Allergic inflammation does not impact chemical-induced carcinogenesis in the lungs of mice

<p>Abstract</p> <p>Background</p> <p>Although the relationship between allergic inflammation and lung carcinogenesis is not clearly defined, several reports suggest an increased incidence of lung cancer in patients with asthma. We aimed at determining the functional impact of allergic inflammation on chemical carcinogenesis in the lungs of mice.</p> <p>Methods</p> <p>Balb/c mice received single-dose urethane (1 g/kg at day 0) and two-stage ovalbumin during tumor initiation (sensitization: days -14 and 0; challenge: daily at days 6-12), tumor progression (sensitization: days 70 and 84; challenge: daily at days 90-96), or chronically (sensitization: days -14 and 0; challenge: daily at days 6-12 and thrice weekly thereafter). In addition, interleukin (IL)-5 deficient and wild-type C57BL/6 mice received ten weekly urethane injections. All mice were sacrificed after four months. Primary end-points were number, size, and histology of lung tumors. Secondary end-points were inflammatory cells and mediators in the airspace compartment.</p> <p>Results</p> <p>Ovalbumin provoked acute allergic inflammation and chronic remodeling of murine airways, evident by airspace eosinophilia, IL-5 up-regulation, and airspace enlargement. Urethane resulted in formation of atypical alveolar hyperplasias, adenomas, and adenocarcinomas in mouse lungs. Ovalbumin-induced allergic inflammation during tumor initiation, progression, or continuously did not impact the number, size, or histologic distribution of urethane-induced pulmonary neoplastic lesions. In addition, genetic deficiency in IL-5 had no effect on urethane-induced lung tumorigenesis.</p> <p>Conclusions</p> <p>Allergic inflammation does not impact chemical-induced carcinogenesis of the airways. These findings suggest that not all types of airway inflammation influence lung carcinogenesis and cast doubt on the idea of a mechanistic link between asthma and lung cancer.</p

Effects of Single Nucleotide Polymorphisms on Human N-Acetyltransferase 2 Structure and Dynamics by Molecular Dynamics Simulation

BACKGROUND: Arylamine N-acetyltransferase 2 (NAT2) is an important catalytic enzyme that metabolizes the carcinogenic arylamines, hydrazine drugs and chemicals. This enzyme is highly polymorphic in different human populations. Several polymorphisms of NAT2, including the single amino acid substitutions R64Q, I114T, D122N, L137F, Q145P, R197Q, and G286E, are classified as slow acetylators, whereas the wild-type NAT2 is classified as a fast acetylator. The slow acetylators are often associated with drug toxicity and efficacy as well as cancer susceptibility. The biological functions of these 7 mutations have previously been characterized, but the structural basis behind the reduced catalytic activity and reduced protein level is not clear. METHODOLOGY/PRINCIPAL FINDINGS: We performed multiple molecular dynamics simulations of these mutants as well as NAT2 to investigate the structural and dynamical effects throughout the protein structure, specifically the catalytic triad, cofactor binding site, and the substrate binding pocket. None of these mutations induced unfolding; instead, their effects were confined to the inter-domain, domain 3 and 17-residue insert region, where the flexibility was significantly reduced relative to the wild-type. Structural effects of these mutations propagate through space and cause a change in catalytic triad conformation, cofactor binding site, substrate binding pocket size/shape and electrostatic potential. CONCLUSIONS/SIGNIFICANCE: Our results showed that the dynamical properties of all the mutant structures, especially in inter-domain, domain 3 and 17-residue insert region were affected in the same manner. Similarly, the electrostatic potential of all the mutants were altered and also the functionally important regions such as catalytic triad, cofactor binding site, and substrate binding pocket adopted different orientation and/or conformation relative to the wild-type that may affect the functions of the mutants. Overall, our study may provide the structural basis for reduced catalytic activity and protein level, as was experimentally observed for these polymorphisms

Cigarette smoke induces endoplasmic reticulum stress and the unfolded protein response in normal and malignant human lung cells

