Publications by authors named "Andrew C Harris"

66 Publications

Magnitude of open-field thigmotaxis during mecamylamine-precipitated nicotine withdrawal in rats is influenced by mecamylamine dose, duration of nicotine infusion, number of withdrawal episodes, and age.

Authors:
Andrew C Harris

Pharmacol Biochem Behav 2021 Apr 6;205:173185. Epub 2021 Apr 6.

Hennepin Healthcare Research Institute, Minneapolis, MN, United States of America; Department of Medicine, University of Minnesota, Minneapolis, MN, United States of America; Department of Psychology, University of Minnesota, Minneapolis, MN, United States of America. Electronic address:

Relief from increases in anxiety during nicotine withdrawal contributes to tobacco addiction. While a variety of anxiogenic stimuli elicit avoidance of the center of an open field (thigmotaxis) in rodents, effects of nicotine withdrawal on thigmotaxis have not been studied extensively. The goal of this study was to evaluate determinants of increases in thigmotaxis during mecamylamine-precipitated nicotine withdrawal in rats. We evaluated several variables implicated in severity of other measures of precipitated nicotine withdrawal: mecamylamine dose, duration of nicotine infusion, number of withdrawal episodes, and age. In Experiment 1, mecamylamine elicited increases in thigmotaxis in adult rats receiving a chronic nicotine infusion (3.2 mg/kg/day for >7 days) at only the highest mecamylamine dose tested (4.0 mg/kg). In Experiment 2, repeated administration of 4.0 mg/kg mecamylamine throughout the course of a 2-week chronic nicotine infusion (3.2 mg/kg/day) did not affect thigmotaxis when administered following 2 days of the infusion, but elicited significant increases in thigmotaxis at longer infusion durations. In Experiment 3, adolescents tested under the same protocol used in adults in Experiment 2 did not exhibit increased thigmotaxis at any point during the 2-week nicotine infusion, even though we used higher nicotine doses (4.7 or 6.4 mg/kg/day) to account for the faster metabolism of nicotine in adolescents compared to adults. Our findings provide the first systematic characterization of determinants of increases in thigmotaxis during precipitated nicotine withdrawal in rats. Further use of this model may be useful for characterizing the mechanisms underlying the anxiogenic component of nicotine withdrawal.
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http://dx.doi.org/10.1016/j.pbb.2021.173185DOI Listing
April 2021

Repeated morphine exposure activates synaptogenesis and other neuroplasticity-related gene networks in the dorsomedial prefrontal cortex of male and female rats.

Drug Alcohol Depend 2021 Apr 13;221:108598. Epub 2021 Feb 13.

Department of Psychology, University of Minnesota, Minneapolis, MN, 55455, United States. Electronic address:

Background: Opioid abuse is a chronic disorder likely involving stable neuroplastic modifications. While a number of molecules contributing to these changes have been identified, the broader spectrum of genes and gene networks that are affected by repeated opioid administration remain understudied.

Methods: We employed Next-Generation RNA-sequencing (RNA-seq) followed by quantitative chromatin immunoprecipitation to investigate changes in gene expression and their regulation in adult male and female rats' dorsomedial prefrontal cortex (dmPFC) after a regimen of daily injection of morphine (5.0 mg/kg; 10 days). Ingenuity Pathway Analysis (IPA) was used to analyze affected molecular pathways, gene networks, and associated regulatory factors. A complementary behavioral study evaluated the effects of the same morphine injection regimen on locomotor activity, pain sensitivity, and somatic withdrawal signs.

Results: Behaviorally, repeated morphine injection induced locomotor hyperactivity and hyperalgesia in both sexes. 90 % of differentially expressed genes (DEGs) in morphine-treated rats were upregulated in both males and females, with a 35 % overlap between sexes. A substantial number of DEGs play roles in synaptic signaling and neuroplasticity. Chromatin immunoprecipitation revealed enrichment of H3 acetylation, a transcriptionally activating chromatin mark. Although broadly similar, some differences were revealed in the gene ontology networks enriched in females and males.

Conclusions: Our results cohere with findings from previous studies based on a priori gene selection. Our results also reveal novel genes and molecular pathways that are upregulated by repeated morphine exposure, with some common to males and females and others that are sex-specific.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.108598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026706PMC
April 2021

Behavioral predictors of individual differences in opioid addiction vulnerability as measured using i.v. self-administration in rats.

Drug Alcohol Depend 2021 Apr 29;221:108561. Epub 2021 Jan 29.

Departments of Psychology, University of Minnesota, United States; Hennepin Healthcare Research Institute, United States; Departments of Medicine, University of Minnesota, United States. Electronic address:

Background: Like other forms of psychopathology, vulnerability to opioid addiction is subject to wide individual differences. Animal behavioral models are valuable in advancing our understanding of mechanisms underlying vulnerability to the disorder's development and amenability to treatment.

Methods: This review provides an overview of preclinical work on behavioral predictors of opioid addiction vulnerability as measured using the intravenous (i.v.) self-administration (SA) model in rats. We also highlight several new approaches to studying individual differences in opioid addiction vulnerability in preclinical models that could have greater sensitivity and lead to more clinically relevant findings.

Results And Conclusions: Evidence for the relationship between various behavioral traits and opioid SA in the preclinical literature is limited. With the possible exceptions of sensitivity to opioid agonist/withdrawal effects and stress reactivity, predictors of individual differences in SA of other drugs of abuse (e.g. sensation-seeking, impulsivity) do not predict vulnerability to opioid SA in rats. Refinement of SA measures and the use of multivariate designs and statistics could help identify predictors of opioid SA and lead to more clinically relevant studies on opioid addiction vulnerability.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.108561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048102PMC
April 2021

Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD.

J Clin Oncol 2021 Jan 15:JCO2001086. Epub 2021 Jan 15.

Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MA.

Purpose: Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in particularly high mortality after HLA-mismatched transplantation. There are no approved agents for AGVHD prevention, underscoring the critical unmet need for novel therapeutics. ABA2 was a phase II trial to rigorously assess safety, efficacy, and immunologic effects of adding T-cell costimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, to test whether abatacept could decrease AGVHD.

