Sentman C.L.,One Medical Center Drive |
Meehan K.R.,Section of Hematology and Oncology
Cancer Journal (United States) | Year: 2014
The NKG2D cell receptor and its ligands have attracted considerable interest as a potential strategy to attack tumor cells. NKG2D ligands are expressed on most types of tumors, and they demonstrate relative selectivity of ligand expression on tumor cells compared to healthy cells. Several different variants of NKG2D-based chimeric antigen receptors (CARs) have been developed, and extensive in vivo mechanistic studies performed demonstrated that cytotoxicity and cytokines are important for the efficacy NKG2D CAR adoptive T-cell therapy. NKG2D CARs target tumor cells, and they also target immunosuppressive cells within the tumor microenvironment. Under certain conditions, NKG2D ligand expression can be found on nontumor tissue, so potential off-tumor toxicity remains. In this article, we review the use of NKG2D as a basis for CAR targeting of tumors. Copyright © 2014 Lippincott Williams & Wilkins.
Jones D.W.,Dartmouth College |
Finlayson S.R.G.,One Medical Center Drive |
Finlayson S.R.G.,White River Junction Outcomes Group
Annals of Surgery | Year: 2010
Objective: To examine the use of surgical procedures for Crohn's disease since the introduction of infliximab. Summary background data: Prior studies have shown that the overall rate of surgery for Crohn's disease has not changed significantly since the introduction of infliximab, an immunomodulator considered particularly effective in treating Crohn's fistulas. How infliximab has affected individual rates of specific types of procedures, particularly surgery for intestinal fistulas, is unknown. Methods: We used the Nationwide Inpatient Sample to identify all hospital admissions for Crohn's disease for each year from 1993 through 2004. Cases of Crohn's disease and relevant surgical interventions were identified using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes. Using US Census data to establish population denominators, trends in population-based rates of use of these procedures were examined over time. Trends were tested for significance with Spearman rank correlation tests. Results: From 1993 to 2004, there was no statistically significant change in population-based rates of small bowel and right colon resection, while rates of left colon resection, other colon resection, and rectal resection declined moderately. However, rates of surgical repair of fistulas of the small intestine, the most commonly performed fistula operation, increased by 60%, from 1.5 per 1,000,000 in 1993 to 2.4 per 1,000,000 in 2004 (P = 0.04). Conclusions: During the period of adoption of infliximab as a novel treatment for Crohn's disease, overall rates of bowel resections have either remained relatively stable or decreased moderately, while rates of small bowel fistula repair have increased significantly. These findings call into question the effectiveness of infliximab in preventing the need for surgery for Crohn's disease at the population level. Copyright © 2010 by Lippincott Williams & Wilkins.
Kerr D.,The Dartmouth Institute for Health Policy and Clinical Practice |
Zhao W.,The Dartmouth Institute for Health Policy and Clinical Practice |
Lurie J.D.,The Dartmouth Institute for Health Policy and Clinical Practice |
Lurie J.D.,One Medical Center Drive
Clinical Orthopaedics and Related Research | Year: 2015
Level of Evidence: Level II, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.Background: Although previous studies have illustrated improvements in surgical cohorts for patients with intervertebral disc herniation, there are limited data on predictors of long-term outcomes comparing surgical and nonsurgical outcomes.Questions/purposes: We assessed outcomes of operative and nonoperative treatment for patients with intervertebral disc herniation and symptomatic radiculopathy at 8 years from the Spine Patient Outcomes Research Trial. We specifically examined subgroups to determine whether certain populations had a better long-term outcome with surgery or nonoperative treatment.Methods: Patients with symptomatic lumbar radiculopathy for at least 6 weeks associated with nerve root irritation or neurologic deficit on examination and a confirmed disc herniation on cross-sectional imaging were enrolled at 13 different clinical sites. Patients consenting to participate in the randomized cohort were assigned to surgical or nonoperative treatment using variable permuted block randomization stratified by site. Those who declined randomization entered the observational cohort group based on treatment preference but were otherwise treated and followed identically to the randomized cohort. Of those in the randomized cohort, 309 of 501 (62%) provided 8-year data and in the observational group 469 of 743 (63%). Patients were treated with either surgical discectomy or usual nonoperative care. By 8 years, only 148 of 245 (60%) of those randomized to surgery had undergone surgery, whereas 122 of 256 (48%) of those randomized to nonoperative treatment had undergone surgery. The primary outcome measures were SF-36 bodily pain, SF-36 physical function, and Oswestry Disability Index collected at 6 weeks, 3 months, 6 months, 12 months, and then annually. Further analysis studied the following factors to determine if any were predictive of long-term outcomes: sex, herniation location, depression, smoking, work status, other joint problems, herniation level, herniation type, and duration of symptoms.Results: The intent-to-treat analysis of the randomized cohort at 8 years showed no difference between surgical and nonoperative treatment for the primary outcome measures. Secondary outcome measures of sciatica bothersomeness, leg pain, satisfaction with symptoms, and self-rated improvement showed greater improvement in the group randomized to surgery despite high levels of crossover. The as-treated analysis of the combined randomized and observational cohorts, adjusted for potential confounders, showed advantages for surgery for all primary outcome measures; however, this has the potential for confounding from other unrecognized variables. Smokers and patients with depression or comorbid joint problems had worse functional outcomes overall (with surgery and nonoperative care) but similar surgical treatment effects. Patients with sequestered fragments, symptom duration greater than 6 months, those with higher levels of low back pain, or who were neither working nor disabled at baseline showed greater surgical treatment effects.Conclusions: The intent-to-treat analysis, which is complicated by high rates of crossover, showed no difference over 8 years for primary outcomes of overall pain, physical function, and back-related disability but did show small advantages for secondary outcomes of sciatica bothersomeness, satisfaction with symptoms, and self-rated improvement. Subgroup analyses identified those groups with sequestered fragments on MRI, higher levels of baseline back pain accompanying radiculopathy, a longer duration of symptoms, and those who were neither working nor disabled at baseline with a greater relative advantage from surgery at 8 years. © 2014, The Association of Bone and Joint Surgeons®.
