An Analysis of Arguments Advanced via Twitter in an Advocacy Campaign to Promote Electronic Nicotine Delivery Systems.

INTRODUCTION: Advocates of electronic nicotine delivery systems (ENDS) increasingly use Twitter to promote liberal ENDS policies. "World Vape Day" (WVD) is an annual campaign organized by pro-ENDS advocacy groups, some of which have links to the nicotine industry (eg, via funding from the "Foundation for a Smoke-Free World"). In 2020, the campaign used dedicated social media accounts to disseminate WVD-branded images and campaign messages. We examined tweets posted as part of WVD 2020 to identify and analyze pro-ENDS policy arguments. AIMS AND METHODS: We extracted tweets posted between 26 May and 3 June 2020 that included the hashtag #WorldVapeDay. We used qualitative thematic analysis to code a random sample (n = 2200) of approximately half the original English language tweets (n = 4387) and used descriptive analysis to identify the most frequently used co-hashtags. RESULTS: Arguments related to four themes: harm reduction, smoking cessation, rights and justice, and opposition to ENDS restrictions. Tweets criticized individuals and groups perceived as opposing liberal ENDS regulation, and used personal testimonials to frame ENDS as a harm reduction tool and life-saving smoking cessation aid. Tweets also advanced rights-based arguments, such as privileging adults' rights over children's rights, and calling for greater recognition of consumers' voices. Tweets frequently used hashtags associated with the WHO and World No Tobacco Day (WNTD). CONCLUSIONS: The WVD campaign presented a series of linked pro-ENDS arguments seemingly aimed at policy-makers, and strategically integrated with the WHO's WNTD campaign. Critically assessing pro-ENDS arguments and the campaigns used to promote these is vital to helping policy actors develop proportionate ENDS policy. IMPLICATIONS: Social media platforms have considerable potential to influence policy actors. Tweets are easily generated and duplicated, creating an impression of sizeable and influential stakeholders. Evidence that the "World Vape Day" campaign was supported by groups with industry links, and targeted-at least in part-at WHO officials and those who follow the WHO World No Tobacco Day campaign, highlights the importance of critically reviewing such campaigns. Further research could examine how health advocates could engage in pro-ENDS campaigns to support balanced messaging and informed policy-making.

Understanding the long-term policy influence strategies of the tobacco industry: two contemporary case studies.

OBJECTIVE: This paper explores transnational tobacco companies' (TTCs) long-term policy influence strategies using two case studies, harm reduction and illicit tobacco, to identify lessons for the tobacco control movement and wider efforts to address the commercial determinants of health. METHODS: Evidence from a broad combination of sources including leaked documents and findings from over two decades of TTC monitoring were reviewed for each case study and categorised using the Policy Dystopia Model, focusing on the primary discursive strategy and key instrumental (action-based) strategies used. RESULTS: In both case studies, TTCs seek to advance their interests by engaging primarily in reputation management, coalition management and information management strategies over the long-term to propagate their over-riding discursive strategy-'we've changed, we are part of the solution'-despite clear evidence from both case studies that this is not the case. These strategies are globally coordinated and attempt primarily to reshape norms towards TTC involvement in tobacco control policy and delivery. Findings also suggest that industry denormalisation and the advent of Article 5.3 have led to the TTCs growing use of increasingly complex and opaque 'webs of influence'. CONCLUSIONS: The tobacco control community must develop its own proactive long-term strategies which should include industry denormalisation, new ways to fund research that reduce industry control, and improved transparency measures for research and policy. These findings, including TTC adaptations to Article 5.3, also indicate the need for more structural solutions, addressing corporate power and the underlying political and economic system. These lessons can be applied to other unhealthy commodity industries.

Exploring the Twitter activity around the eighth meeting of the Conference of the Parties to the WHO Framework Convention on Tobacco Control.

