Tuberculosis screening for patients on biologic Medications: A Single-Center experience and Society guideline Review, Monroe County, New York, 2018-2021.

Rationale: Biologic medications for immune-mediated inflammatory diseases may increase the risk of tuberculosis (TB) reactivation, but data on screening for TB in low TB prevalence areas are limited. Objective: To assess the real-world practice patterns of TB screening among prescribers of biologic medications. Methods: We conducted a retrospective observational study at a single, university-based healthcare facility in a low TB prevalence area. We enrolled adult patients prescribed a biologic medication between October 2018 and December 2021, and collected data on demographics, biologic medications and TB test results. For patients with positive TB tests, further data including prescriber specialty and response to positive tests were obtained. We reviewed pertinent major society guidelines/ consensus statements regarding TB screening among patients treated with biologic medications. Results: 4,085 patients were included. 3024 (74.0%) had at least one screening TB test and 42 were positive. Among patients treated with tumor necrosis factor-alpha (TNFα) inhibitors, 1779 of 2129 patients (83.6%) underwent TB testing and 25 (1.4%) were positive. Most with positive TB test results were prescribed biologic medication by gastroenterology (11 patients, 26%), dermatology (12, 29%), or rheumatology (15, 36%) providers. 32 (76%) patients had imaging and roughly half were treated for latent TB infection. Biologic medications were temporarily held for 27 patients (67%). Nine out of 13 society guidelines recommend TB screening for TNFα inhibitors but have differing recommendations for other biologic medications. Conclusions: Significant practice pattern differences in TB screening for patients receiving biologic medications exist. Multiple society guidelines continue to recommend TB screening even for drugs with no known increased risk of TB reactivation.

Fruit flavors in electronic cigarettes (ECIGs) are associated with nocturnal dry cough: A population longitudinal analysis.

Evidence from in vitro and animal models has identified the pulmonary toxicity of flavors in electronic cigarettes (ECIGs); however, less is known from epidemiological studies about the effects of flavors in the respiratory health. This study examined the longitudinal association between exposure to ECIGs flavors and nocturnal dry cough among ECIGs users. A secondary analysis of data from the Population Assessment of Tobacco and Health Study (2014-2019) was conducted. The study population included adults who provided information (n = 18,925) for a total of 38,638 observations. Weighted-incidence estimates and weighted- generalized estimating equation models were performed to assess unadjusted and adjusted associations. The weighted incidence proportion (WIP) of nocturnal dry cough was significantly higher among current (WIP:16.6%; 95%CI 10.5, 21.2) and former fruit flavored ECIGs users (WIP:16.6%; 95%CI 11.3, 21.9) as compared to non-ECIGs users (WIP:11.1%; 95%CI 10.6, 11.6). Current ECIGs users of fruit flavors showed 40% higher risk of reporting cough than non-ECIGs users (aRR:1.40, 95%CI 1.01, 1.94). Former ECIGs users of multiple flavors and other flavors had 300% and 66% higher risk to develop cough, respectively (aRR:3.33, 95%CI 1.51, 7.34 and aRR:1.66, 95%CI 1.0.9, 2.51), relative to non-ECIGs users. We observed a significantly higher risk of developing nocturnal dry cough in the past 12 months in current and former ECIGs users of fruit flavors and in former ECIGs users of multiple flavors. To the extent that cough may serve as an early indicator of respiratory inflammation and potential disease risk, the association between ECIGs use and cough raises potential concerns.

Are Black and Latino adolescents being asked if they use electronic cigarettes and advised not to use them? Results from a community-based survey.

