to Teach Undergraduate and Graduate Students this Skill as Part of Their Formal Scientific Training.

J Undergrad Neurosci Educ. 2013;12(1):E6-E10

Authors: Brownell SE, Price JV, Steinman L

PMID: 24319399 [PubMed - as supplied by publisher]

Ethical, Legal and Social Issues Surrounding Research on Genetic Contributions to Anti-Social Behavior.

Aggress Violent Behav. 2013 11;18(6)

Authors: Berryessa CM, Martinez-Martin NA, Allyse MA

Abstract
Scientific study of genetic contributions to chronic antisocial behavior has stemmed from many lines of research in recent years. Genetic research involving twin, family, and adoption studies have traditionally been used to compare the health and behavior outcomes of individuals who share the same environment or hereditary lineage; several of these studies have concluded that heredity plays some role in the formation of chronic antisocial behavior, including various forms of aggression and chronic norm-defiance. However, the ethical, social, and legal environment surrounding research on the biological contributions to antisocial behavior in the United States is contentious. Although there has been some discussion in the last few decades regarding the ethical, social, and legal concerns around this type of research within academic and policy circles, analysis and discussion of these concerns rarely appear together. This paper explores the main themes that interact to form the basis of much of the resistance to positing biological contributions to antisocial behavior.

PMID: 24319343 [PubMed - as supplied by publisher]

JAK inhibition in the myeloproliferative neoplasms: lessons learned from the bench and bedside.

Hematology Am Soc Hematol Educ Program. 2013;2013:529-37

Authors: Gotlib J

Abstract
The discovery of the JAK2 V617F mutation in the classic BCR-ABL1-negative myeloproliferative neoplasms in 2005 catalyzed a burst of research efforts that have culminated in substantial dividends for patients. Beyond JAK2 V617F, a more detailed picture of the pathobiologic basis for activated JAK-STAT signaling has emerged. In some patients with myelofibrosis (MF), next-generation sequencing technologies have revealed a complex clonal architecture affecting both genetic and epigenetic regulators of cell growth and differentiation. Although these bench-top findings have informed the clinical development of JAK inhibitors in MF, they have also provided scientific context for some of their limitations. The JAK1/JAK2 inhibitor ruxolitinib is approved for treatment of MF in North America and Europe and other lead JAK inhibitors discussed herein (fedratinib [SAR302503], momelotinib [CYT387], and pacritinib [SB1518]), have entered advanced phases of trial investigation. Uniformly, these agents share the ability to reduce spleen size and symptom burden. A major challenge for practitioners is how to optimize dosing of these agents to secure clinically relevant and durable benefits while minimizing myelosuppression. Suboptimal responses have spurred a "return to the bench" to characterize the basis for disease persistence and to inform new avenues of drug therapy.

PMID: 24319228 [PubMed - in process]

Alterations in White Matter Structure in Young Children With Type 1 Diabetes.

Diabetes Care. 2013 Dec 6;

Authors: Barnea-Goraly N, Raman M, Mazaika P, Marzelli M, Hershey T, Weinzimer SA, Aye T, Buckingham B, Mauras N, White NH, Fox LA, Tansey M, Beck RW, Ruedy KJ, Kollman C, Cheng P, Reiss AL, for the Diabetes Research in Children Network (DirecNet)*

Abstract
OBJECTIVETo investigate whether type 1 diabetes affects white matter (WM) structure in a large sample of young children.RESEARCH DESIGN AND METHODSChildren (ages 4 to <10 years) with type 1 diabetes (n = 127) and age-matched nondiabetic control subjects (n = 67) had diffusion weighted magnetic resonance imaging scans in this multisite neuroimaging study. Participants with type 1 diabetes were assessed for HbA1c history and lifetime adverse events, and glucose levels were monitored using a continuous glucose monitor (CGM) device and standardized measures of cognition.RESULTSBetween-group analysis showed that children with type 1 diabetes had significantly reduced axial diffusivity (AD) in widespread brain regions compared with control subjects. Within the type 1 diabetes group, earlier onset of diabetes was associated with increased radial diffusivity (RD) and longer duration was associated with reduced AD, reduced RD, and increased fractional anisotropy (FA). In addition, HbA1c values were significantly negatively associated with FA values and were positively associated with RD values in widespread brain regions. Significant associations of AD, RD, and FA were found for CGM measures of hyperglycemia and glucose variability but not for hypoglycemia. Finally, we observed a significant association between WM structure and cognitive ability in children with type 1 diabetes but not in control subjects.CONCLUSIONSThese results suggest vulnerability of the developing brain in young children to effects of type 1 diabetes associated with chronic hyperglycemia and glucose variability.

PMID: 24319123 [PubMed - as supplied by publisher]

DATABASE, The Journal of Biological Databases and Curation, is now the official journal of the International Society for Biocuration.