BACKGROUND: Tobacco companies' intentions to influence the WHO Framework Convention on Tobacco Control (FCTC) via the Conference of Parties (COP; the official biannual meeting where Parties review the Convention) are well documented. We aimed to analyse Twitter data to gain insights into tobacco industry tactics, arguments and allies. METHODS: We retrieved 9089 tweets that included #COP8FCTC between 1 and 9 October 2018. We categorised the tweets' content and sentiment through manual coding and machine learning. We used an investigative procedure using publicly available information to categorise the most active Twitter users and investigate tobacco industry links. Network analysis was used to visualise interactions and detect communities. RESULTS: Most tweets were about next-generation products (NGPs) or 'harm reduction' (54%) and tended to argue in support of NGPs; around one-quarter were critical of tobacco control (24%). The largest proportion of most active tweeters were NGP advocates, and slightly over half of those had either links to the Philip Morris International (PMI) funded Foundation for a Smoke-Free World (FSFW) and/or to the International Network of Nicotine Consumer Organisations, a network to whom the FSFW granted US$100 300 in 2018. PMI was the most active transnational tobacco company during COP8. CONCLUSIONS: The nature of the activity on Twitter around COP8, including a substantial online presence by PMI executives and NGP advocates with links to organisations funded directly and indirectly by PMI, is highly consistent with PMI's 2014 corporate affairs strategy, which described engaging tobacco harm reduction advocates to 'amplify and leverage the debate on harm reduction' around events such as the COP.

Analysis of submissions to the EU's public consultation on tobacco traceability and security features.

BACKGROUND: The Protocol to Eliminate Illicit Trade in Tobacco Products requires all parties to establish a tobacco track and trace (T&T) system. In 2016, the European Commission held a public consultation on T&T implementation where parties were asked to respond online to 22 multiple-choice questions and were given additional opportunities to leave comments. In May 2019, the European Union's (EU) T&T system became operational. This paper explores tobacco industry influence over and policy positions within the consultation process. METHODS: We identified consultation respondents and investigated any financial links with the tobacco industry and if these were transparent. Respondent's answers to the consultation's multiple-choice questions were collated to explore whether industry-linked respondents held the same policy positions as transnational tobacco companies (TTCs). Associations between policy positions and respondent's financial link status were tested using χ2 and Cranmer's V tests. FINDINGS: Of the 197 consultation respondents identified, 131 (66.4%) had financial links to the industry; 29 (22.1%) were not transparent about these links. A large number of trade associations responded (87), the majority of which (74/87) had financial links to the industry. There was a clear divide in the policy preferences of respondents with and without a financial link. Collectively, respondents with a financial link supported an industry-operated T&T solution. CONCLUSIONS: There was an extensive lobbying effort by the tobacco industry over the EU's T&T system, with TTCs' interests being represented repeatedly through multiple trade associations. The transparency requirements regarding consultation respondents' affiliations with relevant stakeholders (eg, tobacco manufacturers) should be improved for future consultations.

Illicit tobacco trade is 'booming': UK newspaper coverage of data funded by transnational tobacco companies.

BACKGROUND: Transnational tobacco companies (TTCs) have heavily publicised their argument that standardised tobacco packaging will increase the illicit tobacco trade. Leaked Philip Morris International (PMI) documents suggest that the company may have intended to use third parties to promulgate this argument in the UK. METHODS: We examined articles in UK newspapers (1 April 2013 to 31 March 2015) from LexisNexis for presence and nature of tobacco industry data. We also examined documents released by Freedom of Information requests made to Scottish Councils for evidence of how PMI operationalised its third-party strategy. FINDINGS: Two-thirds of newspaper articles (63%, 99/157) mentioned a PMI consultant; 36% of which did not disclose this industry funding. Most articles mentioned counterfeit tobacco, illicit whites or both (72%, 113/157), while few (4%, 7/157) specifically mentioned tobacco industry illicit tobacco and none explained that the latter can include tobacco-company involvement. Freedom of Information documents revealed that the PMI consultant sought to build relationships with Trading Standards officers, conducted undercover test purchases (UTPs) in illicit tobacco 'hotspots' and may have promoted unrepresentative findings in the media. While the data set featured PMI data predominantly, other TTCs also engaged in third-party techniques to promulgate messages on illicit tobacco. INTERPRETATION: PMI engaged a third party, seemingly with the aim of securing media coverage on illicit tobacco positing that standardised packaging would worsen the problem. The predominant focus of articles which featured industry-funded data and information was on counterfeit tobacco despite official data showing tobacco-industry illicit tobacco as the most prevalent. Other jurisdictions considering the policy should anticipate that third parties will promote the illicit-trade argument.