Objective: This study aimed to explore whether African American/Black and Hispanic/Latino adolescents are being asked about electronic cigarette (e-cigarette) use (vaping) and advised not to use them. Methods: In 2021, adolescents (N = 362) with no vaping history, self-identified as African American/Black and/or Hispanic/Latino, and able to read and speak English and/or Spanish were recruited through partner schools and community-based organizations. Participants completed a survey reporting sociodemographic characteristics (e.g., race/ethnicity, gender, and language of preference) and they were asked about e-cigarette use and/or were advised not to use them by a health professional. Results: In total, 12% of African American/Black and 5% of Hispanic/Latino participants reported not seeing a health professional in the year prior to enrollment. Of the participants who reported visiting a health professional, 50.8% reported being asked and advised about vaping. Over one-quarter (28.4%) of participants were neither asked nor advised regarding vaping. Compared to English-speaking participants, Spanish-speaking participants were significantly less likely to be asked about e-cigarette use (45.2 vs. 63.9%, p = 0.009) and advised not to use them (40.3 vs. 66.9%, p < 0.001). Moreover, compared to African American/Black participants, Hispanic/Latino participants were significantly less likely to be advised not to use e-cigarettes (52.9 vs. 68.6%, p = 0.018). Furthermore, compared to male participants, female participants were significantly less likely to be advised not to use e-cigarettes (51.3 vs. 68.2%, p = 0.003). Conclusion: Compared to English-speaking participants, Spanish-speaking participants were significantly less likely to self-report being asked about e-cigarette use and advised not to use them. Moreover, Hispanic/Latino and female adolescents were significantly less likely to self-report being advised not to use e-cigarettes compared to their Black/African American and male counterparts. Future research is needed to improve health professional attention toward asking about and advising against vaping among adolescents.

Effectively utilizing publicly available databases for cancer target evaluation.

The majority of compounds designed against cancer drug targets do not progress to become approved drugs, mainly due to lack of efficacy and/or unmanageable toxicity. Robust target evaluation is therefore required before progressing through the drug discovery process to reduce the high attrition rate. There are a wealth of publicly available databases that can be mined to generate data as part of a target evaluation. It can, however, be challenging to learn what databases are available, how and when they should be used, and to understand the associated limitations. Here, we have compiled and present key, freely accessible and easy-to-use databases that house informative datasets from in vitro, in vivo and clinical studies. We also highlight comprehensive target review databases that aim to bring together information from multiple sources into one-stop portals. In the post-genomics era, a key objective is to exploit the extensive cell, animal and patient characterization datasets in order to deliver precision medicine on a patient-specific basis. Effective utilization of the highlighted databases will go some way towards supporting the cancer research community achieve these aims.

The E-cigarette or Vaping Product Use-Associated Lung Injury Epidemic: Pathogenesis, Management, and Future Directions: An Official American Thoracic Society Workshop Report.

E-cigarette or vaping product use-associated lung injury (EVALI) is a severe pulmonary illness associated with the use of e-cigarettes or vaping products that was officially identified and named in 2019. This American Thoracic Society workshop was convened in 2021 to identify and prioritize research and regulatory needs to adequately respond to the EVALI outbreak and to prevent similar instances of disease associated with e-cigarette or vaping product use. An interdisciplinary group of 26 experts in adult and pediatric clinical care, public health, regulatory oversight, and toxicology were convened for the workshop. Four major topics were examined: 1) the public health and regulatory response to EVALI; 2) EVALI clinical care; 3) mechanisms contributing to EVALI; and 4) needed actions to address the health effects of EVALI. Oral presentations and group discussion were the primary modes used to identify top priorities for addressing EVALI. Initiatives including a national EVALI case registry and biorepository, integrated electronic medical record coding system, U.S. Food and Drug Administration regulation and enforcement of nicotine e-cigarette standards, regulatory authority over nontobacco-derived e-cigarettes, training in evaluating exogenous exposures, prospective clinical studies, standardized clinical follow-up assessments, ability to more readily study effects of cannabinoid e-cigarettes, and research to identify biomarkers of exposure and disease were identified as critical needs. These initiatives will require substantial federal investment as well as changes to regulatory policy. Overall, the workshop identified the need to address the root causes of EVALI to prevent future outbreaks. An integrated approach from multiple perspectives is required, including public health; clinical, basic, and translational research; regulators; and users of e-cigarettes. Improving the public health response to reduce the risk of another substantial disease-inducing event depends on coordinated actions to better understand the inhalational toxicity of these products, informing the public of the risks, and developing and enforcing regulatory standards for all e-cigarettes.

