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1.
Front Immunol ; 12: 701445, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34650551

RESUMO

As viruses continue to mutate the need for rapid high titer neutralizing antibody responses has been highlighted. To meet these emerging threats, agents that enhance vaccine adjuvant activity are needed that are safe with minimal local or systemic side effects. To respond to this demand, we sought small molecules that would sustain and improve the protective effect of a currently approved adjuvant, monophosphoryl lipid A (MPLA), a Toll-like receptor 4 (TLR4) agonist. A lead molecule from a high-throughput screen, (N-(4-(2,5-dimethylphenyl)thiazol-2-yl)-4-(piperidin-1-ylsulfonyl)benzamide, was identified as a hit compound that sustained NF-κB activation by a TLR4 ligand, lipopolysaccharide (LPS), after an extended incubation (16 h). In vitro, the resynthesized compound (2D216) enhanced TLR4 ligand-induced innate immune activation and antigen presenting function in primary murine bone marrow-derived dendritic cells without direct activation of T cells. In vivo murine vaccination studies demonstrated that compound 2D216 acted as a potent co-adjuvant when used in combination with MPLA that enhanced antigen-specific IgG equivalent to that of AS01B. The combination adjuvant MPLA/2D216 produced Th1 dominant immune responses and importantly protected mice from lethal influenza virus challenge. 2D216 alone or 2D216/MPLA demonstrated minimal local reactogenicity and no systemic inflammatory response. In summary, 2D216 augmented the beneficial protective immune responses of MPLA as a co-adjuvant and showed an excellent safety profile.

2.
mSystems ; : e0079321, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34374562

RESUMO

Wastewater-based surveillance has gained prominence and come to the forefront as a leading indicator of forecasting COVID-19 (coronavirus disease 2019) infection dynamics owing to its cost-effectiveness and its ability to inform early public health interventions. A university campus could especially benefit from wastewater surveillance, as universities are characterized by largely asymptomatic populations and are potential hot spots for transmission that necessitate frequent diagnostic testing. In this study, we employed a large-scale GIS (geographic information systems)-enabled building-level wastewater monitoring system associated with the on-campus residences of 7,614 individuals. Sixty-eight automated wastewater samplers were deployed to monitor 239 campus buildings with a focus on residential buildings. Time-weighted composite samples were collected on a daily basis and analyzed on the same day. Sample processing was streamlined significantly through automation, reducing the turnaround time by 20-fold and exceeding the scale of similar surveillance programs by 10- to 100-fold, thereby overcoming one of the biggest bottlenecks in wastewater surveillance. An automated wastewater notification system was developed to alert residents to a positive wastewater sample associated with their residence and to encourage uptake of campus-provided asymptomatic testing at no charge. This system, integrated with the rest of the "Return to Learn" program at the University of California (UC) San Diego-led to the early diagnosis of nearly 85% of all COVID-19 cases on campus. COVID-19 testing rates increased by 1.9 to 13× following wastewater notifications. Our study shows the potential for a robust, efficient wastewater surveillance system to greatly reduce infection risk as college campuses and other high-risk environments reopen. IMPORTANCE Wastewater-based epidemiology can be particularly valuable at university campuses where high-resolution spatial sampling in a well-controlled context could not only provide insight into what affects campus community as well as how those inferences can be extended to a broader city/county context. In the present study, a large-scale wastewater surveillance was successfully implemented on a large university campus enabling early detection of 85% of COVID-19 cases thereby averting potential outbreaks. The highly automated sample processing to reporting system enabled dramatic reduction in the turnaround time to 5 h (sample to result time) for 96 samples. Furthermore, miniaturization of the sample processing pipeline brought down the processing cost significantly ($13/sample). Taken together, these results show that such a system could greatly ameliorate long-term surveillance on such communities as they look to reopen.