Prospective longitudinal study of tobacco company adaptation to standardised packaging in the UK: identifying circumventions and closing loopholes.

OBJECTIVES: UK standardised packaging legislation was introduced alongside pack size and product descriptor restrictions of the European Union Tobacco Products Directive to end tobacco marketing and misinformation via the pack. This paper aims to assess compliance with the restrictions and identify attempts to continue to market tobacco products and perpetuate misperceptions of harm post legislation. DESIGN, SETTING AND INTERVENTION: A prospective study of the introduction of standardised packaging of tobacco products to the UK. PARTICIPANTS AND OUTCOMES: We analysed commercial sales data to assess whether the legally required changes in pack branding, size and name were implemented. To explore any adaptations to products and packaging we analysed sales data, monthly pack purchases of factory-made (FM) cigarettes and roll-your-own (RYO) tobacco, tobacco advertisements from retail trade magazines and articles on tobacco from commercial literature (retail trade, market analyst and tobacco company publications). RESULTS: One month after full implementation of the UK and European Union policies, 97% FM and 98% RYO was sold in compliant packaging. Nevertheless, tobacco companies made adaptations to tobacco products which enabled continued brand differentiation after the legislation came into force. For example, flavour names previously associated with low tar were systematically changed to colour names arguably facilitating continued misperceptions about the relative harms of products. Tobacco companies used the 1-year sell-through to their advantage by communicating brand name changes and providing financial incentives for retailers to buy large volumes of branded packs. In addition, tobacco companies continued to market their products to retailers and customers by innovating exemptions to the legislation, namely, filters, packaging edges, seals, multipack outers, RYO accessories, cigars and pipe tobacco. CONCLUSIONS: Tobacco companies adapted to packaging restrictions by innovating their tobacco products and marketing activities. These findings should enable policy makers globally to close loopholes and increase the potential efficacy of standardised packaging policies.

Tweeting about public health policy: Social media response to the UK Government's announcement of a Parliamentary vote on draft standardised packaging regulations.

BACKGROUND: Standardised tobacco packaging has been, and remains, a contentious policy globally, attracting corporate, public health, political, media and popular attention. In January 2015, the UK Government announced it would vote on draft regulations for the policy before the May 2015 General Election. We explored reactions to the announcement on Twitter, in comparison with an earlier period of little UK Government activity on standardised packaging. METHODS: We obtained a random sample of 1038 tweets in two 4-week periods, before and after the UK Government's announcement. Content analysis was used to examine the following Tweet characteristics: support for the policy, purpose, Twitter-user's geographical location and affiliation, and evidence citation and quality. Chi-squared analyses were used to compare Tweet characteristics between the two periods. RESULTS: Overall, significantly more sampled Tweets were in favour of the policy (49%) in comparison to those opposed (19%). Yet, at Time 2, following the announcement, a greater proportion of sampled tweets opposed standardised packaging compared to the period sampled at Time 1, prior to the announcement (p<0.001). The quality of evidence and research cited in URLs linked at Time 2 was significantly lower than at Time 1 (p<0.001), with peer-reviewed research more likely to be shared in positive Tweets (p<0.001) and in Tweets linking to URLs originating from the health sector (p<0.001). The decline in the proportion of positive Tweets was mirrored by a reduction in Tweets by health sector Twitter-users at Time 2 (p<0.001). CONCLUSIONS: Microblogging sites can reflect offline policy debates and are used differently by policy proponents and opponents dependent on the policy context. Twitter-users opposed to standardised packaging increased their activity following the Government's announcement, while those in support broadly maintained their rate of Twitter engagement. The findings offer insight into the public health community's options for using Twitter to influence policy and disseminate research. In particular, proliferation of Twitter activity following pro-public health policy announcements could be considered to ensure pro-health messages are not overshadowed by anti-regulation voices.

