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Quit Smoking Magic

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Quit Smoking Magic Summary

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Cigarette Smoking And The Risk Of Stroke

Heavy smoking (> 20 cigarettes day) increases both the incidence 37-41 and mortality from stroke 40,41 , Cigarette smoking is a major modifiable risk factor for subarachnoid hemorrhage 42-48 , In contrast, evidence concerning the role of tobacco in the risk of intracerebral hemorrhage is still controversial, yet it appears that heavy, but not light-to-moderate cigarette smoking, increases the risk 9,38,49,50 , Smoking is dose-dependantly associated with the risk of ischemic stroke 38,46 , Cessation of smoking reduces stroke risk 37,39 , with major reduction within 2-5 years after cessation 37,39,46 , indicating that part of the effects of smoking is reversible. The risk of stroke seems to return to the level of never-smokers in light smokers, but heavy smokers seem to retain an increased risk even though also they benefit from cessation 37 , There are several mechanisms by which smoking may cause stroke. Cigarette smoking causes an immediate, yet reversible increases in blood...

Cigarette Smoking And Cardiovascular Disease

Cigarette smoking-related cardiovascular diseases have been described widely. However, the mechanisms of their effects on cardiovascular system were not totally clear. The effects of nicotine and carbon monoxide on blood vessel walls, unfavorable lipid profiles, increased myocardial work and the decreased oxygen carrying capacity of the blood of smokers contribute to the overall effect of cigarette smoking on cardiovascular disease 3J. Of the increased cardiovascular risk caused by smoking, it is estimated that approximately one-tenth of this is due to smoking-induced changes in serum lipid 4 , The majority of studies indicate elevations in serum cholesterol, phospholipids, triglycerides, low-density lipoprotein (LDL) and increased hepatic lipase activity in smokers, with decreased serum high-density lipoprotein (HDL) cholesterol 5 , A mechanism to explain the link between smoking and some of the observed changes in serum lipid and lipoprotein concentrations includes the...

Animal Models of Lung Cancer

Human Lung Cancer Lung cancer is the leading cause of cancer-associated mortality in both men and women. Although susceptibility to environmental carcinogens may be predetermined and follow a pattern of autosomal dominant Mendelian inheritance 2, 3 , lung cancer results from an accumulation of acquired genetic mutations 4-6 . In fact, it is suggested that 10-20 genetic mutations may be necessary for the development of lung cancer 7 , although the discrete steps for the progression of a hyperplastic bronchial lesion to metaplasia and anaplasia have not been uncovered. Tobacco use is the strongest epidemiologic risk for the development of lung cancer and it is anticipated that approximately 10 of all smokers will develop lung cancer over their lifetime 8 . Current paradigms predict that lung cancer results from the widespread exposure of the carcinogen, leading to a process of field cancerization, whereby the entire aerodigestive track is exposed to the offending agents and leads to...

Subunit composition of nAChRs involved in nicotine addiction

As many drugs of abuse, nicotine is thought to exert its addictive properties through stimulation of DA release in the nucleus accumbens (Nac) (Pontieri et al., 1996 Di Chiara, 2000). This effect of nicotine has been attributed, at least in part, to the direct activation of nAChRs located on DA neurons of the ventral tegmental area (VTA). Indeed, nicotine is known to increase the firing rate of these neurons, both in vitro (Pidoplichko et al., 1997) and in vivo (Grenhoff et al., 1986). In addition, nicotinic antagonists infused into the VTA prevent nicotine-elicited DA release in the Nac and disrupt systemic nicotine self-administration in rats (Corrigall et al., 1994 Nisell et al., 1994). Since nAChR subtypes mediating the reinforcing properties of nicotine should be valuable targets of new pharmacological agents for the treatment of nicotine abuse, much research has been devoted to identifying their subunit composition. For instance, electrophysiological experiments in b2 Ko animals...