Methods: ABA2 enrolled adults and children with hematologic malignancies under two strata: a randomized, double-blind, placebo-controlled stratum (8/8-HLA-matched URD), comparing CNI/MTX plus abatacept with CNI/MTX plus placebo, and a single-arm stratum (7/8-HLA-mismatched URD) comparing CNI/MTX plus abatacept versus CNI/MTX CIBMTR controls. The primary end point was day +100 grade 3-4 AGVHD, with day +180 severe-AGVHD-free-survival (SGFS) a key secondary end point. Sample sizes were calculated using a higher type-1 error (0.2) as recommended for phase II trials, and were based on predicting that abatacept would reduce grade 3-4 AGVHD from 20% to 10% (8/8s) and 30% to 10% (7/8s). ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days).

Results: In 8/8s, grade 3-4 AGVHD was 6.8% (abatacept) versus 14.8% (placebo) ( = .13, hazard ratio = 0.45). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo, = .05). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%, < .001), and the SGFS was better (97.7% 58.7%, < .001). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients.

Conclusion: Adding abatacept to URD HCT was safe, reduced AGVHD, and improved SGFS. These results suggest that abatacept may substantially improve AGVHD-related transplant outcomes, with a particularly beneficial impact on HLA-mismatched HCT.
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http://dx.doi.org/10.1200/JCO.20.01086DOI Listing
January 2021

β-Carbolines found in cigarette smoke elevate intracranial self-stimulation thresholds in rats.

Pharmacol Biochem Behav 2020 11 11;198:173041. Epub 2020 Sep 11.

Hennepin Healthcare Research Institute, Minneapolis, MN, United States of America; Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, United States of America; Department of Psychology, University of Minnesota, Minneapolis, MN, United States of America.

Identifying novel constituents that contribute to tobacco addiction is essential for developing more effective treatments and informing FDA regulation of tobacco products. While preclinical data indicate that monoamine oxidase (MAO) inhibitors can have abuse liability or potentiate the addiction-related effects of nicotine, most of these studies have used clinical MAO inhibitors (e.g., tranylcypromine) that are not present in cigarette smoke. The primary goal of this study was to evaluate the abuse potential of the β-carbolines harmane, norharmane, and harmine - MAO inhibitors that are found in cigarette smoke - in an intracranial self-simulation (ICSS) model in rats. A secondary goal was to evaluate the ability of norharmane to influence nicotine's acute effects on ICSS. None of the β-carbolines lowered ICSS thresholds at any dose studied when administered alone, suggesting a lack of abuse liability. Rather, all three β-carbolines produced dose-dependent elevations in ICSS thresholds, indicating aversive/anhedonic effects. Harmane and harmine also elevated ICSS response latencies, suggesting a disruption of motor function, albeit with reduced potency compared to their ICSS threshold-elevating effects. Norharmane (2.5 mg/kg) modestly attenuated the effects of nicotine on ICSS thresholds. Our findings indicate that these β-carbolines produced only aversive/anhedonic effects in an ICSS model when administered alone, and that norharmane unexpectedly attenuated nicotines acute effects on ICSS. Future work evaluating the addiction-related effects of nicotine combined with these and other MAO inhibitors present in smoke may be useful for understanding the role of MAO inhibition in tobacco addiction and informing FDA tobacco regulation.
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http://dx.doi.org/10.1016/j.pbb.2020.173041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554228PMC
November 2020

Higher anhedonia during withdrawal from initial opioid exposure is protective against subsequent opioid self-administration in rats.

Psychopharmacology (Berl) 2020 Aug 9;237(8):2279-2291. Epub 2020 May 9.

Hennepin Healthcare Research Institute, 701 Park Avenue, Minneapolis, MN, 55415, USA.

Rationale: Understanding factors contributing to individual differences in vulnerability to opioid addiction is essential for developing more effective preventions and treatments, yet few reliable behavioral predictors of subsequent opioid self-administration have been identified in rodents. Sensitivity to the acute effects of initial drug exposure predicts later addiction vulnerability in both humans and animals, but the relationship between sensitivity to withdrawal from initial drug exposure and later drug use vulnerability is unclear.

Objective: The goal of the current study was to evaluate whether the degree of anhedonia experienced during withdrawal from early opioid exposure predicts subsequent vulnerability to opioid self-administration.

Methods: Rats were first tested for withdrawal sensitivity following acute injections of morphine (i.e., "acute dependence"), measured as elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior) during naloxone-precipitated and spontaneous withdrawal. Rats were then tested for addiction-like behavior using various measures of i.v. morphine self-administration (MSA) including acquisition, demand, extinction, and reinstatement induced by morphine, stress, and/or drug-associated cues.

Results: Greater naloxone-precipitated withdrawal across repeated morphine injections and greater peak spontaneous withdrawal severity following a single morphine injection were associated with lower addiction-like behavior on multiple MSA measures. Withdrawal-induced anhedonia predicted a wider range of MSA measures than did any individual measure of MSA itself.

Conclusions: Our data establish WIA as one of the first behavioral measures to predict individual differences in opioid SA in rodents. This model promises to be useful for furthering our understanding of behavioral and neurobiological mechanisms underlying vulnerability to opioid addiction.
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http://dx.doi.org/10.1007/s00213-020-05532-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354901PMC
August 2020

Immune profile differences between chronic GVHD and late acute GVHD: results of the ABLE/PBMTC 1202 studies.

Blood 2020 04;135(15):1287-1298

CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada.

Human graft-versus-host disease (GVHD) biology beyond 3 months after hematopoietic stem cell transplantation (HSCT) is complex. The Applied Biomarker in Late Effects of Childhood Cancer study (ABLE/PBMTC1202, NCT02067832) evaluated the immune profiles in chronic GVHD (cGVHD) and late acute GVHD (L-aGVHD). Peripheral blood immune cell and plasma markers were analyzed at day 100 post-HSCT and correlated with GVHD diagnosed according to the National Institutes of Health consensus criteria (NIH-CC) for cGVHD. Of 302 children enrolled, 241 were evaluable as L-aGVHD, cGVHD, active L-aGVHD or cGVHD, and no cGVHD/L-aGVHD. Significant marker differences, adjusted for major clinical factors, were defined as meeting all 3 criteria: receiver-operating characteristic area under the curve ≥0.60, P ≤ .05, and effect ratio ≥1.3 or ≤0.75. Patients with only distinctive features but determined as cGVHD by the adjudication committee (non-NIH-CC) had immune profiles similar to NIH-CC. Both cGVHD and L-aGVHD had decreased transitional B cells and increased cytolytic natural killer (NK) cells. cGVHD had additional abnormalities, with increased activated T cells, naive helper T (Th) and cytotoxic T cells, loss of CD56bright regulatory NK cells, and increased ST2 and soluble CD13. Active L-aGVHD before day 114 had additional abnormalities in naive Th, naive regulatory T (Treg) cell populations, and cytokines, and active cGVHD had an increase in PD-1- and a decrease in PD-1+ memory Treg cells. Unsupervised analysis appeared to show a progression of immune abnormalities from no cGVHD/L-aGVHD to L-aGVHD, with the most complex pattern in cGVHD. Comprehensive immune profiling will allow us to better understand how to minimize L-aGVHD and cGVHD. Further confirmation in adult and pediatric cohorts is needed.
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http://dx.doi.org/10.1182/blood.2019003186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146024PMC
April 2020

Comparison of the Relative Abuse Liability of Electronic Cigarette Aerosol Extracts and Nicotine Alone in Adolescent Rats: A Behavioral Economic Analysis.

