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The objective of this study was to understand the reasons community-based public health organizations in the United States accept or refuse tobacco industry sponsorship. A formative pilot study involving 13 interviews with representatives of AIDS and Domestic Violence organizations in California or the Northeast was used. Semistructured interviews were conducted with leaders and fund-raisers working at AIDS and domestic violence organizations that either accepted grants from the tobacco industry or explicitly refused tobacco corporate support. Respondents that accepted grants did so because they believed that the tangible benefits of additional capacity to serve their constituents outweighed the minimal effect they believed refusing funds could have on tobacco control and prevention. Organizations that refused sponsorship either saw tobacco prevention as part of their mission of promoting overall health or social justice, or expressed concern about public association with the tobacco industry. Public health responses to this phenomenon are most effective when they are informed by the realities facing nonprofit leaders as they grapple with the question of whether to accept industry funds. Further research is needed to determine whether accepting sponsorship results in a change in public opinion about tobacco control. Possible interventions include creating positive publicity for organizations that refuse tobacco industry philanthropy. [ABSTRACT FROM AUTHOR]

The objectives of the study described in this article were to test whether community-level youth access ordinances reduce adolescents' perceived access to tobacco, purchase attempts, and tobacco use. A telephone survey was performed of a random sample of 3,831 Massachusetts adolescents linked to a database of all town-level youth access ordinances in the state. Respondents' perceived ease of access to tobacco, attempts to purchase tobacco, and tobacco use (ever smoking and current [past 30-day] smoking) were assessed. The association of these outcomes with the characteristics of youth access ordinances in the respondents' town of residence (n = 314) was tested in multilevel analyses that included town-level clustering, controlled for multiple individual and environmental characteristics, including a measure of community-level anti-smoking sentiment. Community-level youth access ordinances were not associated with adolescents' perceived access to tobacco, purchase attempts, or tobacco use, with two exceptions: (1) banning free-standing displays was associated with a 40% reduction in perceived access to tobacco (OR = 0.6; 95% CI, 0.4-0.9) and (2) a vending machine ban was associated a 30% higher report of perceived access to tobacco (OR = 1.3; 95% CI, 1.1-1.5). This study found no consistent associations between community-level youth access ordinances and adolescents' perceived access to tobacco, purchase attempts, or smoking prevalence. [ABSTRACT FROM AUTHOR]

The objective of this study was to assess compliance with Boston's 100% smoke-free bar regulation within the first 3 months of implementation. An observational survey was conducted of a random sample of 102 bars in Boston before and after the smoking ban went into effect. Forty bars were observed both pre- and postban, serving as a true comparison group; 62 additional bars were observed postban only. From preban to postban, highly significant decreases were found in the mean proportion of patrons smoking inside (22.5% to 0.19%, p < 0.0001), in the proportion of bars with smoking patrons (100% to 2.5%, p < 0.0001), and in the average number of ashtrays present in each bar (24 to 0, p < 0.0001). A highly significant increase was found in the average number of 'no smoking' signs posted in each bar (0 to 3.3, p < 0.0001). Within the 3 months immediately following the 100% smoke-free bar regulation in Boston, bars were highly compliant with the ban, including not allowing patrons and employees to smoke, removing ashtrays, and posting signs indicating that smoking is prohibited. Therefore, with proper time and preparation, public health practitioners can change social norms before a ban goes into effect and can implement smoke-free policies smoothly and with immediate compliance. [ABSTRACT FROM AUTHOR]