Role of nAChRs in nicotineelicited analgesia

In an attempt to understand nicotine-induced analgesia, the antinociceptive properties of nicotine were studied in mice lacking the a4 and p2 nAChR subunits (Marubio et al., 1999). In the hot plate test, a model of the supraspinal response to acute thermal nociception, nicotine or epibatidine failed to produce analgesia in both lines of mutant mice. Also, patch-clamp recording from serotoninergic neurons in the raphe magnus showed a loss of nicotine-elicited currents in a4 and p2 Ko animals. These findings are consistent with the notion that supraspinal analgesic actions of nicotine are due to the activation of neurons in this nucleus. Finally, Kin mice expressing a mutant form of the a4 nAChR subunit with increased affinity for agonists are hypersensitive to the analgesic effects of nicotine in the hot plate test (ED50 was 5.3 times lower in Kin animals compared to their Wt controls Fonck et al., 2001). All in all, these results demonstrate that the activation of a4p2* nAChRs is...

How long before surgery must a patient quit smoking to realize any health benefits

All patients who smoke should understand that smoking cessation even immediately before surgery has profound, measurable health benefits. Nicotine is a stimulant and has a half-life of only 1 to 2 hours its adverse effects on systolic blood pressure and heart rate can be seen after only 12 hours of smoking cessation. Carbon monoxide (CO), which diminishes oxygen-carrying capacity, has a half-life of only 4 hours. Diminished levels of nicotine and CO were likely behind the outcome of a study looking at episodes of ST depression in patients who smoked and underwent vascular surgery. This study showed that patients who smoked immediately before surgery had increased episodes of ST segment depression when compared to nonsmokers, prior smokers, and chronic smokers who did not smoke before surgery. The longer a patient can abstain from smoking before surgery, the greater the perioperative health benefit Bronchociliary function improves within 2 to 3 days of cessation, and sputum volume...

Lung Cancer

Changes in the structure of some of the many types of cells that make up the lungs may begin almost immediately upon exposure to carcinogens (cancer-causing substances). Some of the thousands of chemicals contained in tobacco smoke both inhaled directly and released into the air through secondhand smoke are known respiratory carcinogens. Substances such as radon, asbestos, arsenic, uranium, and certain petroleum products also can cause lung cancer. A tumor in one of the bronchi can irritate the lining of the airway and cause a persistent cough, which may cause the tumor to bleed. As it grows, the tumor may block the airway, resulting in repeated bouts of pneumonia or other respiratory infections. A tumor located in the outer part of a lung may not produce any symptoms until it is large enough to press against the chest wall and cause pain. If you experience any of the warning signs of lung cancer (see box), see your doctor as soon as possible. Tests for lung cancer include a chest X...

Smoking cessation

While many patients are aware of its dangers and can quit smoking for a period, it takes an average of three attempts to quit successfully in the long term. However, this is well worth it, as the reduction in mortality is substantial, and has been consistently demonstrated across studies. In 2003, Critchley and Capewell reviewed outcomes of over 12 000 patients in trials of smoking cessation to quantify a 36 relative risk reduction of mortality for those patients who quit smoking (Figure 8.5)11. New agents are also in the pipeline to assist in this challenge, including varenicline, a new nicotine receptor blocker. It proved superior to bupropion in terms of abstainers at the 3- and 12-month marks (Table 8.5)12. However, the absolute percentages of patients who had abstained for a full 12 months (23 in the varenicline group vs. 15 for bupropion) was still low overall, demonstrating both the difficulty of successfully intervening and the progress that has yet to be made in smoking...

Overview Of Patterns Of Asbestos Use And Recognition Of Its Health Consequences

A number of adverse health outcomes are now causally associated with exposure to asbestos. An approximate timeline for recognition of the adverse consequences is provided in this section, as drawn from published sources. The first to be recognized was asbestosis, a pneumoconiosis characterized by fibrosis of the lung and reduction of lung function (Table 1.1), first reported as early as 1907 (Hamilton and Hardy 1974, as cited in Becklake 1976). Iron-coated fibers, called asbestos bodies, are typically found in the tissues of affected lungs. Mesothelioma, an uncommon tumor of the pleural and peritoneal mesothelium (tissues lining the thoracic and abdominal cavities and the organs in them), was linked to asbestos in the early 1960s in clinical case reports, and the increased risk was then further shown in cohort studies of asbestos workers. In the 1950s, epidemiologic studies documented the association of lung cancer with asbestos exposure, and the risk was found to be particularly...

