Preliminary evidence of different and clinically meaningful opioid withdrawal phenotypes.

Opioid use disorder (OUD) is a public health crisis. Differences in opioid withdrawal severity that predict treatment outcome could facilitate the process of matching patients to treatments. This is a secondary analysis of a randomized controlled trial (RCT) that enrolled treatment seeking heroin-users (N = 89, males = 78) into a residential study. Participants maintained on morphine (30 mg, subcutaneous, four-times daily) underwent a naloxone (0.4 mg, IM = intramuscular) challenge session to precipitate withdrawal. Area-under-the-curve (AUC) values from self-reported withdrawal ratings during the challenge session were analyzed using K-means clustering, revealing two phenotype groups. Withdrawal and retention from the subsequent 14-day double-blind, double-dummy RCT comparing three study medications (clonidine, tramadol-ER, and buprenorphine) were evaluated as a function of phenotype. Cluster analyses suggested HIGH (N = 37; mean [SD] subjective opiate withdrawal scale [SOWS]-AUC 123.7 [65.8]) and LOW (N = 52; SOWS-AUC 68.0 [47.7]) withdrawal phenotype groups. HIGH participants were significantly more female and had lower body mass indices than LOW participants; no drug-use variables were significant. Regarding RCT outcomes, HIGH phenotype participants were less likely to be retained in the study (P = 0.02) and had higher mean self-reported withdrawal (P = 0.05) than LOW phenotype participants. A significant interaction in RCT retention was observed between phenotype (P = 0.02) and study medication (P < 0.01). Self-reported withdrawal was significant for phenotype (P = 0.02); study medication trended towards significance (P = 0.07). Results suggest patients have meaningfully different experiences of opioid withdrawal that may predict differential response to opioid pharmacotherapies during supervised withdrawal. Additional prospective research to replicate and more thoroughly evaluate withdrawal phenotype correlates and sex differences is warranted.

Sex Differences in Escalated Methamphetamine Self-Administration and Altered Gene Expression Associated With Incubation of Methamphetamine Seeking.

BACKGROUND: Methamphetamine (METH) use disorder is prevalent worldwide. There are reports of sex differences in quantities of drug used and relapses to drug use among individuals with METH use disorder. However, the molecular neurobiology of these potential sex differences remains unknown. METHODS: We trained rats to self-administer METH (0. 1 mg/kg/infusion, i.v.) on an fixed-ratio-1 schedule for 20 days using two 3-hour daily METH sessions separated by 30-minute breaks. At the end of self-administration training, rats underwent tests of cue-induced METH seeking on withdrawal days 3 and 30. Twenty-four hours later, nucleus accumbens was dissected and then used to measure neuropeptide mRNA levels. RESULTS: Behavioral results show that male rats increased the number of METH infusions earlier during self-administration training and took more METH than females. Both male and female rats could be further divided into 2 phenotypes labeled high and low takers based on the degree of escalation that they exhibited during the course of the METH self-administration experiment. Both males and females exhibited incubation of METH seeking after 30 days of forced withdrawal. Females had higher basal mRNA levels of dynorphin and hypocretin/orexin receptors than males, whereas males expressed higher vasopressin mRNA levels than females under saline and METH conditions. Unexpectedly, only males showed increased expression of nucleus accumbens dynorphin after METH self-administration. Moreover, there were significant correlations between nucleus accumbens Hcrtr1, Hcrtr2, Crhr2, and Avpr1b mRNA levels and cue-induced METH seeking only in female rats. CONCLUSION: Our results identify some behavioral and molecular differences between male and female rats that had self-administered METH. Sexual dimorphism in responses to METH exposure should be considered when developing potential therapeutic agents against METH use disorder.

Inclusive Public Health Preparedness Program to Promote Resilience in Rural Appalachia (2016-2018).