Tobacco industry data on illicit tobacco trade: a systematic review of existing assessments.

OBJECTIVE: To examine the quality of tobacco industry-funded data on the illicit tobacco trade (ITT) through a systematic review of existing assessments of industry-funded data on ITT. DATA SOURCES: Papers and reports assessing tobacco industry-funded data on ITT were obtained via searches of 8 academic databases, Google searches and correspondence with ITT experts. STUDY SELECTION: Inclusion criteria identified 35 English-language papers containing an original assessment of tobacco industry-funded data. DATA EXTRACTION: Using a coding framework, information was extracted from the assessments regarding the quality of tobacco industry data. Documents were second-coded, achieving 94% intercoder reliability with all disagreements resolved. DATA SYNTHESIS: Of the 35 assessments reviewed, 31 argued that tobacco industry estimates were higher than independent estimates. Criticisms identified problems with data collection (29), analytical methods (22) and presentation of results (21), which resulted in inflated ITT estimates or data on ITT that were presented in a misleading manner. Lack of transparency from data collection right through to presentation of findings was a key issue with insufficient information to allow replication of the findings frequently cited. CONCLUSIONS: Tobacco industry data on ITT are not reliable. At present, the tobacco industry continues to fund and disseminate ITT research through initiatives such as PMI IMPACT. If industry data on ITT cannot meet the standards of accuracy and transparency set by high-quality research publications, a solution may be to tax tobacco companies and administer the resulting funds to experts, independent of the tobacco industry, who use previously developed reliable models for measuring ITT.

IRS2 copy number gain, KRAS and BRAF mutation status as predictive biomarkers for response to the IGF-1R/IR inhibitor BMS-754807 in colorectal cancer cell lines.

Insulin-like growth factor receptor 1 (IGF-1R)-targeting therapies are currently at an important crossroad given the low clinical response rates seen in unselected patients. Predictive biomarkers for patient selection are critical for improving clinical benefit. Coupling in vitro sensitivity testing of BMS-754807, a dual IGF-1R/IR inhibitor, with genomic interrogations in 60 human colorectal cancer cell lines, we identified biomarkers correlated with response to BMS-754807. The results showed that cell lines with BRAF(V600E) or KRAS(G13D) mutation were resistant, whereas cell lines with wild-type of both KRAS and BRAF were particularly sensitive to BMS-754807 if they have either higher RNA expression levels of IR-A or lower levels of IGFBP6. In addition, the cell lines with KRAS mutations, those with either insulin receptor substrate 2 (IRS2) copy number gain (CNG) or higher IGF-1R expression levels, were more sensitive to the drug. Furthermore, cell lines with IRS2 CNG had higher levels of ligand-stimulated activation of IGF-1R and AKT, suggesting that these cell lines with IGF-IR signaling pathways more actively coupled to AKT signaling are more responsive to IGF-1R/IR inhibition. IRS2 siRNA knockdown reduced IRS2 protein expression levels and decreased sensitivity to BMS-754807, providing evidence for the functional involvement of IRS2 in mediating the drug response. The prevalence of IRS2 CNG in colorectal cancer tumors as measured by qPCR-CNV is approximately 35%. In summary, we identified IRS2 CNG, IGF-1R, IR-A, and IGFBP6 RNA expression levels, and KRAS and BRAF mutational status as candidate predictive biomarkers for response to BMS-754807. This work proposed clinical development opportunities for BMS-754807 in colorectal cancer with patient selection to improve clinical benefit.

A critical evaluation of the volume, relevance and quality of evidence submitted by the tobacco industry to oppose standardised packaging of tobacco products.