Association between weight loss and mortality in idiopathic pulmonary fibrosis.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease that has no cure. Many current research efforts center on diagnostic and therapeutic modalities for IPF while other risk factors affecting disease pathogenesis receive less attention. Emerging data support the clinical importance of weight loss in patients with IPF. However, factors associated with weight loss and the impact of weight loss on mortality remain incompletely explored. OBJECTIVES: Explore the association between weight loss and transplant-free survival in patients with IPF and identify clinical variables associated with weight loss in this population. METHODS: Kaplan-Meier and Cox proportional hazard regression analyses were generated and stratified by weight loss or use of antifibrotic medications. Conditional logistic regression was used to evaluate for factors associated with weight loss. RESULTS: There was a significant increase in mortality in patients who lost ≥ 5% of their body weight loss (HR 2.21, [1.29, 4.43] p = .021). The use of supplemental oxygen (adjusted OR 13.16), and ≥ 200 mL loss of FVC over 1 year (adjusted OR 5.44) were both associated with a ≥ 5% weight loss in the year following a diagnosis of IPF. The use of antifibrotic medication did not significantly change median transplant-free survival in patients who lost more than ≥ 5% of their body mass. CONCLUSIONS: Weight loss over the first year following a diagnosis of IPF is strongly associated with decreased transplant-free survival. More research is needed to determine the mechanisms surrounding weight loss in patients with IPF.

The effect of air pollution on the transcriptomics of the immune response to respiratory infection.

Combustion related particulate matter air pollution (PM) is associated with an increased risk of respiratory infections in adults. The exact mechanism underlying this association has not been determined. We hypothesized that increased concentrations of combustion related PM would result in dysregulation of the innate immune system. This epidemiological study includes 111 adult patients hospitalized with respiratory infections who underwent transcriptional analysis of their peripheral blood. We examined the association between gene expression at the time of hospitalization and ambient measurements of particulate air pollutants in the 28 days prior to hospitalization. For each pollutant and time lag, gene-specific linear models adjusting for infection type were fit using LIMMA (Linear Models For Microarray Data), and pathway/gene set analyses were performed using the CAMERA (Correlation Adjusted Mean Rank) program. Comparing patients with viral and/or bacterial infection, the expression patterns associated with air pollution exposure differed. Adjusting for the type of infection, increased concentrations of Delta-C (a marker of biomass smoke) and other PM were associated with upregulation of iron homeostasis and protein folding. Increased concentrations of black carbon (BC) were associated with upregulation of viral related gene pathways and downregulation of pathways related to antigen presentation. The pollutant/pathway associations differed by lag time and by type of infection. This study suggests that the effect of air pollution on the pathogenesis of respiratory infection may be pollutant, timing, and infection specific.

E-cigarette exposures, respiratory tract infections, and impaired innate immunity: a narrative review.

Electronic cigarettes (e-cigarettes) are commonly used devices by adolescents and young adults. Since their introduction, the popularity of e-cigarettes has increased significantly with close to twenty percent of United States high school students reporting current use in 2020. As the number of e-cigarette users has increased, so have reports of vaping related health complications. Overall, respiratory tract infections remain one of the top ten leading causes of death in the US for every age group. Specific to the pediatric population, lower respiratory tract infections are the leading cause for hospitalization. This review highlights the current evidence behind e-cigarette exposure and its association with impaired innate immune function and the risk of lower respiratory tract infections. To date, various preclinical models have evaluated the direct effects of e-cigarette exposure on the innate immune system. More specifically, e-cigarette exposure impairs certain cell types of the innate immune system including the airway epithelium, lung macrophage and neutrophils. Identified effects of e-cigarette exposure common to the lung's innate immunity include abnormal mucus composition, reduced epithelial barrier function, impaired phagocytosis and elevated systemic markers of inflammation. These identified impairments in the lung's innate immunity have been shown to increase adhesion of certain bacteria and fungi as well as to increase virulence of common respiratory pathogens such as influenza virus, Staphylococcus aureus or Streptococcus pneumoniae. Information summarized in this review will provide guidance to healthcare providers, policy advocates and researchers for making informed decisions regarding the associated respiratory health risks of e-cigarette use in pediatric and young adults.

Perceptions of Tobacco Product-Specific COVID-19 Risk and Changes in Tobacco Use Behaviors Among Smokers, E-Cigarette Users, and Dual Users.