3.
JAMA Netw Open ; 4(8): e2121387, 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34347057

RESUMO

Importance: The US Food and Drug Administration's implementation of graphic warning labels (GWLs) on cigarette packs is under challenge in US courts. Objective: To determine whether GWLs can affect US smokers' perceptions about their cigarettes or health consequences and changes in smoking behavior. Design, Setting, and Participants: This study was a randomized clinical trial of the effect of a 3-month, real-world experience of cigarettes with GWL packaging. Community recruitment was done from September 2016 through December 2019 of daily smokers from San Diego, California, aged 21 to 65 years, who were not ready to quit. Participants were randomized to purchase and receive cigarettes in 1 of 3 pack designs: GWL, blank, or standard US pack. Data analysis was performed from July 2020 to February 2021. Interventions: The study manufactured GWL cigarette packs (3 versions with Australian-licensed images) and packs devoid of marketing. For 3 months, participants purchased GWL, blank, or standard US pack cigarettes that were delivered to their home. Main Outcomes and Measures: Smoking-related cognitions and behavior were queried by daily and weekly interactive text messages. Smoking behavior was self-reported before and after the intervention by 96% of randomized participants and was biochemically validated on a subsample. Results: The study sample included 357 participants (195 women [54.6%]; mean [SD] age, 39.5 [11.9] years); 116 were randomized to the standard US pack group, 118 were randomized to the GWL pack group, and 125 were randomized to the blank pack group. Over the 3 months, participants who received the GWL packs had reduced positive perceptions of recent cigarettes smoked compared with participants who received the branded US pack (mean difference, -0.46 SD; 95% CI, -0.73 SD to -0.20 SD; P < .001). Health concerns increased in all groups, with a significant increase in the GWL group vs the US pack group (mean difference, 0.35 SD; 95% CI, 0.09 SD to 0.62 SD; P = .002). Quitting cognitions increased in all study groups, with a peak mean change of 0.60 SD for GWL participants vs 0.34 SD for US pack participants (mean difference, 0.55 SD; 95% CI, 0.28 SD to 0.81 SD; P < .001). GWL participants had slightly more cigarette abstinence periods per week than the US pack group, but the difference was not significant (adjusted odds ratio, 1.06; 95% CI, 0.99 to 1.13). At 3 months, there was no between-group difference in any smoking behavior. The blank pack group was similar to the US pack group on all measures. Conclusions and Relevance: These findings suggest that the introduction of GWL packs appears to decrease positive perceptions of cigarettes and increase quitting cognitions in the short term. However, additional complementary tobacco control strategies may be necessary for GWL packs to be associated with reduced smoking behavior. Trial Registration: ClinicalTrials.gov Identifier: NCT02676193.

4.
J Biomed Inform ; 121: 103879, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34329789

RESUMO

PURPOSE: Standardized approaches for rigorous validation of phenotyping from large-scale electronic health record (EHR) data have not been widely reported. We proposed a methodologically rigorous and efficient approach to guide such validation, including strategies for sampling cases and controls, determining sample sizes, estimating algorithm performance, and terminating the validation process, hereafter referred to as the San Diego Approach to Variable Validation (SDAVV). METHODS: We propose sample size formulae which should be used prior to chart review, based on pre-specified critical lower bounds for positive predictive value (PPV) and negative predictive value (NPV). We also propose a stepwise strategy for iterative algorithm development/validation cycles, updating sample sizes for data abstraction until both PPV and NPV achieve target performance. RESULTS: We applied the SDAVV to a Department of Veterans Affairs study in which we created two phenotyping algorithms, one for distinguishing normal colonoscopy cases from abnormal colonoscopy controls and one for identifying aspirin exposure. Estimated PPV and NPV both reached 0.970 with a 95% confidence lower bound of 0.915, estimated sensitivity was 0.963 and specificity was 0.975 for identifying normal colonoscopy cases. The phenotyping algorithm for identifying aspirin exposure reached a PPV of 0.990 (a 95% lower bound of 0.950), an NPV of 0.980 (a 95% lower bound of 0.930), and sensitivity and specificity were 0.960 and 1.000. CONCLUSIONS: A structured approach for prospectively developing and validating phenotyping algorithms from large-scale EHR data can be successfully implemented, and should be considered to improve the quality of "big data" research.

5.
PLoS One ; 16(7): e0254635, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34264974

RESUMO

BACKGROUND: Statins have anti-inflammatory and immunomodulatory effects that may reduce the severity of coronavirus disease 2019 (COVID-19), in which organ dysfunction is mediated by severe inflammation. Large studies with diverse populations evaluating statin use and outcomes in COVID-19 are lacking. METHODS AND RESULTS: We used data from 10,541 patients hospitalized with COVID-19 through September 2020 at 104 US hospitals enrolled in the American Heart Association's COVID-19 Cardiovascular Disease (CVD) Registry to evaluate the associations between statin use and outcomes. Prior to admission, 42% of subjects (n = 4,449) used statins (7% on statins alone, 35% on statins plus anti-hypertensives). Death (or discharge to hospice) occurred in 2,212 subjects (21%). Outpatient use of statins, either alone or with anti-hypertensives, was associated with a reduced risk of death (adjusted odds ratio [aOR] 0.59, 95% CI 0.50-0.69), adjusting for demographic characteristics, insurance status, hospital site, and concurrent medications by logistic regression. In propensity-matched analyses, use of statins and/or anti-hypertensives was associated with a reduced risk of death among those with a history of CVD and/or hypertension (aOR 0.68, 95% CI 0.58-0.81). An observed 16% reduction in odds of death among those without CVD and/or hypertension was not statistically significant. CONCLUSIONS: Patients taking statins prior to hospitalization for COVID-19 had substantially lower odds of death, primarily among individuals with a history of CVD and/or hypertension. These observations support the continuation and aggressive initiation of statin and anti-hypertensive therapies among patients at risk for COVID-19, if these treatments are indicated based upon underlying medical conditions.