Emergencies range from unexpected injuries to natural disasters. Populations with access and functional needs are more likely than other populations to experience adverse health outcomes during an emergency. The three-county Appalachian District Health Department engaged a collaborative array of community partners to build an all-inclusive, all-hazards emergency plan. Tabletop and full-scale exercises demonstrated the plan's ability to meet the needs of community members with access and functional needs.

A Comprehensive Multistate Model Analyzing Associations of Various Risk Factors With the Course of Breast Cancer in a Population-Based Cohort of Breast Cancer Cases.

We employed a semi-Markov multistate model for the simultaneous analysis of various endpoints describing the course of breast cancer. Results were compared with those from standard analyses using a Cox proportional hazards model. We included 3,012 patients with invasive breast cancer newly diagnosed between 2001 and 2005 who were recruited in Germany for a population-based study, the Mamma Carcinoma Risk Factor Investigation (MARIE Study), and prospectively followed up until the end of 2009. Locoregional recurrence and distant metastasis were included as intermediate states, and deaths from breast cancer, secondary cancer, and other causes were included as competing absorbing states. Tumor characteristics were significantly associated with all breast cancer-related endpoints. Nodal involvement was significantly related to local recurrence but more strongly related to distant metastases. Smoking was significantly associated with mortality from second cancers and other causes, whereas menopausal hormone use was significantly associated with reduced distant metastasis and death from causes other than cancer. The presence of cardiovascular disease at diagnosis was solely associated with mortality from other causes. Compared with separate Cox models, multistate models allow for dissection of prognostic factors and intermediate events in the analysis of cause-specific mortality and can yield new insights into disease progression and associated pathways.

Zonisamide Reduces Withdrawal Symptoms But Does Not Enhance Varenicline-Induced Smoking Cessation.

INTRODUCTION: Varenicline (Chantix) is a first-line treatment for smoking cessation but does not produce cessation in many individuals. It may be possible to improve abstinence by co-administering varenicline with other medications. Zonisamide (Zonegran) has a similar pharmacologic profile to topiramate, which has been shown to reduce smoking, but is better tolerated. This study evaluated whether combined zonisamide and varenicline reduced tobacco withdrawal and increased abstinence among smokers trying to quit, relative to varenicline and placebo. METHODS: This was a double-blind, randomized, placebo-controlled pilot trial of zonisamide + varenicline versus placebo + varenicline for smoking cessation. Smokers received brief counseling and study medications, and completed weekly assessments for 10 consecutive weeks. The primary outcome was continuous abstinence rates (biochemically verified) during the final 4 weeks of treatment. RESULTS: Results are presented as intent-to-treat and completer analyses. Seventy-four individuals were enrolled; 45 completed the study. Overall, 14.9% (intent-to-treat) and 25.0% (completer) of participants maintained sustained abstinence during the final 4 weeks of treatment. There were no differences between groups for biochemically-verified smoking, but zonisamide + varenicline reduced self-reported smoking, nicotine withdrawal, and craving compared to placebo + varenicline. CONCLUSIONS: Zonisamide decreased nicotine withdrawal and craving, though not of sufficient magnitude to modify smoking behavior. The sample size was small and low rates of abstinence across groups suggest the study population was difficult to treat. Additional evaluation of zonisamide or other medications that increase GABA or decrease glutamate in larger or more diverse populations may yield positive clinical benefit for nicotine/tobacco cessation. IMPLICATIONS: This study provides support for layering novel medications with varenicline for smoking cessation, for investigating medications that target the GABA and glutamate system, and for assessing the contribution that reductions in nicotine withdrawal have on ultimate cessation outcomes.

Child and case influences on recidivism in a statewide dissemination of Multisystemic Therapy for juvenile offenders.