Cadherins and Cyclooxygenase

Cyclooxygenase 2 (COX-2) and its metabolite prostaglandin E2 (PGE2) are critical for regulating diverse cellular functions under both physiological and pathological condi-tions.94-97 COX-2 is overexpressed in human non-small cell lung cancers, and its inhibition causes tumor reduction in vivo in murine lung cancer models.94,98 COX-2 activity is identified throughout the progression of a premalignant lesion to the metastatic phenotype.94,99 Higher COX-2 expression has been identified in lung adenocarcinoma lymph node metastases.94,99 COX-2 overexpression has been associated with angiogenesis, decreased host immunity, and enhanced invasion and metastasis, and therefore COX-2 has been considered to have an important role in multiple pathways in lung cancer carcinogenesis, suggesting it has a multifa-ceted role in conferring malignant and metastatic phenotypes.94,100-104 COX-2 may be a central element in orchestrating the multiple genetic alterations required for lung cancer invasion and...

General Approach To Evidence Review

The committee was charged with assessing the evidence concerning the causation of selected cancers, other than lung cancer and mesothelioma, by exposure to asbestos fibers. The charge required that the committee compile and review the available evidence, attempting to identify all relevant epidemiologic studies, and then evaluate whether the evidence was sufficient to infer the existence of a causal relationship. There are now well-established models for meeting the charge, dating as far back as the landmark 1964 report of the US surgeon general on smoking and health (HEW 1964), which reached the conclusion that smoking causes lung cancer and other diseases. That report assembled the full body of relevant scientific evidence and evaluated it according to formal guidelines. Abundant, comprehensive reviews of various other agents have since been conducted to gauge whether the sets of evidence associating them with particular health outcomes warrant causal conclusions. Effect...

Criteria For Evidence Evaluation Fiber Type

The committee recognized that there is evidence suggesting that the risk associated with asbestos exposure for development of mesothelioma (and possibly of lung cancer) may vary by fiber type. Controversy continues (for example, Hessel et al. 2004, Rice and Heineman 2003) as to whether there is an absolute difference in the toxicity of amphibole and serpentine (chryso-tile only) forms of asbestos and whether only amphibole fibers have carcinogenic potential, particularly for mesothelioma, the neoplasm for which a difference seems most apparent. Recent reviews suggest that rather than having no carcinogenic activity, chrysotile has a generally lesser degree of potency than amphibole fibers, and that the various types of amphibole fibera differ in the extent of their biological activity (Britton 2002, IPCS 1998, Roggli 2006, Roggli et al. 1997, Suzuki et al. 2005). In its initial assessment of its charge, the committee evaluated whether its report could address whether associations of...

Asbestosrelated Pulmonary Diseases And Their Mechanisms

The causal association between asbestos exposure and nonmalignant and malignant diseases of the lungs and mesothelial linings is well established and supported by epidemiologic, animal, and mechanistic toxico-logic studies (IARC 1987). The biologic mechanisms responsible for asbestos-related disease are complex and reflect a chronic, multistep process involving interactions between genetic predisposition and possibly other exposures, including exposure to viruses. Those mechanisms will be discussed in detail after a brief summary of the clinical features and risk factors of lung cancer and malignant mesothelioma. fuse interstitial fibrosis) of the lungs and visceral pleural fibrosis and parietal pleural plaques of the pleural linings (Table 5.1). In the pleura, bilateral and symmetric fibrotic plaques usually reflect environmental or occupational exposure to asbestos fibers, and consequently pleural plaques are considered to be markers of asbestos exposure (Travis et al. 2002). These...