Assuntos
Anti-Hipertensivos/administração & dosagem , COVID-19/epidemiologia , Doenças Cardiovasculares/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Sistema de Registros/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , American Heart Association , Anti-Hipertensivos/uso terapêutico , COVID-19/mortalidade , Doenças Cardiovasculares/tratamento farmacológico , Uso de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Grupos Populacionais/estatística & dados numéricos , Estados Unidos
6.
Proc Natl Acad Sci U S A ; 118(23)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34078669

RESUMO

Vaccine adjuvants enhance and prolong pathogen-specific protective immune responses. Recent reports indicate that host factors-such as aging, pregnancy, and genetic polymorphisms-influence efficacies of vaccines adjuvanted with Toll-like receptor (TLR) or known pattern-recognition receptor (PRR) agonists. Although PRR independent adjuvants (e.g., oil-in-water emulsion and saponin) are emerging, these adjuvants induce some local and systemic reactogenicity. Hence, new TLR and PRR-independent adjuvants that provide greater potency alone or in combination without compromising safety are highly desired. Previous cell-based high-throughput screenings yielded a small molecule 81 [N-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide], which enhanced lipopolysaccharide-induced NF-κB and type I interferon signaling in reporter assays. Here compound 81 activated innate immunity in primary human peripheral blood mononuclear cells and murine bone marrow-derived dendritic cells (BMDCs). The innate immune activation by 81 was independent of TLRs and other PRRs and was significantly reduced in mitochondrial antiviral-signaling protein (MAVS)-deficient BMDCs. Compound 81 activities were mediated by mitochondrial dysfunction as mitophagy inducers and a mitochondria specific antioxidant significantly inhibited cytokine induction by 81. Both compound 81 and a derivative obtained via structure-activity relationship studies, 2F52 [N-benzyl-N-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide] modestly increased mitochondrial reactive oxygen species and induced the aggregation of MAVS. Neither 81 nor 2F52 injected as adjuvants caused local or systemic toxicity in mice at effective concentrations for vaccination. Furthermore, vaccination with inactivated influenza virus adjuvanted with 2F52 demonstrated protective effects in a murine lethal virus challenge study. As an unconventional and safe adjuvant that does not require known PRRs, compound 2F52 could be a useful addition to vaccines.

7.
Lancet Oncol ; 22(6): 883-892, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33989559

RESUMO

BACKGROUND: Pembrolizumab (PD-1 inhibitor) and cetuximab (EGFR inhibitor) are active as single agents and in combination with cytotoxic chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Given each drug's single agent activity and unique mechanism of action, we aimed to evaluate the anti-tumour activity of PD-1 blockade with EGFR inhibition in recurrent or metastatic HNSCC. METHODS: This study is an open-label, non-randomised, multi-arm, phase 2 trial done at four academic centres in the USA. Participants were required to have platinum-resistant or platinum-ineligible, recurrent or metastatic HNSCC, be at least 18 years old, have an Eastern Cooperative Oncology Group performance status 0-1, have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and to have received no previous immunotherapy or EGFR inhibition. All participants received pembrolizumab 200 mg intravenously every 3 weeks, combined with an initial loading dose of cetuximab 400 mg/m2 intravenously followed by 250 mg/m2 intravenously weekly (21 day cycle). The primary endpoint was overall response rate defined as the proportion of participants with a partial or complete responses (per RECIST version 1.1) by 6 months in the intention-to-treat population. The safety population included all participants who received at least one dose of pembrolizumab. Herein, the final analysis of cohort 1 (no previous PD-1, PD-L1, or EGFR inhibition for recurrent or metastatic HNSCC) is reported. Three additional cohorts (two for participants with a previous response to immunotherapy followed by relapse or progression, with or without previous cetuximab exposure, and one for cutaneous HNSCC) will be reported separately once fully accrued. This study is registered with ClinicalTrials.gov, NCT03082534, and remains open as the three additional cohorts are actively accruing participants. FINDINGS: Between March 22, 2017, and July 16, 2019, 33 participants were enrolled to cohort 1. All 33 participants received at least one dose of pembrolizumab. Median follow-up duration was 7·3 months (IQR 3·9-10·9). By 6 months, the overall response rate was 45% (95% CI 28-62), with 15 of 33 participants achieving a partial response. The most common grade 3-4 treatment-related adverse event was oral mucositis (three [9%] of 33 participants), and serious treatment-related adverse events occurred in five (15%) participants. No treatment-related deaths occurred. INTERPRETATION: Pembrolizumab combined with cetuximab shows promising clinical activity for recurrent or metastatic HNSCC, and merits further investigation. FUNDING: Merck Sharp & Dohme.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cetuximab/administração & dosagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/genética , Cetuximab/efeitos adversos , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Receptor de Morte Celular Programada 1/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
8.
Radiol Imaging Cancer ; 3(1): e200062, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33575659