Database (Oxford). 2013;2013(0):bat077

Authors: Gaudet P, Munoz-Torres M, Robinson-Rechavi M, Attwood T, Bateman A, Cherry JM, Kania R, O'Donovan C, Yamasaki C

PMID: 24319113 [PubMed - in process]

Clinical Reminders to Providers of Patients with Reduced Left Ventricular Ejection Fraction Increase Defibrillator Referral: A Randomized Trial.

Circ Heart Fail. 2013 Dec 6;

Authors: Gupta A, Gholami P, Turakhia MP, Friday K, Heidenreich PA

Abstract
BACKGROUND: -Many patients who are candidates for defibrillators (ICDs) are not referred for potential implantation. We sought to determine if a simple provider reminder would increase referrals.
METHODS AND RESULTS: -We identified consecutive patients from 1/2007 through 7/2010 in the VA Palo Alto Healthcare System with a left ventricular ejection fraction (LVEF) below 35% on echocardiography. Patients were excluded using available administrative data only (no chart review) if they were known to have an ICD, if they were ≥ 80 years old, or if they did not have a current primary care or cardiology provider within the system. We randomized patients to no intervention or a clinical note to the provider in the medical record. The outcomes were referral for consideration of defibrillator implantation (primary) and documented discussion (secondary). Of 330 patients with LVEF ≤ 35%, 128 patients were known to have an ICD, 85 were no longer followed in the healthcare system, and 28 were ≥ 80 years old, leaving 89 patients to be randomized. 46 patients were randomized to intervention and 43 to control. Eleven of 46 (24%) intervention patients were referred for consideration of ICD implantation during the following six months versus 1 of 43 (2%) control patients (P=0.004). Overall, 31 of 46 (67%) intervention patients versus 19 of 43 (44%) control patients had documentation discussing potential candidacy for defibrillators (p=0.05).
CONCLUSIONS: -In patients with low LVEF, a simple electronic medical record-based intervention directed to their providers improved the rates of referral for ICD implantation. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01217827.

PMID: 24319096 [PubMed - as supplied by publisher]

Evolution at two levels of gene expression in yeast.

Genome Res. 2013 Dec 6;

Authors: Artieri CG, Fraser HB

Abstract
Despite the greater functional importance of protein levels, our knowledge of gene expression evolution is based almost entirely on studies of mRNA levels. In contrast, our understanding of how translational regulation evolves has lagged far behind. Here we have applied ribosome profiling- which measures both global mRNA levels and their translation rates- to two species of Saccharomyces yeast and their interspecific hybrid in order to assess the relative contributions of changes in mRNA abundance and translation to regulatory evolution. We report that both cis and trans-acting regulatory divergence in translation are abundant, affecting at least 35% of genes. The majority of translational divergence acts to buffer changes in mRNA abundance, suggesting a widespread role for stabilizing selection acting across regulatory levels. Nevertheless, we observe evidence of lineage-specific selection acting on a number of yeast functional modules, including instances of reinforcing selection acting at both levels of regulation. Finally, we also uncover multiple instances of stop-codon readthrough that are conserved between species. Our analysis reveals the underappreciated complexity of post-transcriptional regulatory divergence and indicates that partitioning the search for the locus of selection into the binary categories of 'coding' vs. 'regulatory' may overlook a significant source of selection, acting at multiple regulatory levels along the path from genotype to phenotype.

PMID: 24318729 [PubMed - as supplied by publisher]

Upregulation of the microRNA cluster at the Dlk1-Dio3 locus in lung adenocarcinoma.

Oncogene. 2013 Dec 9;

Authors: Valdmanis PN, Roy-Chaudhuri B, Kim HK, Sayles LC, Zheng Y, Chuang CH, Caswell DR, Chu K, Zhang Y, Winslow MM, Sweet-Cordero EA, Kay MA

Abstract
Mice in which lung epithelial cells can be induced to express an oncogenic Kras(G12D) develop lung adenocarcinomas in a manner analogous to humans. A myriad of genetic changes accompany lung adenocarcinomas, many of which are poorly understood. To get a comprehensive understanding of both the transcriptional and post-transcriptional changes that accompany lung adenocarcinomas, we took an omics approach in profiling both the coding genes and the non-coding small RNAs in an induced mouse model of lung adenocarcinoma. RNAseq transcriptome analysis of Kras(G12D) tumors from F1 hybrid mice revealed features specific to tumor samples. This includes the repression of a network of GTPase-related genes (Prkg1, Gnao1 and Rgs9) in tumor samples and an enrichment of Apobec1-mediated cytosine to uridine RNA editing. Furthermore, analysis of known single-nucleotide polymorphisms revealed not only a change in expression of Cd22 but also that its expression became allele specific in tumors. The most salient finding, however, came from small RNA sequencing of the tumor samples, which revealed that a cluster of ∼53 microRNAs and mRNAs at the Dlk1-Dio3 locus on mouse chromosome 12qF1 was markedly and consistently increased in tumors. Activation of this locus occurred specifically in sorted tumor-originating cancer cells. Interestingly, the 12qF1 RNAs were repressed in cultured Kras(G12D) tumor cells but reactivated when transplanted in vivo. These microRNAs have been implicated in stem cell pleuripotency and proteins targeted by these microRNAs are involved in key pathways in cancer as well as embryogenesis. Taken together, our results strongly imply that these microRNAs represent key targets in unraveling the mechanism of lung oncogenesis.Oncogene advance online publication, 9 December 2013; doi:10.1038/onc.2013.523.

