Distinctive epigenomic alterations in NF1-deficient cutaneous and plexiform neurofibromas drive differential MKK/p38 signaling.

Benign peripheral nerve sheath tumors are the clinical hallmark of Neurofibromatosis Type 1. They account for substantial morbidity and mortality in NF1. Cutaneous (CNF) and plexiform neurofibromas (PNF) share nearly identical histology, but maintain different growth rates and risk of malignant conversion. The reasons for this disparate clinical behavior are not well explained by recent genome or transcriptome profiling studies. We hypothesized that CNFs and PNFs are epigenetically distinct tumor types that exhibit differential signaling due to genome-wide and site-specific methylation events. We interrogated the methylation profiles of 45 CNFs and 17 PNFs from NF1 subjects with the Illumina EPIC 850K methylation array. Based on these profiles, we confirm that CNFs and PNFs are epigenetically distinct tumors with broad differences in higher-order chromatin states and specific methylation events altering genes involved in key biological and cellular processes, such as inflammation, RAS/MAPK signaling, actin cytoskeleton rearrangement, and oxytocin signaling. Based on our identification of two separate DMRs associated with alternative leading exons in MAP2K3, we demonstrate differential RAS/MKK3/p38 signaling between CNFs and PNFs. Epigenetic reinforcement of RAS/MKK/p38 was a defining characteristic of CNFs leading to pro-inflammatory signaling and chromatin conformational changes, whereas PNFs signaled predominantly through RAS/MEK. Tumor size also correlated with specific CpG methylation events. Taken together, these findings confirm that NF1 deficiency influences the epigenetic regulation of RAS signaling fates, accounting for observed differences in CNF and PNF clinical behavior. The extension of these findings is that CNFs may respond differently than PNFs to RAS-targeted therapeutics raising the possibility of targeting p38-mediated inflammation for CNF treatment.

Characteristics and abstinence outcomes among tobacco quitline enrollees using varenicline or nicotine replacement therapy.

INTRODUCTION: Telephone counseling through quitlines combined with cessation medication is an effective strategy to support tobacco cessation. This study assessed the characteristics of quitline enrollees selecting varenicline (Chantix) compared with nicotine replacement therapy (NRT) medication and evaluated the cessation outcomes (7-day point prevalence) among these enrollees at 3 and 6 months after program completion. METHODS: A retrospective study analyzed demographic, tobacco use history, and abstinence outcome information of participants who enrolled in the Montana Tobacco Quit Line program and selected varenicline (n = 3,116) or NRT (n = 3,697). RESULTS: Participants selecting varenicline had significantly different demographic characteristics and tobacco use histories compared with enrollees selecting NRT. In the bivariate analyses, the odds of abstinence were greater among persons using varenicline compared with NRT at 3 months (22% and 13%; odds ratio [OR] = 1.85 95% CI 1.50-2.29) and 6 months (17% and 11%; OR = 1.66 95% CI 1.23-2.24). Independently, varenicline use, increasing age, having health insurance, and a greater number of counseling sessions were associated with tobacco use abstinence at 3 months. Only increasing age and a greater number of counseling sessions were independently associated with 6-month abstinence. DISCUSSION: Organizations providing varenicline as part of their quitline services should anticipate that participants selecting this medication have different demographic characteristics and tobacco use histories. The findings suggest that the addition of varenicline enhances 3-month abstinence rates and that the tobacco user's commitment to quit may be the most important predictor of successfully quitting.

Tracheostomy tube manometry: evaluation of speaking valves, capping and need for downsizing.