Gun violence prevention is often viewed as polarizing, although gun owners actually support many gun safety policies. The aim of this paper was to investigate the relationship between gun owners' perceptions of other gun owners' support for gun policies and their own individual support for such policies. NORC at the University of Chicago, which uses a panel of adults recruited through probability sampling, conducted an online/phone survey of 1,078 adult gun owners. Respondents were asked about their individual support for seven gun safety policies and their perceptions of other gun owners' support for those policies. We used two-sample t-tests and multivariate logistic regression analyses to explore the relationship between perceived and individual support. We found that gun owners underestimated fellow gun owners' support for gun violence prevention policy, especially if they personally opposed that policy. Gun owners' perception of fellow gun owners' support for a policy was significantly associated with the likelihood of individual support for that policy for all laws examined. These findings have important implications for correcting misperceptions of the level of gun owner support for gun safety policies as well as conducting and targeting educational campaigns to respond to and correct media misinformation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Suicide is a leading cause of mortality and firearm suicide accounts for the majority of fatalities. Firearm owners are a diverse population and firearm-specific suicide prevention programs should be tailored to distinct at-risk firearm-owning groups. This study set out to identify groups of firearm owners with differential suicide risk having unique characteristics that could be used to customize suicide prevention efforts. We conducted a nationally-representative survey of 2646 firearm owners to assess individual suicide risk, suicide risk factors, and demographic characteristics. A Latent Class Analysis identified unique segments of firearm owners at increased risk of suicide with similar underlying suicide risk factors and demographic characteristics. We found almost one in ten (9.6%) of firearm owners were at increased risk of suicide with 25% reporting suicide ideation, 6.6% reporting suicide planning, and 1.8% reporting previous suicide attempts. We identified three unique groups of firearm owners with higher than average suicide risk. Relative to other groups of firearm owners, one at-risk group were more affluent with a history of adverse experiences and mental health challenges, a second group had more male veterans with high levels of alcohol consumption, and third group had more non-heterosexual women who experienced trauma. We conclude that there are three unique groups of firearm owners with higher than average suicide risk with very different characteristics. In addition to broad suicide prevention efforts, customized firearm suicide prevention programs should be developed individually for these different firearm-owning populations, taking into consideration the unique suicide risk factors and demographics of each group., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Firearm injury remains a major cause of morbidity and mortality in the United States. Because of prior lack of comprehensive data sources, there is a paucity of literature on nonfatal firearm injury. Associations have previously been shown between state-level firearm laws and firearm fatalities, but few studies have examined the effects of these laws on nonfatal firearm hospitalization rates. Our objective was to examine the relationship between state firearm laws and firearm injury-related hospitalization rates across all 50 states over a 17-year period., Methods: In this panel study design, we used fixed effects multivariate regression models to analyze the relationship between 12 laws and firearm state-level injury-related hospitalization rates from 2000 to 2016 using the RAND Corporation Inpatient Hospitalizations for Firearm Injury Database. We used difference-in-differences to determine the impact of law passage in a given state compared with those states without the law, controlling for state-level covariates. The main outcome measure was the change in annual firearm injury-related inpatient hospitalization rates after passage or repeal of a state-level firearm law., Results: Examining each law individually, passage of violent misdemeanor, permitting, firearm removal from domestic violence offenders, and 10-round limit laws were associated with significant firearm injury-related hospitalization rate reductions. Examining multiple laws in the same model, passage of violent misdemeanor laws was associated with a 19.9% (confidence interval, 11.6%-27.4%) reduction, and removal of firearms from domestic violence offenders was associated with a 17.0% (confidence interval, 9.9%-23.6%) reduction in hospitalization rates., Conclusion: State laws related to preventing violent offenders from possessing firearms are associated with firearm injury-related hospitalization rate reductions. Given significant physical, mental, and social burdens of nonfatal firearm injury, determining the efficacy of firearm-related policy is critical to violence and injury prevention efforts., Level of Evidence: Prognostic and Epidemiologic; Level IV., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: A better understanding of the lawful use of guns and the symbolic meaning of guns to gun owners is essential to bridge the divide in public opinion regarding policies to reduce gun violence in the U.S., Methods: A national, prerecruited Internet panel of U.S. adults in 2019 was used to survey gun owners (n=2,086) to ascertain their gun-related attitudes and practices. Data were analyzed in 2020., Results: The primary reason given for owning a gun was defense (59.4%), followed by recreation (26.8%). A minority of the gun owners in the sample (22.9%) reported taking part in any gun-related activity more than rarely. The proportion of respondents who agreed that guns are an important part of their identity was just 10.0%. The majority of the gun owners viewed gun control advocates as wanting to take away all guns (58.5%). Nearly 70% of gun owners reported that a reason for their reluctance to engage in gun violence prevention was that they feel alienated because they perceive gun control advocates as blaming them for the gun violence problem, not understanding gun ownership, and not understanding much about guns., Conclusions: For most of the gun owners, gun ownership plays a practical role as a method of self-protection and has a symbolic association with freedom. Public health practitioners must develop novel communication strategies that avoid alienating gun owners by creating a perception that the ultimate aim is to take their guns away., (Copyright © 2020 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Determining whether the prevalence of gun ownership is associated with youth suicide is critical to inform policy to address this problem. The objective of this study is to investigate the relationship between the prevalence of household gun ownership in a state and that state's rate of youth suicide., Methods: This study, conducted in 2018, involved a secondary analysis of state-level data for the U.S. using multivariable linear regression. The relationship between the prevalence of household gun ownership and youth (aged 10-19 years) suicide rates was examined in a time-lagged analysis of state-level household gun ownership in 2004 and youth suicide rates in the subsequent decade (2005-2015), while controlling for the prevalence of youth suicide attempts and other risk factors., Results: Household gun ownership was positively associated with the overall youth suicide rate. For each 10 percentage-point increase in household gun ownership, the youth suicide rate increased by 26.9% (95% CI=14.0%, 39.8%)., Conclusions: Because states with high levels of household gun ownership are likely to experience higher youth suicide rates, these states should be especially concerned about implementing programs and policies to ameliorate this risk., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The role of electronic cigarettes (e-cigarettes) in product transitions has been debated., Methods: We used nationally representative data from the Population Assessment of Tobacco and Health Study waves 1 (2013-2014) and 2 (2014-2015) to investigate the associations between e-cigarette initiation and cigarette cessation/reduction in the USA. We limited the sample to current cigarette smokers aged 25+ years who were not current e-cigarette users at wave 1. We modelled 30-day cigarette cessation and substantial reduction in cigarette consumption as a function of e-cigarette initiation between surveys using multivariable logistic regression., Results: Between waves 1 and 2, 6.9% of cigarette smokers who were not current e-cigarette users transitioned to former smokers. After adjusting for covariates, cigarette smokers who initiated e-cigarette use between waves and reported they used e-cigarettes daily at wave 2 had 7.88 (95% CI 4.45 to 13.95) times the odds of 30-day cigarette cessation compared with non-users of e-cigarettes at wave 2. Cigarette smokers who began using e-cigarettes every day and did not achieve cessation had 5.70 (95% CI 3.47 to 9.35) times the odds of reducing their average daily cigarette use by at least 50% between waves 1 and 2 compared with e-cigarette non-users., Conclusions: Daily e-cigarette initiators were more likely to have quit smoking cigarettes or reduced use compared with non-users. However, less frequent e-cigarette use was not associated with cigarette cessation/reduction. These results suggest incorporating frequency of e-cigarette use is important for developing a more thorough understanding of the association between e-cigarette use and cigarette cessation., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose: HER2 + breast cancer (BC) is an aggressive subtype with high rates of brain metastases (BCBM). Two-thirds of HER2 + BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy. This phase II study evaluated everolimus (E), a brain-permeable mTOR inhibitor, trastuzumab (T), and vinorelbine (V) in patients with HER2 + BCBM., Patients and Methods: Eligible patients had progressive HER2 + BCBM. The primary endpoint was intracranial response rate (RR); secondary objectives were CNS clinical benefit rate (CBR), extracranial RR, time to progression (TTP), overall survival (OS), and targeted sequencing of tumors from enrolled patients. A two-stage design distinguished intracranial RR of 5% versus 20%., Results: 32 patients were evaluable for toxicity, 26 for efficacy. Intracranial RR was 4% (1 PR). CNS CBR at 6 mos was 27%; at 3 mos 65%. Median intracranial TTP was 3.9 mos (95% CI 2.2-5). OS was 12.2 mos (95% CI 0.6-20.2). Grade 3-4 toxicities included neutropenia (41%), anemia (16%), and stomatitis (16%). Mutations in TP53 and PIK3CA were common in BCBM. Mutations in the PI3K/mTOR pathway were not associated with response. ERBB2 amplification was higher in BCBM compared to primary BC; ERBB2 amplification in the primary BC trended toward worse OS., Conclusion: While intracranial RR to ETV was low in HER2 + BCBM patients, one-third achieved CNS CBR; TTP/OS was similar to historical control. No new toxicity signals were observed. Further analysis of the genomic underpinnings of BCBM to identify tractable prognostic and/or predictive biomarkers is warranted., Clinical Trial: (NCT01305941).

Background: Characterizing electronic cigarette (e-cigarette) use patterns is important for guiding tobacco regulatory policy and projecting the future burden of tobacco-related diseases. Few studies have examined patterns of e-cigarette use in individuals with cardiovascular disease (CVD)., Methods and Results: We examined e-cigarette use in adults aged 18 to 89 years with a history of CVD, using data from the 2014 National Health Interview Survey. We investigated associations between ever and current e-cigarette use and smoking with multivariable logistic regression. In a secondary analysis, we modeled the association between e-cigarette use and a quit attempt over the past year. Former smokers with CVD who quit smoking within the past year showed 1.85 (95% confidence interval, 1.03, 3.33) times the odds of having ever used e-cigarettes as compared with those who reported being "some days" current smokers. Current smokers who attempted to quit smoking within the past year showed significantly increased odds of ever having used e-cigarettes (odds ratio, 1.70; 95% confidence interval, 1.25, 2.30) and currently using e-cigarettes (odds ratio, 1.97; 95% confidence interval, 1.32, 2.95) as compared with smokers who had not attempted to quit over the past year., Conclusions: Individuals with CVD who recently quit smoking or reported a recent quit attempt were significantly more likely to use e-cigarettes than current smokers and those who did not report a quit attempt. Our findings may indicate that this population is using e-cigarettes as an aid to smoking cessation. Characterizing emerging e-cigarette use behaviors in adults with CVD may help to inform outreach activities aimed at this high-risk population., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Breast cancer metastasis remains a clinical challenge, even within a single patient across multiple sites of the disease. Genome-wide comparisons of both the DNA and gene expression of primary tumors and metastases in multiple patients could help elucidate the underlying mechanisms that cause breast cancer metastasis. To address this issue, we performed DNA exome and RNA sequencing of matched primary tumors and multiple metastases from 16 patients, totaling 83 distinct specimens. We identified tumor-specific drivers by integrating known protein-protein network information with RNA expression and somatic DNA alterations and found that genetic drivers were predominantly established in the primary tumor and maintained through metastatic spreading. In addition, our analyses revealed that most genetic drivers were DNA copy number changes, the TP53 mutation was a recurrent founding mutation regardless of subtype, and that multiclonal seeding of metastases was frequent and occurred in multiple subtypes. Genetic drivers unique to metastasis were identified as somatic mutations in the estrogen and androgen receptor genes. These results highlight the complexity of metastatic spreading, be it monoclonal or multiclonal, and suggest that most metastatic drivers are established in the primary tumor, despite the substantial heterogeneity seen in the metastases.

