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Ligand binding hotspots are regions of protein surfaces that form particularly favourable interactions with small molecule pharmacophores. Targeting interactions with these hotspots maximises the efficiency of ligand binding. Existing methods are capable of identifying hotspots but often lack assays to quantify ligand binding and direct elaboration at these sites. Herein, we describe a fragment‐based competitive 19F Ligand Based NMR (LB‐NMR) screening platform that enables routine, quantitative ligand profiling focused at ligand‐binding hotspots. As a proof of concept, the method was applied to 4′‐phosphopantetheine adenylyltransferase (PPAT) from Mycobacterium abscessus (Mabs). X‐ray crystallographic characterisation of the hits from a 960‐member fragment screen identified three ligand‐binding hotspots across the PPAT active site. From the fragment hits a collection of 19F reporter candidates were designed and synthesised. By rigorous prioritisation and use of optimisation workflows, a single 19F reporter molecule was generated for each hotspot. Profiling the binding of a set of structurally characterised ligands by competitive 19F LB‐NMR with this suite of 19F reporters recapitulated the binding affinity and site ID assignments made by ITC and X‐ray crystallography. This quantitative mapping of ligand binding events at hotspot level resolution establishes the utility of the fragment‐based competitive 19F LB‐NMR screening platform for hotspot‐directed ligand profiling [ABSTRACT FROM AUTHOR]

The coenzyme A (CoA) biosynthesis pathway has attracted attention as a potential target for much‐needed novel antimicrobial drugs, including for the treatment of tuberculosis (TB), the lethal disease caused by Mycobacterium tuberculosis (Mtb). Seeking to identify inhibitors of Mtb phosphopantetheine adenylyltransferase (MtbPPAT), the enzyme that catalyses the penultimate step in CoA biosynthesis, we performed a fragment screen. In doing so, we discovered three series of fragments that occupy distinct regions of the MtbPPAT active site, presenting a unique opportunity for fragment linking. Here we show how, guided by X‐ray crystal structures, we could link weakly‐binding fragments to produce an active site binder with a KD <20 μM and on‐target anti‐Mtb activity, as demonstrated using CRISPR interference. This study represents a big step toward validating MtbPPAT as a potential drug target and designing a MtbPPAT‐targeting anti‐TB drug. [ABSTRACT FROM AUTHOR]

Fragment‐based drug discovery (FBDD) is a method of identifying small molecule hits that can be elaborated rationally through fragment growing, merging and linking, to afford high‐affinity ligands for biological targets. Despite the promised theoretical potential of fragment linking, examples are still surprisingly sparse and remain overshadowed by the successes of fragment growing. The aim of this review was to outline a number of key examples of fragment‐linking strategies and discuss their strengths and limitations. Structure‐based approaches including X‐ray crystallography and in silico methods of fragment optimization are discussed, as well as fragment linking guided by NMR experiments. Target‐guided approaches, exploiting the biological target to assemble its own inhibitors through dynamic combinatorial chemistry (DCC) and kinetic target‐guided synthesis (KTGS), are identified as alternative efficient methods for fragment linking. [ABSTRACT FROM AUTHOR]

Background: Urologists frequently treat patients for tobacco‐related conditions but infrequently engage in evidence‐based practices (EBPs) that screen for and treat tobacco use. Improving the use of EBPs will help to identify smokers, promote cessation, and improve patients' health outcomes. Methods: A prospective type I hybrid effectiveness‐implementation study was performed to test the feasibility and effectiveness of using a multilevel implementation strategy to improve the use of tobacco EBPs. All urology providers at outpatient urology clinics within the Veterans Health Administration Greater Los Angeles and all patients presenting for a new urology consultation were included. The primary outcome was whether a patient was screened for tobacco use at the time of consultation. Secondary outcomes included a patient's willingness to quit, chosen quit strategy, and subsequent engagement in quit attempts. Results: In total, 5706 consecutive veterans were seen for a new consultation during the 30‐month study period. Thirty‐six percent of all visits were for a tobacco‐related urologic diagnosis. The percentage of visits that included tobacco use screening increased from 18% (before implementation) to 57% in the implementation phase and to 60% during the maintenance phase. There was significant provider‐level variation in adherence to screening. Of all screened patients, 38% were willing to quit, and most patients chose a "cold turkey" method; 22% of the patients elected referral to a formal smoking cessation clinic, and 24% chose telephone counseling. Among those willing to quit, 39% and 49% made a formal quit attempt by 3 and 6 months, respectively. Conclusions: A strategy that includes provider education and a customized clinical decision support tool can facilitate provider use of tobacco EBPs in a surgery subspecialty clinic. Urologists frequently treat tobacco‐related conditions. The use of tobacco screening and treatment by providers in the urology clinic can be improved through the implementation of a multilevel intervention. [ABSTRACT FROM AUTHOR]