INTRODUCTION: Readiness to speak is a major problem for many tracheostomized patients. Evaluation for tracheostomy tube capping or speaking valve is often subjective. OBJECTIVES: We first wanted to assess whether there were differences among speaking valves. We developed a care pathway for tracheostomy tube evaluation and management including manometry, which we wanted to evaluate. METHODS: Three different speaking valves were assessed using manometry and measuring dyspnea in 21 patients. Subsequently, 100 consecutive patients referred for tracheostomy tube evaluation in a long-term acute-care rehabilitation hospital were studied using our care pathway with manometry before and after tracheostomy tube changes. RESULTS: Inspiratory pressures differed among the speaking valves. Borg scale was higher among patients with high expiratory pressures. Of the 100 patients, following our care pathway, speech (speaking valve or capping) was recommended for 78 patients with their initial tube, and for 93 patients within 2 days of their initial evaluation. Tracheostomy tube downsizing was recommended in 94 patients. Downsizing led to significant reductions in airway pressures. Capping was initially recommended for 12 patients and for 71 following downsizing. Women had higher pressures than men for the same size tubes. CONCLUSION: Tracheostomy tube manometry is very helpful in objectively guiding recommendations for speaking valve use, capping, and changing tracheostomy tubes. Speech is an early recommendation for most patients.

Tobacco quitline use: enhancing benefit and increasing abstinence.

OBJECTIVE: This study sought to evaluate the impact on the quitline utilization and abstinence rates of increasing a free nicotine-replacement therapy (NRT) benefit from 4 weeks to 6 weeks. METHODS: Intake data were utilized to assess the number of callers to the quitline during the time period in which 4 weeks of free NRT was provided (January-November 2006) and the time period of the enhanced NRT benefit (December 2006-June 2007). Abstinence rates at 3 and 6 months were calculated for people utilizing the quitline program during both time periods. RESULTS: The mean number of intake calls to the quitline increased from 397 (range 326-509) prior to the enhanced NRT benefit to 712 (range 592-1227) during the 6-week NRT benefit period. The 6-month tobacco abstinence rates were significantly higher among people receiving the 6-week NRT benefit compared to those receiving the 4-week benefit (OR=1.51; 95% CI=1.07, 1.66). CONCLUSIONS: The findings suggest that the promotion of an expanded NRT benefit can increase quitline utilization and abstinence rates.

Utilization of a tobacco quit line prior to and after a tobacco tax increase.

OBJECTIVE: To evaluate the utilization of a tobacco quit line prior to and after an increase in tobacco taxes. METHODS: Intake data were utilized to assess the number of callers to the quit line between May 2004 and April 2006. The characteristics of callers were also compared over three time periods; the 5 months prior to a voter initiative to increase the tax (May-September 2004), the 3 months just prior to the tax increase (October-December 2004), and the 5 months after the tax became effective (January-May 2005). RESULTS: The mean number of intake calls to the quit line between May 2004 and April 2006 was 388 per month (range = 200-1 088). The number of calls per month increased just prior to and just after the tax increase (3-month moving average = 691-731 calls). Persons completing an intake between October to December 2004 and January to May 2005 were more likely to be younger than 45 years, woman, White, smoke one or more packs of cigarettes per day, and were less likely to have tried to quit using tobacco in the past year than did persons calling between May and September 2004. CONCLUSIONS: Organizations supporting quit lines should anticipate an increase in the utilization of these services and changes in the characteristics of callers prior to and following an increase in tobacco taxes.

Recognition accuracy and reaction time of vocal expressions of emotion by African-American and Euro-American college women.

This study examined the relationship of racial group membership and vocal expressions of emotion. Recognition accuracy and reaction time were examined using the Diagnostic Assessment of Nonverbal Accuracy 2 Receptive Paralanguage subtests with 18 young Euro-American and African-American women. Participants listened to Euro-American children and adults speaking a neutral sentence, and identified the emotion as happy, sad, angry, or fearful. Analysis identified a significant effect for race on reaction time. Euro-American participants had faster mean RT than the African-American women for the recognition of vocal expression of emotion portrayed by Euro-Americans. However, no significant differences were found in mean accurate identification between the two groups. The finding of a significant difference in recognition RT but not in accuracy between the stimuli spoken by an adult and a child was unexpected. Both racial groups had faster mean RT in response to vocal expression of emotion by children.