Background: Three medications are FDA-approved and recommended for treating alcohol use disorders (AUD) but they are not offered to most patients with AUD. Primary care (PC) may be an optimal setting in which to offer and prescribe AUD medications, but multiple barriers are likely., Objective: This qualitative study used social marketing theory, a behavior change approach that employs business marketing techniques including "segmenting the market," to describe (1) barriers and facilitators to prescribing AUD medications in PC, and (2) beliefs of PC providers after they were segmented into groups more and less willing to prescribe AUD medications., Design: Qualitative, interview-based study., Participants: Twenty-four providers from five VA PC clinics., Approach: Providers completed in-person semi-structured interviews, which were recorded, transcribed, and analyzed using social marketing theory and thematic analysis. Providers were divided into two groups based on consensus review., Key Results: Barriers included lack of knowledge and experience, beliefs that medications cannot replace specialty addiction treatment, and alcohol-related stigma. Facilitators included training, support for prescribing, and behavioral staff to support follow-up. Providers more willing to prescribe viewed prescribing for AUD as part of their role as a PC provider, framed medications as a potentially effective "tool" or "foot in the door" for treating AUD, and believed that providing AUD medications in PC might catalyze change while reducing stigma and addressing other barriers to specialty treatment. Those less willing believed that medications could not effectively treat AUD, and that treating AUD was the role of specialty addiction treatment providers, not PC providers, and would require time and expertise they do not have., Conclusions: We identified barriers to and facilitators of prescribing AUD medications in PC, which, if addressed and/or capitalized on, may increase provision of AUD medications. Providers more willing to prescribe may be the optimal target of a customized implementation intervention to promote changes in prescribing.

Background: Non-fatal firearm injuries constitute approximately 70% of all firearm trauma injuries in the United States. Patterns of severity of these injuries are poorly understood. We analyzed the overall, age-, sex- and intent-specific temporal trends in the injury severity of firearm hospitalizations from 1993 to 2014., Methods: We assessed temporal trends in the severity of patients hospitalized for firearm using Nationwide Inpatient Sample (NIS) data over a 22 year period. Firearm hospitalization was identified using assault (E965x), unintentional (E922x), intentional self-harm (E955x), legal (E970) and undetermined (E985x) International Classification of Diseases, Ninth Revision, Clinical Modification (ICD9) codes. Injury severity was measured using the computed New Injury Severity Score (NISS). We used survey weighted means, SD and annual percent change (APC), and joinpoint regression to analyze temporal trends., Results: A weighted total of 648 662 inpatient admissions for firearm injury were analyzed. Firearm injury severity demonstrated a significant annual increase of 1.4% (95% CI=1.3 to 1.6), and was driven by annual increases among young adults (APC=1.4%, 95% CI=1.3 to 1.5), older adults (APC=1.5%, 95% CI=1.3 to 1.6), female (APC=1.5%, 95% CI=1.3 to 1.6) and male (APC=1.4%, 95% CI=1.3 to 1.6) hospitalizations. The annual increase among assault/legal injuries was 1.4% (95% CI=1.3 to 1.5), similar to unintentional (APC=1.4%, 95% CI=1.3 to 1.6), intentional self-harm (APC=1.5%, 95% CI=1.4 to 1.6) and undetermined (APC=1.4%, 95% CI=1.3 to 1.6)., Conclusions: The severity of hospitalized firearm injuries increased significantly from 1993 to 2014. This annual increase reflects a move towards hospitalization of more serious injuries, and outpatient management of less serious injuries across the board, suggesting a mounting burden on the US healthcare system., Level of Evidence: Level IV., Competing Interests: Competing interests: None declared.

Glioma is a unique neoplastic disease that develops exclusively in the central nervous system (CNS) and rarely metastasizes to other tissues. This feature strongly implicates the tumor-host CNS microenvironment in gliomagenesis and tumor progression. We investigated the differences and similarities in glioma biology as conveyed by transcriptomic patterns across four mammalian hosts: rats, mice, dogs, and humans. Given the inherent intra-tumoral molecular heterogeneity of human glioma, we focused this study on tumors with upregulation of the platelet-derived growth factor signaling axis, a common and early alteration in human gliomagenesis. The results reveal core neoplastic alterations in mammalian glioma, as well as unique contributions of the tumor host to neoplastic processes. Notable differences were observed in gene expression patterns as well as related biological pathways and cell populations known to mediate key elements of glioma biology, including angiogenesis, immune evasion, and brain invasion. These data provide new insights regarding mammalian models of human glioma, and how these insights and models relate to our current understanding of the human disease.

