Telomere function and the radiosensitivity of squamous carcinoma of the head and neck

This thesis considers whether the alteration of telomere function by manipulation of the telomerase enzyme can affect the radiosensitivity of in vivo derived SCCHN cells and hence whether telomere dysfunction inducing strategies are likely to be synergistic with ionising radiation in the management of SCCHN. The role of telomerase in radioprotecting cancer cells is investigated using the ectopic expression of hTERT in cell lines with high and low levels of telomerase. The effect of inhibiting telomerase expression is examined using a dominant negative telomerase gene. This approach had little success in SCCHN cells and so further experiments designed to elaborate the effect of telomerase inhibition on radiosensitivity were carried out using the small molecule reverse transcriptase inhibitor 3’ – azido, 3’ – deoxythymidine (AZT). These showed both telomerase suppression and increased radiosensitivity in cells exposed to AZT in culture. Other suggested factors which may affect the success of radiotherapy for cancer include the missense mutation of the p53 gene. A common polymorphism at codon 72 gives rise to Arginine or proline forms of the protein. This thesis investigates whether this variation affects radiosensitivity in SCCHN cells by assessing a panel of in vivo derived SCCHN cell lines. If the level of telomerase expression does not impact on radiosensitivity, then the use of antitelomerase strategies may be less effective with higher levels of telomerase expression in tumours. Continued selective pressure during tumour progression may mean the emergence of clonal variants with improved telomere function via greater levels of telomerase. This is investigated by anaphase bridge scoring of primary and recurrent archival tumour material. Analysis of cells from primary lesions and then from recurrent disease in the same patient provides information in this regard

Does familial risk for alcohol use disorder predict alcohol hangover?

Positive family history of alcohol use disorder (FHP), a variable associated with propensity for alcohol use disorder (AUD), has been linked with elevated hangover frequency and severity, after controlling for alcohol use. This implies that hangover experiences may be related to AUD. However, inadequate control of alcohol consumption levels, low alcohol dose and testing for hangover during the intoxication phase detract from these findings. Here, we present further data pertinent to understanding the relationship between family history and alcohol hangover. Study 1 compared past year hangover frequency in a survey of 24 FHP and 118 family history negative (FHN) individuals. Study 2 applied a quasi-experimental naturalistic approach assessing concurrent hangover severity in 17 FHP and 32 FHN individuals the morning after drinking alcohol. Both studies applied statistical control for alcohol consumption levels. In Study 1, both FHP status and estimated blood alcohol concentration on the heaviest drinking evening of the past month predicted the frequency of hangover symptoms experienced over the previous 12 months. In Study 2, estimated blood alcohol concentration the previous evening predicted hangover severity but FHP status did not. FHP, indicating familial risk for AUD, was not associated with concurrent hangover severity but was associated with increased estimates of hangover frequency the previous year

Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs

Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies1-3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity

Effects of upward and downward social comparison information on the efficacy of an appearance-based sun protection intervention: a randomized, controlled experiment

This experiment examined the impact of adding upward and/or downward social comparison information on the efficacy of an appearance-based sun protection intervention (UV photos and photoaging information). Southern California college students (N = 126) were randomly assigned to one of four conditions: control, intervention, intervention plus upward social comparison, intervention plus downward social comparison. The results demonstrated that all those who received the basic UV photo/photoaging intervention reported greater perceived susceptibility to photoaging (d = .74), less favorable tanning cognitions (d = .44), and greater intentions to sun protect (d = 1.32) relative to controls. Of more interest, while the basic intervention increased sun protective behavior during the subsequent 5 weeks relative to controls (d = .44), the addition of downward comparison information completely negated this benefit. Upward comparison information produced sun protection levels that were only slightly (and nonsignificantly) greater than in the basic intervention condition and, as such, does not appear to be a cost-effective addition. Possible mechanisms that may have reduced the benefits of upward comparison information and contributed to the undermining effects of downward comparison information are discussed

Sun Protection Intervention for Highway Workers: Long-Term Efficacy of UV Photography and Skin Cancer Information on Men’s Protective Cognitions and Behavior