Penrod N.M.,Dartmouth College |
Cowper-Sal-Lari R.,Dartmouth College |
Moore J.H.,One Medical Center Drive |
Moore J.H.,Dartmouth College
Trends in Pharmacological Sciences | Year: 2011
The collection and analysis of genomic data has the potential to reveal novel druggable targets by providing insight into the genetic basis of disease. However, the number of drugs targeting new molecular entities, approved by the US Food and Drug Administration has not increased in the years since the collection of genomic data has become commonplace. The paucity of translatable results can be partly attributed to conventional analysis methods that test one gene at a time in an effort to identify disease-associated factors as candidate drug targets. By disengaging genetic factors from their position within the genetic regulatory system, much of the information stored within the genomic data set is lost. Here we discuss how genomic data is used to identify disease-associated genes or genomic regions, how disease-associated regions are validated as functional targets, and the role network analysis can play in bridging the gap between data generation and effective drug target identification. © 2011 Elsevier Ltd.
Dasari S.,One Medical Center Drive |
Gulledge A.T.,One Medical Center Drive
Journal of Neurophysiology | Year: 2011
Acetylcholine (ACh), acting at muscarinic ACh receptors (mAChRs), modulates the excitability and synaptic connectivity of hippocampal pyramidal neurons. CA1 pyramidal neurons respond to transient ("phasic") mAChR activation with biphasic responses in which inhibition is followed by excitation, whereas prolonged ("tonic") mAChR activation increases CA1 neuron excitability. Both phasic and tonic mAChR activation excites pyramidal neurons in the CA3 region, yet ACh suppresses glutamate release at the CA3-to-CA1 synapse (the Schaffer- collateral pathway). Using mice genetically lacking specific mAChRs (mAChR knockout mice), we identified the mAChR subtypes responsible for cholinergic modulation of hippocampal pyramidal neuron excitability and synaptic transmission. Knockout of M1 receptors significantly reduced, or eliminated, most phasic and tonic cholinergic responses in CA1 and CA3 pyramidal neurons. On the other hand, in the absence of other G q-linked mAChRs (M3 and M5), M1 receptors proved sufficient for all postsynaptic cholinergic effects on CA1 and CA3 pyramidal neuron excitability. M3 receptors were able to participate in tonic depolarization of CA1 neurons, but otherwise contributed little to cholinergic responses. At the Schaffer- collateral synapse, bath application of the cholinergic agonist carbachol suppressed stratum radiatum-evoked excitatory postsynaptic potentials (EPSPs) in wildtype CA1 neurons and in CA1 neurons from mice lacking M1 or M2 receptors. However, Schaffer- collateral EPSPs were not significantly suppressed by carbachol in neurons lacking M4 receptors. We therefore conclude that M1 and M4 receptors are the major mAChR subtypes responsible for direct cholinergic modulation of the excitatory hippocampal circuit. Copyright © 2011 The American Physiological Society.
McAllister T.W.,One Medical Center Drive
PM and R | Year: 2010
Wide variation in outcomes after neurotrauma, despite apparently similar injury severity, suggests that host factors may influence the recovery process. Genetically determined individual differences might be one such factor. The study of the genetic modulation of outcome after neurotrauma is at an early stage. Nevertheless, several important components of the response to neurotrauma can be identified in which genetic differences contribute to variability in outcome. These components include genetic modulators of pre- and postinjury cognitive reserve and behavioral homeostasis, and processes that modulate cytotoxic injury cascades (extent of injury) and injury repair. This work reviews what is knownof the role of genetic variation in outcome after neurotrauma with a focus on clinical outcomes after traumatic brain injury. Polymorphisms reported to influence outcome after traumatic brain injury that illustrate important underlying mechanisms are emphasized.