Multisystemic Therapy (MST) is an evidence-based treatment for high-risk youth and their families shown to reduce subsequent delinquent activity. This study investigated (1) re-arrest rates of a statewide MST dissemination; and (2) the relation of child, family, and case characteristics to re-arrest rates following receipt of MST. Analyses examined outcomes for 633 youth following referral to MST. Separate models examined predictors of general re-arrest of any type and of more serious misdemeanor or felony arrests. Sixty-five percent of youth experienced a new arrest of any type within 12-months of MST initiation; fewer (53%) experienced a misdemeanor or felony charge in that timeframe. Recipients who were younger, had an externalizing behavior disorder, and had a greater number and severity of pre-MST charges were more likely to recidivate. Findings highlight potential child and case factors that may account for variability in treatment effects when MST is implemented broadly within a system.

Cannabis withdrawal in chronic, frequent cannabis smokers during sustained abstinence within a closed residential environment.

OBJECTIVES: Chronic, frequent cannabis smokers may experience residual and offset effects, withdrawal, and craving when abstaining from the drug. We characterized the prevalence, duration, and intensity of these effects in chronic frequent cannabis smokers during abstinence on a closed research unit. METHODS: Non-treatment-seeking participants (N = 29 on admission, 66% and 34% remaining after 2 and 4 weeks) provided subjective effects data. A battery of five instruments was computer-administered daily to measure psychological, sensory, and physical symptoms associated with cannabinoid intoxication and withdrawal. Plasma and oral fluid specimens were concurrently collected and analyzed for cannabinoids. Outcome variables were evaluated as change from admission (Day 0) with regression models. RESULTS: Most abstinence effects, including irritability and anxiety were greatest on Days 0-3 and decreased thereafter. Cannabis craving significantly decreased over time, whereas decreased appetite began to normalize on Day 4. Strange dreams and difficulty getting to sleep increased over time, suggesting intrinsic sleep problems in chronic cannabis smokers. Symptoms likely induced by residual drug effects were at maximum intensity on admission and positively correlated with plasma and oral fluid cannabinoid concentrations on admission but not afterward; these symptoms showed overall prevalence higher than cannabis withdrawal symptoms. CONCLUSIONS: The combined influence of residual/offset drug effects, withdrawal, and craving was observed in chronic cannabis smokers during monitored abstinence. Abstinence symptoms were generally more intense in the initial phase, implying importance of early intervention in cannabis quit attempts. Sleep disturbance persisting for an extended period suggests that hypnotic medications could be beneficial in treating cannabis dependence.

A Review of the Psychology That Underpins the Creation of a Diversity, Equity, and Inclusion Committee.

Although all committee work can be fraught with difficulty and laborious time commitments, committees designed to disrupt the cycle of inequity and bias are particularly fraught with social and emotional land mines that come as baggage to years of unaddressed inequity. As such, leaders must take special care and attend to the complex psychology that underpins the difficult discussions that must be had by these committees as they begin to address topics of inequity within professional medical institutions. The authors describe, in an accessible summary format, how to lay the foundations for a smooth transition into the work of a diversity, equity, and inclusion committee, the best steps to build a team, and the core concepts that should underpin all diversity, equity, and inclusion work, starting from the intrapersonal level and moving toward the organizational level. This is done with the help of available scientific data where they are available, including literature on teamwork, health equity, and psychological safety, among other topics.

FDG PET in a Patient on a GLP-1 Agonist/Insulin Secretagogue.

ABSTRACT: With the increase in use of GLP-1 receptor agonists such as semaglutide (Ozempic, Wegovy, Rybelsus) in the population, nuclear medicine physicians should be aware of the possibility of nondiagnostic FDG PET scans due to these medications, which work partly by increasing insulin secretion. We demonstrate a case where a patient's use of such a medication presumptively led to muscular and myocardial uptake, complicating scan interpretation considerably. Clinicians should be aware of the presence of these drugs and their potential effect on biodistribution in FDG PET. Further study is needed to best understand the effects of these medications on FDG biodistribution.

PET/Computed Tomography Transformation of Oncology: Kidney and Urinary Tract Cancers.

