Lower Nicotine Cigarettes may not Lower Harm

In 2005, nearly 21% of American adults smoked cigarettes, and 81% of them smoked every day. For smokers unable or unwilling to quit, tobacco products that reduce the adverse health effects of smoking may be an attractive option. Potentially reduced exposure products (PREPs) were developed by the tobacco industry in response to smokers’ health concerns. PREPs purportedly lower the tar and/or nicotine levels of cigarettes, although the actual harm reduced remains questionable. One of the most recent additions to this product class are cigarettes that use genetically modified tobacco to reduce nicotine levels. This Issue Brief summarizes studies that investigate [1] how this product is used and [2] the messages smokers take away from product marketing. These complementary studies send a cautionary signal about the ability of these new cigarettes to reduce the harmful effects of smoking

Desire Versus Efficacy in Smokers’ Paradoxical Reactions to Pictorial Health Warnings for Cigarettes

Pictorial health warnings on cigarette packs create aversive emotional reactions to smoking and induce thoughts about quitting; however, contrary to models of health behavior change, they do not appear to alter intentions to quit smoking. We propose and test a novel model of intention to quit an addictive habit such as smoking (the efficacy-desire model) that can explain this paradoxical effect. At the core of the model is the prediction that self-efficacy and desire to quit an addictive habit are inversely related. We tested the model in an online experiment that randomly exposed smokers (N = 3297) to a cigarette pack with one of three increasing levels of warning intensity. The results supported the model’s prediction that despite the effects of warnings on aversion to smoking, intention to quit smoking is an inverted U-shape function of the smoker’s self-efficacy for quitting. In addition, smokers with greater (lesser) quit efficacy relative to smoking efficacy increase (decrease) intentions to quit. The findings show that previous failures to observe effects of pictorial warning labels on quit intentions can be explained by the contradictory individual differences that warnings produce. Thus, the model explains the paradoxical finding that quit intentions do not change at the population level, even though smokers recognize the implications of warnings. The model suggests that pictorial warnings are effective for smokers with stronger quit-efficacy beliefs and provides guidance for how cigarette warnings and tobacco control strategies can be designed to help smokers quit

Graphic Warning Labels Elicit Affective and Thoughtful Responses from Smokers: Results of a Randomized Clinical Trial

Objective Observational research suggests that placing graphic images on cigarette warning labels can reduce smoking rates, but field studies lack experimental control. Our primary objective was to determine the psychological processes set in motion by naturalistic exposure to graphic vs. text-only warnings in a randomized clinical trial involving exposure to modified cigarette packs over a 4-week period. Theories of graphic-warning impact were tested by examining affect toward smoking, credibility of warning information, risk perceptions, quit intentions, warning label memory, and smoking risk knowledge. Methods Adults who smoked between 5 and 40 cigarettes daily (N = 293; mean age = 33.7), did not have a contra-indicated medical condition, and did not intend to quit were recruited from Philadelphia, PA and Columbus, OH. Smokers were randomly assigned to receive their own brand of cigarettes for four weeks in one of three warning conditions: text only, graphic images plus text, or graphic images with elaborated text. Results Data from 244 participants who completed the trial were analyzed in structural-equation models. The presence of graphic images (compared to text-only) caused more negative affect toward smoking, a process that indirectly influenced risk perceptions and quit intentions (e.g., image-\u3enegative affect-\u3erisk perception-\u3equit intention). Negative affect from graphic images also enhanced warning credibility including through increased scrutiny of the warnings, a process that also indirectly affected risk perceptions and quit intentions (e.g., image-\u3enegative affect-\u3erisk scrutiny-\u3ewarning credibility-\u3erisk perception-\u3equit intention). Unexpectedly, elaborated text reduced warning credibility. Finally, graphic warnings increased warning-information recall and indirectly increased smoking-risk knowledge at the end of the trial and one month later. Conclusions In the first naturalistic clinical trial conducted, graphic warning labels are more effective than text-only warnings in encouraging smokers to consider quitting and in educating them about smoking’s risks. Negative affective reactions to smoking, thinking about risks, and perceptions of credibility are mediators of their impact

Reduced prefrontal and temporal processing and recall of high sensation value ads