Int J Environ Res Public Health 2020 01 30;17(3). Epub 2020 Jan 30.

Department of Medicine, Hennepin Healthcare Research Institute, Minneapolis, MN 55415, USA.

Characterizing the determinants of the abuse liability of electronic cigarettes (ECs) in adolescents is needed to inform product regulation by the United States Food and Drug Administration (FDA). We recently reported that Vuse Menthol EC aerosol extract containing nicotine and a range of non-nicotine constituents (e.g., menthol, propylene glycol) had reduced aversive effects compared to nicotine alone in adolescent rats, whereas Aroma E-Juice EC aerosol extract did not. The current study used a behavioral economic approach to compare the relative abuse liability of these EC extracts and nicotine alone in an i.v. self-administration (SA) model in adolescents. Adolescents were tested for the SA of EC extracts prepared using an ethanol (ETOH) solvent or nicotine and saline, with and without 4% ETOH (i.e., the same concentration in the EC extracts) in 23 h/day sessions. Results. Although acquisition of SA was faster for nicotine + ETOH compared to all other formulations, the elasticity of demand for all nicotine-containing formulations was similar. Conclusions: EC aerosol extracts did not have greater abuse liability than nicotine alone in adolescents. These data suggest that nicotine may be the primary determinant of the abuse liability of these ECs in youth, at least in terms of the primary reinforcing effects of ECs mediated within the central nervous system.
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http://dx.doi.org/10.3390/ijerph17030860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037300PMC
January 2020

Using CD19 chimeric antigen receptor-T cell therapy in a 4-month-old patient with infantile acute lymphoblastic leukemia.

Pediatr Blood Cancer 2020 04 11;67(4):e28155. Epub 2020 Jan 11.

Division of Pediatric Hematology/Oncology, University of Utah School of Medicine, Salt Lake City, Utah.

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http://dx.doi.org/10.1002/pbc.28155DOI Listing
April 2020

Immunoglobulin replacement and quality of life after CAR T-cell therapy - Authors' reply.

Lancet Oncol 2020 01;21(1):e7

Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.

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http://dx.doi.org/10.1016/S1470-2045(19)30814-9DOI Listing
January 2020

Patient-reported quality of life after tisagenlecleucel infusion in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukaemia: a global, single-arm, phase 2 trial.

Lancet Oncol 2019 12 9;20(12):1710-1718. Epub 2019 Oct 9.

Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.

Background: The ELIANA trial showed that 61 (81%) of 75 paediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia achieved overall remission after treatment with tisagenlecleucel, a chimeric antigen receptor targeted against the CD19 antigen. We aimed to evaluate patient-reported quality of life in these patients before and after tisagenlecleucel infusion.

Methods: ELIANA, a global, single-arm, open-label, phase 2 trial, was done in 25 hospitals across Australia, Austria, Belgium, Canada, France, Germany, Italy, Japan, Norway, Spain, and the USA. Patients with B-cell acute lymphoblastic leukaemia aged at least 3 years at the time of screening and 21 years or younger at the time of initial diagnosis who were in second or greater bone marrow relapse, chemorefractory, relapsed after allogeneic stem-cell transplantation, or were otherwise ineligible for allogeneic stem-cell transplantation were enrolled. Patients received a single intravenous administration of a target dose of 0·2-5 × 10 transduced viable T cells per kg for patients weighing 50 kg or less or 0·1-2·5 × 10 transduced viable T cells for patients weighing more than 50 kg. The primary outcome, reported previously, was the proportion of patients who achieved remission. A prespecified secondary endpoint, reported here, was patient-reported quality of life measured with the Pediatric Quality of Life Inventory (PedsQL) and European Quality of Life-5 Dimensions questionnaire (EQ-5D). Patients completed the questionnaires at baseline, day 28, and months 3, 6, 9, and 12 after treatment. The data collected were summarised using descriptive statistics and post-hoc mixed models for repeated measures. Change from baseline response profiles were illustrated with cumulative distribution function plots. The proportion of patients achieving the minimal clinically important difference and normative mean value were reported. Analysis was per protocol. This study is registered with ClinicalTrials.gov, NCT02435849.

Findings: Between April 8, 2015, and April 25, 2017, 107 patients were screened, 92 were enrolled, and 75 received tisagenlecleucel. 58 patients aged 8-23 years were included in the analysis of quality of life. At baseline, 50 (86%) patients had completed the PedsQL questionnaire and 48 (83%) had completed the EQ-5D VAS. Improvements in patient-reported quality-of-life scores were observed for all measures at month 3 after tisagenlecleucel infusion (mean change from baseline to month 3 was 13·3 [95% CI 8·9-17·6] for the PedsQL total score and 16·8 [9·4-24·3] for the EQ-5D visual analogue scale). 30 (81%) of 37 patients achieved the minimal clinically important difference at month 3 for the PedsQL total score and 24 (67%) of 36 patients achieved this for the EQ-5D visual analogue scale.

Interpretation: These findings, along with the activity and safety results of ELIANA, suggest a favourable benefit-risk profile of tisagenlecleucel in the treatment of paediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia.

Funding: Novartis.
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http://dx.doi.org/10.1016/S1470-2045(19)30493-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480957PMC
December 2019

Non-nicotine constituents in e-cigarette aerosol extract attenuate nicotine's aversive effects in adolescent rats.

Drug Alcohol Depend 2019 10 1;203:51-60. Epub 2019 Aug 1.

Department of Medicine, Hennepin Healthcare Research Institute, Minneapolis, MN, USA; Department of Medicine, University of Minnesota, Minneapolis, MN, USA; Department of Psychology, University of Minnesota, Minneapolis, MN, USA.