PMID: 24317514 [PubMed - as supplied by publisher]

Germline Mutations in Driver Oncogenes and Inherited Lung Cancer Risk Independent of Smoking History.

J Natl Cancer Inst. 2013 Dec 7;

Authors: Oxnard GR, Nguyen KS, Costa DB

PMID: 24317178 [PubMed - as supplied by publisher]

Otolaryngology: "It's All Greek to Me"

Otolaryngol Head Neck Surg. 2013 Dec 6;

Authors: Jackler RK, Mudry A

Abstract
This study explores the origins and evolution of the specialty name for what is now primarily known in the English-speaking world as otolaryngology-head and neck surgery. This appellation is the longest and least pronounceable of all medical specialties. While it is reasonably well understood among medical professionals, surveys show that only a small fraction of health consumers understand its meaning. The ideal medical specialty name should have a meaning recognizable to a large segment of the public, be easily pronounceable, be reasonably short, and serve to communicate the type of illnesses treated. The cumbersomeness of the specialty name has led to nearly universal use of informal substitutes, which do not covey the scope of contemporary practice (eg, ear, nose, and throat) and to abbreviations (eg, ENT, ORL, OHNS). Based on the commercial experience, it is clear that shorter is better. The authors advocate that dialog be opened, guided by the experience from instances of successful corporate rebranding, to consider possible alternatives.

PMID: 24316790 [PubMed - as supplied by publisher]

Mining the ultimate phenome repository.

Nat Biotechnol. 2013 Dec 6;31(12):1095-7

Authors: Shah NH

PMID: 24316646 [PubMed - in process]

A rapid, sensitive method for quantitative analysis of underivatized amino acids by liquid chromatography-tandem mass spectrometry (LC-MS/MS).

J Chromatogr B Analyt Technol Biomed Life Sci. 2013 Nov 18;944C:166-174

Authors: Le A, Ng A, Kwan T, Cusmano-Ozog K, Cowan TM

Abstract
The quantitation of free amino acids from physiologic samples is essential for diagnosing and monitoring patients with inherited metabolic disorders. Current methods are hindered by long preparative and/or analysis times, expensive reagents, and often suboptimal performance characteristics. To overcome these challenges, a improved method for amino acid analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed and validated. Samples were deproteinized with sulfosalicylic acid and supernatants diluted with tridecafluoroheptanoic acid. Chromatographic separation of amino acids occurred using two columns, with conditions favoring resolution of isobaric compounds and minimizing ion suppression. Eluted compounds were detected by selective reaction monitoring, and quantitated by relating peak areas of amino acids to externally run standards. Validation studies evaluated linearity, within- and between-run imprecision, lower limits of detection and quantification for 33 amino acids, and correlation with the Biochrom 30 Amino Acid Analyzer. Total run time including re-equilibration was 15min per sample. Within-run precision averaged 2.8% for all compounds, with an average linear correlation coefficient of 0.995. The majority of compounds were reliably quantitated at ≤0.1μM. Between-run precision averaged 4.0%. Results showed excellent correlation with the Biochrom 30 amino acid analyzer with an average overall correlation of 0.908. We conclude that our method is extremely sensitive, specific and reproducible and represents an improvement over other currently available technologies.

PMID: 24316529 [PubMed - as supplied by publisher]

The Will to Persevere Induced by Electrical Stimulation of the Human Cingulate Gyrus.

Neuron. 2013 Dec 4;

Authors: Parvizi J, Rangarajan V, Shirer WR, Desai N, Greicius MD

Abstract
Anterior cingulate cortex (ACC) is known to be involved in functions such as emotion, pain, and cognitive control. While studies in humans and nonhuman mammals have advanced our understanding of ACC function, the subjective correlates of ACC activity have remained largely unexplored. In the current study, we show that electrical charge delivery in the anterior midcingulate cortex (aMCC) elicits autonomic changes and the expectation of an imminent challenge coupled with a determined attitude to overcome it. Seed-based, resting-state connectivity analysis revealed that the site of stimulation in both patients was at the core of a large-scale distributed network linking aMCC to the frontoinsular and frontopolar as well as some subcortical regions. This report provides compelling, first-person accounts of electrical stimulation of this brain network and suggests its possible involvement in psychopathological conditions that are characterized by a reduced capacity to endure psychological or physical distress.