Environmental Factors Influencing LOH

Exposures to tobacco smoke from cigarette use and tobacco in smokeless products have both been linked to increased risk of cancer.33 Lung cancer is the most well known association, but tobacco smoking is a major cause of bladder cancer as well. The evidence linking exposure to tobacco smoke and lung cancer is overwhelming, with smoking named as the greatest etiological factor contributing to an individual's risk of developing lung cancer.34-37 The mechanisms by which tobacco carcinogens contribute to the development and progression of lung cancer are multivariate and are only partially understood. Tobacco smoke produces reactive chemical species, including benzo a pyrenes and polycyclic aromatic hydrocarbons (PAH). Smokeless tobacco is a major source of nitrosamines and is linked to increased risk of oral, esophageal, and pancreatic cancers.33 When adolescents smoke, it is believed that normal lung epithelium is preconditioned by exposure to tobacco carcinogens at a time of critical...

Patterns of LOH in Cancers

Lung cancer Small cell lung cancer The best described and best documented gene targeted for LOH in nearly all lung cancers is the fragile histidine triad (FHIT), on 3p14. LOH at 3p14 is strongly correlated with exposure to tobacco smoke and occurs early in carcinogen-exposed lung epithelium.20,58-63 The linkage between tobacco carcinogen exposure and LOH on chromosome 3p is particularly strong in individuals who initiated smoking at an early age.37 In two studies, LOH at a locus near the hMLH1 gene on chromosome 3p21 was correlated strongly with early age of smoking initiation and with the level of DNA adducts.35,64 The FHIT gene encodes a small protein with diadenos-ine triphosphate hydrolase activity, but its tumor suppressor activity is presumed to be independent from this enzymatic activity.62 The microregion of the FHIT gene is frequently targeted for LOH in tumors however, this association alone does not confirm tumor suppressor activity. Evidence for FHIT as a tumor suppressor...

Multicolor Whole Chromosome Painting MFISH and

FISH detection of lung cancer in bronchoscopic brushing specimens using the LAVysion probe set 5p15 (green), CEP6 (aqua) , 7p12 (red) , and 8q24 (gold) . Note that the two normal cells on the left show only two copies for each of the four probes whereas the malignant cell on the right shows extra copies for all four probes .

Knockout Mouse Models

Knockout mouse production implies mutation or ablation of an endogenous gene by homologous recombination in embryonic stem (ES) cells. Basically, the ES cells with the appropriate target are injected into the blastocyst of a mouse embryo mice born contain cells from both the host embryo and the targeted ES cells. If these ES cells incorporate themselves into the germline, the mutation can be transmitted to future generations.59 There are limitations for the use of these models in lung cancer because the mutated or knockout gene either provides a silent phenotype or will not allow the study of new neoplastic transformation in the adult mouse.

Gene Mutations in Cancer

Each of these ras family of oncogenes have been found to be mutated with varying frequencies in major forms of human cancer. 1 30 K-ras is mutated in cancers of the lung, colon, and pancreas, as well as in myelodysplastic syndrome and some other cancers (such as seminoma). The frequency of K-ras mutation in pancreatic cancer is estimated to be 90 ,130 suggesting that this gene mutation is very important in the malignant conversion of this tissue. H-ras is mutated in cancers of the bladder, kidney, and thyroid, and N-ras is mutated in seminoma, thyroid, and acute myelogenous leu-kemia.130 In lung cancer, the majority of ras mutations occur in the K-ras gene. 1 31132 K-ras is mutated in 15-20 of all NSCLC and in 30-50 of lung adenocarcinomas,29 131 133-137 but it is infrequently mutated in other lung cancer types.29134 In lung adenocarcinomas, 85 of K-ras mutations affect codon 12. 1 32 Certain carcinogens found in cigarette smoke, such as benzo a pyrene, have been shown to...

Role of Immunohistochemistry in Biomarker Testing

More recently, detection of the excision repair cross-complementation group 1 (ERCC1) protein by IHC has been shown to be useful as both a prognostic indicator and a predictor of response to chemotherapy in patients with non-small cell lung cancer. Patients with ERCC1(+) tumors survive longer than those whose tumors do not express ERCC1. More importantly, patients with ERCC1(-) tumors may benefit from adjuvant cisplatin whereas those with ERCC1(+) tumors appear resistant to platinum-based chemotherapy.2 targeting that same molecule. Cetuximab is a monoclonal antibody that has a high affinity for the epidermal growth factor receptor (EGFR). The drug was initially shown to be effective in some patients with EGFR(+) colorectal carcinoma, but similar response rates were subsequently described in patients whose tumors were negative for EGFR by IHC.3 Similarly, response to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib in non-small cell lung cancer is related to the presence of...

