Growth Stimulation of Pulmonary Adenocarcinoma and their Cells of Origin by Chemopreventive Agents that Increase Intracellular cAMP

Lung cancer is the leading cause of cancer mortality for men and women in the United States, with a high mortality rate and a five-year survival rate of less than 15%. Cancer ranks second as a cause of death for Americans after cardiovascular disease. The American Cancer Society (ACS) reported 171,900 new cases of lung cancer for 2003 (ACS, 2003). Peripheral adenocarcinoma (PAC) of the lung has increased dramatically over the last 20 years and is the leading histological type of lung cancer in smokers and nonsmokers in industrialized countries, including the United States. Among the four main histological lung cancer types (small-cell carcinoma, squamous-cell carcinoma, adenocarcinoma and large-cell carcinoma), adenocarcinoma that is derived from small-airway epithelia with features of Clara cells accounts for about 35-40% of all lung cancer cases. Unlike other histological lung cancer types, adenocarcinoma also develops in a significant number of non-smokers. Smoking remains the greatest contributor to the development of lung cancer, with 90% of all lung cancer cases estimated to be smoking related. Cigarette smoke contains about 4,000 toxic chemicals including the highly carcinogenic nitrosamine, 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanone (NNK). NNK is the most potent carcinogen in laboratory animals and has therefore been implicated as a significant cause of tobacco-associated cancers in human. Dietary and genetically determined factors appear to play an important role in modulating individual susceptibility to smoking-associated cancer and are closely linked to the chemoprevention approach. Chemoprevention is defined as the use of naturally occurring or synthetic agents to prevent, inhibit or reverse the process of carcinogenesis. This relatively new approach of cancer prevention has precedence in other areas of medicine such as cardiovascular diseases. Earlier studies have shown the presence of a β-adrenergic/cAMP growth-regulating pathway in PAC. Therefore, β-adrenergic stimulants in various drugs that are used for the treatment of chronic respiratory and cardiovascular diseases have been proposed as potential risk factors for the development of PAC. Furthermore, little is known about the downstream effectors of this pathway and their role in the regulation of proliferation of PAC and their normal cells of origin. Using assays for the assessment of cAMP production, PKA activity, MAPK activation, CREB activation, and cell proliferation, we have identified a mitogenic pathway, which activates cAMP in cell lines derived from human peripheral adenocarcinomas that express features of Clara cells and their normal cells of origin, small airway epithelial cells (SAEC). β -carotene and a substance contained in green and black tea, theophylline are widely believed to have cancer preventive effect. However, our current data show that each of these agents increases cAMP/PKA activity, ERK1/2 and CREB resulting in a significant growth stimulation of PAC and SAEC. Accordingly, and pending on the exact level targeted by a given chemopreventive agents, such treatments will likely promote the development of PAC. While some of these agents may inhibit the metabolic activation of tobacco carcinogens, such as NNK, former smokers who start chemoprevention will not benefit from such effects as they start chemopreventive treatment of after discontinuation of exposure to tobacco carcinogens. Currently, there is no agent that has been shown to be effective in preventing lung cancer. Accordingly, the most effective prevention of lung-cancer is never to smoke and to avoid exposure to second hand smoke. Our study findings suggest that the widely advertised cancer preventive agents that currently are still tested by several laboratories as “chemopreventive” agents such as β-carotene and a substance contained in green and black tea, theophylline are unsafe to be used by smoker or by ex-smokers due to their tumor promoting effects via stimulation of cAMP on initiated cells of Clara cell lineage

On Generalized Closed Sets and Generalized Pre-Closed Sets in Neutrosophic Topological Spaces

In this paper, the concept of generalized neutrosophic pre-closed sets and generalized neutrosophic pre-open sets are introduced. We also study relations and various properties between the other existing neutrosophic open and closed sets. In addition, we discuss some applications of generalized neutrosophic pre-closed sets, namely neutrosophic pT12 space and neutrosophic gpT12 space. The concepts of generalized neutrosophic connected spaces, generalized neutrosophic compact spaces and generalized neutrosophic extremally disconnected spaces are established. Some interesting properties are investigated in addition to giving some examples

(Φ, Ψ)-Weak Contractions in Neutrosophic Cone Metric Spaces via Fixed Point Theorems