OBJECTIVES: To examine the volume, relevance and quality of transnational tobacco corporations' (TTCs) evidence that standardised packaging of tobacco products 'won't work', following the UK government's decision to 'wait and see' until further evidence is available. DESIGN: Content analysis. SETTING: We analysed the evidence cited in submissions by the UK's four largest TTCs to the UK Department of Health consultation on standardised packaging in 2012. OUTCOME MEASURES: The volume, relevance (subject matter) and quality (as measured by independence from industry and peer-review) of evidence cited by TTCs was compared with evidence from a systematic review of standardised packaging . Fisher's exact test was used to assess differences in the quality of TTC and systematic review evidence. 100% of the data were second-coded to validate the findings: 94.7% intercoder reliability; all differences were resolved. RESULTS: 77/143 pieces of TTC-cited evidence were used to promote their claim that standardised packaging 'won't work'. Of these, just 17/77 addressed standardised packaging: 14 were industry connected and none were published in peer-reviewed journals. Comparison of TTC and systematic review evidence on standardised packaging showed that the industry evidence was of significantly lower quality in terms of tobacco industry connections and peer-review (p<0.0001). The most relevant TTC evidence (on standardised packaging or packaging generally, n=26) was of significantly lower quality (p<0.0001) than the least relevant (on other topics, n=51). Across the dataset, TTC-connected evidence was significantly less likely to be published in a peer-reviewed journal (p=0.0045). CONCLUSIONS: With few exceptions, evidence cited by TTCs to promote their claim that standardised packaging 'won't work' lacks either policy relevance or key indicators of quality. Policymakers could use these three criteria-subject matter, independence and peer-review status-to critically assess evidence submitted to them by corporate interests via Better Regulation processes.

Dual IGF-1R/InsR inhibitor BMS-754807 synergizes with hormonal agents in treatment of estrogen-dependent breast cancer.

Insulin-like growth factor (IGF) signaling has been implicated in the resistance to hormonal therapy in breast cancer. Using a model of postmenopausal, estrogen-dependent breast cancer, we investigated the antitumor effects of the dual IGF-1R/InsR tyrosine kinase inhibitor BMS-754807 alone and in combination with letrozole or tamoxifen. BMS-754807 exhibited antiproliferative effects in vitro that synergized strongly in combination with letrozole or 4-hydroxytamoxifen and fulvestrant. Similarly, combined treatment of BMS-754807 with either tamoxifen or letrozole in vivo elicited tumor regressions not achieved by single-agent therapy. Notably, hormonal therapy enhanced the inhibition of IGF-1R/InsR without major side effects in animals. Microarray expression analysis revealed downregulation of cell-cycle control and survival pathways and upregulation of erbB in response to BMS-754807 plus hormonal therapy, particularly tamoxifen. Overall, these results offer a preclinical proof-of-concept for BMS-754807 as an antitumor agent in combination with hormonal therapies in hormone-sensitive breast cancer. Cooperative cell-cycle arrest, decreased proliferation, and enhanced promotion of apoptosis may contribute to antitumor effects to be gauged in future clinical investigations justified by our findings.

Differential mechanisms of acquired resistance to insulin-like growth factor-i receptor antibody therapy or to a small-molecule inhibitor, BMS-754807, in a human rhabdomyosarcoma model.

Agents targeting insulin-like growth factor-I receptor (IGF-IR), including antibodies and small-molecule inhibitors, are currently in clinical development for the treatment of cancers including sarcoma. However, development of resistance is a common phenomenon resulting in failures of anticancer therapies. In light of this problem, we developed two resistant models from the rhabdomyosarcoma cell line Rh41: Rh41-807R, with acquired resistance to BMS-754807, a small-molecule dual-kinase inhibitor targeting IGF-IR and insulin receptor (IR), and Rh41-MAB391R, with resistance to MAB391, an IGF-IR-blocking antibody. In addition, tumor xenograft models were established from Rh41 and Rh41-807R cell lines. Gene expression and DNA copy number analyses of these models revealed shared as well as unique acquired resistance mechanisms for the two types of IGF-IR inhibitors. Each resistant model used different signaling pathways as a mechanism for proliferation. Platelet-derived growth factor receptor α (PDGFRα) was amplified, overexpressed, and constitutively activated in Rh41-807R cells and tumors. Knockdown of PDGFRα by small interfering RNA in Rh41-807R resensitized the cells to BMS-754807. Synergistic activities were observed when BMS-754807 was combined with PDGFRα inhibitors in the Rh41-807R model in vitro. In contrast, AXL expression was highly elevated in Rh41-MAB391R but downregulated in Rh41-807R. Notably, BMS-754807 was active in Rh41-MAB391R cells and able to overcome resistance to MAB391, but MAB391 was not active in Rh41-807R cells, suggesting potentially broader clinical activity of BMS-754807. This is the first study to define and compare acquired resistance mechanisms for IGF-IR-targeted therapies. It provides insights into the differential acquired resistance mechanisms for IGF-IR/IR small-molecule inhibitor versus anti-IGF-IR antibody.