RESUMO

Purpose: To assess the cell-specific, intracellular partial pressure of oxygen (Po2) dynamics of both tumor and chimeric antigen receptor (CAR) T cells in a murine immunotherapy model. Materials and Methods: Human glioblastoma cells or human T cells were intracellularly labeled with perfluorocarbon nanoemulsion droplet sensors prior to in vivo injection in severe combined immunodeficient mice to measure Po2 in the two cell types in response to treatment. Two main sets of experiments were performed: (a) mice were injected in the flank with perfluorocarbon-labeled human glioblastoma cells and were then inoculated with either CAR T cells or untransduced T cells or were untreated 5 days after tumor inoculation; and (b) mice with unlabeled glioblastoma tumors were inoculated with perfluorocarbon-labeled CAR T cells or untransduced T cells 5 days after tumor inoculation. Longitudinal fluorine 19 (19F) spin-lattice relaxation time measurements of the tumor mass were used to ascertain absolute Po2 in vivo. Results were analyzed for significance using an analysis of variance, a linear mixed-effect model, and a Pearson correlation coefficient test, as appropriate. Results: The intracellular tumor cell Po2 temporal dynamics exhibited delayed, transient hyperoxia at 3 days after infusion of CAR T cells, commensurate with significant tumor cell killing and CAR T-cell infiltration, as observed by bioluminescence imaging and histologic findings. Conversely, no significant changes were detected in CAR or untransduced T-cell intracellular Po2 over time in tumor using these same methods. Moreover, it was observed that the total 19F tumor cell signal quenches with treatment, consistent with rapid tissue clearance of probe from apoptotic tumor cells. Conclusion: Cell-specific Po2 measurements using perfluorocarbon probes can provide insights into effector cell function and tumor response in cellular immunotherapeutic cancer models.Keywords: Animal Studies, MR-Imaging, MR-Spectroscopy, Molecular Imaging-Cancer, Molecular Imaging-Immunotherapy Supplemental material is available for this article. © RSNA, 2021See also commentary by Bulte in this issue.


Assuntos
Glioma , Receptores de Antígenos Quiméricos , Animais , Terapia Baseada em Transplante de Células e Tecidos , Modelos Animais de Doenças , Imageamento por Ressonância Magnética , Camundongos , Camundongos SCID , Oximetria
9.
Pediatrics ; 147(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33431589

RESUMO

OBJECTIVES: To identify predictors of becoming a daily cigarette smoker over the course of 4 years. METHODS: We identified 12- to 24-year-olds at wave 1 of the US Population Assessment of Tobacco and Health Study and determined ever use, age at first use, and daily use through wave 4 for 12 tobacco products. RESULTS: Sixty-two percent of 12- to 24-year-olds (95% confidence interval [CI]: 60.1% to 63.2%) tried tobacco, and 30.2% (95% CI: 28.7% to 31.6%) tried ≥5 tobacco products by wave 4. At wave 4, 12% were daily tobacco users, of whom 70% were daily cigarette smokers (95% CI: 67.4% to 73.0%); daily cigarette smoking was 20.8% in 25- to 28-year-olds (95% CI: 18.9% to 22.9%), whereas daily electronic cigarette (e-cigarette) vaping was 3.3% (95% CI: 2.4% to 4.4%). Compared with single product triers, the risk of progressing to daily cigarette smoking was 15 percentage points higher (adjusted risk difference [aRD] 15%; 95% CI: 12% to 18%) among those who tried ≥5 products. In particular, e-cigarette use increased the risk of later daily cigarette smoking by threefold (3% vs 10%; aRD 7%; 95% CI: 6% to 9%). Daily smoking was 6 percentage points lower (aRD -6%; 95% CI: -8% to -4%) for those who experimented after age 18 years. CONCLUSIONS: Trying e-cigarettes and multiple other tobacco products before age 18 years is strongly associated with later daily cigarette smoking. The recent large increase in e-cigarette use will likely reverse the decline in cigarette smoking among US young adults.


Assuntos
Fumar Cigarros/epidemiologia , Fumar Cigarros/tendências , Sistemas Eletrônicos de Liberação de Nicotina , Produtos do Tabaco , Vaping/epidemiologia , Vaping/tendências , Adolescente , Criança , Feminino , Humanos , Estudos Longitudinais , Masculino , Vigilância da População , Fumar/epidemiologia , Fumar/tendências , Estados Unidos/epidemiologia , Adulto Jovem
10.
Nicotine Tob Res ; 23(6): 909-919, 2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-33196799