Introduction: Multiple myeloma (MM) is an incurable plasma cell malignancy, in which aggressive relapses might require salvage cytotoxic infusional chemotherapy. Several clinical trials that reported the efficacy of bortezomib led to institutional practice changes in which vincristine was replaced with bortezomib in the modified hyperCVAD regimen, creating a new treatment regimen, named "bortezomib-hyperCAD.", Patients and Methods: We retrospectively describe the effectiveness and tolerability of 2 chemotherapy regimens among 33 patients with relapsed and/or refractory MM. Patients who received ≥ 1 cycle of modified hyperCVAD or bortezomib-hyperCAD between 2011 and 2015 were assessed., Results: The median number of cycles administered in each arm was 2. The overall response rate was 40% (6 partial responses) in the modified hyperCVAD group and 44.4% (1 complete response, 1 very good partial response, and 6 partial responses) in the bortezomib-hyperCAD group (Fisher exact P = .80). Median progression-free survival (PFS) and median overall survival (OS) for patients in the modified hyperCVAD group was 6.3 months and 11.1 months, respectively. This was comparable with patients in the bortezomib-hyperCAD group, who had a median PFS of 6.6 months and a median OS of 13.8 months (log rank P = .54 and .66, respectively). There was no statistically significant association between treatment arm and febrile neutropenia, emergency department visits, hospitalizations, or peripheral neuropathy (all Fisher exact P values > .05)., Conclusion: Overall effectiveness and tolerability outcomes were similar between modified hyperCVAD and bortezomib-hyperCAD, with both regimens showing an impressive response rate among refractory and heavily pretreated patients with relapsed MM., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Prognosis remains poor despite multimodal therapy. Developing alternative treatments is essential. Drugs targeting kinases within the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) effectors of receptor tyrosine kinase (RTK) signaling represent promising candidates., Methods: We previously developed a non-germline genetically engineered mouse model of GBM in which PI3K and MAPK are activated via Pten deletion and KrasG12D in immortalized astrocytes. Using this model, we examined the influence of drug potency on target inhibition, alternate pathway activation, efficacy, and synergism of single agent and combination therapy with inhibitors of these 2 pathways. Efficacy was then examined in GBM patient-derived xenografts (PDX) in vitro and in vivo., Results: PI3K and mitogen-activated protein kinase kinase (MEK) inhibitor potency was directly associated with target inhibition, alternate RTK effector activation, and efficacy in mutant murine astrocytes in vitro. The kinomes of GBM PDX and tumor samples were heterogeneous, with a subset of the latter harboring MAPK hyperactivation. Dual PI3K/MEK inhibitor treatment overcame alternate effector activation, was synergistic in vitro, and was more effective than single agent therapy in subcutaneous murine allografts. However, efficacy in orthotopic allografts was minimal. This was likely due to dose-limiting toxicity and incomplete target inhibition., Conclusion: Drug potency influences PI3K/MEK inhibitor-induced target inhibition, adaptive kinome reprogramming, efficacy, and synergy. Our findings suggest that combination therapies with highly potent, brain-penetrant kinase inhibitors will be required to improve patient outcomes., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: Triple-negative breast cancer (TNBC), lacking expression of hormone and human epidermal growth factor receptor 2 receptors, is an aggressive subtype that frequently metastasizes to the brain and has no FDA-approved systemic therapies. Previous literature demonstrates mitogen-activated protein kinase kinase (MEK) pathway activation in TNBC brain metastases. Thus, we aimed to discover rational combinatorial therapies with MEK inhibition, hypothesizing that co-inhibition using clinically available brain-penetrant inhibitors would improve survival in preclinical models of TNBC brain metastases., Methods: Using human-derived TNBC cell lines, synthetic lethal small interfering RNA kinase screens were evaluated with brain-penetrant inhibitors against MEK1/2 (selumetinib, AZD6244) or phosphatidylinositol-3 kinase (PI3K; buparlisib, BKM120). Mice bearing intracranial TNBC tumors (SUM149, MDA-MB-231Br, MDA-MB-468, or MDA-MB-436) were treated with MEK, PI3K, or platelet derived growth factor receptor (PDGFR; pazopanib) inhibitors alone or in combination. Tumors were analyzed by western blot and multiplexed kinase inhibitor beads/mass spectrometry to assess treatment effects., Results: Screens identified MEK+PI3K and MEK+PDGFR inhibitors as tractable, rational combinations. Dual treatment of selumetinib with buparlisib or pazopanib was synergistic in TNBC cells in vitro. Both combinations improved survival in intracranial SUM149 and MDA-MB-231Br, but not MDA-MB-468 or MDA-MB-436. Treatments decreased mitogen-activated protein kinase (MAPK) and PI3K (Akt) signaling in sensitive (SUM149 and 231Br) but not resistant models (MDA-MB-468). Exploratory analysis of kinome reprogramming in SUM149 intracranial tumors after MEK ± PI3K inhibition demonstrates extensive kinome changes with treatment, especially in MAPK pathway members., Conclusions: Results demonstrate that rational combinations of the clinically available inhibitors selumetinib with buparlisib or pazopanib may prove to be promising therapeutic strategies for the treatment of some TNBC brain metastases. Additionally, effective combination treatments cause widespread alterations in kinase pathways, including targetable potential resistance drivers., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: Gliomas are diverse neoplasms with multiple molecular subtypes. How tumor-initiating mutations relate to molecular subtypes as these tumors evolve during malignant progression remains unclear., Methods: We used genetically engineered mouse models, histopathology, genetic lineage tracing, expression profiling, and copy number analyses to examine how genomic tumor diversity evolves during the course of malignant progression from low- to high-grade disease., Results: Knockout of all 3 retinoblastoma (Rb) family proteins was required to initiate low-grade tumors in adult mouse astrocytes. Mutations activating mitogen-activated protein kinase signaling, specifically KrasG12D, potentiated Rb-mediated tumorigenesis. Low-grade tumors showed mutant Kras-specific transcriptome profiles but lacked copy number mutations. These tumors stochastically progressed to high-grade, in part through acquisition of copy number mutations. High-grade tumor transcriptomes were heterogeneous and consisted of 3 subtypes that mimicked human mesenchymal, proneural, and neural glioblastomas. Subtypes were confirmed in validation sets of high-grade mouse tumors initiated by different driver mutations as well as human patient-derived xenograft models and glioblastoma tumors., Conclusion: These results suggest that oncogenic driver mutations influence the genomic profiles of low-grade tumors and that these, as well as progression-acquired mutations, contribute strongly to the genomic heterogeneity across high-grade tumors., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Although targeted therapies are often effective systemically, they fail to adequately control brain metastases. In preclinical models of breast cancer that faithfully recapitulate the disparate clinical responses in these microenvironments, we observed that brain metastases evade phosphatidylinositide 3-kinase (PI3K) inhibition despite drug accumulation in the brain lesions. In comparison to extracranial disease, we observed increased HER3 expression and phosphorylation in brain lesions. HER3 blockade overcame the resistance of HER2 -amplified and/or PIK3CA -mutant breast cancer brain metastases to PI3K inhibitors, resulting in marked tumor growth delay and improvement in mouse survival. These data provide a mechanistic basis for therapeutic resistance in the brain microenvironment and identify translatable treatment strategies for HER2 -amplified and/or PIK3CA -mutant breast cancer brain metastases., (Copyright © 2017, American Association for the Advancement of Science.)

Changes in the quantity of genetic material, known as somatic copy number alterations (CNAs), can drive tumorigenesis. Many methods exist for assessing CNAs using microarrays, but considerable technical issues limit current CNA calling based upon DNA sequencing. We present SynthEx, a novel tool for detecting CNAs from whole exome and genome sequencing. SynthEx utilizes a "synthetic-normal" strategy to overcome technical and financial issues. In terms of accuracy and precision, SynthEx is highly comparable to array-based methods and outperforms sequencing-based CNA detection tools. SynthEx robustly identifies CNAs using sequencing data without the additional costs associated with matched normal specimens.