BACKGROUND The objective of this study was to determine tobacco use knowledge and attribution of cause in patients with newly diagnosed bladder cancer. METHODS A stratified, random sample of bladder cancer survivors diagnosed between 2006 and 2009 was obtained from the California Cancer Registry. Respondents were surveyed about tobacco use, risk factors, and sources of information on the causes of bladder cancer. Contingency tables and logistic regression analyses were used to evaluate tobacco use knowledge and beliefs. RESULTS Of 1198 eligible participants, 790 (66%) completed the survey. Sixty-eight percent of the cohort had a history of tobacco use, and 19% were active smokers at diagnosis. Tobacco use was the most cited risk factor for bladder cancer, with active smokers more knowledgeable than former smokers or never smokers (90% vs 64% vs 61%, respectively; P<.001). Urologists were the predominant source of information and were cited most often by active smokers (82%). In multivariate analyses, active smokers had 6.37 times greater odds (95% confidence interval, 3.35-12.09) than never smokers of endorsing tobacco use as a risk factor for bladder cancer, and smokers who named the urologist as their information source had 2.80 times greater odds (95% confidence interval, 1.77-4.43) of believing tobacco use caused their cancer. CONCLUSIONS Patients' smoking status and primary source of information were associated with knowledge of the harms of tobacco use and, in smokers, acknowledgment that tobacco use increased the risk of their own disease. Urologists play a critical role in ensuring patients' knowledge of the connection between smoking and bladder cancer, particularly for active smokers who may be motivated to quit. Cancer 2014;120:3914-3922. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

In this chapter we review the epidemiology of lung cancer incidence and mortality among never smokers/nonsmokers and describe the never smoker lung cancer risk models used by the Cancer Intervention and Surveillance Network (CISNET) modelers. Our review focuses on those influences likely to have measurable population impact on never smoker risk, such as secondhand smoke, even though the individual-level impact may be small. Occupational exposures may also contribute importantly to the population attributable risk of lung cancer. We examine the following risk factors in this chapter: age, environmental tobacco smoke, cooking fumes, ionizing radiation including radon gas, inherited genetic susceptibility, selected occupational exposures, preexisting lung disease, and oncogenic viruses. We also compare the prevalence of never smokers between the three CISNET smoking scenarios and present the corresponding lung cancer mortality estimates among never smokers as predicted by a typical CISNET model. [ABSTRACT FROM AUTHOR]

To better understand the contribution of cigarette smoking, and its changing role in lung cancer, this article provides an introduction to a special issue of Risk Analysis, which considers the relationship between smoking and lung cancer death rates during the period 1975-2000 for U.S. men and women aged 30-84 years. Six models are employed, which are part of a consortium of lung cancer modelers funded by National Cancer Institute's Cancer Intervention and Surveillance Modeling Network (CISNET). Starting with birth-cohort-specific smoking histories derived from National Health Interview Surveys, three scenarios are modeled: Actual Tobacco Control (observed trends in smoking), Complete Tobacco Control (a counter-factual lower bound on smoking rates that could have been achieved had all smoking ceased after the first Surgeon General's report in 1964), and No Tobacco Control (a counterfactual upper bound on smoking rates if smoking patterns that prevailed before the first studies in the 1950s began to inform the public about the hazards of smoking). Using these three scenarios and the lung cancer models, the number and percentage of lung cancer deaths averted from 1975-2000, among all deaths that could have been averted if tobacco control efforts been immediate and perfect, can be estimated. The variability of the results across multiple models provides a measure of the robustness of the results to model assumptions and structure. The results provide not only a portrait of the achieved impact of tobacco control on lung cancer mortality, but also the bounds of what still needs to be achieved. [ABSTRACT FROM AUTHOR]

In this chapter we review the epidemiology of lung cancer incidence and mortality among never smokers/nonsmokers and describe the never smoker lung cancer risk models used by the Cancer Intervention and Surveillance Network (CISNET) modelers. Our review focuses on those influences likely to have measurable population impact on never smoker risk, such as secondhand smoke, even though the individual-level impact may be small. Occupational exposures may also contribute importantly to the population attributable risk of lung cancer. We examine the following risk factors in this chapter: age, environmental tobacco smoke, cooking fumes, ionizing radiation including radon gas, inherited genetic susceptibility, selected occupational exposures, preexisting lung disease, and oncogenic viruses. We also compare the prevalence of never smokers between the three CISNET smoking scenarios and present the corresponding lung cancer mortality estimates among never smokers as predicted by a typical CISNET model. [ABSTRACT FROM AUTHOR]