RESUMO

INTRODUCTION: This study compared tobacco use and cessation for African Americans (AA), Asians/Pacific Islanders (API), Hispanics/Latinos (H/L), American Indian/Alaskan Natives (AI/AN), and non-Hispanic Whites (NHW) in the United States to California (CA), the state with the longest continually funded tobacco control program. The purpose of this study was to identify tobacco use disparities across racial/ethnic groups across time. METHODS: Cigarette use prevalence (uptake and current use), consumption (mean number of cigarettes smoked per day [CPD]), and quit ratios were calculated across survey years, and trends were examined within each race/ethnic group and comparing between CA and the United States, utilizing the 1992-2019 Tobacco Use Supplements to the Current Population Survey. RESULTS: Prevalence decreased for all race/ethnic groups. Current use among CA NHW showed significant decline compared with US counterparts, whereas US H/L showed greater decline than CA counterparts. CPD decreased by approximately 30% across race/ethnic groups, with CA groups having lower numbers. The greatest decrease occurred among AA in CA (average 10.3 CPD [95% confidence interval (CI): 10.3, 12.6] in 1992/1993 to 3 CPD [95% CI: 2.4, 3.7] in 2018/2019). Quit ratios increased from 1992/1993 to 2018/2019 for CA H/L 52.4% (95% CI: 49.8, 53.0) to 59.3 (95% CI: 55.8, 62.5) and CA NHWs 61.5% (95% CI: 60.7, 61.9) to 63.8% (95% CI: 63.9, 66.9). CONCLUSIONS: Although overall prevalence decreased over time for each racial/ethnic group, declines in CA outpaced the United States only for NHWs. Reductions in CPD were encouraging but the quit ratio points to the need to increase tobacco control efforts toward cessation. IMPLICATIONS: The successes in reduced cigarette use uptake and prevalence across time for both California and the rest of the United States were observed largely among non-Hispanic White populations. Although reductions in the number of cigarettes smoked per day are a notable success, particularly among the Californian African Americans, efforts to support quitting across racial/ethnic groups, especially marginalized groups, need to be prioritized.

11.
Tob Control ; 30(3): 312-319, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32345609

RESUMO

INTRODUCTION: Graphic warning labels on cigarette packaging are mandated in 118 countries and are under consideration in the USA. We propose an appeal-aversion assessment tool to help regulators choose among graphic packaging options. METHODS: After familiarisation with different cigarette packaging, adult daily smokers (n=338) from San Diego, California, USA completed a discrete choice appeal-aversion purchasing task and provided information on nicotine dependence and sociodemographics (2017-2019). The conjoint analysis estimated the importance and price utility for product attributes (ie, packaging, price, tobacco origin and quitline number). The price premiums that smokers would be willing to pay to avoid purchasing graphic packaging were calculated. RESULTS: Among purchase determinants, the price was the most important attribute (65.5%), followed by packaging design (27.1%). Compared with blank packaging without marketing, branded industry packs had appeal valuations (US$0.54; 95% CI: US$0.44 to US$0.65), whereas graphic warning packs had aversion valuations that varied with the salience of the image (blindness=-US$2.53, 95% CI: -US$2.76 to -US$2.31; teeth damage=-US$2.90, 95% CI: -US$3.17 to -US$2.63; and gangrenous foot=-US$3.70, 95% CI: -US$4.01 to -US$3.39). The aversion was such that 46.2% of participants were willing to pay a 50+% premium over their current cigarette price to have their branded packs rather than a graphic pack. These appeal-aversion valuations were moderated by sex, income and nicotine dependence (p<0.05). CONCLUSIONS: Smokers indicated a willingness to pay substantial premiums to avoid purchasing graphic packaging. Results suggest that mandating graphic warnings on US cigarette packs would induce price aversion and may deter cigarette purchasing. Price valuations from this appeal-aversion tool could be useful for regulators to differentiate between graphic warning labels.

13.
J Nucl Med ; 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33277399

RESUMO

Inflammation is associated with a range of serious human conditions including autoimmune and cardiovascular diseases and cancer. The ability to image active inflammatory processes greatly enhances our ability to diagnose and treat these diseases at an early stage. We describe molecular compositions enabling sensitive and precise imaging of inflammatory hotspots in vivo. Methods: Functionalized fluorocarbon nanoemulsion, with fluorous-encapsulated radiometal chelate (FERM), serves as a platform for multimodal imaging probe development. The 19F-containing FERM nanoemulsion encapsulates 89Zr in the fluorous oil, via fluorinated hydroxamic acid chelate. Simple mixing of radiometal with pre-formed aqueous nanoemulsion prior to use yields FERM, a stable in vivo cell tracer, enabling whole-body 89Zr positron emission tomography (PET) and 19F magnetic resonance imaging (19F MRI) following a single intravenous injection. Results: FERM nanoemulsion is intrinsically taken up by phagocytic immune cells, particularly macrophages, with high specificity. FERM stability is demonstrated by a high correlation between 19F and 89Zr content in blood (correlation coefficient > 0.99). Image sensitivity is observed in an acute infection rodent model at low dose (37 kBq). The versatility of FERM is further demonstrated in inflammatory bowel disease and 4T1 tumor models. Conclusion: Multimodal detection using FERM yields robust whole-body lesion detection and leverages the strengths of combined PET/19F MRI. FERM nanoemulsion production is scalable and potentially useful for precise diagnosis, stratification and treatment monitoring of inflammatory diseases.