Insulin receptor (IR) pathway hyperactivity in IGF-IR null cells and suppression of downstream growth signaling using the dual IGF-IR/IR inhibitor, BMS-754807.

The biology of IGF-IR/IR signaling was studied in normal mouse embryonic fibroblasts (MEFs) that were either wild type (wt), heterozygous (het), or null for the IGF-IR. The ability of IGF-I, IGF-II, or insulin to stimulate serum-starved MEFs was characterized by gene expression profiling and biochemical analyses for activation of downstream signals. Each genotypic group of MEFs exhibited distinct patterns of expression both while resting and in response to stimulation. The insulin receptor (IR) pathway in IGF-IR null MEFs was hypersensitive to insulin ligand stimulation resulting in greater AKT phosphorylation than in wt or het MEFs stimulated with the same ligand. Interestingly, the IR pathway hypersensitivity in IGF-IR null MEFs occurred with no observed changes in the levels of IR isoforms A or B. A new small molecule IGF-IR inhibitor (BMS-754807), having equipotent activity against both IGF-IR and IR, proved effective in suppressing both AKT and ERK phosphorylation from both the IGF-IR and IR pathways by all three ligands tested in wt, het, and null MEFs. The use of a dual IGF-IR/IR inhibitor addresses concerns about the use of growth inhibiting therapies directed against the IGF-IR receptor in certain cancers. Lastly, comparison of the antiproliferative effects (IC(50)s) of various compounds in wt vs. null MEFs demonstrates that genetically characterized MEFs provide a simple and inexpensive tool with which to define compounds as having mostly on-target or off-target IGF-IR activities because off-target compounds affect both wt and null MEFs equally.

The mechanisms of differential sensitivity to an insulin-like growth factor-1 receptor inhibitor (BMS-536924) and rationale for combining with EGFR/HER2 inhibitors.

Overexpression and enhanced activity of insulin-like growth factor-I receptor (IGF-IR) in diverse tumor types make it an attractive target for cancer therapy. BMS-536924 is a potent small molecule inhibitor of IGF-IR, which shows antitumor activity in multiple tumor models, including sarcoma. To facilitate the development of IGF-IR inhibitors as cancer therapy, identification of biomarkers for selecting patients most likely to derive clinical benefit is needed. To do so, 28 sarcoma and neuroblastoma cell lines were screened for in vitro response to BMS-536924 to identify sensitive and resistant cell lines. Notably, Ewing's sarcoma, rhabdomyosarcoma, and neuroblastoma are more responsive to BMS-536924, suggesting these specific subtypes may represent potential targeted patient subpopulations for the IGF-IR inhibitor. Gene expression and protein profiling were performed on these cell lines, and candidate biomarkers correlating with intrinsic and/or acquired resistance to BMS-536924 were identified. IGF-I, IGF-II, and IGF-IR were highly expressed in sensitive cell lines, whereas IGFBP-3 and IGFBP-6 were highly expressed in resistant lines. Overexpression of epidermal growth factor receptor (EGFR) and its ligands in resistant cell lines may represent one possible resistance mechanism by the adaptation of IGF-IR-independent growth using alternative signaling pathways. Based on cross-talk between IGF-IR and EGFR pathways, combination studies to target both pathways were performed, and enhanced inhibitory activities were observed. These results provide a strategy for testing combinations of IGF-IR inhibitors with other targeted therapies in clinical studies to achieve improved patient outcomes. Further exploration of mechanisms for intrinsic and acquired drug resistance by these preclinical studies may lead to more rationally designed drugs that target multiple pathways for enhanced antitumor efficacy.