INTRODUCTION: Coronavirus Disease 2019 (COVID-19) is a public health crisis, but its effects on tobacco users remain ill-defined. This report aimed to assess the relationship between tobacco product-specific risk perceptions for COVID-19 and changes in tobacco use since the start of the pandemic. METHODS: A sample (n = 776) of past-30 day exclusive smokers (n = 238), exclusive e-cigarette users (n = 143), and dual users (n = 395) residing in the US and aged 18 or older were collected using Mechanical Turk from April 27 to June 8, 2020. Adjusted associations between tobacco product-specific COVID-19 risk perceptions (ie risk that smokers/vapers are at for COVID-19 relative to non-smokers/non-vapers) and changes in tobacco use since the pandemic began were assessed using partial proportional odds models. RESULTS: A majority of those who used cigarettes (63.7%) and e-cigarettes (56.1%) felt that the risk of COVID-19 was greater for users of their tobacco product than for non-users. Twenty-four percent of smokers had increased their cigarette use since the start of the pandemic and 28.0% had decreased. Similarly, 27.3% of e-cigarette users had increased their e-cigarette use since the start of the pandemic and 23.8% had decreased. Higher risk perceptions for COVID-19 were associated with reductions in tobacco use since the pandemic began for exclusive e-cigarette users and dual users. CONCLUSIONS: These findings provide the support that tobacco product-specific COVID-19 risk perceptions may be an important correlate of changes in tobacco use during the pandemic. Targeted information to inform tobacco users regarding their risks for COVID-19 is needed during this public health crisis. IMPLICATIONS: Few published studies have investigated the relationship between tobacco product-specific risk perceptions for COVID-19 and changes in tobacco product use since the pandemic began. This study enhances the current literature by providing evidence that higher tobacco product-specific risk perceptions for COVID-19 are associated with reductions in tobacco use since the pandemic began for exclusive e-cigarette users and dual users of cigarettes and e-cigarettes. Additionally, daily tobacco users may be more likely to have increased their tobacco use than non-daily users. These findings emphasize the importance of disseminating targeted health information to tobacco users regarding COVID-19 risks.

Acute myocardial infarction associated with unconventional natural gas development: A natural experiment.

BACKGROUND: Whereas it is plausible that unconventional natural gas development (UNGD) may adversely affect cardiovascular health, little is currently known. We investigate whether UNGD is associated with acute myocardial infarction (AMI). METHODS: In this observational study leveraging the natural experiment generated by New York's ban on hydraulic fracturing, we analyzed the relationship between age- and sex-specific county-level AMI hospitalization and mortality rates and three UNGD drilling measures. This longitudinal panel analysis compares Pennsylvania and New York counties on the Marcellus Shale observed over 2005-2014 (N = 2840 county-year-quarters). RESULTS: A hundred cumulative wells is associated with 0.26 more hospitalizations per 10,000 males 45-54y.o. (95% CI 0.07,0.46), 0.40 more hospitalizations per 10,000 males 65-74y.o. (95% CI 0.09,0.71), 0.47 more hospitalizations per 10,000 females 65-74y.o. (95% CI 0.18,0.77) and 1.11 more hospitalizations per 10,000 females 75y.o.+ (95% CI 0.39,1.82), translating into 1.4-2.8% increases. One additional well per square mile is associated with 2.63 more hospitalizations per 10,000 males 45-54y.o. (95% CI 0.67,4.59) and 9.7 hospitalizations per 10,000 females 75y.o.+ (95% CI 1.92,17.42), 25.8% and 24.2% increases, respectively. As for mortality rates, a hundred cumulative wells is associated with an increase of 0.09 deaths per 10,000 males 45-54y.o. (95% CI 0.02,0.16), a 5.3% increase. CONCLUSIONS: Cumulative UNGD is associated with increased AMI hospitalization rates among middle-aged men, older men and older women as well as with increased AMI mortality among middle-aged men. Our findings lend support for increased awareness about cardiovascular risks of UNGD and scaled-up AMI prevention as well as suggest that bans on hydraulic fracturing can be protective for public health.

The association between statewide vaping prevalence and COVID-19.

Existing literature indicated electronic cigarette users (vapers) have impaired immune response that might increase vulnerability to coronavirus disease 2019 (COVID-19) infection and death. However, whether vapers are more susceptible to COVID-19 is unknown. Using integrated data in each US state from the 2018 Behavioral Risk Factor Surveillance System (BRFSS), United States Census Bureau and the 1Point3Acres.com website, generalized estimating equation (GEE) models with negative binomial distribution assumption and log link functions were used to examine the association of statewide e-cigarette use prevalence with number of COVID-19 cases and deaths in the US on a state level from January 21, 2020 to April 25, 2020. The weighted proportion of vapers who used e-cigarettes every day or some days ranged from 2.86% to 6.42% for US states. Statistically significant associations were observed between the weighted proportion of vapers and number of COVID-19 cases as well as COVID-19 deaths in the US after adjusting for the weighted proportion of smokers and other significant covariates in the GEE models. With every one percent increase in weighted proportion of vapers in each state, the number of COVID-19 cases increase by 0.3139 (95% CI: 0.0554-0.5723) and the number of COVID-19 deaths increase by 0.3730 (95% CI: 0.0815-0.6646) in log scale in each US state. The positive associations between the proportion of vapers and the number of COVID-19 cases and deaths in each US state in this ecological study suggest an increased susceptibility of vapers to COVID-19 on a state level and warrants further investigation.