Public service announcements (PSAs) are non-commercial broadcast ads that are an important part of televised public health campaigns. “Message sensation value” (MSV), a measure of sensory intensity of audio, visual, and content features of an ad, is an important factor in PSA impact. Some communication theories propose that higher message sensation value brings increased attention and cognitive processing, leading to higher ad impact. Others argue that the attention-intensive format could compete with ad\u27s message for cognitive resources and result in reduced processing of PSA content and reduced overall effectiveness. Brain imaging during PSA viewing provides a quantitative surrogate measure of PSA impact and addresses questions of PSA evaluation and design not accessible with traditional subjective and epidemiological methods. We used Blood Oxygenation Level Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) and recognition memory measures to compare high and low MSV anti-tobacco PSAs and neutral videos. In a short-delay, forced-choice memory test, frames extracted from PSAs were recognized more accurately than frames extracted from the NV. Frames from the low MSV PSAs were better recognized than frames from the high MSV PSAs. The accuracy of recognition of PSA frames was positively correlated with the prefrontal and temporal, and negatively correlated with the occipital cortex activation. The low MSV PSAs were associated with greater prefrontal and temporal activation, than the high MSV PSAs. The high MSV PSAs produced greater activation primarily in the occipital cortex. These findings support the “dual processing” and “limited capacity” theories of communication that postulate a competition between ad\u27s content and format for the viewers\u27 cognitive resources and suggest that the “attention-grabbing” high MSV format could impede the learning and retention of an ad. These findings demonstrate the potential of using neuroimaging in the design and evaluation of mass media public health communications

Content Matters: Neuroimaging Investigation of Brain and Behavioral Impact of Televised Anti-Tobacco Public Service Announcements

Televised public service announcements are video ads that are a key component of public health campaigns against smoking. Understanding the neurophysiological correlates of anti-tobacco ads is an important step toward novel objective methods of their evaluation and design. In the present study, we used functional magnetic resonance imaging (fMRI) to investigate the brain and behavioral effects of the interaction between content ( argument strength, AS) and format ( message sensation value, MSV) of anti-smoking ads in humans. Seventy-one nontreatment-seeking smokers viewed a sequence of 16 high or 16 low AS ads during an fMRI scan. Dependent variables were brain fMRI signal, the immediate recall of the ads, the immediate change in intentions to quit smoking, and the urine levels of a major nicotine metabolite cotinine at a 1 month follow-up. Whole-brain ANOVA revealed that AS and MSV interacted in the inferior frontal, inferior parietal, and fusiform gyri; the precuneus; and the dorsomedial prefrontal cortex (dMPFC). Regression analysis showed that the activation in the dMPFC predicted the urine cotinine levels 1 month later. These results characterize the key brain regions engaged in the processing of persuasive communications and suggest that brain fMRI response to anti-smoking ads could predict subsequent smoking severity in nontreatment-seeking smokers. Our findings demonstrate the importance of the quality of content for objective ad outcomes and suggest that fMRI investigation may aid the prerelease evaluation of televised public health ads

Coordinated repression of BIM and PUMA by Epstein-Barr virus latent genes maintains the survival of Burkitt lymphoma cells.

While the association of Epstein-Barr virus (EBV) with Burkitt lymphoma (BL) has long been recognised, the precise role of the virus in BL pathogenesis is not fully resolved. EBV can be lost spontaneously from some BL cell lines, and these EBV-loss lymphoma cells reportedly have a survival disadvantage. Here we have generated an extensive panel of EBV-loss clones from multiple BL backgrounds and examined their phenotype comparing them to their isogenic EBV-positive counterparts. We report that, while loss of EBV from BL cells is rare, it is consistently associated with an enhanced predisposition to undergo apoptosis and reduced tumorigenicity in vivo. Importantly, reinfection of EBV-loss clones with EBV, but surprisingly not transduction with individual BL-associated latent viral genes, restored protection from apoptosis. Expression profiling and functional analysis of apoptosis-related proteins and transcripts in BL cells revealed that EBV inhibits the upregulation of the proapoptotic BH3-only proteins, BIM and PUMA. We conclude that latent EBV genes cooperatively enhance the survival of BL cells by suppression of the intrinsic apoptosis pathway signalling via inhibition of the potent apoptosis initiators, BIM and PUMA.Cell Death and Differentiation advance online publication, 29 September 2017; doi:10.1038/cdd.2017.150

Standards in Pupillography

The number of research groups studying the pupil is increasing, as is the number of publications. Consequently, new standards in pupillography are needed to formalize the methodology including recording conditions, stimulus characteristics, as well as suitable parameters of evaluation. Since the description of intrinsically photosensitive retinal ganglion cells (ipRGCs) there has been an increased interest and broader application of pupillography in ophthalmology as well as other fields including psychology and chronobiology. Color pupillography plays an important role not only in research but also in clinical observational and therapy studies like gene therapy of hereditary retinal degenerations and psychopathology. Stimuli can vary in size, brightness, duration, and wavelength. Stimulus paradigms determine whether rhodopsin-driven rod responses, opsin-driven cone responses, or melanopsin-driven ipRGC responses are primarily elicited. Background illumination, adaptation state, and instruction for the participants will furthermore influence the results. This standard recommends a minimum set of variables to be used for pupillography and specified in the publication methodologies. Initiated at the 32nd International Pupil Colloquium 2017 in Morges, Switzerland, the aim of this manuscript is to outline standards in pupillography based on current knowledge and experience of pupil experts in order to achieve greater comparability of pupillographic studies. Such standards will particularly facilitate the proper application of pupillography by researchers new to the field. First we describe general standards, followed by specific suggestions concerning the demands of different targets of pupil research: the afferent and efferent reflex arc, pharmacology, psychology, sleepiness-related research and animal studies

Flexible Usage and Interconnectivity of Diverse Cell Death Pathways Protect against Intracellular Infection.