Assembly of Literature Database

The biomedical literature concerning asbestos is vast (about 25,000 citations in the searchable reference databases MEDLINE and EMBASE), but much of it exclusively addresses asbestos's role in causing asbestosis, lung cancer, and mesothelioma. Given the committee's circumscribed task of answering the question of whether this known carcinogen plays a causal role in producing pharyngeal, laryngeal, esophageal, stomach, or colorectal cancer (selected cancers), the committee saw no need to revisit the entire body of information on asbestos's biologic activity or even to review the entire epidemiologic literature on asbestos exhaustively. The subset of epi-demiologic literature referring to the selected cancer sites, however, did need to be identified comprehensively, retrieved when possibly pertinent to the task, and thoroughly reviewed when found to be relevant. The secondary literature (e.g., ATSDR 2001 Becklake 1979 EPA 1986 IARC 1977, 1987 Kleinfeld 1973 Landrigan et al. 1999 Li et...

LOH in Benign Diseases

Idiopathic pulmonary fibrosis (IPF) is a serious disease believed to be the result of immune response to tissue damage in the lung.127 Although IPF is a benign disease, it progresses to bronchogenic carcinoma in about 10 of IPF patients.126 The observation that the incidence of lung cancer in IPF patients is much higher than the incidence in the general population lends support to the hypothesis that IPF contains precancer-ous lesions that may progress to peripheral-type lung tumors through the inactivation of critical tumor suppressor genes.128 Indeed, LOH at several common loci (3p21, 5q32, 9p21, and 17p13) has been documented in IPF.96 Sarcoidosis is a multisystem disease characterized by the formation of noncaseating granulomatous lesions in affected organs, especially the lungs. These lesions can progress to cause fibrosis and, similar to IPF, lead to a higher incidence of lung cancer. 1 26 Studies of LOH have identified targeted loci on 9p, 9q, and 17q.129,130 The genes targeted...

Epimutations in Cancer

Epimutations in Lung Cancer Several genes are known to be hypermethylated in lung cancer, resulting in gene silencing.205 Among these genes, p16I NK4A is found to be methylated in more than 40 of lung cancers examined.206,207 Although it is recognized that hyper-methylation of p16I NK4A occurs frequently in lung cancer, there is debate regarding the importance of this mechanism of inactivation among lung cancer patients who are smokers versus nonsmokers (or never smokers). In one study, deletion or mutation of the p16I NK4A gene was only observed in the lung cancers of smokers, while hypermethylation was found only among nonsmokers.208 In contrast, other studies have found hypermethylation of p16I NK4A as the prevalent mechanism of inactivation among lung cancers from smok-ers.209 Other epigenetically regulated genes in lung cancer include CDH1,210 CDKN1A,211 DAPK1,212 ESR1,213 GJB2,214 GSTP1,215 HS3ST2,216 PRDM2,217 PRKCDBP,218 RASSF1,219 and SFN.120 Similar to p16 K4A1 RASSF1 may be...

Anatomic Pathology Testing for Infectious Agents

The ras oncogenes in human lung cancer. Am Rev Respir Dis. 1990 142 S27-S30. 5. Westra WH, Slebos RJ, Offerhaus GJ, et al. K-ras oncogene activation in lung adenocarcinomas from former smokers. Evidence that K-ras mutations are an early and irreversible event in the development of adenocarcinoma of the lung. Cancer (Phila). 1993 72 432-438. 6. Nelson HH, Christiani DC, Mark EJ, et al. Implications and prognostic value of K-ras mutation for early-stage lung cancer in women. JNatl CancerInst. 1999 91 2032-2038. 7. Chapman AD , Kerr KM . The association between atypical ade-nomatous hyperplasia and primary lung cancer. Br J Cancer. 2000 83 632 - 636 . 9. Mao L, Hruban RH, Boyle JO, et al. Detection of oncogene mutations in sputum precedes diagnosis of lung cancer. Cancer Res. 1994 54 1634-1637. 10. Ronai Z, Yabubovskaya MS, Zhang E, et al. K-ras mutation in sputum of patients with or without lung cancer. J Cell Biochem. Suppl 1996 25 172-176. 11. Nakajima E,...