PMID: 24316296 [PubMed - as supplied by publisher]

An Anti-inflammatory NOD-like Receptor Is Required for Microglia Development.

Cell Rep. 2013 Dec 3;

Authors: Shiau CE, Monk KR, Joo W, Talbot WS

Abstract
Microglia are phagocytic cells that form the basis of the brain's immune system. They derive from primitive macrophages that migrate into the brain during embryogenesis, but the genetic control of microglial development remains elusive. Starting with a genetic screen in zebrafish, we show that the noncanonical NOD-like receptor (NLR) nlrc3-like is essential for microglial formation. Although most NLRs trigger inflammatory signaling, nlrc3-like acts cell autonomously in microglia precursor cells to suppress unwarranted inflammation in the absence of overt immune challenge. In nlrc3-like mutants, primitive macrophages initiate a systemic inflammatory response with increased proinflammatory cytokines and actively aggregate instead of migrating into the brain to form microglia. NLRC3-like requires both its pyrin and NACHT domains, and it can bind the inflammasome component apoptosis-associated speck-like protein. Our studies suggest that NLRC3-like may regulate the inflammasome and other inflammatory pathways. Together, these results demonstrate that NLRC3-like prevents inappropriate macrophage activation, thereby allowing normal microglial development.

PMID: 24316075 [PubMed - as supplied by publisher]

Is the J wave or the ST slope malignant…or neither?

J Am Coll Cardiol. 2013 Nov 25;

Authors: Yong C, Froelicher V, Wagner G

PMID: 24315921 [PubMed - as supplied by publisher]

A prize for membrane magic.

Cell. 2013 Dec 5;155(6):1203-6

Authors: Pfeffer SR

Abstract
The 2013 Nobel Prize in Physiology or Medicine has been awarded to James Rothman, Randy Schekman, and Thomas Südhof "for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells". I present a personal view of the membrane trafficking field, highlighting the contributions of these three Nobel laureates in a historical context.

PMID: 24315088 [PubMed - in process]

Trends in pharmacotherapy in patients referred to a bipolar specialty clinic, 2000-2011.

J Affect Disord. 2013 Nov 21;

Authors: Hooshmand F, Miller S, Dore J, Wang PW, Hill SJ, Portillo N, Ketter TA

Abstract
OBJECTIVE: To assess mood stabilizer (MS) and second-generation antipsychotic (SGA) prescribing trends in bipolar disorder (BD) outpatients referred to a bipolar disorder specialty clinic over the past 12 years.
METHOD: BD outpatients referred to the Stanford University Bipolar Disorder Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Prescription rates for MSs and SGAs were compared during the first (2000-2005) and second (2006-2011) six years.
RESULTS: Among 597 BD patients (mean±SD age 35.4±8.6 years; 58.1% female; 40.7% Type I, 43.6% Type II, and 15.7% Type Not Otherwise Specified; taking 2.6±1.7 prescription psychotropic medications), lamotrigine, quetiapine, and aripiprazole usage more than doubled, from 14.7% to 37.2% (p<0.0001), 7.2% to 19.7% (p<0.0001), and 3.1% to 10.9% (p=0.0003), respectively, while olanzapine and risperidone use decreased by more than half from 15.0% to 6.6% (p=0.0043), and from 8.7% to 3.8% (p=0.039), respectively. SGA use increased from 34.1% to 44.8% (p=0.013), although MS use continued to be more common (in 65.2% for 2006-2011). Use of other individual MSs and SGAs and MSs as a class did not change significantly.
CONCLUSIONS: Over 12 years, in patients referred to a BD specialty clinic, lamotrigine, quetiapine, and aripiprazole use more than doubled, and olanzapine and risperidone use decreased by more than half. Tolerability (for lamotrigine, aripiprazole, olanzapine, and risperidone) more than efficacy (for quetiapine) differences may have driven these findings. Additional studies are needed to explore the relative influences of enhanced tolerability versus efficacy upon prescribing practices in BD patients.

PMID: 24314912 [PubMed - as supplied by publisher]

Reply to the Comments on the "No-Prop" algorithm.

Neural Netw. 2013 Dec;48C:204

Authors: Widrow B

PMID: 24314855 [PubMed - as supplied by publisher]

Author Reply.

Ophthalmology. 2013 Dec 5;

Authors: Singh K

PMID: 24314821 [PubMed - as supplied by publisher]