Programmed cell death contributes to host defense against pathogens. To investigate the relative importance of pyroptosis, necroptosis, and apoptosis during Salmonella infection, we infected mice and macrophages deficient for diverse combinations of caspases-1, -11, -12, and -8 and receptor interacting serine/threonine kinase 3 (RIPK3). Loss of pyroptosis, caspase-8-driven apoptosis, or necroptosis had minor impact on Salmonella control. However, combined deficiency of these cell death pathways caused loss of bacterial control in mice and their macrophages, demonstrating that host defense can employ varying components of several cell death pathways to limit intracellular infections. This flexible use of distinct cell death pathways involved extensive cross-talk between initiators and effectors of pyroptosis and apoptosis, where initiator caspases-1 and -8 also functioned as executioners when all known effectors of cell death were absent. These findings uncover a highly coordinated and flexible cell death system with in-built fail-safe processes that protect the host from intracellular infections.Wellcome Trus

Structural Basis for Apoptosis Inhibition by Epstein-Barr Virus BHRF1

Epstein-Barr virus (EBV) is associated with human malignancies, especially those affecting the B cell compartment such as Burkitt lymphoma. The virally encoded homolog of the mammalian pro-survival protein Bcl-2, BHRF1 contributes to viral infectivity and lymphomagenesis. In addition to the pro-apoptotic BH3-only protein Bim, its key target in lymphoid cells, BHRF1 also binds a selective sub-set of pro-apoptotic proteins (Bid, Puma, Bak) expressed by host cells. A consequence of BHRF1 expression is marked resistance to a range of cytotoxic agents and in particular, we show that its expression renders a mouse model of Burkitt lymphoma untreatable. As current small organic antagonists of Bcl-2 do not target BHRF1, the structures of it in complex with Bim or Bak shown here will be useful to guide efforts to target BHRF1 in EBV-associated malignancies, which are usually associated with poor clinical outcomes

Suppression of MMP-2 Attenuates TNF-α Induced NF-κB Activation and Leads to JNK Mediated Cell Death in Glioma

BACKGROUND: Abrogation of apoptosis for prolonged cell survival is essential in cancer progression. In our previous studies, we showed the MMP-2 downregulation induced apoptosis in cancer cell lines. Here, we attempt to investigate the exact molecular mechanism of how MMP-2 depletion leads to apoptosis in glioma xenograft cell lines. METHODOLOGY/PRINCIPAL FINDINGS: MMP-2 transcriptional suppression by MMP-2siRNA (pM) induces apoptosis associated with PARP, caspase-8 and -3 cleavage in human glioma xenograft cells 4910 and 5310. Western blotting and cytokine array showed significant decrease in the cellular and secreted levels of TNF-α with concomitant reduction in TNFR1, TRADD, TRAF2, RIP, IKKβ and pIκBα expression levels resulting in inhibition of p65 phosphorylation and nuclear translocation in pM-treated cells when compared to mock and pSV controls. In addition MMP-2 suppression led to elevated Fas-L, Fas and FADD expression levels along with increased p38 and JNK phosphorylation. The JNK-activity assay showed prolonged JNK activation in pM-transfected cells. Specific inhibition of p38 with SB203580 did not show any effect whereas inhibition of JNK phosphorylation with SP600125 notably reversed pM-induced cleavage of PARP, caspase-8 and -3, demonstrating a significant role of JNK in pM-induced cell death. Supplementation of rhMMP-2 counteracted the effect of pM by remarkably elevating TNF-α, TRADD, IKKβ and pIκBα expression and decreasing FADD, Fas-L, and phospho-JNK levels. The EMSA analysis indicated significant reversal of pM-inhibited NF-κB activity by rhMMP-2 treatment which rescued cells from pM-induced cell death. In vivo studies indicated that pM treatment diminished intracranial tumor growth and the immuno histochemical analysis showed decreased phospho-p65 and enhanced phospho-JNK levels that correlated with increased TUNEL-positive apoptotic cells in pM-treated tumor sections. CONCLUSION/SIGNIFICANCE: In summary, our study implies a role of MMP-2 in the regulation of TNF-α mediated constitutive NF-κB activation and Fas-mediated JNK mediated apoptosis in glioma xenograft cells in vitro and in vivo