Background: Development of preclinical methodology for evaluating the abuse liability of electronic cigarettes (ECs) in adolescents is urgently needed to inform FDA regulation of these products. We previously reported reduced aversive effects of EC liquids containing nicotine and a range of non-nicotine constituents (e.g., propylene glycol, minor tobacco alkaloids) compared to nicotine alone in adult rats as measured using intracranial self-stimulation. The goal of this study was to compare the aversive effects of nicotine alone and EC aerosol extracts in adolescent rats as measured using conditioned taste aversion (CTA), which can be conducted during the brief adolescent period.

Methods And Results: In Experiment 1, nicotine alone (1.0 or 1.5 mg/kg, s.c.) produced significant CTA in adolescent rats in a two-bottle procedure, thereby establishing a model to study the effects of EC extracts. At a nicotine dose of 1.0 mg/kg, CTA to Vuse Menthol EC extract, but not Aroma E-Juice EC extract, was attenuated compared to nicotine alone during repeated two-bottle CTA tests (Experiment 2a). At a nicotine dose of 0.5 mg/kg, CTA to Vuse Menthol EC extract did not differ from nicotine alone during the first two-bottle CTA test but extinguished more rapidly across repeated two-bottle tests (Experiment 2b).

Conclusions: Non-nicotine constituents in Vuse Menthol EC extracts attenuated CTA in a two-bottle procedure in adolescents. This model may be useful for anticipating the abuse liability of ECs in adolescents and for modeling FDA-mandated changes in product standards for nicotine or other constituents in ECs.
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http://dx.doi.org/10.1016/j.drugalcdep.2019.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941564PMC
October 2019

Benefits and challenges with diagnosing chronic and late acute GVHD in children using the NIH consensus criteria.

Blood 2019 07 1;134(3):304-316. Epub 2019 May 1.

British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.

Chronic graft-versus-host disease (cGVHD) and late acute graft-versus-host disease (L-aGVHD) are understudied complications of allogeneic hematopoietic stem cell transplantation in children. The National Institutes of Health Consensus Criteria (NIH-CC) were designed to improve the diagnostic accuracy of cGVHD and to better classify graft-versus-host disease (GVHD) syndromes but have not been validated in patients <18 years of age. The objectives of this prospective multi-institution study were to determine: (1) whether the NIH-CC could be used to diagnose pediatric cGVHD and whether the criteria operationalize well in a multi-institution study; (2) the frequency of cGVHD and L-aGVHD in children using the NIH-CC; and (3) the clinical features and risk factors for cGVHD and L-aGVHD using the NIH-CC. Twenty-seven transplant centers enrolled 302 patients <18 years of age before conditioning and prospectively followed them for 1 year posttransplant for development of cGVHD. Centers justified their cGVHD diagnosis according to the NIH-CC using central review and a study adjudication committee. A total of 28.2% of reported cGVHD cases was reclassified, usually as L-aGVHD, following study committee review. Similar incidence of cGVHD and L-aGVHD was found (21% and 24.7%, respectively). The most common organs involved with diagnostic or distinctive manifestations of cGVHD in children include the mouth, skin, eyes, and lungs. Importantly, the 2014 NIH-CC for bronchiolitis obliterans syndrome perform poorly in children. Past acute GVHD and peripheral blood grafts are major risk factors for cGVHD and L-aGVHD, with recipients ≥12 years of age being at risk for cGVHD. Applying the NIH-CC in pediatrics is feasible and reliable; however, further refinement of the criteria specifically for children is needed.
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http://dx.doi.org/10.1182/blood.2019000216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911839PMC
July 2019

Propylene glycol, a major electronic cigarette constituent, attenuates the adverse effects of high-dose nicotine as measured by intracranial self-stimulation in rats.

Drug Alcohol Depend 2018 12 18;193:162-168. Epub 2018 Oct 18.

Hennepin Healthcare Research Institute, 701 Park Avenue, Minneapolis, MN USA; Departments of Medicine, University of Minnesota Medical School, Variety Club Research Center (VCRC), 401 East River Parkway, 1(st) Floor - Suite 131, Minneapolis, MN 55455, USA; Departments of Psychology, University of Minnesota Medical School, N218 Elliott Hall, 75 E River Rd, Minneapolis, MN 55455, USA.

Background: Non-nicotine tobacco constituents may contribute to the abuse liability of tobacco products. We previously reported that electronic cigarette (EC) refill liquids containing nicotine and a range of non-nicotine constituents attenuated the anhedonic/aversive effects of nicotine in an intracranial self-stimulation (ICSS) model. The alcohol propylene glycol (PG) is a primary ingredient in these and other EC liquids, yet its abuse potential has not been established. The goal of this study was to evaluate the effects of parenteral administration of PG alone and PG combined with nicotine on ICSS in rats.

Methods And Results: PG alone did not affect ICSS at concentrations up to 100%. PG (25% or 60%) did not affect nicotine's reinforcement-enhancing (ICSS threshold-decreasing) effects at low to moderate nicotine doses, but attenuated nicotine's reinforcement-attenuating/aversive (ICSS threshold-increasing) effects at a high nicotine dose. PG concentrations similar to those in EC liquid doses used in our previous studies (1% or 3%) modestly attenuated the ICSS threshold-elevating effects of a high nicotine dose.

Conclusions: PG attenuated elevations in ICSS thresholds induced by high-dose nicotine, which may reflect an attenuation of nicotine's acute aversive/anhedonic and/or toxic effects. PG may have contributed to the attenuated ICSS threshold-elevating effects of EC liquids reported previously. Further examination of PG in models of addiction and toxicity is needed to understand the consequences of EC use and to inform the development of EC product standards by the FDA.
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http://dx.doi.org/10.1016/j.drugalcdep.2018.08.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278948PMC
December 2018

Status and Future Directions of Preclinical Behavioral Pharmacology in Tobacco Regulatory Science.

Behav Anal (Wash D C) 2018 Aug 9;18(3):252-274. Epub 2018 Jul 9.

Department of Medicine, Minneapolis Medical Research Foundation.