In this manuscript, we obtain common fixed point theorems in the neutrosophic cone metric space. Also, notion of (Φ, Ψ)-weak contraction is defined in the neutrosophic cone metric space by using the idea of altering distance function. Finally, we review many examples of cone metric spaces to verify some properties

Female authorship in major endocrinology journals: a 25-year progression

Context: The number of women in academic medicine has increased significantly in recent years. However, female authors are underrepresented in major medical journals.Objective: The aim was to determine the distribution of female first and senior authors of original articles in four American endocrinology journals over a period of 25 years.Design: A retrospective analysis of the literature was undertaken.Setting: Four journals were selected: Journal of Clinical Endocrinology & Metabolism; Thyroid; Journal of Bone and Mineral Research and Diabetes Care.Participants: The first and senior authors of all original articles published in 1991, 1996, 2001, 2006 and 2015 were included.Intervention: none.Results: The main outcome measure was the distribution of female first and senior authors of original articles. A total of 4 148 articles were included. Of these, 28.9% (1 199) articles were authored by females of whom 751 (62%) were first authors. Over the study period, there was a shift towards female authorship. A statistically significant trend was observed (p < 0.001).Keywords: authorship and gender, endocrinolog

Cooperative Regulation of Non-Small Cell Lung Carcinoma by Nicotinic and Beta-Adrenergic Receptors: A Novel Target for Intervention

Lung cancer is the leading cause of cancer death; 80–85% of lung cancer cases are non-small cell lung cancer (NSCLC). Smoking is a documented risk factor for the development of this cancer. Although nicotine does not have the ability to initiate carcinogenic events, recent studies have implicated nicotine in growth stimulation of NSCLC. Using three NSCLC cell lines (NCI-H322, NCI-H441 and NCI-H1299), we identified the cooperation of nicotinic acetylcholine receptors (nAChRs) and β-adrenergic receptors (β-ARs) as principal regulators of these effects. Proliferation was measured by thymidine incorporation and MTT assays, and Western blots were used to monitor the upregulation of the nAChRs and activation of signaling molecules. Noradrenaline and GABA were measured by immunoassays. Nicotine-treated NSCLC cells showed significant induction of the α7nAChR and α4nAChR, along with significant inductions of p-CREB and p-ERK1/2 accompanied by increases in the stress neurotransmitter noradrenaline, which in turn led to the observed increase in DNA synthesis and cell proliferation. Effects on cell proliferation and signaling proteins were reversed by the α7nAChR antagonist α-BTX or the β-blocker propranolol. Nicotine treatment also down-regulated expression of the GABA synthesizing enzyme GAD 65 and the level of endogenous GABA, while treatment of NSCLC cells with GABA inhibited cell proliferation. Interestingly, GABA acts by reducing β-adrenergic activated cAMP signaling. Our findings suggest that nicotine-induced activation of this autocrine noradrenaline-initiated signaling cascade and concomitant deficiency in inhibitory GABA, similar to modulation of these neurotransmitters in the nicotine-addicted brain, may contribute to the development of NSCLC in smokers. Our data suggest that exposure to nicotine either by tobacco smoke or nicotine supplements facilitates growth and progression of NSCLC and that pharmacological intervention by β blocker may lower the risk for NSCLC development among smokers and could be used to enhance the clinical outcome of standard cancer therapy