<p>Abstract</p> <p>Background</p> <p>Although lung cancer is among the few malignancies for which we know the primary etiological agent (i.e., cigarette smoke), a precise understanding of the temporal sequence of events that drive tumor progression remains elusive. In addition to finding that cigarette smoke (CS) impacts the functioning of key pathways with significant roles in redox homeostasis, xenobiotic detoxification, cell cycle control, and endoplasmic reticulum (ER) functioning, our data highlighted a defensive role for the unfolded protein response (UPR) program. The UPR promotes cell survival by reducing the accumulation of aberrantly folded proteins through translation arrest, production of chaperone proteins, and increased degradation. Importance of the UPR in maintaining tissue health is evidenced by the fact that a chronic increase in defective protein structures plays a pathogenic role in diabetes, cardiovascular disease, Alzheimer's and Parkinson's syndromes, and cancer.</p> <p>Methods</p> <p>Gene and protein expression changes in CS exposed human cell cultures were monitored by high-density microarrays and Western blot analysis. Tissue arrays containing samples from 110 lung cancers were probed with antibodies to proteins of interest using immunohistochemistry.</p> <p>Results</p> <p>We show that: 1) CS induces ER stress and activates components of the UPR; 2) reactive species in CS that promote oxidative stress are primarily responsible for UPR activation; 3) CS exposure results in increased expression of several genes with significant roles in attenuating oxidative stress; and 4) several major UPR regulators are increased either in expression (i.e., BiP and eIF2α) or phosphorylation (i.e., phospho-eIF2α) in a majority of human lung cancers.</p> <p>Conclusion</p> <p>These data indicate that chronic ER stress and recruitment of one or more UPR effector arms upon exposure to CS may play a pivotal role in the etiology or progression of lung cancers, and that phospho-eIF2α and BiP may have diagnostic and/or therapeutic potential. Furthermore, we speculate that upregulation of UPR regulators (in particular BiP) may provide a pro-survival advantage by increasing resistance to cytotoxic stresses such as hypoxia and chemotherapeutic drugs, and that UPR induction is a potential mechanism that could be attenuated or reversed resulting in a more efficacious treatment strategy for lung cancer.</p

Regional Image Features Model for Automatic Classification between Normal and Glaucoma in Fundus and Scanning Laser Ophthalmoscopy (SLO) Images

Glaucoma is one of the leading causes of blindness. There is no cure for glaucoma but detection at its earliest stage and subsequent treatment can aid patients to prevent blindness. Currently, optic disc and retinal imaging facilitates glaucoma detection but this method still requires manual post-imaging modifications that are time-consuming and do not totally remove subjectivity in image assessment. Therefore, it is necessary to automate this process. In this work, we have first proposed a novel computer aided approach for automatic glaucoma detection based on Regional Image Features Model (RIFM) which can automatically perform classification between normal and glaucoma images on the basis of regional information. Different from all the existing methods, our approach can extract both geometric (e.g. morphometric properties) and non-geometric based properties (e.g. pixel appearance/intensity values, texture) from images and significantly increase the classification performance. Our proposed approach consists of three new major contributions including automatic localisation of optic disc, automatic segmentation of disc, and classification between normal and glaucoma based on geometric and non-geometric properties of different regions of an image. We have compared our method with existing approaches and tested it on both fundus and Scanning laser ophthalmoscopy (SLO) images. The experimental results show that our proposed approach outperforms the state-of-the-art approaches using either geometric or non-geometric properties. The overall glaucoma classification accuracy for fundus is 94.4% and accuracy of detection of suspicion of glaucoma in SLO images is 93.9%

Measurement of quarkonium production cross sections in pp collisions at root s=13 TeV

Differential production cross sections of prompt J/psi and psi(2S) charmonium and Upsilon(nS) (n = 1, 2, 3) bottomonium states are measured in proton-proton collisions at root s = 13 TeV, with data collected by the CMS detector at the LHC, corresponding to an integrated luminosity of 2.3 fb(-1) for the J/psi and 2.7 fb(-1) for the other mesons. The five quarkonium states are reconstructed in the dimuon decay channel, for dimuon rapidity vertical bar y vertical bar <1.2. The double-differential cross sections for each state are measured as a function of y and transverse momentum, and compared to theoretical expectations. In addition, ratios are presented of cross sections for prompt psi(2S) to J/psi, Upsilon(2S) to Upsilon(1S), and Upsilon(3S) to Upsilon(1S) production. (C) 2018 The Author(s). Published by Elsevier B.V.Peer reviewe