To better understand the contribution of cigarette smoking, and its changing role in lung cancer, this article provides an introduction to a special issue of Risk Analysis, which considers the relationship between smoking and lung cancer death rates during the period 1975-2000 for U.S. men and women aged 30-84 years. Six models are employed, which are part of a consortium of lung cancer modelers funded by National Cancer Institute's Cancer Intervention and Surveillance Modeling Network (CISNET). Starting with birth-cohort-specific smoking histories derived from National Health Interview Surveys, three scenarios are modeled: Actual Tobacco Control (observed trends in smoking), Complete Tobacco Control (a counterfactual lower bound on smoking rates that could have been achieved had all smoking ceased after the first Surgeon General's report in 1964), and No Tobacco Control (a counterfactual upper bound on smoking rates if smoking patterns that prevailed before the first studies in the 1950s began to inform the public about the hazards of smoking). Using these three scenarios and the lung cancer models, the number and percentage of lung cancer deaths averted from 1975-2000, among all deaths that could have been averted if tobacco control efforts been immediate and perfect, can be estimated. The variability of the results across multiple models provides a measure of the robustness of the results to model assumptions and structure. The results provide not only a portrait of the achieved impact of tobacco control on lung cancer mortality, but also the bounds of what still needs to be achieved. [ABSTRACT FROM AUTHOR]

Context: Commercial marketing is a critical but understudied element of the sociocultural environment influencing Americans' food and beverage preferences and purchases. This marketing also likely influences the utilization of goods and services related to physical activity and sedentary behavior. A growing literature documents the targeting of racial/ethnic and income groups in commercial advertisements in magazines, on billboards, and on television that may contribute to sociodemographic disparities in obesity and chronic disease risk and protective behaviors. This article examines whether African Americans, Latinos, and people living in low-income neighborhoods are disproportionately exposed to advertisements for high-calorie, low nutrient–dense foods and beverages and for sedentary entertainment and transportation and are relatively underexposed to advertising for nutritious foods and beverages and goods and services promoting physical activities. Methods: Outdoor advertising density and content were compared in zip code areas selected to offer contrasts by area income and ethnicity in four cities: Los Angeles, Austin, New York City, and Philadelphia. Findings: Large variations were observed in the amount, type, and value of advertising in the selected zip code areas. Living in an upper-income neighborhood, regardless of its residents' predominant ethnicity, is generally protective against exposure to most types of obesity-promoting outdoor advertising (food, fast food, sugary beverages, sedentary entertainment, and transportation). The density of advertising varied by zip code area race/ethnicity, with African American zip code areas having the highest advertising densities, Latino zip code areas having slightly lower densities, and white zip code areas having the lowest densities. Conclusions: The potential health and economic implications of differential exposure to obesity-related advertising are substantial. Although substantive legal questions remain about the government's ability to regulate advertising, the success of limiting tobacco advertising offers lessons for reducing the marketing contribution to the obesigenicity of urban environments. [ABSTRACT FROM AUTHOR]

The article presents a study using Adult Use of Tobacco Survey (AUTS) data to demonstrate that smokers, while acknowledging increased risk for illness, still show evidence of an optimistic bias in their perception of the risk of their usual brand of cigarette. The survey was conducted by the U.S. Department of Health and Human Services in 1990. The AUTS sample was drawn from the noninstitutionalized civilian population of the United States, including Hawaii and Alaska. It is opined that if the majority of a group claim that their chances of a negative outcome are less than average, it provides evidence for an optimistic bias in the assessment of risk. It was found that cigarette smokers are optimistic both about the general health of their usual brand of cigarette and its content of a primary carcinogen, tar. Smokers do not evidence an optimistic bias regarding their health risks relative to nonsmokers because of pervasive public health information, not because they cannot find a self-charitable way to think about smoking.

Two hundred and twenty-one males and 518 females were followed for 8 years from early adolescence. A causal model was proposed that related five constructs measured in adolescence to four corresponding constructs measured 8 years later. The predictor constructs included smoking involvement, academic lifestyle orientation, emotional well-being, social impact efficacy, and peer smoking behavior. Academic lifestyle orientation was found to be a central organizing construct, with the strongest within-time and across-time correlations with other constructs. The relatively weak causal influences of teenage smoking and teenage social impact efficacy suggested an explanation for the limited impact of past drug abuse prevention programs. Policy implications are discussed. [ABSTRACT FROM AUTHOR]