Association of flavored electronic nicotine delivery system (ENDS) use with self-reported chronic obstructive pulmonary disease (COPD): Results from the Population Assessment of Tobacco and Health (PATH) study, Wave 4.

INTRODUCTION: Flavors other than tobacco flavor have been identified as a major reason for electronic nicotine delivery system (ENDS) initiation in youth and are thought to contribute to the continued use of ENDS in users of all ages. Our previous research showed a significant association between overall ENDS use and COPD. This study aims to identify the association of ENDS flavor categories with self-reported COPD. METHODS: The data analysis included 4909 adults from Population Assessment of Tobacco and Health (PATH) Wave 4 data who were ever established ENDS users and responded to an item about diagnosis of COPD. Weighted multivariable logistic regression models were used to examine the association between different ENDS flavors and self-reported COPD considering complex sampling design. RESULTS: Among 4909 ever established ENDS users, 418 adults (weighted percentage 9.8%) had self-reported COPD. Self-reported COPD prevalence differed between different ENDS flavor categories, with the highest (weighted percentage 19.9%) occurring among tobacco flavor users. Compared to non-tobacco flavor categories, tobacco flavor category showed significantly higher association with self-reported COPD (AOR=2.05; 95% CI: 1.20-3.53), after adjusting for potential confounding variables. No significant associations with self-reported COPD were found for other examined ENDS flavor categories including menthol/mint, fruit, candy/ desserts/other-sweets, and other flavors, compared to their corresponding non-users. CONCLUSIONS: Tobacco flavored ENDS use was significantly associated with self-reported COPD. Future studies are needed to confirm the biological and epidemiological association of flavored ENDS use with COPD.

Are Vapers More Susceptible to COVID-19 Infection?

Background COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a global pandemic in March 2020. Electronic cigarette use (vaping) rapidly gained popularity in the US in recent years. Whether electronic cigarette users (vapers) are more susceptible to COVID-19 infection is unknown. Methods Using integrated data in each US state from the 2018 Behavioral Risk Factor Surveillance System (BRFSS), United States Census Bureau and the 1Point3Acres.com website, generalized estimating equation (GEE) models with negative binomial distribution assumption and log link functions were used to examine the association of weighted proportions of vapers with number of COVID-19 infections and deaths in the US. Results The weighted proportion of vapers who used e-cigarettes every day or some days ranged from 2.86% to 6.42% for US states. Statistically significant associations were observed between the weighted proportion of vapers and number of COVID-19 infected cases as well as COVID-19 deaths in the US after adjusting for the weighted proportion of smokers and other significant covariates in the GEE models. With every one percent increase in weighted proportion of vapers in each state, the number of COVID-19 infected cases increase by 0.3139 (95% CI: 0.0554 - 0.5723) and the number of COVID-19 deaths increase by 0.3705 (95% CI: 0.0623 - 0.6786) in log scale in each US state. Conclusions The positive associations between the proportion of vapers and the number of COVID-19 infected cases and deaths in each US state suggest an increased susceptibility of vapers to COVID-19 infections and deaths.

The Interplay Between Respiratory Microbiota and Innate Immunity in Flavor E-Cigarette Vaping Induced Lung Dysfunction.