Committee Approach

The committee was aware that fiber type may be a determinant of risk of developing mesothelioma (and possibly lung cancer) following asbestos exposure. The committee considered whether it should evaluate asbestos-associated risk for the designated cancers in terms of exposure to specific fiber types. In light of the almost universally mixed nature of actual occupational exposure, however, there was not sufficient evidence to have carried out such a review for the selected cancer sites. Consequently, the committee's report describes the level of causal inference in relation to asbestos, without specifying the type.

DNA Damage Repair

The enzyme O6-meG-DNA methyltransferase (MGMT AGT) repairs O6-meG and other alkylated bases in the direct damage reversal (DR) pathway.240-249 O6-Methylguanine (O6-meG) formed by alkylating compounds in tobacco smoke may mismatch with thymine during DNA replication if not repaired.

Closing Comments

The committee was charged with reviewing evidence on a widely used material that is known to cause respiratory malignancy. Asbestos has been extensively investigated, epidemiologically and experimentally, as a cause of mesothelioma and lung cancer. However, its potential to cause malignancy at other sites that may also receive a substantial dose of asbestos fibers has not been as extensively investigated.

Current Legislation

People who have a diagnosis of asbestosis, lung cancer, or mesothelioma will be eligible to file a claim documenting their asbestos exposure. Eligibility may also be extended to any additional cancers that are found to be causally associated with asbestos by the report of the present IOM expert committee delineated as item (e) under Subtitle C, Section 121 Medical criteria. The IOM report will be binding on the administrator and the physicians' panel that processes claims against the trust fund. The pending legislation was reported out of the Committee on the Judiciary on June 16, 2005, and was expected to be voted on early in 2006. Asbestos fibers are known to be carcinogenic. The uniqueness and completeness of the carcinogenic activity of asbestos in mesothelial tissues is clear and undisputed. Most cases of mesothelioma are attributable to asbestos exposure. The role of asbestos in producing lung cancer, particularly in smokers, is also clear. Cancers at the sites included in the...

Cadherins

The cadherin-catenin interaction is necessary for cadherin-mediated adhesion and association of the complexes with the cytoskeleton.6,57 The cadherin family contains 16 members, of which the most significant is E-cadherin (epithelial cadherin), which is found in epithelial tissues and is involved in formation and maintenance of cell histoarchitecture.6 Other important cadherins include N-cadherin (neural cadherin), found in neural and muscle tissues, P-cadherin (placental cadherin), R-cadherin (retinal cadherin), and VE-cadherin (vascular endothelial cadherin).6,58 Loss of function or secretion of the E-cadherin-catenin complex, or any of its components, eliminates a cell's capacity to adhere, with resulting loss of normal tissue architecture.6 Altered or absent E-cad-herin expression has been identified in various cancers, including stomach, head and neck, bladder, prostate, breast, and colon.6,59-63 a-Catenin absence or alteration has been identified in breast, gastric, and...

Cadherin

Cadherins are essential for tight junctions between cells, and E-cadherin is the cadherin most strongly expressed in epithelial cells.54,75,76 Cadherins form a complex with cyto-plasmic proteins known as catenins, and the resulting complex, along with other cytoskeletal components such as actin, constitutes the intercellular adherence junction.54,75-77 Transmembrane single-chain glycoproteins, cadherins have an extracellular domain, a transmembrane domain, and an intracellular domain, and play a primary role in maintaining physical cell-cell adhesion by mediating calcium-dependent homotypic intercellular adhesion in epithelial issues.8,78,79 Cadherin-mediated cell adhesion suppresses invasion of cancer cells in vitro, and dysfunction of the E-cadherin system correlates with cancer invasion in human cancers.-5,80-84 The human lung cancer cell line PC9 expresses an aberrant a-catenin mRNA, and the cells have very loose cell-cell associations.-5,85,86 a-Cadherin is considered by some...