Stanger C.,One Medical Center Drive |
Budney A.J.,One Medical Center Drive |
Bickel W.K.,Virginia Polytechnic Institute and State University
Psychology of Addictive Behaviors | Year: 2013
This paper provides a developmental overview of relevant theory and research on delay discounting and neuroeconomics, and their implications for contingency management (CM) approaches to treatment. Recent advances in the neuroscience of decision making have the potential to inform treatment development for adolescent substance use in general, and CM treatments in particular. CM interventions may be informed by research on delay discounting, a type of decision making that reflects how individuals value immediate versus delayed rewards. Delay discounting reliably distinguishes substance abusers from nonabusers and is a significant predictor of individual differences in response to substance use treatments. Discounting may also be important in predicting response to CM, as CM attempts to directly influence this decision-making process, shifting the preference from the immediate rewards of use to delayed rewards for choosing not to use. Multiple neural processes underlie decision making, and those processes have implications for adolescent substance abuse. There are significant neurodevelopmental processes that differentiate adolescents from adults. These processes are implicated in delay discounting, suggesting that adolescence may reflect a period of plasticity in temporal decision making. Understanding the neural mechanisms of delay discounting has led to promising working memory interventions directly targeting the executive functions that underlie individual choices. These interventions may be particularly helpful in combination with CM interventions that offer immediate rewards for brief periods of abstinence, and may show particular benefit in adolescence due to the heightened neural plasticity of systems that underlie temporal discounting in adolescence. © 2012 American Psychological Association.
Mulligan-Kehoe M.J.,One Medical Center Drive
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2010
The vasa vasorum form a network of microvasculature that originate primarily in the adventitial layer of large arteries. These vessels supply oxygen and nutrients to the outer layers of the arterial wall. The expansion of the vasa vasorum to the second order is associated with neovascularization related to progression of atherosclerosis. Immunohistological analysis of human plaques from autopsied aortas have defined plaque progression and show a significant correlation with vasa vasorum neovascularization. Recent technological advances in microcomputed tomography have enabled investigation of vasa vasorum structure and function in nondiseased large arteries from pigs and dogs. Smaller mammals, particularly mice with genetic modifications that enable disease development, have been used extensively to study the vasa vasorum in diseased vessels. Despite the fact that most mouse models that are used to study atherosclerosis are unable to develop plaque to the extent found in humans, studies in both humans and mice underscore the importance of angiogenic vasa vasorum in progression of atherosclerosis. Those who have examined the vasa vasorum in occluded vessels of nondiseased pigs and dogs find that inhibition of the vasa vasorum makes the animals atheroprone. Atherosclerosis is a multifactorial disease. There is increasing evidence that factors, produced in response to changes in the arterial wall, collaborate with the vasa vasorum to enhance the disease process. Copyright © 2010 the American Physiological Society.
Leib D.A.,One Medical Center Drive
Cell Host and Microbe | Year: 2012
Herpes simplex encephalitis (HSE) is a devastating infection of the central nervous system (CNS). Lafaille et al. (2012) show that susceptibility to HSE is due to mutations in Toll-like receptor response pathways that directly reduce the intrinsic resistance of neurons and other cells in the CNS to HSV infection. © 2012 Elsevier Inc.
Cowling V.H.,University of Dundee |
Cole M.D.,One Medical Center Drive
Genes and Cancer | Year: 2010
The c-myc proto-oncogene regulates the expression of 15% to 20% of all genes, depending on the cell type, and the regulation is usually odest (1.5- to 2.0-fold). The authors discovered that in addition to regulating mRNA abundance, c-Myc regulates the formation of the 7-methylguanosine cap on many mRNAs, including transcriptional target genes and others not transcriptionally activated. Because the 7-methylguanosine cap is required for effective translation, enhanced methyl cap formation leads to increased protein production from Myc-responsive genes that exceeds the transcriptional induction. Increased cap methylation is linked to Myc-dependent enhanced activity of 2 critical kinases, TFIIH and p-TEFb, which phosphorylate the RNA polymerase II carboxy-terminal domain (CTD). Phosphorylation of the CTD recruits RNGTT and RNMT, the enzymes involved in mRNA capping, to the nascent transcript. Evidence is accumulating that enhanced cap methylation makes a significant contribution to Mycdependent gene regulation and protein production. © The Author(s) 2010.