Behavioral pharmacology is a branch of the experimental analysis of behavior that has had great influence in drug addiction research and policy. This paper provides an overview of recent behavioral pharmacology research in the field of tobacco regulatory science, which provides the scientific foundation for the Food and Drug Administration Center for Tobacco Products (FDA CTP) to set tobacco control policies. The rationale and aims of tobacco regulatory science are provided, including the types of preclinical operant behavioral models it deems important for assessing the abuse liability of tobacco products and their constituents. We then review literature relevant to key regulatory actions being considered by the FDA CTP, including regulations over nicotine and menthol content of cigarettes, and conclude with suggesting some directions for future research. The current era of tobacco regulatory science provides great opportunities for behavioral pharmacologists to address the leading cause of preventable death and disease worldwide.
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http://dx.doi.org/10.1037/bar0000113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130840PMC
August 2018

Survival signal REG3α prevents crypt apoptosis to control acute gastrointestinal graft-versus-host disease.

J Clin Invest 2018 11 24;128(11):4970-4979. Epub 2018 Sep 24.

The Tisch Cancer Institute and Division of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai Hospital, New York, New York, USA.

Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract remains the major cause of morbidity and nonrelapse mortality after BM transplantation (BMT). The Paneth cell protein regenerating islet-derived 3α (REG3α) is a biomarker specific for GI GVHD. REG3α serum levels rose in the systematic circulation as GVHD progressively destroyed Paneth cells and reduced GI epithelial barrier function. Paradoxically, GVHD suppressed intestinal REG3γ (the mouse homolog of human REG3α), and the absence of REG3γ in BMT recipients intensified GVHD but did not change the composition of the microbiome. IL-22 administration restored REG3γ production and prevented apoptosis of both intestinal stem cells (ISCs) and Paneth cells, but this protection was completely abrogated in Reg3g-/- mice. In vitro, addition of REG3α reduced the apoptosis of colonic cell lines. Strategies that increase intestinal REG3α/γ to promote crypt regeneration may offer a novel, nonimmunosuppressive approach for GVHD and perhaps for other diseases involving the ISC niche, such as inflammatory bowel disease.
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http://dx.doi.org/10.1172/JCI99261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205404PMC
November 2018

Comparison of pediatric allogeneic transplant outcomes using myeloablative busulfan with cyclophosphamide or fludarabine.

Blood Adv 2018 06;2(11):1198-1206

Mount Sinai Medical Center, New York, NY.

Busulfan combined with cyclophosphamide (BuCy) has long been considered a standard myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (HCT), including both nonmalignant conditions and myeloid diseases. Substituting fludarabine for cyclophosphamide (BuFlu) to reduce toxicity without an increase in relapse has been increasingly performed in children, but without comparison with BuCy. We retrospectively analyzed 1781 children transplanted from 2008 to 2014 to compare the effectiveness of BuCy with BuFlu. Nonmalignant and malignant disease populations were analyzed separately. Overall mortality was comparable for children with nonmalignant conditions who received BuFlu or BuCy (relative risk [RR], 1.14, = .52). Lower incidences of sinusoidal obstruction syndrome ( = .04), hemorrhagic cystitis ( = .04), and chronic graft-versus-host disease ( = .02) were observed after BuFlu, but the influence of the conditioning regimen could not be assessed by multivariate analysis because of the low frequency of these complications. Children transplanted for malignancies were more likely to receive BuFlu if they had higher hematopoietic cell transplantation-comorbidity index scores ( < .001) or their donor was unrelated and HLA-mismatched ( = .004). Nevertheless, there were no differences in transplant toxicities and comparable transplant-related mortality (RR, 1.2; = .46), relapse (RR, 1.2; = .15), and treatment failure (RR, 1.2; = .12). BuFlu was associated with higher overall mortality (RR, 1.4; = .008) related to inferior postrelapse survival ( = .001). Our findings demonstrated that outcomes after BuFlu are similar to those for BuCy for children, but for unclear reasons, those receiving BuFlu for malignancy may be at risk for shorter postrelapse survival.
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http://dx.doi.org/10.1182/bloodadvances.2018016956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998928PMC
June 2018

MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD.

Blood 2018 06 15;131(25):2846-2855. Epub 2018 Mar 15.

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

Acute graft-versus-host disease (GVHD) is treated with systemic corticosteroid immunosuppression. Clinical response after 1 week of therapy often guides further treatment decisions, but long-term outcomes vary widely among centers, and more accurate predictive tests are urgently needed. We analyzed clinical data and blood samples taken 1 week after systemic treatment of GVHD from 507 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC), dividing them into a test cohort (n = 236) and 2 validation cohorts separated in time (n = 142 and n = 129). Initial response to systemic steroids correlated with response at 4 weeks, 1-year nonrelapse mortality (NRM), and overall survival (OS). A previously validated algorithm of 2 MAGIC biomarkers (ST2 and REG3α) consistently separated steroid-resistant patients into 2 groups with dramatically different NRM and OS ( < .001 for all 3 cohorts). High biomarker probability, resistance to steroids, and GVHD severity (Minnesota risk) were all significant predictors of NRM in multivariate analysis. A direct comparison of receiver operating characteristic curves showed that the area under the curve for biomarker probability (0.82) was significantly greater than that for steroid response (0.68, = .004) and for Minnesota risk (0.72, = .005). In conclusion, MAGIC biomarker probabilities generated after 1 week of systemic treatment of GVHD predict long-term outcomes in steroid-resistant GVHD better than clinical criteria and should prove useful in developing better treatment strategies.
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http://dx.doi.org/10.1182/blood-2018-01-822957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014357PMC
June 2018

Substitutability of nicotine alone and an electronic cigarette liquid using a concurrent choice assay in rats: A behavioral economic analysis.

Drug Alcohol Depend 2018 04 5;185:58-66. Epub 2018 Feb 5.

Minneapolis Medical Research Foundation, 914 S. 8th Street, Minneapolis, MN, United States; Department of Medicine, University of Minnesota Medical School, 420 Delaware Street, SE, Minneapolis, MN, United States; Department of Psychology, University of Minnesota, 75 E. River Road, Minneapolis, MN, United States.

Background: For the Food and Drug Administration to effectively regulate tobacco products, the contribution of non-nicotine tobacco constituents to the abuse liability of tobacco must be well understood. Our previous work compared the abuse liability of electronic cigarette refill liquids (EC liquids) and nicotine (Nic) alone when each was available in isolation and found no difference in abuse liability (i.e., demand elasticity). Another, and potentially more sensitive measure, would be to examine abuse liability in a choice context, which also provides a better model of the tobacco marketplace.

Methods: Demand elasticity for Nic alone and an EC liquid were measured when only one formulation was available (alone-price demand) and when both formulations were concurrently available (own-price demand), allowing an assessment of the degree to which each formulation served as a substitute (cross-price demand) when available at a low fixed-price.