Oncogenic NRAS has multiple effects on the malignant phenotype of human melanoma cells cultured in vitro.

Activating mutations in the NRAS gene, which occur predominantly in codon 61 (Q61R, Q61K) are among the most common genetic events in malignant melanoma. NRAS protein with oncogenic codon 61 mutations may therefore be good therapeutic targets. In the present study, we used gene expression profiling as a method for global characterization of gene expression alterations that resulted from treatment of melanoma cells with siRNA specifically targeting NRAS(Q61R). Sixteen probe sets representing 15 unique genes were identified whose expression was significantly altered by siRNA against NRAS(Q61R) in 2 melanoma cell lines. The genes with altered expression are involved in several functions, including modulation of cell growth, invasion and migration. The results suggest that downregulation of cyclin E2 and cyclin D1 and also upregulation of the negative cell-cycle regulator HBP1 in NRAS(Q61R) knockdown cells contribute to the inhibition of cell proliferation. Furthermore, suppression of oncogenic NRAS results in reduced migration and invasion, which is accompanied by downregulation of EphA2 (a receptor tyrosine kinase), uPAR (urokinase receptor) and cytoskeleton proteins such as leupaxin, paxillin and vinculin. These studies support the concept that suppression of oncogenic NRAS by siRNA can induce growth arrest and inhibit invasion of human melanoma cells by modulating the levels of these gene products.

The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers: a randomized controlled trial.

OBJECTIVE: To determine whether self-regulated flexible dosing with varenicline tartrate is safe and effective for smoking cessation. RESEARCH DESIGN AND METHODS: 320 healthy, motivated-to-quit smokers (> or =10 cigarettes/day) aged 18-65 years, entered a multicenter, randomized, double-blind, placebo-controlled study - conducted between December 26, 2001 and June 24, 2003 - with a 12-week treatment phase and 40-week, double-blind, non-treatment follow-up. Treatment consisted of varenicline or placebo in fixed doses (Week 1: titrated from 0.5 to 1.0 mg/day) followed by a self-regulated flexible schedule (Weeks 2-12: 0.5-2.0 mg/day). MAIN OUTCOME MEASURES: Primary outcomes included carbon monoxide-confirmed continuous abstinence rate (CAR) from smoking for Weeks 4 through 7, 9 through 12, and 9 through 52. Secondary outcomes included CAR from Weeks 9 through 24, 7-day point prevalence of abstinence, safety assessments, and measures of craving, withdrawal, and smoking reward. RESULTS: Superior CARs were observed in varenicline-treated (n = 157) versus placebo participants (n=155) for Weeks 4 through 7 (38.2 vs. 11.6%), 9 through 12 (40.1 vs. 11.6%), 9 through 24 (28.0 vs. 9.0%), and 9 through 52 (22.3 vs. 7.7%) (all p<0.001). Seven-day point prevalence was higher in varenicline-treated than placebo participants at Weeks 12 (46.5 vs. 14.2%; p<0.001), 24 (32.5 vs. 13.5%; p<0.001), and 52 (28.0 vs. 13.5%; p=0.001). Overall, medication compliance was high, although varenicline-treated, but not placebo, participants tended to taper down their dosage over time. Total treatment-emergent AEs were 77.1% (varenicline: 121/157) and 65.8% (placebo: 102/155). Few AEs led to treatment discontinuation (varenicline: 11/157, 7.0% and placebo: 7/155, 4.5%). Participants were primarily healthy Caucasians, so more research is necessary to determine how applicable these findings are to other populations. CONCLUSIONS: A self-regulated, flexible dosing regimen of varenicline is well tolerated, with superior effectiveness versus placebo for smoking cessation.