Renal cell carcinoma (RCC) and urothelial carcinoma (UC) are two of the most common genitourinary malignancies. 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) can play an important role in the evaluation of patients with RCC and UC. In addition to the clinical utility of 18F-FDG PET to evaluate for metastatic RCC or UC, the shift in molecular imaging to focus on specific ligand-receptor interactions should provide novel diagnostic and therapeutic opportunities in genitourinary malignancies. In combination with the rise of artificial intelligence, our ability to derive imaging biomarkers that are associated with treatment selection, response assessment, and overall patient prognostication will only improve.

Around-the-clock oral THC effects on sleep in male chronic daily cannabis smokers.

BACKGROUND AND OBJECTIVES: Δ9-tetrahydrocannabinol (THC) promotes sleep in animals; clinical use of THC is associated with somnolence. Human laboratory studies of oral THC have not shown consistent effects on sleep. We prospectively evaluated self-reported sleep parameters during controlled oral THC administration to research volunteers. METHODS: Thirteen male chronic daily cannabis smokers (mean ± SD age 24.6± 3.7 years, self-reported smoking frequency of 5.5 ± 5.9 (range 1-24) joint-equivalents daily at study entry) were administered oral THC doses (20 mg) around-the-clock for 7 days (40-120 mg daily) starting the afternoon after admission. The St. Mary's Hospital Sleep Questionnaire was completed every morning. Plasma THC and 11-OH-THC (active metabolite) concentrations were measured in venous blood samples collected every evening. Changes in sleep characteristics over time and associations between sleep characteristics and plasma cannabinoid concentrations were evaluated with repeated measures mixed linear regression. RESULTS: Higher evening THC and 11-OH-THC concentrations were significantly associated with shorter sleep latency, less difficulty falling asleep, and more daytime sleep the following day. In contrast, the duration of calculated and self-reported nighttime sleep decreased slightly (3.54 and 5.34 minutes per night, respectively) but significantly during the study. CONCLUSIONS: These findings suggest that tolerance to the somnolent effects of THC may have occurred, but results should be considered preliminary due to design limitations. SCIENTIFIC SIGNIFICANCE: Somnolence from oral THC may dissipate with chronic, high-dose use. This has implications for patients who may take chronic oral THC for medicinal purposes, including cannabis dependence treatment. (Am J Addict 2013;22:510-514).

Workforce Pathway Development: Evaluation of an Educational Seminar to Increase Student Interest in Nuclear Medicine.

RATIONALE AND OBJECTIVES: Attracting more students to nuclear medicine is imperative to improving diversity and meeting growing staffing needs. In this study, we implemented a short seminar about nuclear medicine and evaluated its impact on student perceptions of the field. MATERIALS AND METHODS: We developed and presented 30-minute "Introduction to Nuclear Medicine" seminars to undergraduate college students and preclinical medical students. After the seminars, participants completed a post-pre survey to determine perceived changes to their perspective of nuclear medicine. Responses were coded on a Likert 1-5 scale with pre- and post- seminar results compared using T-test of means and analysis of variance. RESULTS: Of the 83 students who attended the seminar, 79 (95.1%) students participated in the survey including 67 preclinical medical students and 12 undergraduate students. Of the 78 participants who provided demographic information, there were 38 (48.7%) women, 5 (6.4%) first-generation college students, and 39 (50.0%) people who identified as either multiracial or a race other than White/Caucasian. Among all participants (n = 79), there was a significant increase in perceived understanding of nuclear medicine (p < 0.001), confidence in ability to pursue nuclear medicine (p < 0.001), and interest in becoming a nuclear medicine professional (p < 0.001). Perceived increases in knowledge were highest among first-year medical students (p = 0.031), while interest (p = 0.40) and confidence (p = 0.85) in pursuing nuclear medicine did not vary by educational level. CONCLUSION: Perceptions of student interest in nuclear medicine can be improved using an easily implemented, short seminar at the undergraduate college and preclinical medical school level.

CB1 - cannabinoid receptor antagonist effects on cortisol in cannabis-dependent men.