Results: Own-price demand for both formulations were more elastic compared to alone-price demand, indicating that availability of a substitute increased demand elasticity. During concurrent access, consumption of the fixed-price formulation increased as the unit-price of the other formulation increased. The rate of increase was similar between formulations, indicating that they served as symmetrical substitutes.

Conclusion: The cross-price model reliably quantified the substitutability of both nicotine formulations and indicated that the direct CNS effects of non-nicotine constituents in EC liquid did not alter its abuse liability compared to Nic. These data highlight the sensitivity of this model and its potential utility for examining the relative abuse liability and substitutability of tobacco products.
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http://dx.doi.org/10.1016/j.drugalcdep.2017.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889753PMC
April 2018

Effects of nicotine-containing and "nicotine-free" e-cigarette refill liquids on intracranial self-stimulation in rats.

Drug Alcohol Depend 2018 04 1;185:1-9. Epub 2018 Feb 1.

Department of Medicine, Minneapolis Medical Research Foundation, Minneapolis, MN, USA; Department of Medicine, University of Minnesota, Minneapolis, MN, USA; Department of Psychology, University of Minnesota, Minneapolis, MN, USA.

Background: Animal models are needed to inform FDA regulation of electronic cigarettes (ECs) because they avoid limitations associated with human studies. We previously reported that an EC refill liquid produced less aversive/anhedonic effects at a high nicotine dose than nicotine alone as measured by elevations in intracranial self-stimulation (ICSS) thresholds, which may reflect the presence of behaviorally active non-nicotine constituents (e.g., propylene glycol) in the EC liquids. The primary objective of this study was to assess the generality of our prior ICSS findings to two additional EC liquids. We also compared effects of "nicotine-free" varieties of these EC liquids on ICSS, as well as binding affinity and/or functional activity of nicotine alone, nicotine-containing EC liquids, and "nicotine-free" EC liquids at nicotinic acetylcholine receptors (nAChRs).

Methods And Results: Nicotine alone and nicotine dose-equivalent concentrations of both nicotine-containing EC liquids produced similar lowering of ICSS thresholds at low to moderate nicotine doses, indicating similar reinforcement-enhancing effects. At high nicotine doses, nicotine alone elevated ICSS thresholds (a measure of anhedonia-like behavior) while the EC liquids did not. Nicotine-containing EC liquids did not differ from nicotine alone in terms of binding affinity or functional activity at nAChRs. "Nicotine-free" EC liquids did not affect ICSS, but bound with low affinity at some (e.g., α4ß2) nAChRs.

Conclusions: These findings suggest that non-nicotine constituents in these EC liquids do not contribute to their reinforcement-enhancing effects. However, they may attenuate nicotine's acute aversive/anhedonic and/or toxic effects, which may moderate the abuse liability and/or toxicity of ECs.
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http://dx.doi.org/10.1016/j.drugalcdep.2017.11.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889751PMC
April 2018

Locomotor activity does not predict individual differences in morphine self-administration in rats.

Pharmacol Biochem Behav 2018 03 2;166:48-56. Epub 2018 Feb 2.

Minneapolis Medical Research Foundation, Minneapolis, MN, United States; Department of Psychology, University of Minnesota, Minneapolis, MN, United States; Department of Medicine, University of Minnesota, Minneapolis, MN, United States. Electronic address:

Understanding factors contributing to individual differences in opioid addiction vulnerability is essential for developing more effective preventions and treatments. Sensation seeking has been implicated in addiction to several drugs of abuse, yet its relationship with individual differences in opioid addiction vulnerability has not been well established. The primary goal of this study was to evaluate the relationship between locomotor activity in a novel environment, a preclinical model of sensation-seeking, and individual differences in acquisition of i.v. morphine self-administration (SA) in rats. A secondary goal was to evaluate the relationship between activity and elasticity of demand (reinforcing efficacy) for morphine measured using a behavioral economic approach. Following an initial locomotor activity screen, animals were allowed to acquire morphine SA at a unit dose of 0.5 mg/kg/infusion in 4 hour/day sessions (Experiment 1) or 0.2 mg/kg/infusion in 2 hour/day sessions (Experiment 2) until infusion rates were stable. Unit price was subsequently manipulated via progressive reductions in unit dose (Experiment 1) or increases in response requirement per infusion (Experiment 2). Activity levels were not correlated with acquisition of morphine SA in either experiment. Morphine consumption was generally well described by an exponential demand function in both experiments (R values > 0.95 for rats as a group), but activity did not correlate with behavioral economic measures. Locomotor activity in a novel environment did not predict individual differences in acquisition of morphine SA. These data complement findings from some human studies and suggest that the role of sensation seeking in individual differences in opioid addiction vulnerability may be limited.
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http://dx.doi.org/10.1016/j.pbb.2018.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821250PMC
March 2018

Consortium on Methods Evaluating Tobacco: Research Tools to Inform US Food and Drug Administration Regulation of Snus.

Nicotine Tob Res 2018 09;20(11):1292-1300

Masonic Cancer Center, University of Minnesota, Minneapolis, MN.

Introduction: The US Food and Drug Administration (FDA) has purview over tobacco products. To set policy, the FDA must rely on sound science, yet most existing tobacco research methods have not been designed to specifically inform regulation. The NCI and FDA-funded Consortium on Methods Evaluating Tobacco (COMET) was established to develop and assess valid and reliable methods for tobacco product evaluation. The goal of this article is to describe these assessment methods using a US manufactured "snus" as the test product.

Methods: In designing studies that could inform FDA regulation, COMET has taken a multidisciplinary approach that includes experimental animal models and a range of human studies that examine tobacco product appeal, addictiveness, and toxicity. This article integrates COMET's findings over the last 4 years.

Results: Consistency in results was observed across the various studies, lending validity to our methods. Studies showed low abuse liability for snus and low levels of consumer demand. Toxicity was less than cigarettes on some biomarkers but higher than medicinal nicotine.

Conclusions: Using our study methods and the convergence of results, the snus that we tested as a potential modified risk tobacco product is likely to neither result in substantial public health harm nor benefit.

Implications: This review describes methods that were used to assess the appeal, abuse liability, and toxicity of snus. These methods included animal, behavioral economics, consumer perception studies, and clinical trials. Across these varied methods, study results showed low abuse-liability and appeal of the snus product we tested. In several studies, demand for snus was lower than for less toxic nicotine gum. The consistency and convergence of results across a range of multi-disciplinary studies lends validity to our methods and suggests that promotion of snus as a modified risk tobacco products is unlikely to produce substantial public health benefit or harm.
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http://dx.doi.org/10.1093/ntr/ntx228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154989PMC
September 2018

Self-Administration of Smokeless Tobacco Products in Rats.