Investigating firearm injury trends over the past decade, we examined temporal trends overall and according to race/ethnicity and intent in fatal and nonfatal firearm injuries (FFIs and NFIs) in United States during 2001-2013. Counts of FFIs and estimated counts of NFIs were obtained from the Centers for Disease Control and Prevention's Web-based Injury Statistics Query and Reporting System. Poisson regression was used to analyze overall and subgroup temporal trends and to estimate annual change per 100,000 persons (change). Total firearm injuries (n = 1,328,109) increased annually by 0.36 (Ptrend < 0.0001). FFIs remained constant (change = 0.02; Ptrend = 0.22) while NFIs increased (change = 0.35; Ptrend < 0.0001). Homicide FFIs declined (change = -0.05; Ptrend < 0.0001) while homicide NFIs increased (change = 0.43; Ptrend < 0.0001). Suicide FFIs increased (change = 0.07; Ptrend < 0.0001) while unintentional FFIs and NFIs declined (changes = -0.01 and -0.09, respectively; Ptrend < 0.0001 and 0.005). Among whites, FFIs (change = 0.15; Ptrend < 0.0001) and NFIs (change = 0.13; Ptrend < 0.0001) increased; among blacks, FFIs declined (change = -0.20; Ptrend < 0.0001). Among Hispanics, FFIs declined (change = -0.28; Ptrend < 0.0001) while NFIs increased (change = 0.55; Ptrend = 0.014). The endemic firearm-related injury rates during the first decade of the 21st century mask a shift from firearm deaths towards a rapid rise in nonfatal injuries., (© The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Orphan GPCRs provide an opportunity to identify potential pharmacological targets, yet their expression patterns and physiological functions remain challenging to elucidate. Here, we have used a genetically engineered knockin reporter mouse to map the expression pattern of the Gpr182 during development and adulthood. We observed that Gpr182 is expressed at the crypt base throughout the small intestine, where it is enriched in crypt base columnar stem cells, one of the most active stem cell populations in the body. Gpr182 knockdown had no effect on homeostatic intestinal proliferation in vivo, but led to marked increases in proliferation during intestinal regeneration following irradiation-induced injury. In the ApcMin mouse model, which forms spontaneous intestinal adenomas, reductions in Gpr182 led to more adenomas and decreased survival. Loss of Gpr182 enhanced organoid growth efficiency ex vivo in an EGF-dependent manner. Gpr182 reduction led to increased activation of ERK1/2 in basal and challenge models, demonstrating a potential role for this orphan GPCR in regulating the proliferative capacity of the intestine. Importantly, GPR182 expression was profoundly reduced in numerous human carcinomas, including colon adenocarcinoma. Together, these results implicate Gpr182 as a negative regulator of intestinal MAPK signaling-induced proliferation, particularly during regeneration and adenoma formation., Competing Interests: The authors have declared that no conflict of interest exists.

Introduction: Obesity is a pervasive public health problem in the U.S. Reducing soda consumption is important for stemming the obesity epidemic. However, several articles and one book suggest that soda companies are using their resources to impede public health interventions that might reduce soda consumption. Although corporate sponsorship by tobacco and alcohol companies has been studied extensively, there has been no systematic attempt to catalog sponsorship activities of soda companies. This study investigates the nature, extent, and implications of soda company sponsorship of U.S. health and medical organizations, as well as corporate lobbying expenditures on soda- or nutrition-related public health legislation from 2011 to 2015., Methods: Records of corporate philanthropy and lobbying expenditures on public health legislation by soda companies in the U.S. during 2011-2015 were found through Internet and database searches., Results: From 2011 to 2015, the Coca-Cola Company and PepsiCo were found to sponsor a total of 95 national health organizations, including many medical and public health institutions whose specific missions include fighting the obesity epidemic. During the study period, these two soda companies lobbied against 29 public health bills intended to reduce soda consumption or improve nutrition., Conclusions: There is surprisingly pervasive sponsorship of national health and medical organizations by the nation's two largest soda companies. These companies lobbied against public health intervention in 97% of cases, calling into question a sincere commitment to improving the public's health. By accepting funding from these companies, health organizations are inadvertently participating in their marketing plans., (Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Metastasis is the main cause of cancer patient deaths and remains a poorly characterized process. It is still unclear when in tumor progression the ability to metastasize arises and whether this ability is inherent to the primary tumor or is acquired well after primary tumor formation. Next-generation sequencing and analytical methods to define clonal heterogeneity provide a means for identifying genetic events and the temporal relationships between these events in the primary and metastatic tumors within an individual., Methods and Findings: We performed DNA whole genome and mRNA sequencing on two primary tumors, each with either four or five distinct tissue site-specific metastases, from two individuals with triple-negative/basal-like breast cancers. As evidenced by their case histories, each patient had an aggressive disease course with abbreviated survival. In each patient, the overall gene expression signatures, DNA copy number patterns, and somatic mutation patterns were highly similar across each primary tumor and its associated metastases. Almost every mutation found in the primary was found in a metastasis (for the two patients, 52/54 and 75/75). Many of these mutations were found in every tumor (11/54 and 65/75, respectively). In addition, each metastasis had fewer metastatic-specific events and shared at least 50% of its somatic mutation repertoire with the primary tumor, and all samples from each patient grouped together by gene expression clustering analysis. TP53 was the only mutated gene in common between both patients and was present in every tumor in this study. Strikingly, each metastasis resulted from multiclonal seeding instead of from a single cell of origin, and few of the new mutations, present only in the metastases, were expressed in mRNAs. Because of the clinical differences between these two patients and the small sample size of our study, the generalizability of these findings will need to be further examined in larger cohorts of patients., Conclusions: Our findings suggest that multiclonal seeding may be common amongst basal-like breast cancers. In these two patients, mutations and DNA copy number changes in the primary tumors appear to have had a biologic impact on metastatic potential, whereas mutations arising in the metastases were much more likely to be passengers., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: CMP is an equity stock holder of BioClassifier LLC and University Genomics, and ERM, CMP, and JSP have filed a patent on the PAM50 subtyping assay. ERM served as guest editor on PLOS Medicine’s Special Issue on Cancer Genomics.

Objective: Although studies demonstrate that exposure to brand-specific alcohol advertising is associated with an increased likelihood of youth consuming particular brands, the relationship between quantity of brand-specific advertising exposure and quantity of brand-specific consumption has not been firmly established., Method: Using the Alcohol Brand Research Among Underage Drinkers (ABRAND) national sample of 1,031 young drinkers (ages 13-20), this study examined the relationship between their aggregated past-year exposure to advertising (in adstock units, a measure based on gross rating points) for 61 alcohol brands that advertised on the 20 most popular nonsports television programs viewed by underage youth and their aggregated total consumption of those same brands during the past 30 days. Predictive models adjusted for other media exposure, predictors of youth's alcohol consumption, and the consumption of brands not advertised on the 20 shows., Results: For the fully adjusted models, each 100 adstock unit increase in exposure (about 1 SD) was associated with an increase of 5.9 drinks (95% CI [0.9, 11.0 drinks]) consumed during the past 30 days among those with less than 300 units of advertising exposure, and an increase of 55.7 drinks (95% CI [13.9, 97.4 drinks]) among those with 300 or more adstock units of exposure., Conclusions: Among underage youth, the quantity of brand-specific advertising exposure is positively associated with the total quantity of consumption of those advertised brands, even after controlling for the consumption of non-advertised brands. Future research should examine exposure-consumption relationships longitudinally and in other media.

Background: Alcohol research focused on underage drinkers has not comprehensively assessed the landscape of brand-level drinking behaviors among youth. This information is needed to profile youth alcohol use accurately, explore its antecedents, and develop appropriate interventions., Methods: We collected national data on the alcohol brand-level consumption of underage drinkers in the United States and then examined the association between those preferences and several factors including youth exposure to brand-specific alcohol advertising, corporate sponsorships, popular music lyrics, and social networking sites, and alcohol pricing. This paper summarizes our findings, plus the results of other published studies on alcohol branding and youth drinking., Results: Our findings revealed several interesting facts regarding youth drinking. For example, we found that: 1) youth are not drinking the cheapest alcohol brands; 2) youth brand preferences differ from those of adult drinkers; 3) underage drinkers are not opportunistic in their alcohol consumption, but instead consume a very specific set of brands; 4) the brands that youth are heavily exposed to in magazines and television advertising correspond to the brands they most often report consuming; and 5) youth consume more of the alcohol brands to whose advertising they are most heavily exposed., Conclusion: The findings presented here suggests that brand-level alcohol research will provide important insight into youth drinking behaviors, the factors that contribute to youth alcohol consumption, and potential avenues for effective public health surveillance and programming.