BACKGROUND: The endocannabinoid system modulates the hypothalamic-pituitary-adrenal (HPA) axis, but the effect of cannabinoid type 1 (CB1) receptor antagonism following chronic CB1 receptor stimulation in humans is unknown. OBJECTIVES: To evaluate effects of the CB1 receptor antagonist rimonabant on the HPA axis in cannabis-dependent individuals. METHODS: Fourteen daily cannabis smokers received increasingly frequent 20 mg oral Δ9-tetrahydrocannabinol (THC) doses (60-120 mg/day) over 8 days to standardize cannabis tolerance. Concurrent with the last THC dose, double-blind placebo or rimonabant (20 or 40 mg) was administered. Cannabinoid, rimonabant, and cortisol plasma concentrations were measured 1.5 hours prior to rimonabant administration and 2.0, 5.5, and 12.5 hours post-dose. RESULTS: Ten participants completed before premature study termination due to rimonabant's withdrawal from development. Five participants received 20 mg, three received 40 mg, and two placebo. There was a significant positive association between rimonabant concentration and change in cortisol concentration from baseline (r = .53, p < .01). There also was a borderline significant association between rimonabant dose and cortisol concentrations when the dose-by-time interaction was included. Four of eight participants receiving rimonabant (none of two receiving placebo) had greater cortisol concentrations 2 hours after dosing (at 11:30) than at 08:00, while normal diurnal variation should have peak concentrations at 08:00. CONCLUSION: Rimonabant 20 or 40 mg did not significantly increase plasma cortisol concentrations, consistent with an absence of antagonist-elicited cannabis withdrawal. SCIENTIFIC SIGNIFICANCE: Rimonabant doses >40 mg might elicit cortisol changes, confirming a role for CB1 receptors in modulating the HPA axis in humans.

Nuclear imaging in the identification of aberrant vascular anatomy prior to hepatic arterial infusion.

Hepatic arterial infusion (HAI) pumps are a specialized therapeutic modality designed to deliver high dose local chemotherapy to hepatic metastases in carefully selected patients resulting in improved survival, with patients living an average of 2 years longer than those who did not receive HAI pumps. While beneficial, these chemoinfusion pumps require a multidisciplinary approach to ensure safe and effective treatment for the patient. Here, we present a case where scintigraphic evaluation by the nuclear medicine department directly affected management of a patient with a hepatic arterial infusion pump. Variant vascular anatomy was initially discovered on the postoperative Tc-99m MAA SPECT/CT and was ultimately embolized by interventional radiology prior to initiation of chemoinfusion. This case report demonstrates the utility of obtaining nuclear medicine scintigraphy prior to chemoinfusion in patients with hepatic arterial infusion pumps.

Discordance Between Oncology Clinician-Perceived and Radiologist-Intended Meaning of the Postradiotherapy Positron Emission Tomography/Computed Tomography Freeform Report for Head and Neck Cancer.

Importance: Assessment of response after radiotherapy (RT) using 18F-fluorodeoxyglucose positron emission tomography (PET) with computed tomography (CT) is routine in managing head and neck squamous cell carcinoma (HNSCC). Freeform reporting may contribute to a clinician's misunderstanding of the nuclear medicine (NM) physician's image interpretation, with important clinical implications. Objective: To assess clinician-perceived freeform report meaning and discordance with NM interpretation using the modified Deauville score (MDS). Design, Setting, and Participants: In this retrospective cohort study that was conducted at an academic referral center and National Cancer Institute-designated Comprehensive Cancer Center and included patients with HNSCC treated with RT between January 2014 and December 2019 with a posttreatment PET/CT and 1 year or longer of follow-up, 4 masked clinicians independently reviewed freeform PET/CT reports and assigned perceived MDS responses. Interrater reliability was determined. Clinician consensus-perceived MDS was then compared with the criterion standard NM MDS response derived from image review. Data analysis was conducted between December 2021 and February 2022. Exposures: Patients were treated with RT in either the definitive or adjuvant setting, with or without concurrent chemotherapy. They then underwent posttreatment PET/CT response assessment. Main Outcomes and Measures: Clinician-perceived (based on the freeform PET/CT report) and NM-defined response categories were assigned according to MDS. Clinical outcomes included locoregional control, progression-free survival, and overall survival. Results: A total of 171 patients were included (45 women [26.3%]; median [IQR] age, 61 [54-65] years), with 149 (87%) with stage III to IV disease. Of these patients, 52 (30%) received postoperative RT and 153 (89%) received concurrent chemotherapy. Interrater reliability was moderate (κ = 0.68) among oncology clinicians and minimal (κ = 0.36) between clinician consensus and NM. Exact agreement between clinician consensus and the NM was 64%. The NM-rated MDS was significantly associated with locoregional control, progression-free survival, and overall survival. Conclusions and Relevance: The results of this cohort study suggest that considerable variation in perceived meaning exists among oncology clinicians reading freeform HNSCC post-RT PET/CT reports, with only minimal agreement between MDS derived from clinician perception and NM image interpretation. The NM use of a standardized reporting system, such as MDS, may improve clinician-NM communication and increase the value of HNSCC post-RT PET/CT reports.