Abstract P5-12-11: Evaluating overweight/obesity and physical activity rates in an ethnically diverse sample of breast cancer survivors

Abstract Introduction: Overweight/obesity are associated with higher risk of recurrence and poorer survival after a breast cancer diagnosis. According to The Centers for Disease Control and Prevention (CDC) Behavioral Risk Factor Surveillance System (BRFSS) data for 2011, in South Carolina, 74.6% of African American (AA) and 62.5% of European American (EA) adult women are overweight/obese. Methods: Prevalence of overweight/obesity and level of physical activity (PA) are evaluated in an ongoing, ethnically-diverse statewide study of adult women with recently-diagnosed invasive breast cancer. Participants are identified within 18 months post-diagnosis through the South Carolina Central Cancer Registry (SCCCR). Participants who opt in to the study are interviewed via telephone and self-report their body weight, height and physical activities. Published CDC body mass index (BMI) categories and 2008 PA guidelines are used to characterize BMI and PA guideline adherence. Results: During the first 10 months of the study, 98 women (56 AA, 42 EA) were interviewed and results analyzed. Age: Participants ranged in age from 26 to 90 years (mean 60.2 years, SD 12.8), with AAs 3.7 years younger than EAs (p = 0.16). Education: Almost two-thirds of participants (61%) had more than a high school diploma (55% of AAs and 69% of EAs, p = 0.29). BMI: The BMI mean was 30.1 (SD 6.6, median 26.6) which was significantly higher in AAs (31.3 compared to 28.6 in EAs, p = 0.04). Among all women combined, 79% were overweight/obese, with no statistically significant difference by race (p = 0.15). Overweight was equally frequent among AAs (34%) and EAs (33%). However, obesity was more frequent among AAs (50%) than EAs (38%). Physical Activity (PA): CDC guideline adherence of ≥150 minutes/week of moderate PA was reported by only 32% of participants (25% of AAs, 41% of EAs; p = 0.10). A total of 28% reported no physical activity (30% of AAs and 24% of EAs, p = 0.47). Meeting CDC PA guidelines was associated with lower risk of being overweight/obese (OR = 0.41, p = 0.080), but this was statistically significant only among EAs (OR = 0.21, p = 0.035). Conclusions: Prevalence of overweight/obesity is high, regardless of ethnicity, and physical activity is low in this group of breast cancer survivors. It is imperative to identify effective strategies to reduce overweight and obesity, and to increase PA, in order to reduce the risk of recurrence and improve survival. In this regard, the study team is developing an National Institutes of Health R01 grant application to evaluate the effectiveness of an intervention, which combines a reduced-energy diet with increased PA, in reducing levels of cancer-related inflammatory biomarkers linked to breast cancer recurrence. Updated results of our on-going study, including associations of BMI and PA with breast cancer stage and phenotype, will be presented. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-12-11.</jats:p

New insights into the sympathetic, endothelial and coronary effects of nicotine.

1. Nicotine is a well studied pleiotropic agent which occurs naturally in tobacco smoke and has been largely accused for many of the adverse effects of smoking on the cardiovascular system, including autonomic imbalance, endothelial dysfunction and coronary blood flow dysregulation. 2. The acute sympathoexcitatory effects of smoking on the cardiovascular system are partially mediated by catecholamine release, muscle sympathetic nerve excitation and peripheral chemoreceptor sensitivity increase, consecutive to nicotinic receptor stimulation in the autonomic nervous system. 3. Recent animal data suggest that nicotine promotes the oxidative and inflammatory stress to the endothelium and induces pathological angiogenesis, leading to the progression of the atherosclerotic lesions. 4. Nicotine increases myocardial work without impairing the physiological coronary vasodilatation. Consequently, nicotine per se cannot explain the sudden reduction in coronary flow reserve after exposure to both active and passive smoking. 5. Nicotine's biological effects are characterized by a rapid onset of tolerance, which can explain why nicotine administration does not elicit acute coronary and chemoreflex side-effect in smokers.Journal ArticleResearch Support, Non-U.S. Gov'tReviewFLWINinfo:eu-repo/semantics/publishe