Purpose: Despite significant therapeutic progress in multiple myeloma, drug resistance is uniformly inevitable and new treatments are needed. Our aim was to identify novel, efficacious small-molecule combinations for use in drug resistant multiple myeloma., Experimental Design: A panel of 116 small molecule inhibitors was used to screen resistant myeloma cell lines for potential therapeutic targets. Agents found to have enhanced activity in the bortezomib or melphalan resistant myeloma cell lines were investigated further in combination. Synergistic combinations of interest were evaluated in primary patient cells., Results: The overall single-agent drug sensitivity profiles were dramatically different between melphalan and bortezomib resistant cells, however, the bromodomain inhibitor, CPI203, was observed to have enhanced activity in both the bortezomib and melphalan resistant lines compared to their wild-type counterparts. The combination of bortezomib and CPI203 was found to be synergistic in both the bortezomib and melphalan resistant cell lines as well as in a primary multiple myeloma sample from a patient refractory to recent proteasome inhibitor treatment. The CPI203-bortezomib combination led to enhanced apoptosis and anti-proliferative effects. Finally, in contrast to prior reports of synergy between bortezomib and other epigenetic modifying agents, which implicated MYC downregulation or NOXA induction, our analyses suggest that CPI203-bortezomib synergy is independent of these events., Conclusion: Our preclinical data supports a role for the clinical investigation of the bromodomain inhibitor CPI203 combined with bortezomib or alkylating agents in resistant multiple myeloma.

The recent FDA approval of the MiSeqDx platform provides a unique opportunity to develop targeted next generation sequencing (NGS) panels for human disease, including cancer. We have developed a scalable, targeted panel-based assay termed UNCseq, which involves a NGS panel of over 200 cancer-associated genes and a standardized downstream bioinformatics pipeline for detection of single nucleotide variations (SNV) as well as small insertions and deletions (indel). In addition, we developed a novel algorithm, NGScopy, designed for samples with sparse sequencing coverage to detect large-scale copy number variations (CNV), similar to human SNP Array 6.0 as well as small-scale intragenic CNV. Overall, we applied this assay to 100 snap-frozen lung cancer specimens lacking same-patient germline DNA (07-0120 tissue cohort) and validated our results against Sanger sequencing, SNP Array, and our recently published integrated DNA-seq/RNA-seq assay, UNCqeR, where RNA-seq of same-patient tumor specimens confirmed SNV detected by DNA-seq, if RNA-seq coverage depth was adequate. In addition, we applied the UNCseq assay on an independent lung cancer tumor tissue collection with available same-patient germline DNA (11-1115 tissue cohort) and confirmed mutations using assays performed in a CLIA-certified laboratory. We conclude that UNCseq can identify SNV, indel, and CNV in tumor specimens lacking germline DNA in a cost-efficient fashion.

Purpose: The purpose of this study was to identify reasons why youth choose to drink specific brands of alcohol and to determine if these reasons are associated with problem drinking patterns and outcomes., Methods: We conducted an Internet survey of 1,031 youth aged 13-20 years who reported drinking within the past 30 days. Of these, 541 youth who reported having a choice of multiple brands of alcohol the last time they drank stated (yes/no) whether each of 16 different reasons had influenced their choice of a specific brand. We reduced these 16 reasons to three principal components and used latent class modeling to identify five groups of youth with similar reasons for selecting a brand, which we then profiled., Results: We grouped respondents into the following brand selection groups: "Brand Ambassadors" who were distinguished from other clusters by selecting a brand because they identified with it (32.5% of respondents), "Tasters" who selected a brand because they expected it to taste good (27.2%), "Bargain Hunters" who selected a brand because it was inexpensive (18.5%), "Copycats" who selected a brand because they had seen adults drinking it or seen it consumed in movies or other media (10.4%), and "Others" (11.5%). Brand ambassadors and copycats reported the largest amount of alcohol consumed and had the greatest prevalence of both heavy episodic drinking and negative alcohol-related health consequences., Conclusions: Underage drinkers who cite marketing influences and adult or media modeling of brand choices as their reasons for selecting alcohol brands are likely to drink more and incur adverse consequences from drinking., (Copyright © 2015 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Patients with breast cancer brain metastases have extremely limited survival and no approved systemic therapeutics. Triple-negative breast cancer (TNBC) commonly metastasizes to the brain and predicts poor prognosis. TNBC frequently harbors BRCA mutations translating to platinum sensitivity potentially augmented by additional suppression of DNA repair mechanisms through PARP inhibition. We evaluated brain penetrance and efficacy of carboplatin ± the PARP inhibitor ABT888, and investigated gene-expression changes in murine intracranial TNBC models stratified by BRCA and molecular subtype status. Athymic mice were inoculated intracerebrally with BRCA-mutant: SUM149 (basal), MDA-MB-436 (claudin-low); or BRCA-wild-type (wt): MDA-MB-468 (basal), MDA-MB-231BR (claudin-low). TNBC cells were treated with PBS control [intraperitoneal (IP), weekly], carboplatin (50 mg/kg/wk, IP), ABT888 (25 mg/kg/d, oral gavage), or their combination. DNA damage (γ-H2AX), apoptosis (cleaved caspase-3, cC3), and gene expression were measured in intracranial tumors. Carboplatin ± ABT888 significantly improved survival in BRCA-mutant intracranial models compared with control, but did not improve survival in BRCA-wt intracranial models. Carboplatin + ABT888 revealed a modest survival advantage versus carboplatin in BRCA-mutant models. ABT888 yielded a marginal survival benefit in the MDA-MB-436, but not in the SUM149 model. BRCA-mutant SUM149 expression of γ-H2AX and cC3 proteins was elevated in all treatment groups compared with control, whereas BRCA-wt MDA-MB-468 cC3 expression did not increase with treatment. Carboplatin treatment induced common gene-expression changes in BRCA-mutant models. Carboplatin ± ABT888 penetrates the brain and improves survival in BRCA-mutant intracranial TNBC models with corresponding DNA damage and gene-expression changes. Combination therapy represents a potential promising treatment strategy for patients with TNBC brain metastases warranting further clinical investigation., (©2015 American Association for Cancer Research.)

Background: A significant body of research has demonstrated an association between adolescent alcohol consumption and subsequent fights and injuries. To date, however, no research has identified which brands are associated with alcohol-related fights and injuries among underage drinkers., Objectives: We aimed to: (1) report the prevalence of alcohol-related fights and injuries among a national sample of underage drinkers in the U.S. and (2) describe the relationship between specific alcohol brand consumption and these alcohol-related negative consequences., Methods: We recruited 1,031 self-reported drinkers (ages 13-20 years) via an internet panel maintained by Knowledge Networks to complete an online survey. Respondents reported their past-month overall and brand-specific alcohol consumption, risky drinking behavior, and past-year alcohol-related fights and injuries., Results: Over one-quarter of the respondents (26.7%, N = 232) reported at least one alcohol-related fight or injury in the past year. Heavy episodic drinkers were over six times more likely to report one of these negative alcohol-related consequences (AOR: 6.4, 95% CI: 4.1-9.9). Respondents of black race and those from higher-income households were also significantly more likely to report that experience (AOR: 2.2, 95% CI: 1.3-3.7; AOR: 1.8, 95% CI: 1.1-3.0 and 1.1-3.2, respectively). We identified eight alcohol brands that were significantly associated with alcohol-related fights and injuries. CONCLUSIONS/IMPORTANCE: Alcohol-related fights and injuries were frequently reported by adolescent respondents. Eight alcohol brands were significantly more popular among drinkers who experienced these adverse consequences. These results point to the need for further research on brand-specific correlates of underage drinking and negative health outcomes.