14.
PLoS One ; 15(9): e0237938, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32877429

RESUMO

BACKGROUND: More smokers report using e-cigarettes to help them quit than FDA-approved pharmacotherapy. OBJECTIVE: To assess the association of e-cigarettes with future abstinence from cigarette and tobacco use. DESIGN: Cohort study of US sample, with annual follow-up. PARTICIPANTS: US adult (ages 18+) daily cigarette smokers identified at Wave 1 (W1; 2013-14) of the PATH Study, who reported a quit attempt before W2 and completed W3 (n = 2443). EXPOSURES: Use of e-cigarettes, pharmacotherapy (including nicotine replacement therapy), or no product for last quit attempt (LQA), and current daily e-cigarette use at W2. ANALYSIS: Propensity score matching (PSM) of groups using different methods to quit. OUTCOME MEASURES: 12+ months abstinence at W3 from cigarettes and from all tobacco (including e-cigarettes). 30+ days abstinence at W3 was a secondary outcome. RESULTS: Among daily smokers with an LQA, 23.5% used e-cigarettes, 19.3% used pharmacotherapy only (including NRT) and 57.2% used no product. Cigarette abstinence for 12+ months at W3 was ~10% in each group. Half of the cigarette abstainers in the e-cigarette group were using e-cigarettes at W3. Different methods to help quitting had statistically comparable 12+ month cigarette abstinence at W3 (e-cigarettes vs no product: Risk Difference (RD) = 0.01, 95% CI: -0.04 to 0.06; e-cigarettes vs pharmacotherapy: RD = 0.02, 95% CI:-0.04 to 0.09). Likewise, daily e-cigarette users at W2 did not show a cessation benefit over comparable no-e-cigarette users and this finding was robust to sensitivity analyses. Abstinence for 30+ days at W3 was also similar across products. LIMITATIONS: The frequency of e-cigarette use during the LQA was not assessed, nor was it possible to assess continuous abstinence from the LQA. CONCLUSION: Among US daily smokers who quit cigarettes in 2014-15, use of e-cigarettes in that attempt compared to approved cessation aids or no products showed similar abstinence rates 1-2 years later.


Assuntos
Fumar Cigarros/efeitos adversos , Tratamento Farmacológico/estatística & dados numéricos , Sistemas Eletrônicos de Liberação de Nicotina/estatística & dados numéricos , Abandono do Hábito de Fumar/métodos , Tabagismo/terapia , Vaping/efeitos adversos , Adolescente , Adulto , Terapia Comportamental , Fumar Cigarros/psicologia , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Abandono do Hábito de Fumar/psicologia , Fatores de Tempo , Dispositivos para o Abandono do Uso de Tabaco/efeitos adversos , Tabagismo/epidemiologia , Tabagismo/etiologia , Estados Unidos/epidemiologia , Adulto Jovem
15.
Contemp Clin Trials ; 98: 106152, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32966877

RESUMO

BACKGROUND: The US lags behind >120 countries in implementing graphic warning labels (GWLs) on cigarette packs. US courts prevented implementation of FDA's 2012 rule requiring GWLs citing the need for more evidence on effectiveness. After more research, in 2020, the FDA proposed a revised rule mandating GWLs. This trial will test how the introduction of GWLs influence cognitions and behavior in US smokers. METHOD: To investigate the "real-world" impact of GWLs in US smokers, we are conducting a randomized trial involving a 3-month intervention and 8-month follow-up. The study recruited California smokers between September 2016 through December 2019 and randomly assigned them into 3 groups (1) Blank Pack devoid of any cigarette branding; (2) GWL Pack featuring 1 of 3 rotating images added to blank pack; or (3) their usual Standard US Pack. Throughout the 3-month intervention, participants purchased study-packaged cigarettes and reported daily cognitions and behavior through ecological momentary assessments. We will validate self-reported tobacco use with saliva cotinine concentrations following the 3-month intervention and 8-month follow-up. RESULTS: The trial enrolled 359 participants (average age 39 years; average cigarette consumption half a pack/day). The 3 study groups were balanced on age, gender, race-ethnicity, education and income (17% low income) as well as on smoking related variables. CONCLUSIONS: This 3-month real-world randomized trial will test the effect of repackaging cigarettes from standard US packs to GWL plain packs on smokers' perceptions of the risks of smoking, their perception of the appeal of their cigarettes, and on their smoking behavior.