Global usage of electronic nicotine delivery systems (ENDS) has been increasing in the last decade. ENDS are non-combustible tobacco products that heat and aerosolize a liquid containing humectants, with added flavorings and often nicotine. Though ENDS are promoted as a less harmful alternative to smoking, current evidence links their use to a wide range of deleterious health effects including acute and chronic lung damage. ENDS can elicit an inflammatory response and impair the innate immune response in the lungs. Exposure to ENDS flavorings results in abnormal activation of the lung epithelial cells and ß-defensins, dysfunction of the macrophage phagocytic activity, increased levels of mucin (MUC5AC) and abnormal activation of the neutrophilic response (NETosis). ENDS menthol flavorings disrupt innate immunity and might be associated with allergies and asthma through activation of transient receptor potential ankyrin 1 (TRAP1). Recent studies have expanded our understanding of the relationship between the homeostasis of lung innate immunity and the immunomodulatory effect of the host-microbiota interaction. Alterations of the normal respiratory microbiota have been associated with chronic obstructive pulmonary disease (COPD), asthma, atopy and cystic fibrosis complications which are strongly associated with smoking and potentially with ENDS use. Little is known about the short-and long-term effects of ENDS on the respiratory microbiota, their impact on the innate immune response and their link to pulmonary health and disease. Here we review the interaction between the innate immune system and the respiratory microbiota in the pathogenesis of ENDS-induced pulmonary dysfunction and identify future areas of research.

E-cigarette, or vaping, product use associated lung injury (EVALI): case series and diagnostic approach.

BACKGROUND: Since June, 2019, more than 1000 new cases of e-cigarette, or vaping, product use associated lung injury (EVALI) have been reported in the USA. Patients presented with dyspnoea, cough, and were found to be hypoxaemic with bilateral airspace opacities on chest imaging. Most patients required management in the intensive care unit and steroid therapy. All patients recovered with cessation of vaping, supportive care, and steroid therapy and remained symptom free at follow up. E-cigarette use continues to rapidly escalate in the USA, particularly among youth. METHODS: Cases were defined as patients admitted to the University of Rochester Medical Center (Rochester, NY, USA) who had used e-cigarettes or another vaping device in the 30 days before presentation, and who had bilateral airspace opacification on chest imaging (CT or x-ray). Case details were obtained via medical record review and patient interviews over the past 3 months including symptomatology, physical exam data, imaging studies, laboratory data, vaping history, and subsequent outpatient follow-up data. In collaboration with the New York State Department of Health, our hospital developed a novel clinical practice algorithm based on statewide physician feedback along with input from experts in environmental health, medical toxicology, infectious disease, epidemiology, and chronic disease prevention. FINDINGS: We report 12 cases treated for suspected EVALI at our medical centre between June 6, 2019, and Sept 15, 2019. Ten (83%) patients had dyspnoea, fever, and emesis and nine (75%) had cough. 11 (92%) patients reported the use of e-cigarette cartridges containing tetrahydrocannabinol oil. Although eight (67%) patients required admission to the intensive care unit for hypoxaemic respiratory failure, no deaths occurred. The median hospitalisation duration was 7 days (IQR 7-8). All patients completing follow up (6 [50%]) had resolution of previous chest CT findings and normal spirometry. The clinical algorithm focuses on the key signs and symptoms of EVALI and the importance of ruling out infection and other cardiopulmonary conditions before making a presumptive diagnosis of EVALI. INTERPRETATION: Patients with suspected EVALI in our cohort had life-threatening hypoxaemia, with 67% requiring management in the intensive care unit. Despite the severity of presentation, similar to previous reports of patients with EVALI, most patients improved within 1-2 weeks of initial presentation after vaping cessation and administration of systemic corticosteroids when needed. Almost all (92%) patients with suspected EVALI reported vaping a THC product, making THC containing e-liquids or oils a key focus on the ongoing nationwide investigations into the cause of EVALI. Additional research is required to understand the potential toxins, underlying pathophysiological mechanisms, and identification of susceptible individuals at higher risk for hospitalisation due to EVALI. To our knowledge we present the first clinical practice algorithm for the evaluation and management of EVALI, which will be useful for both acute management and improved accurate reporting of this life-threatening respiratory illness. FUNDING: None.

Structure-based design, synthesis and biological evaluation of a novel series of isoquinolone and pyrazolo[4,3-c]pyridine inhibitors of fascin 1 as potential anti-metastatic agents.

Fascin is an actin binding and bundling protein that is not expressed in normal epithelial tissues but overexpressed in a variety of invasive epithelial tumors. It has a critical role in cancer cell metastasis by promoting cell migration and invasion. Here we report the crystal structures of fascin in complex with a series of novel and potent inhibitors. Structure-based elaboration of these compounds enabled the development of a series with nanomolar affinities for fascin, good physicochemical properties and the ability to inhibit fascin-mediated bundling of filamentous actin. These compounds provide promising starting points for fascin-targeted anti-metastatic therapies.