Perfusion-only imaging in pregnant women: A comparative reader study with implications for practice patterns.

This study seeks to understand the value of ventilation imaging in pregnant patients imaged for suspected pulmonary embolism (PE). Ventilation-perfusion (VQ) scans in this high-risk population were compared to ventilation-only scans. We hypothesize that in this relatively healthy population, the exclusion of ventilation scans will not impact the rate of scans interpreted as positive. This retrospective blinded comparative reader study on collated VQ scans performed on pregnant patients in the course of routine clinical care in a > 5 year period (03/2012 to 07/2017). Each set of VQ and perfusion only (Q) studies were reviewed by 8 readers (4 nuclear radiology fellows and 4 nuclear medicine faculty) in random order; the Q scans simply omitted the ventilation images. Readers recorded each study as PE, no PE, or non-diagnostic (prospective investigative study of acute PE diagnosis classifications). Logistic mixed effects models were used to test the association between scan type (VQ vs Q). 203 pairs of studies in 197 patients were included (6 patients had 2 scans). Subjects ranged from 14 to 45 years of age, with a median 28 years. A significant association between scan type and positive/negative classification. Q-scans received more positive classifications than VQ-scans (median of 7.6% vs 6.7%). No association was seen between scan type and positive/indeterminate classification, nor between scan type and negative/indeterminate classification. The exclusion of ventilation images in VQ-scans was associated with a higher rate of positive studies, but this difference was small (<1%). Given the overwhelmingly normal percentage of Q-exams (>90% in our study), and the benefits of omitting ventilation imaging, perfusion-only imaging should be considered a reasonable option for imaging the pregnant patient to exclude PE.

Suppression of cytokine-mediated complement factor gene expression through selective activation of the Ah receptor with 3',4'-dimethoxy-α-naphthoflavone.

We have characterized previously a class of aryl hydrocarbon receptor (AHR) ligand termed selective AHR modulators (SAhRMs). SAhRMs exhibit anti-inflammatory properties, including suppression of cytokine-mediated acute phase genes (e.g., Saa1), through dissociation of non-dioxin-response element (DRE) AHR activity from DRE-dependent xenobiotic gene expression. The partial AHR agonist α-naphthoflavone (αNF) mediates the suppressive, non-DRE dependent effects on SAA1 expression and partial DRE-mediated CYP1A1 induction. These observations suggest that αNF may be structurally modified to a derivative exhibiting only SAhRM activity. A screen of αNF derivatives identifies 3',4'-dimethoxy-αNF (DiMNF) as a candidate SAhRM. Competitive ligand binding validates DiMNF as an AHR ligand, and DRE-dependent reporter assays with quantitative mRNA analysis of AHR target genes reveal minimal agonist activity associated with AHR binding. Consistent with loss of agonist activity, DiMNF fails to promote AHR binding to DRE probes as determined through electromobility shift assay. Importantly, mRNA analysis indicates that DiMNF retains the suppressive capacity of αNF regarding cytokine-mediated SAA1 expression in Huh7 cells. Interestingly, predictive docking modeling suggests that DiMNF adopts a unique orientation within the AHR ligand binding pocket relative to αNF and may facilitate the rational design of additional SAhRMs. Microarray studies with a non-DRE binding but otherwise functional AHR mutant identified complement factor C3 as a potential SAhRM target. We confirmed this observation in Huh7 cells using 10 µM DiMNF, which significantly repressed C3 mRNA and protein. These data expand the classes of AHR ligands exerting DRE-independent anti-inflammatory SAhRM activity, suggesting SAhRMs may have application in the amelioration of inflammatory disorders.