16.
Am J Cardiol ; 136: 149-155, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32946859

RESUMO

The impact of statins, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) on coronavirus disease 2019 (COVID-19) severity and recovery is important given their high prevalence of use among individuals at risk for severe COVID-19. We studied the association between use of statin/angiotensin-converting enzyme inhibitors/ARB in the month before hospital admission, with risk of severe outcome, and with time to severe outcome or disease recovery, among patients hospitalized for COVID-19. We performed a retrospective single-center study of all patients hospitalized at University of California San Diego Health between February 10, 2020 and June 17, 2020 (n = 170 hospitalized for COVID-19, n = 5,281 COVID-negative controls). Logistic regression and competing risks analyses were used to investigate progression to severe disease (death or intensive care unit admission), and time to discharge without severe disease. Severe disease occurred in 53% of COVID-positive inpatients. Median time from hospitalization to severe disease was 2 days; median time to recovery was 7 days. Statin use prior to admission was associated with reduced risk of severe COVID-19 (adjusted OR 0.29, 95%CI 0.11 to 0.71, p < 0.01) and faster time to recovery among those without severe disease (adjusted HR for recovery 2.69, 95%CI 1.36 to 5.33, p < 0.01). The association between statin use and severe disease was smaller in the COVID-negative cohort (p for interaction = 0.07). There was potential evidence of faster time to recovery with ARB use (adjusted HR 1.92, 95%CI 0.81 to 4.56). In conclusion, statin use during the 30 days prior to admission for COVID-19 was associated with a lower risk of developing severe COVID-19, and a faster time to recovery among patients without severe disease.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pneumonia Viral/epidemiologia , Adulto , Idoso , COVID-19 , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/terapia , Cuidados Críticos , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/terapia , Recuperação de Função Fisiológica , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença
17.
Front Immunol ; 11: 1207, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32636840

RESUMO

The limited efficacy of seasonal influenza vaccines is usually attributed to ongoing variation in the major antigenic targets for protective antibody responses including hemagglutinin (HA) and neuraminidase (NA). Hence, vaccine development has largely focused on broadening antigenic epitopes to generate cross-reactive protection. However, the vaccine adjuvant components which can accelerate, enhance and prolong antigenic immune responses, can also increase the breadth of these responses. We previously demonstrated that the combination of synthetic small-molecule Toll-like receptor 4 (TLR4) and TLR7 ligands is a potent adjuvant for recombinant influenza virus HA, inducing rapid, and sustained antibody responses that are protective against influenza viruses in homologous and heterologous murine challenge models. To further enhance adjuvant efficacy, we performed a structure-activity relationship study for the TLR4 ligand, N-cyclohexyl-2-((5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyrimido[5,4-b]indol-2-yl)thio)acetamide (C25H26N4O2S; 1Z105), and identified the 8-(furan-2-yl) substituted pyrimido[5,4-b]indole analog (C29H28N4O3S; 2B182C) as a derivative with higher potency in activating both human and mouse TLR4-NF-κB reporter cells and primary cells. In a prime-boost immunization model using inactivated influenza A virus [IIAV; A/California/04/2009 (H1N1)pdm09], 2B182C used as adjuvant induced higher serum anti-HA and anti-NA IgG1 levels compared to 1Z105, and also increased the anti-NA IgG2a responses. In combination with a TLR7 ligand, 1V270, 2B182C induced equivalent levels of anti-NA and anti-HA IgG1 to 1V270+1Z105. However, the combination of 1V270+2B182C induced 10-fold higher anti-HA and anti-NA IgG2a levels compared to 1V270+1Z105. A stable liposomal formulation of 1V270+2B182C was developed, which synergistically enhanced anti-HA and anti-NA IgG1 and IgG2a responses without demonstrable reactogenicity after intramuscular injection. Notably, vaccination with IIAV plus the liposomal formulation of 1V270+2B182C protected mice against lethal homologous influenza virus (H1N1)pdm09 challenge and reduced lung viral titers and cytokine levels. The combination adjuvant induced a greater diversity in B cell clonotypes of immunoglobulin heavy chain (IGH) genes in the draining lymph nodes and antibodies against a broad spectrum of HA epitopes encompassing HA head and stalk domains and with cross-reactivity against different subtypes of HA and NA. This novel combination liposomal adjuvant contributes to a more broadly protective vaccine while demonstrating an attractive safety profile.


Assuntos
Adjuvantes Imunológicos/farmacologia , Anticorpos Antivirais/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/imunologia , Infecções por Orthomyxoviridae/imunologia , Animais , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Humanos , Lipossomos , Camundongos , Neuraminidase/imunologia , Receptor 4 Toll-Like/imunologia , Receptor 7 Toll-Like/imunologia
18.
Am J Epidemiol ; 189(12): 1529-1537, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32715314

RESUMO

Electronic cigarettes (e-cigarettes) are the preferred smoking-cessation aid in the United States; however, there is little evidence regarding long-term effectiveness among those who use them. We used the Population Assessment of Tobacco and Health Study to compare long-term abstinence between matched US smokers who tried to quit with and without use of e-cigarettes as a cessation aid. We identified a nationally representative cohort of 2,535 adult US smokers in 2014-2015 (baseline assessment), who, in 2015-2016 (exposure assessment), reported a past-year attempt to quit and the cessation aids used, and reported smoking status in 2016-2017 (outcome assessment; self-reported ≥12 months continuous abstinence). We used propensity-score methods to match each e-cigarette user with similar nonusers. Among US smokers who used e-cigarettes to help quit, 12.9% (95% confidence interval (CI): 9.1%, 16.7%) successfully attained long-term abstinence. However, there was no difference compared with matched non-e-cigarette users (cigarette abstinence difference: 2%; 95% CI: -3%, 7%). Furthermore, fewer e-cigarette users were abstinent from nicotine products in the long term (nicotine abstinence difference: -4%; 95% CI: -7%, -1%); approximately two-thirds of e-cigarette users who successfully quit smoking continued to use e-cigarettes. These results suggest e-cigarettes may not be an effective cessation aid for adult smokers and, instead, may contribute to continuing nicotine dependence.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina/estatística & dados numéricos , Abandono do Hábito de Fumar/estatística & dados numéricos , Adolescente , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Estados Unidos , Adulto Jovem
19.
J Transl Med ; 18(1): 214, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32466781