Tob Regul Sci 2016 Oct;2(4):329-342

Department of Medicine, Minneapolis Medical Research Foundation, Minneapolis, MN.

Objective: Preclinical abuse liability assessment is an essential component of tobacco regulatory science. The goal of this project was to evaluate the relative abuse liability of smokeless tobacco products in rats using aqueous extracts of those products. These extracts provide exposure to an extensive range of nicotine and non-nicotine tobacco constituents as occurs in humans.

Methods: Rats were trained to self-administer either nicotine alone or extracts of Camel Snus or Kodiak smokeless tobacco at an equivalent nicotine unit dose. In Experiment 1, the relative reinforcing efficacy of these formulations was assessed in adults and adolescents using a progressive ratio schedule under limited-access conditions. In Experiment 2, relative reinforcing efficacy was assessed in adolescents under unlimited-access conditions using behavioral economic demand curve analysis.

Results: The reinforcing efficacy of nicotine formulations was higher in adolescents than adults, but no difference was observed between formulations in either age group. Similarly, there was no difference in elasticity of demand between formulations in adolescents.

Conclusions: The present findings suggest that the abuse liability of these smokeless tobacco products is similar to nicotine alone, and that nicotine dose is the primary determinant of the reinforcing efficacy of systemic exposure to these products.
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http://dx.doi.org/10.18001/TRS.2.4.5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321097PMC
October 2016

An early-biomarker algorithm predicts lethal graft-versus-host disease and survival.

JCI Insight 2017 02 9;2(3):e89798. Epub 2017 Feb 9.

Tisch Cancer Institute, the Icahn School of Medicine at Mount Sinai.

No laboratory test can predict the risk of nonrelapse mortality (NRM) or severe graft-versus-host disease (GVHD) after hematopoietic cellular transplantation (HCT) prior to the onset of GVHD symptoms. Patient blood samples on day 7 after HCT were obtained from a multicenter set of 1,287 patients, and 620 samples were assigned to a training set. We measured the concentrations of 4 GVHD biomarkers (ST2, REG3α, TNFR1, and IL-2Rα) and used them to model 6-month NRM using rigorous cross-validation strategies to identify the best algorithm that defined 2 distinct risk groups. We then applied the final algorithm in an independent test set ( = 309) and validation set ( = 358). A 2-biomarker model using ST2 and REG3α concentrations identified patients with a cumulative incidence of 6-month NRM of 28% in the high-risk group and 7% in the low-risk group ( < 0.001). The algorithm performed equally well in the test set (33% vs. 7%, < 0.001) and the multicenter validation set (26% vs. 10%, < 0.001). Sixteen percent, 17%, and 20% of patients were at high risk in the training, test, and validation sets, respectively. GVHD-related mortality was greater in high-risk patients (18% vs. 4%, < 0.001), as was severe gastrointestinal GVHD (17% vs. 8%, < 0.001). The same algorithm can be successfully adapted to define 3 distinct risk groups at GVHD onset. A biomarker algorithm based on a blood sample taken 7 days after HCT can consistently identify a group of patients at high risk for lethal GVHD and NRM. The National Cancer Institute, American Cancer Society, and the Doris Duke Charitable Foundation.
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http://dx.doi.org/10.1172/jci.insight.89798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291735PMC
February 2017

Infectious Risk after Allogeneic Hematopoietic Cell Transplantation Complicated by Acute Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2017 Mar 22;23(3):522-528. Epub 2016 Dec 22.

Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, Michigan; Division of Pediatric Infectious Disease, University of Michigan, Ann Arbor, Michigan; Blood and Marrow Transplant Program, Icahn School of Medicine at Mount Sinai, New York, New York.

The occurrence of infections after allogeneic hematopoietic stem cell transplantation (HCT) is nearly universal. However, the relationship between infections and graft-versus-host disease (GVHD) is complex and attribution of infectious-related mortality is highly inconsistent, making comparison of infectious complication rates across allogeneic HCT clinical studies difficult. We categorized infectious complications from diagnosis or 1 year before HCT (whichever occurred later) through 2 years after HCT according to timing, frequency, causative organism, severity, and contribution to mortality for 431 consecutive patients who underwent allogeneic HCT from 2008 to 2011. We then assessed the contribution of risk factors, such as the frequency of pre-HCT infections and post-HCT GVHD, on post-HCT infection frequency and severity. We found that each pre-HCT bacterial infection/year leads to an additional 2.15 post-HCT bacterial infection/year (P = .004). Pre-HCT viral and fungal infections were not predictors for post-HCT infections. Acute GVHD (aGVHD) significantly increased the risk of developing life-threatening (hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.33 to 2.90) and fatal (HR, 2.8; 95% CI, 1.10 to 7.08) infections. Furthermore, patients who develop aGVHD experienced ~60% more infections than patients who never develop aGVHD. Quantification of infection frequency and severity for patients with and without GVHD may facilitate comparison of infectious outcomes across allogeneic HCT trials.
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http://dx.doi.org/10.1016/j.bbmt.2016.12.630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551893PMC
March 2017

A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study.

Lancet Haematol 2015 Jan 23;2(1):e21-9. Epub 2014 Dec 23.

Blood & Marrow Transplant Program, University of Michigan, Ann Arbor, MI, USA; The Tisch Cancer Institute, The Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA. Electronic address:

Background: Graft-versus-host disease (GVHD) is the major cause of non-relapse mortality after allogeneic haemopoietic stem-cell transplantation (SCT). The severity of symptoms at the onset of GVHD does not accurately define risk, and thus most patients are treated alike with high dose systemic corticosteroids. We aimed to define clinically meaningful risk strata for patients with newly diagnosed acute GVHD using plasma biomarkers.

Methods: Between April 13, 2000, and May 7, 2013, we prospectively collected plasma from 492 SCT patients with newly diagnosed acute GVHD and randomly assigned (2:1) using a random number generator, conditional on the final two datasets having the same median day of onset, into training (n=328) and test (n=164) sets. We used the concentrations of three recently validated biomarkers (TNFR1, ST2, and Reg3α) to create an algorithm that computed the probability of non-relapse mortality 6 months after GVHD onset for individual patients in the training set alone. We rank ordered the probabilities and identified thresholds that created three distinct non-relapse mortality scores. We evaluated the algorithm in the test set, and again in an independent validation set of an additional 300 patients who underwent stem cell transplant and were enrolled on multicentre clinical trials of primary therapy for acute GVHD.