Background: Adolescent alcohol consumption remains common and is associated with many negative health outcomes. Unfortunately, common alcohol surveillance methods often underestimate consumption. Improved alcohol use measures are needed to characterize the landscape of youth drinking., Objectives: We aimed to compare a standard quantity-frequency measure of youth alcohol consumption to a novel brand-specific measure., Methods: We recruited a sample of 1031 respondents across the United States to complete an online survey. Analyses included 833 male and female underage drinkers ages 13-20. Respondents reported on how many of the past 30 days they consumed alcohol, and the number of drinks consumed on an average drinking day. Using our brand-specific measure, respondents identified which brands they consumed, how many days they consumed each brand, and how many drinks per brand they usually had., Results: Youth reported consuming significantly more alcohol (on average, 11 drinks more per month) when responding to the brand-specific versus the standard measure (p < 0.001). The two major predictors of the difference between the two measures were being a heavy episodic drinker (p < 0.001, 95% CI = 4.1-12.0) and the total number of brands consumed (p < 0.001, 95% CI = 2.0-2.8)., Conclusion: This study contributes to the field of alcohol and adolescent research first by investigating a potentially more accurate alcohol surveillance method, and secondly by promoting the assessment of alcohol use among adolescents vulnerable to risky alcohol use. Finally, our survey addresses the potential impact of alcohol marketing on youth and their subsequent alcohol brand preferences and consumption.

Aims: We aimed to describe the sources from which youth in the USA commonly obtain alcohol, their role in selecting the brands they drink and the relationship of these variables to their indicated alcohol brand preferences., Methods: We recruited 1031 underage drinkers in the age range of 13-20 through an internet panel managed by Knowledge Networks. Respondents completed an online survey assessing their recent brand-specific alcohol use, the source of their most recently consumed alcohol and whether the respondent or another person selected the brand they drank., Results: Alcohol sources were more often passive than transactional. Nearly equal proportions of youth reported that they did versus did not choose the brand of their most recent drink. Analysis revealed that the brand preferences of passive versus active source drinkers were highly similar, as were the brand preferences of respondent versus non-respondent choice drinkers. Stratification of respondents by age did not significantly change these results., Conclusion: Our findings suggest that youth are consuming a homogenous list of preferred brands regardless of the source of their most recently obtained alcohol or who selected the brand they drank., (© The Author 2014. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Objective: Recently published research has identified the alcohol brands most frequently consumed by underage youth. The present study examines alcohol magazine advertising in 2011 to report age- and sex-specific exposure to advertisements for these brands in contrast with other magazine advertising brands less popular with youth., Method: We licensed magazine advertising occurrence data from Nielsen and magazine audience data from the research company GfK MRI (Growth from Knowledge, Mediamark Research & Intelligence) for national full-run editions for 2011. We contrasted per capita advertising exposure, considering different age- and sex-specific groups, for popular youth brands versus all other magazine brands. For each brand, we reported the age group receiving the highest level of per capita advertising exposure, as well as other age groups within 10% of that peak level., Results: Underage males ages 18-20 were the most heavily exposed age group for 11 of the top 25 brands they consumed and were within 10% of the most heavily exposed group for another 6 brands. Underage females ages 18-20 were most heavily exposed for 16 of the top 25 brands they consumed and were within 10% of the most heavily exposed group for another 2 brands. In contrast, those ages 18-20 were the most heavily exposed group for fewer than 10% of the remaining 308 magazine advertising brands for either sex., Conclusions: These findings suggest a relationship between advertising exposure and youth alcohol brand consumption. Current alcohol industry self-regulatory codes may not be sufficiently protective of youth.

Brain metastases remain a significant challenge in the treatment of breast cancer patients due to the unique environment posed by the central nervous system. A better understanding of the biology of breast cancer cells that have metastasized to the brain is required to develop improved therapies. A recent Proceedings of the National Academy of Sciences article demonstrates that breast cancer cells in the brain microenvironment express γ-aminobutyric acid (GABA)-related genes, enabling them to utilize GABA as an oncometabolite, thus gaining a proliferative advantage. In this viewpoint, we highlight these findings and their potential impact on the treatment of breast cancer brain metastases.

Introduction: This study examined changes in smokers' readiness and confidence to quit smoking, smoking behavior, nicotine withdrawal symptoms, and tobacco product preference following electronic cigarette (EC) experimentation and 1 week of ad libitum use., Methods: Current cigarette smokers, with no prior use of ECs and uninterested in quitting, completed 3 study phases: baseline assessment (N = 20), experimentation (N = 19), and ad libitum use (N = 16). Baseline assessment consisted of completion of assessment measures and exhaled carbon monoxide measurements. Experimentation phases consisted of four, 75-min sessions in which participants completed assessment measures and sampled 3 EC brands and their own brand of cigarette (OBC). Ad libitum use included participants selecting and being provided their preferred EC brand from the experimentation phase to be used "as you want" for 1 week. Outcome measures included readiness and confidence to quit smoking, nicotine withdrawal symptoms, product preference/satisfaction, and smoking behavior items., Results: Readiness and confidence to quit increased significantly during the experimentation period and continued to increase during ad libitum use. There were no significant differences in reported effectiveness in reducing smoking urges and cravings between OBC and EC though OBC were rated as more enjoyable and satisfying. During ad libitum use, regular cigarette smoking decreased by approximately 44% from baseline levels with overall tobacco use (EC + OBC) remaining the same., Conclusions: Among a small convenience sample of unmotivated cigarette smokers, EC experimentation and 1 week of ad libitum use increased readiness and confidence to quit regular cigarettes and reduced regular cigarette smoking.

Malignant melanoma is characterized by a propensity for early lymphatic and hematogenous spread. The hypoxia-inducible factor (HIF) family of transcription factors is upregulated in melanoma by key oncogenic drivers. HIFs promote the activation of genes involved in cancer initiation, progression, and metastases. Hypoxia has been shown to enhance the invasiveness and metastatic potential of tumor cells by regulating the genes involved in the breakdown of the ECM as well as genes that control motility and adhesion of tumor cells. Using a Pten-deficient, Braf-mutant genetically engineered mouse model of melanoma, we demonstrated that inactivation of HIF1α or HIF2α abrogates metastasis without affecting primary tumor formation. HIF1α and HIF2α drive melanoma invasion and invadopodia formation through PDGFRα and focal adhesion kinase-mediated (FAK-mediated) activation of SRC and by coordinating ECM degradation via MT1-MMP and MMP2 expression. These results establish the importance of HIFs in melanoma progression and demonstrate that HIF1α and HIF2α activate independent transcriptional programs that promote metastasis by coordinately regulating cell invasion and ECM remodeling.