RESUMO

BACKGROUND: Immunotherapeutic regulation of the tumor microenvironment in prostate cancer patients is not understood. Most antibody immunotherapies have not succeeded in prostate cancer. We showed previously that high-risk PCa patients have a higher density of tumor infiltrating B-cells in prostatectomy specimens. In mouse models, anti-CD20 antibody ablation of B-cells delayed PCa regrowth post-treatment. We sought to determine whether neoadjuvant anti-CD20 immunotherapy with rituximab could reduce CD20+ B cell infiltration of prostate tumors in patients. METHODS: An open label, single arm clinical trial enrolled eight high-risk PCa patients to receive one cycle of neoadjuvant rituximab prior to prostatectomy. Eleven clinical specimens with similar characteristics were selected as controls. Treated and control samples were concurrently stained for CD20 and digitally scanned in a blinded fashion. A new method of digital image quantification of lymphocytes was applied to prostatectomy sections of treated and control cases. CD20 density was quantified by a deconvolution algorithm in pathologist-marked tumor and adjacent regions. Statistical significance was assessed by one sided Welch's t-test, at 0.05 level using a gatekeeper strategy. Secondary outcomes included CD3+ T-cell and PD-L1 densities. RESULTS: Mean CD20 density in the tumor regions of the treated group was significantly lower than the control group (p = 0.02). Mean CD3 density in the tumors was significantly decreased in the treated group (p = 0.01). CD20, CD3 and PD-L1 staining primarily occurred in tertiary lymphoid structures (TLS). Neoadjuvant rituximab was well-tolerated and decreased B-cell and T-cell density within high-risk PCa tumors compared to controls. CONCLUSIONS: This is the first study to treat patients prior to surgical prostate removal with an immunotherapy that targets B-cells. Rituximab treatment reduced tumor infiltrating B and T-cell density especially in TLSs, thus, demonstrating inter-dependence between B- and T-cells in prostate cancer and that Rituximab can modify the immune environment in prostate tumors. Future studies will determine who may benefit from using rituximab to improve their immune response against prostate cancer. Trial registration NCT01804712, March 5th, 2013 https://clinicaltrials.gov/ct2/show/NCT01804712?cond=NCT01804712&draw=2&rank=1.


Assuntos
Terapia Neoadjuvante , Neoplasias da Próstata , Animais , Antígeno B7-H1 , Humanos , Linfócitos do Interstício Tumoral , Masculino , Camundongos , Prostatectomia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/cirurgia , Rituximab/uso terapêutico , Linfócitos T , Microambiente Tumoral
20.
Br J Cancer ; 123(4): 568-579, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32457362

RESUMO

BACKGROUND: Regorafenib is an inhibitor of multiple kinases with aberrant expression and activity in neuroblastoma tumours that have potential roles in neuroblastoma pathogenesis. METHODS: We evaluated neuroblastoma cells treated with regorafenib for cell viability and confluence, and analysed treated cells for apoptosis and cell cycle progression. We evaluated the efficacy of regorafenib in vivo using an orthotopic xenograft model. We evaluated regorafenib-mediated inhibition of kinase targets and performed reverse-phase protein array (RPPA) analysis of neuroblastoma cells treated with regorafenib. Lastly, we evaluated the efficacy and effects of the combination of regorafenib and 13-cis-retinoic acid on intracellular signalling. RESULTS: Regorafenib treatment resulted in reduced neuroblastoma cell viability and confluence, with both induction of apoptosis and of cell cycle arrest. Regorafenib treatment inhibits known receptor tyrosine kinase targets RET and PDGFRß and intracellular signalling through the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways. Regorafenib is effective against neuroblastoma tumours in vivo, and the combination of regorafenib and 13-cis-retinoic acid demonstrates enhanced efficacy compared with regorafenib alone. CONCLUSIONS: The effects of regorafenib on multiple intracellular signalling pathways and the potential additional efficacy when combined with 13-cis-retinoic acid represent opportunities to develop treatment regimens incorporating regorafenib for children with neuroblastoma.


Assuntos
Isotretinoína/administração & dosagem , Neuroblastoma/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Isotretinoína/farmacologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Compostos de Fenilureia/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Piridinas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas ras/metabolismo
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