Findings: In all three datasets (training, test, and validation), the cumulative incidence of 6-month non-relapse mortality significantly increased as the Ann Arbor GVHD score increased. In the multicentre validation set, scores were 8% (95% CI 3-16) for score 1, 27% (20-34) for score 2, and 46% (33-58) for score 3 (p<0·0001). Conversely, the response to primary GVHD treatment within 28 days decreased as the GVHD score increased 86% for score 1, 67% for score 2, and 46% for score 3 in the multicentre validation set, p<0·0001).

Interpretation: Biomarker-based scores can be used to guide risk-adapted therapy at the onset of acute GVHD. High risk patients with a score of 3 are candidates for intensive primary therapy, while low risk patients with a score of 1 are candidates for rapid tapers of systemic steroid therapy.

Funding: The National Cancer Institute, the National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious Diseases, the Doris Duke Charitable Fund, the American Cancer Society, and the Judith Devries Fund.
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http://dx.doi.org/10.1016/S2352-3026(14)00035-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340092PMC
January 2015

A Two-Day Continuous Nicotine Infusion Is Sufficient to Demonstrate Nicotine Withdrawal in Rats as Measured Using Intracranial Self-Stimulation.

PLoS One 2015 11;10(12):e0144553. Epub 2015 Dec 11.

Minneapolis Medical Research Foundation, Minneapolis, MN, United States of America.

Avoidance of the negative affective (emotional) symptoms of nicotine withdrawal (e.g., anhedonia, anxiety) contributes to tobacco addiction. Establishing the minimal nicotine exposure conditions required to demonstrate negative affective withdrawal signs in animals, as well as understanding moderators of these conditions, could inform tobacco addiction-related research, treatment, and policy. The goal of this study was to determine the minimal duration of continuous nicotine infusion required to demonstrate nicotine withdrawal in rats as measured by elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior). Administration of the nicotinic acetylcholine receptor antagonist mecamylamine (3.0 mg/kg, s.c.) on alternate test days throughout the course of a 2-week continuous nicotine infusion (3.2 mg/kg/day via osmotic minipump) elicited elevations in ICSS thresholds beginning on the second day of infusion. Magnitude of antagonist-precipitated withdrawal did not change with further nicotine exposure and mecamylamine injections, and was similar to that observed in a positive control group receiving mecamylamine following a 14-day nicotine infusion. Expression of a significant withdrawal effect was delayed in nicotine-infused rats receiving mecamylamine on all test days rather than on alternate test days. In a separate study, rats exhibited a transient increase in ICSS thresholds following cessation of a 2-day continuous nicotine infusion (3.2 mg/kg/day). Magnitude of this spontaneous withdrawal effect was similar to that observed in rats receiving a 9-day nicotine infusion. Our findings demonstrate that rats exhibit antagonist-precipitated and spontaneous nicotine withdrawal following a 2-day continuous nicotine infusion, at least under the experimental conditions studied here. Magnitude of these effects were similar to those observed in traditional models involving more prolonged nicotine exposure. Further development of these models, including evaluation of more clinically relevant nicotine dosing regimens and other measures of nicotine withdrawal (e.g., anxiety-like behavior, somatic signs), may be useful for understanding the development of the nicotine withdrawal syndrome.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0144553PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684239PMC
June 2016

Blockade of cholinergic transmission elicits somatic signs in nicotine-naïve adolescent rats.

Front Pharmacol 2015 20;6:239. Epub 2015 Oct 20.

Minneapolis Medical Research Foundation , Minneapolis, MN, USA ; Department of Psychology, University of Minnesota , Minneapolis, MN, USA ; Department of Medicine, University of Minnesota , Minneapolis, MN, USA.

High doses of the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine can elicit somatic signs resembling those associated with nicotine withdrawal in nicotine-naïve adult rats. Understanding this phenomenon, and its possible modulation by acute nicotine and age, could inform the use of mecamylamine as both an experimental tool and potential pharmacotherapy for tobacco dependence and other disorders. This study evaluated the ability of high-dose mecamylamine to elicit somatic signs in adolescent rats, and the potential for acute nicotine pretreatment to potentiate this effect as previously reported in adults. Single or repeated injections of mecamylamine (1.5 or 3.0 mg/kg, s.c.) elicited somatic signs in nicotine-naïve adolescents, but this effect was not influenced by 2 h pretreatment with acute nicotine (0.5 mg/kg, s.c.). In an initial evaluation of the effects of age in this model, mecamylamine (2.25 mg/kg, s.c.) elicited somatic signs in nicotine-naïve adolescents and adults. This effect was modestly enhanced following acute nicotine injections in adults but not in adolescents, even when a higher nicotine dose (1.0 rather than 0.5 mg/kg, s.c.) was used in adolescents to account for age differences in nicotine pharmacokinetics. These studies are the first to show that mecamylamine elicits somatic signs in nicotine-naïve adolescent rats, an effect that should be considered when designing and interpreting studies examining effects of high doses of mecamylamine in adolescents. Our findings also provide preliminary evidence that these signs may be differentially modulated by acute nicotine pretreatment in adolescents versus adults.
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http://dx.doi.org/10.3389/fphar.2015.00239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4611158PMC
November 2015

International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium.

Biol Blood Marrow Transplant 2016 Jan 16;22(1):4-10. Epub 2015 Sep 16.

Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan; Blood and Marrow Transplantation Program, The Icahn School of Medicine at Mount Sinai Hospital, New York, New York. Electronic address:

Acute graft-versus-host disease (GVHD) remains a leading cause of morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation. The clinical staging of GVHD varies greatly between transplant centers and is frequently not agreed on by independent reviewers. The lack of standardized approaches to handle common sources of discrepancy in GVHD grading likely contributes to why promising GVHD treatments reported from single centers have failed to show benefit in randomized multicenter clinical trials. We developed guidelines through international expert consensus opinion to standardize the diagnosis and clinical staging of GVHD for use in a large international GVHD research consortium. During the first year of use, the guidance followed discussion of complex clinical phenotypes by experienced transplant physicians and data managers. These guidelines increase the uniformity of GVHD symptom capture, which may improve the reproducibility of GVHD clinical trials after further prospective validation.
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http://dx.doi.org/10.1016/j.bbmt.2015.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4706482PMC
January 2016