New Challenges in Neutrosophic Theory and Applications

Neutrosophic theory has representatives on all continents and, therefore, it can be said to be a universal theory. On the other hand, according to the three volumes of “The Encyclopedia of Neutrosophic Researchers” (2016, 2018, 2019), plus numerous others not yet included in Encyclopedia book series, about 1200 researchers from 73 countries have applied both the neutrosophic theory and method. Neutrosophic theory was founded by Professor Florentin Smarandache in 1998; it constitutes further generalization of fuzzy and intuitionistic fuzzy theories. The key distinction between the neutrosophic set/logic and other types of sets/logics lies in the introduction of the degree of indeterminacy/neutrality (I) as an independent component in the neutrosophic set. Thus, neutrosophic theory involves the degree of membership-truth (T), the degree of indeterminacy (I), and the degree of non-membership-falsehood (F). In recent years, the field of neutrosophic set, logic, measure, probability and statistics, precalculus and calculus, etc., and their applications in multiple fields have been extended and applied in various fields, such as communication, management, and information technology. We believe that this book serves as useful guidance for learning about the current progress in neutrosophic theories. In total, 22 studies have been presented and reflect the call of the thematic vision. The contents of each study included in the volume are briefly described as follows. The first contribution, authored by Wadei Al-Omeri and Saeid Jafari, addresses the concept of generalized neutrosophic pre-closed sets and generalized neutrosophic pre-open sets in neutrosophic topological spaces. In the article “Design of Fuzzy Sampling Plan Using the Birnbaum-Saunders Distribution”, the authors Muhammad Zahir Khan, Muhammad Farid Khan, Muhammad Aslam, and Abdur Razzaque Mughal discuss the use of probability distribution function of Birnbaum–Saunders distribution as a proportion of defective items and the acceptance probability in a fuzzy environment. Further, the authors Derya Bakbak, Vakkas Uluc¸ay, and Memet S¸ahin present the “Neutrosophic Soft Expert Multiset and Their Application to Multiple Criteria Decision Making” together with several operations defined for them and their important algebraic properties. In “Neutrosophic Multigroups and Applications”, Vakkas Uluc¸ay and Memet S¸ahin propose an algebraic structure on neutrosophic multisets called neutrosophic multigroups, deriving their basic properties and giving some applications to group theory. Changxing Fan, Jun Ye, Sheng Feng, En Fan, and Keli Hu introduce the “Multi-Criteria Decision-Making Method Using Heronian Mean Operators under a Bipolar Neutrosophic Environment” and test the effectiveness of their new methods. Another decision-making study upon an everyday life issue which empowered us to organize the key objective of the industry developing is given in “Neutrosophic Cubic Einstein Hybrid Geometric Aggregation Operators with Application in Prioritization Using Multiple Attribute Decision-Making Method” written by Khaleed Alhazaymeh, Muhammad Gulistan, Majid Khan, and Seifedine Kadry

Gamma-aminobutyric acid, a potential tumor suppressor for small airway-derived lung adenocarcinoma

Pulmonary adenocarcinoma (PAC) is the leading type of lung cancer in smokers and non-smokers that arises in most cases from small airway epithelial cells. PAC has a high mortality due to its aggressive behavior and resistance to cancer therapeutics. We have shown previously that the proliferation of human PAC cells NCI-H322 and immortalized human small airway epithelial cells HPL1D is stimulated by cyclic adenosine monophosphate (cAMP)/protein kinase A-dependent phosphorylation of cyclic adenosine monophosphate response element-binding (CREB) protein and transactivation of the epidermal growth factor receptor and that this pathway is activated by beta-1-adrenoreceptors (β1-ARs) and the non-genomic estrogen receptor beta. Our current in vitro studies with HPL1D and NCI-H322 cells showed that signaling via the gamma-amino butyric acid receptor (GABABR) strongly inhibited base level and isoproterenol-induced cAMP, p-CREB, cyclic adenosine monophosphate response element-luciferase activity and p-extracellular regulated kinase-1 (ERK1)/2 and effectively blocked DNA synthesis and cell migration. The inhibitory effects of gamma-amino butyric acid (GABA) were disinhibited by the GABABR antagonist CGP-35348 or GABABR knockdown. Immunohistochemical investigation of hamster lungs showed significant underexpression of GABA in animals with small airway-derived PACs induced by the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These findings suggest that GABA may have tumor suppressor function in small airway epithelia and the PACs derived from them and that downregulation of GABA by NNK may contribute to the development of this cancer in smokers. Our findings suggest that marker-guided treatment with GABA or a GABABR agonist of individuals with downregulated pulmonary GABA may provide a novel targeted approach for the prevention of PAC in smokers

Race-Free Estimated Glomerular Filtration Rate Equation in Kidney Transplant Recipients: Development and Validation Study