The risk for skin cancer is increased among older males and outdoor workers who have high levels of ultraviolet (UV) exposure. This study was designed to examine the long-term efficacy of UV photography interventions on male outdoor workers, the potential mediators of its impact, and the efficacy of UV photography and skin cancer vs. aging information with this population. One hundred forty-eight male outdoor workers were randomly assigned to one of four intervention conditions or a control condition in a two by two plus one factorial design. The men in the intervention conditions received or did not receive a UV photo of their face and watched either a photoaging or skin cancer educational video. Participants completed pre-intervention, immediate post-intervention, and 2-month and 1-year follow-up assessments. Analysis of covariance and structural equation modeling revealed that participants in the UV photography and cancer information interventions reported higher levels of sun protection cognitions, which were significant partial mediators of increases in sun protection behaviors and decreases in skin color. This study provides evidence for effective sun protection interventions on male outdoor workers that may help reduce skin cancer risk

Pain coping skills training for African Americans with osteoarthritis (STAART): study protocol of a randomized controlled trial

Background: African Americans bear a disproportionate burden of osteoarthritis (OA), with higher prevalence rates, more severe pain, and more functional limitations. One key barrier to addressing these disparities has been limited engagement of African Americans in the development and evaluation of behavioral interventions for management of OA. Pain Coping Skills Training (CST) is a cognitive-behavioral intervention with shown efficacy to improve OA-related pain and other outcomes. Emerging data indicate pain CST may be a promising intervention for reducing racial disparities in OA symptom severity. However, there are important gaps in this research, including incorporation of stakeholder perspectives (e.g. cultural appropriateness, strategies for implementation into clinical practice) and testing pain CST specifically among African Americans with OA. This study will evaluate the effectiveness of a culturally enhanced pain CST program among African Americans with OA. Methods/Design: This is a randomized controlled trial among 248 participants with symptomatic hip or knee OA, with equal allocation to a pain CST group and a wait list (WL) control group. The pain CST program incorporated feedback from patients and other stakeholders and involves 11 weekly telephone-based sessions. Outcomes are assessed at baseline, 12 weeks (primary time point), and 36 weeks (to assess maintenance of treatment effects). The primary outcome is the Western Ontario and McMaster Universities Osteoarthritis Index, and secondary outcomes include self-efficacy, pain coping, pain interference, quality of life, depressive symptoms, and global assessment of change. Linear mixed models will be used to compare the pain CST group to the WL control group and explore whether participant characteristics are associated with differential improvement in the pain CST program. This research is in compliance with the Helsinki Declaration and was approved by the Institutional Review Boards of the University of North Carolina at Chapel Hill, Durham Veterans Affairs Medical Center, East Carolina University, and Duke University Health System. Discussion: This culturally enhanced pain CST program could have a substantial impact on outcomes for African Americans with OA and may be a key strategy in the reduction of racial health disparities.Funded by Patient-Centered Outcomes Research Institute (PCORI) Award (AD-1408-19519)

Attention to pain! A neurocognitive perspective on attentional modulation of pain in neuroimaging studies

Several studies have used neuroimaging techniques to investigate brain correlates of the attentional modulation of pain. Although these studies have advanced the knowledge in the field, important confounding factors such as imprecise theoretical definitions of attention, incomplete operationalization of the construct under exam, and limitations of techniques relying on measuring regional changes in cerebral blood flow have hampered the potential relevance of the conclusions. Here, we first provide an overview of the major theories of attention and of attention in the study of pain to bridge theory and experimental results. We conclude that load and motivational/affective theories are particularly relevant to study the attentional modulation of pain and should be carefully integrated in functional neuroimaging studies. Then, we summarize previous findings and discuss the possible neural correlates of the attentional modulation of pain. We discuss whether classical functional neuroimaging techniques are suitable to measure the effect of a fluctuating process like attention, and in which circumstances functional neuroimaging can be reliably used to measure the attentional modulation of pain. Finally, we argue that the analysis of brain networks and spontaneous oscillations may be a crucial future development in the study of attentional modulation of pain, and why the interplay between attention and pain, as examined so far, may rely on neural mechanisms shared with other sensory modalities