Mechanistic insights into the events that lead to synergistic induction of interleukin 6 transcription upon activation of the aryl hydrocarbon receptor and inflammatory signaling.

The aryl hydrocarbon receptor (AHR) is the ligand-activated transcription factor responsible for mediating the toxicological effects of dioxin and xenobiotic metabolism. However, recent evidence has implicated the AHR in additional, nonmetabolic physiological processes, including immune regulation. Certain tumor cells are largely nonresponsive to cytokine-mediated induction of the pro-survival cytokine interleukin (IL) 6. We have demonstrated that multiple nonresponsive tumor lines are able to undergo synergistic induction of IL6 following combinatorial treatment with IL1beta and the AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin. Such data implicate the AHR in tumor expansion, although the mechanistic basis for the AHR-dependent synergistic induction of IL6 has not been determined. Here, we demonstrate that ligand-activated AHR is involved in priming the IL6 promoter through binding to nonconsensus dioxin response elements located upstream of the IL6 start site. Such binding appears to render the promoter more permissive to IL1beta-induced binding of NF-kappaB components. The nature of the AHR-dependent increases in IL6 promoter transcriptional potential has been shown to involve a reorganization of repressive complexes as exemplified by the presence of HDAC1 and HDAC3. Dismissal of these HDACs correlates with post-translational modifications of promoter-bound NF-kappaB components in a time-dependent manner. Thus the AHR plays a role in derepressing the IL6 promoter, leading to synergistic IL6 expression in the presence of inflammatory signals. These observations may explain the association between enhanced expression of AHR and tumor aggressiveness. It is likely that AHR-mediated priming is not restricted to the IL6 promoter and may contribute to the expression of a variety of genes, which do not have consensus dioxin response elements.

Ah receptor antagonism inhibits constitutive and cytokine inducible IL6 production in head and neck tumor cell lines.

There is increasing evidence that the aryl hydrocarbon receptor (AHR) plays a role in tumor progression through numerous mechanisms. We have previously shown that, in certain cancer cell lines that are typically nonresponsive to cytokine-mediated IL6 induction, activation of the AHR with the agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin derepresses the IL6 promoter and allows for synergistic induction following IL1ß treatment. The mechanism by which this occurs involves liganded AHR binding upstream from the transcription start site and dismissing HDAC-containing corepressor complexes, giving rise to a promoter structure that is more amenable to NF-κB activation. This fact, combined with observations of multiple endogenously produced chemicals activating the AHR, led us to study its role in basal expression among high cytokine-producing cancer cell lines. The current study provides evidence that several head and neck squamous cell carcinoma cell lines have a level of constitutively bound AHR at the IL6 promoter, allowing for higher basal and readily inducible IL6 transcription. Treatment of these cell lines with an AHR antagonist led to dismissal of the AHR from the IL6 promoter and recruitment of corepressor complexes, thus diminishing cytokine expression. Head and neck squamous cell carcinoma is typically a high cytokine-producing tumor type, with IL6 expression levels correlating with disease aggressiveness. For this reason, AHR antagonist treatment could represent a novel adjuvant therapy for patients, lowering pro-growth and antiapoptotic signaling with minimal systemic side effects.