OBJECTIVE: To compare the performance of a newly developed race-free kidney recipient specific glomerular filtration rate (GFR) equation with the three current main equations for measuring GFR in kidney transplant recipients. DESIGN: Development and validation study SETTING: 17 cohorts in Europe, the United States, and Australia (14 transplant centres, three clinical trials). PARTICIPANTS: 15 489 adults (3622 in development cohort (Necker, Saint Louis, and Toulouse hospitals, France), 11 867 in multiple external validation cohorts) who received kidney transplants between 1 January 2000 and 1 January 2021. MAIN OUTCOME MEASURE: The main outcome measure was GFR, measured according to local practice. Performance of the GFR equations was assessed using P RESULTS: The study included 15 489 participants, with 50 464 mGFR and eGFR values. The mean GFR was 53.18 mL/min/1.73m2 (SD 17.23) in the development cohort and 55.90 mL/min/1.73m2 (19.69) in the external validation cohorts. Among the current GFR equations, the race-free CKD-EPI 2021 equation showed the lowest performance compared with the MDRD and CKD-EPI 2009 equations. When race was included in the kidney recipient specific GFR equation, performance did not increase. The race-free kidney recipient specific GFR equation showed significantly improved performance compared with the race-free CKD-EPI 2021 equation and performed well in the external validation cohorts (P30 ranging from 73.0% to 91.3%). The race-free kidney recipient specific GFR equation performed well in several subpopulations of kidney transplant recipients stratified by race (P30 73.0-91.3%), sex (72.7-91.4%), age (70.3-92.0%), body mass index (64.5-100%), donor type (58.5-92.9%), donor age (68.3-94.3%), treatment (78.5-85.2%), creatinine level (72.8-91.3%), GFR measurement method (73.0-91.3%), and timing of GFR measurement post-transplant (72.9-95.5%). An online application was developed that estimates GFR based on recipient’s creatinine level, age, and sex (https://transplant-prediction-system.shinyapps.io/eGFR_equation_KTX/). CONCLUSION: A new race-free kidney recipient specific GFR equation was developed and validated using multiple, large, international cohorts of kidney transplant recipients. The equation showed high accuracy and outperformed the race-free CKD-EPI 2021 equation that was developed in individuals with native kidneys

Race-free estimated glomerular filtration rate equation in kidney transplant recipients:development and validation study

OBJECTIVE: To compare the performance of a newly developed race-free kidney recipient specific glomerular filtration rate (GFR) equation with the three current main equations for measuring GFR in kidney transplant recipients.DESIGN: Development and validation study SETTING: 17 cohorts in Europe, the United States, and Australia (14 transplant centres, three clinical trials).PARTICIPANTS: 15 489 adults (3622 in development cohort (Necker, Saint Louis, and Toulouse hospitals, France), 11 867 in multiple external validation cohorts) who received kidney transplants between 1 January 2000 and 1 January 2021.MAIN OUTCOME MEASURE: The main outcome measure was GFR, measured according to local practice. Performance of the GFR equations was assessed using P 30 (proportion of estimated GFR (eGFR) within 30% of measured GFR (mGFR)) and correct classification (agreement between eGFR and mGFR according to GFR stages). The race-free equation, based on creatinine level, age, and sex, was developed using additive and multiplicative linear regressions, and its performance was compared with the three current main GFR equations: Modification of Diet in Renal Disease (MDRD) equation, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation, and race-free CKD-EPI 2021 equation. RESULTS: The study included 15 489 participants, with 50 464 mGFR and eGFR values. The mean GFR was 53.18 mL/min/1.73m 2 (SD 17.23) in the development cohort and 55.90 mL/min/1.73m 2 (19.69) in the external validation cohorts. Among the current GFR equations, the race-free CKD-EPI 2021 equation showed the lowest performance compared with the MDRD and CKD-EPI 2009 equations. When race was included in the kidney recipient specific GFR equation, performance did not increase. The race-free kidney recipient specific GFR equation showed significantly improved performance compared with the race-free CKD-EPI 2021 equation and performed well in the external validation cohorts (P 30 ranging from 73.0% to 91.3%). The race-free kidney recipient specific GFR equation performed well in several subpopulations of kidney transplant recipients stratified by race (P 30 73.0-91.3%), sex (72.7-91.4%), age (70.3-92.0%), body mass index (64.5-100%), donor type (58.5-92.9%), donor age (68.3-94.3%), treatment (78.5-85.2%), creatinine level (72.8-91.3%), GFR measurement method (73.0-91.3%), and timing of GFR measurement post-transplant (72.9-95.5%). An online application was developed that estimates GFR based on recipient's creatinine level, age, and sex (https://transplant-prediction-system.shinyapps.io/eGFR_equation_KTX/). CONCLUSION: A new race-free kidney recipient specific GFR equation was developed and validated using multiple, large, international cohorts of kidney transplant recipients. The equation showed high accuracy and outperformed the race-free CKD-EPI 2021 equation that was developed in individuals with native kidneys.TRIAL REGISTRATION: ClinicalTrials.gov NCT05229939.</p