Student public commitment in a school-based diabetes prevention project: impact on physical health and health behavior

<p>Abstract</p> <p>Background</p> <p>As concern about youth obesity continues to mount, there is increasing consideration of widespread policy changes to support improved nutritional and enhanced physical activity offerings in schools. A critical element in the success of such programs may be to involve students as spokespeople for the program. Making such a public commitment to healthy lifestyle program targets (improved nutrition and enhanced physical activity) may potentiate healthy behavior changes among such students and provide a model for their peers. This paper examines whether student's "public commitment"--voluntary participation as a peer communicator or in student-generated media opportunities--in a school-based intervention to prevent diabetes and reduce obesity predicted improved study outcomes including reduced obesity and improved health behaviors.</p> <p>Methods</p> <p>Secondary analysis of data from a 3-year randomized controlled trial conducted in 42 middle schools examining the impact of a multi-component school-based program on body mass index (BMI) and student health behaviors. A total of 4603 students were assessed at the beginning of sixth grade and the end of eighth grade. Process evaluation data were collected throughout the course of the intervention. All analyses were adjusted for students' baseline values. For this paper, the students in the schools randomized to receive the intervention were further divided into two groups: those who participated in public commitment activities and those who did not. Students from comparable schools randomized to the assessment condition constituted the control group.</p> <p>Results</p> <p>We found a lower percentage of obesity (greater than or equal to the 95^thpercentile for BMI) at the end of the study among the group participating in public commitment activities compared to the control group (21.5% vs. 26.6%, p = 0.02). The difference in obesity rates at the end of the study was even greater among the subgroup of students who were overweight or obese at baseline; 44.6% for the "public commitment" group, versus 53.2% for the control group (p = 0.01). There was no difference in obesity rates between the group not participating in public commitment activities and the control group (26.4% vs. 26.6%).</p> <p>Conclusions</p> <p>Participating in public commitment activities during the HEALTHY study may have potentiated the changes promoted by the behavioral, nutrition, and physical activity intervention components.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov number, <a href="http://www.clinicaltrials.gov/ct2/show/NCT00458029">NCT00458029</a></p

Global wealth disparities drive adherence to COVID-safe pathways in head and neck cancer surgery

Peer reviewe

Not all non-drinkers with HIV are equal: demographic and clinical comparisons among current non-drinkers with and without a history of prior alcohol use disorders *

Studies of persons living with HIV (PLWH) have compared current non-drinkers to at-risk drinkers without differentiating whether current non-drinkers had a prior alcohol use disorder (AUD). The purpose of this study was to compare current non-drinkers with and without a prior AUD on demographic and clinical characteristics to understand the impact of combining them. We included data from 6 sites across the US from 1/2013–3/2015. Patients completed tablet-based clinical assessments at routine clinic appointments using the most recent assessment. Current non-drinkers were identified by AUDIT-C scores of 0. We identified a prior probable AUD by a prior AUD diagnosis in the electronic medical record (EMR) or a report of attendance at alcohol treatment in the clinical assessment. We used multivariate logistic regression to examine factors associated with prior AUD. Among 2235 PLWH who were current non-drinkers, 36% had a prior AUD with more patients with an AUD identified by the clinical assessment than the EMR. Higher proportions with a prior AUD were male, depressed, and reported current drug use compared to non-drinkers without a prior AUD. Former cocaine/crack (70% vs. 25%), methamphetamine/crystal (49% vs. 16%) and opioid/heroin use (35% vs. 7%) were more commonly reported by those with a prior AUD. In adjusted analyses, male sex, past methamphetamine/crystal use, past marijuana use, past opioid/heroin use, past and current cocaine/crack use and cigarette use were associated with a prior AUD. In conclusion, this study found that among non-drinking PLWH in routine clinical care, 36% had a prior AUD. We found key differences between those with and without prior AUD in demographic and clinical characteristics including drug use and depression. These results suggest non-drinkers are heterogeneous and need further differentiation in studies and that prior alcohol misuse including alcohol treatment should be included in behavioral health assessments as part of clinical care