In the United States, several states have made policy decisions regarding whether and how to use familial searching of the Combined DNA Index System (CODIS) database in criminal investigations. Familial searching pushes DNA typing beyond merely identifying individuals to detecting genetic relatedness, an application previously reserved for missing persons identifications and custody battles. The intentional search of CODIS for partial matches to an item of evidence offers law enforcement agencies a powerful tool for developing investigative leads, apprehending criminals, revitalizing cold cases and exonerating wrongfully convicted individuals. As familial searching involves a range of logistical, social, ethical and legal considerations, states are now grappling with policy options for implementing familial searching to balance crime fighting with its potential impact on society. When developing policies for familial searching, legislators should take into account the impact of familial searching on select populations and the need to minimize personal intrusion on relatives of individuals in the DNA database. This review describes the approaches used to narrow a suspect pool from a partial match search of CODIS and summarizes the economic, ethical, logistical and political challenges of implementing familial searching. We examine particular US state policies and the policy options adopted to address these issues. The aim of this review is to provide objective background information on the controversial approach of familial searching to inform policy decisions in this area. Herein we highlight key policy options and recommendations regarding effective utilization of familial searching that minimize harm to and afford maximum protection of US citizens.

Background: Electronic cigarettes (e-cigarettes) are battery-powered devices that deliver nicotine without any combustion or smoke. These devices have generated much publicity among the smoking-cessation community and support from dedicated users; however, little is known about the efficacy of the device as a smoking-cessation tool., Purpose: This study aimed to examine the effectiveness of e-cigarettes for smoking cessation using a survey of smokers who had tried e-cigarettes., Methods: Using as a sampling frame a cohort of all first-time purchasers of a particular brand of e-cigarettes during a 2-week period, a cross-sectional, online survey was conducted in 2010 to describe e-cigarette use patterns and their effectiveness as a smoking-cessation tool. There were 222 respondents, with a survey response rate of 4.5%. The primary outcome variable was the point prevalence of smoking abstinence at 6 months after initial e-cigarette purchase., Results: The primary finding was that the 6-month point prevalence of smoking abstinence among the e-cigarette users in the sample was 31.0% (95% CI=24.8%, 37.2%). A large percentage of respondents reported a reduction in the number of cigarettes they smoked (66.8%) and almost half reported abstinence from smoking for a period of time (48.8%). Those respondents using e-cigarettes more than 20 times per day had a quit rate of 70.0%. Of respondents who were not smoking at 6 months, 34.3% were not using e-cigarettes or any nicotine-containing products at the time., Conclusions: Findings suggest that e-cigarettes may hold promise as a smoking-cessation method and that they are worthy of further study using more-rigorous research designs., (Copyright © 2011 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Very little is known about the types of alcoholic beverages preferred by youth in the U.S. and the relationship between beverage preference and demographic and behavioral characteristics of these youth., Purpose: To determine the type of alcoholic beverages consumed by adolescent drinkers and how it varies by drinking patterns., Methods: In 2010, an analysis was performed using 2007 data from the Youth Risk Behavior Survey (YRBS) conducted among public school students in eight states that included a question on the type of alcohol usually consumed. Analysis was restricted to the 7723 youth who reported consuming at least one drink of alcohol in the past 30 days. Beverage type preferences were analyzed by demographic factors, drinking patterns, and other health-risk behaviors. Logistic regression analyses were conducted to examine the correlates of type-specific alcohol consumption., Results: Liquor was the strongly preferred alcoholic beverage of choice (43.8%), followed by beer (19.2%) and malt beverages (17.4%), with a very low preference for wine (3.7%) or wine coolers (3.4%). A higher preference for liquor or beer was observed among older youth, among those with a riskier pattern of alcohol consumption (e.g., greater frequency of consumption, binge drinking, or drinking and driving), and among youth who engaged in other risk behaviors., Conclusions: Riskier patterns of drinking and other health-risk behaviors are associated with an increased preference for hard liquor and beer. Improved surveillance of alcoholic beverage preferences among youth will enable a better understanding of the factors related to youth drinking, allowing the development of more effective interventions., (Copyright © 2011 American Journal of Preventive Medicine. All rights reserved.)

Objective: To test whether community-level restrictions on youth access to tobacco (including both ordinances and enforcement) are associated with less smoking initiation or less progression to established smoking among adolescents., Design: Prospective cohort study of a random sample of adolescents in Massachusetts whose smoking status was assessed by telephone interviews at baseline and 2-year follow-up, and linked to a state-wide database of town-level youth-access ordinances and enforcement practices., Participants: A random sample of 2623 adolescents aged 12-17 years who lived in 295 towns in Massachusetts in 2001-2 and were followed in 2003-4., Main Outcome Measures: The relationship between the strength of local youth access restrictions (including both ordinances and level of enforcement) and (1) never-smokers' smoking initiation rates and (2) experimenters' rate of progression to established smoking was tested in a multilevel analysis that accounted for town-level clustering and adjusted for potential individual, household and town-level confounders., Results: Over 2 years, 21% of 1986 never-smokers initiated smoking and 25% of 518 experimenters became established smokers. The adjusted odds ratio (OR) for smoking initiation was 0.89 (95% CI 0.61 to 1.31) for strong versus weak youth-access policies and 0.93 (95% CI 0.67 to 1.29) for medium versus weak policies. The adjusted OR for progression to established smoking among adolescents who had experimented with smoking was 0.79 (95% CI 0.45 to 1.39) for strong versus weak local smoking restrictions and 0.85 (95% CI 0.50 to 1.45) for medium versus weak restrictions., Conclusions: This prospective cohort study found no association between community-level youth-access restrictions and adolescents' rate of smoking initiation or progression to established smoking over 2 years.

Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is a diarrheal pathogen that causes attaching and effacing (A/E) lesions on intestinal epithelial cells. Strains of the O157 serogroup carry the large virulence plasmid pO157, which encodes the etp type II secretion system that secretes the genetically linked zinc metalloprotease StcE. The Ler regulator controls expression of many genes involved in A/E lesion formation, as well as StcE, suggesting StcE may be important at a similar time during colonization. Our laboratory has previously demonstrated that StcE cleaves C1-esterase inhibitor, a regulator of multiple inflammation pathways. Here we report two new substrates for StcE, mucin 7 and glycoprotein 340, and that purified StcE reduces the viscosity of human saliva. We tested the hypothesis that StcE contributes to intimate adherence of EHEC to host cells by cleavage of glycoproteins from the cell surface. The fluorescent actin stain (FAS) test was used to observe the intimate adherence represented by fluorescently stained bacteria colocalized with regions of bundled actin formed on HEp-2 cells. An E. coli O157:H7 strain with a stcE gene deletion was not affected in its ability to generally adhere to HEp-2 cells, but it did score threefold lower on the FAS test than wild-type or complemented strains. Addition of exogenous recombinant StcE increased intimate adherence of the mutant to wild-type levels. Thus, StcE may help block host clearance of E. coli O157:H7 by destruction of some classes of glycoproteins, and it contributes to intimate adherence of E. coli O157:H7 to the HEp-2 cell surface.