Cadherins and EGFR

Epidermal growth factor receptor (EGFR) is overexpressed in many non-small cell lung cancers (NSCLC), and treatment with the EGFR tyrosine kinase inhibitors gefitinib and erlotinib has shown improved survival in some chemotherapy-resistant NSCLC patients.108-111 Nonetheless, about half these NSCLC patients have tumor progression within 8 months and show no treatment benefit.108 Activating mutations in the EGFR tyrosine kinase domain have been shown to increase EGFR copy number and or expression of EGFR protein correlating with response and survival after EGFR tyrosine kinase inhibitor therapy.108,112,113 EGFR activation and signaling through its downstream targets are modulated by E-cadherin specifically, E-cadherin inhibits EGFR ligand activation and enhances AKT activation in neighboring cells.108,110-113 High phosphorylated AKT levels may predict tumor response to EGFR tyrosine kinase inhib-itors.110,114 In lung cancer cell lines, E-cadherin expression is regulated by P-catenin...

Summary

Molecular pathogenesis of lung cancer. J Thorac Cardiovasc Surg. 1999 118 1136-1152. 5. Sekido Y, Fong KM, Minna JD. Progress in understanding the molecular pathogenesis of human lung cancer. Biochim Biophys Acta. 1998 1378 F21-F59. 11. Kim SK , Ro JY, Kemp BL , et al . Identification of two distinct tumor-suppressor loci on the long arm of chromosome 10 in small cell lung cancer. Oncogene. 1998 17 1749-1753. 18. Powell CA, Klares S, O'Connor G, Brody JS. Loss of heterozy-gosity in epithelial cells obtained by bronchial brushing clinical utility in lung cancer. Clin Cancer Res. 1999 5 2025-2034. 25. Song L, Yan W, Zhao T, et al. Mycobacterium tuberculosis infection and FHIT gene alterations in lung cancer. Cancer Lett. 2005 219 155-162. 31. D'Agostino J, Zhang X, Wu H, et al. Characterization of CYP2A13*2, a variant cytochrome P450 allele previously found to be associated with decreased incidences of lung adenocarcinoma in smokers. Drug Metab Dispos. 2008...

Selectins

Sialyl Lewis x (sLe-x) and sailyl Lewis a (sLe-a) are cancer-associated carbohydrate antigens involved in metas-tasis.131 Both serve as ligands for P selectin, I selectin, and E selectin that are found on the surfaces of platelets, leukocytes, and endothelial cells, and both mediate adhesion of tumor cells to endothelial cells.131132 Their importance in tumor metastasis is supported by the findings that (1) their antibodies block tumor cell adhesion on endothelial cells in vitro, (2) their expression is associated with increased metastatic potential of tumor cells, and (3) their antibodies have inhibitory effects on angiogenesis.131,133 Increased sLe-x and sLe-a antigen expression is often found in cancers.131134 A correlation between their expression and poor prognosis has been shown in breast and colon cancers, but its correlation in lung cancer is controversial.131134

Study Designs

The primary outcomes for cancer etiology studies are typically cancer mortality and cancer incidence (diagnosis). Cancer mortality is usually ascertained from the underlying cause of death indicated on a death certificate. The National Death Index is an electronic nationwide resource for specific causes of death in the United States some other countries maintain similar data. The validity of a recording of cancer on a death certificate has been examined and found to be fairly reliable for epidemiologic studies for rapidly fatal cancers (such as lung cancer) (D'Amico et al. 1999, Percy et al. 1981, Sathiakumar et al. 1998). Cancers that metastasize, however, may be The cohort studies considered by the committee were carried out in multiple locations, and their findings were reported from the 1950s on. In most of the studies, cause-specific mortality was the principal outcome measure. Mortality is a useful indicator of disease occurrence (incidence) for diseases with poor survival, such...

Mullur Rama Mirtharm

Tobacco Smoke and Involuntary Smoking. IARC Monographs on the Evaluation of Carcinogenic Risks to Human Vol. 83. Lyon, France World Health Organization, IARC. Kim DH, Nelson HH, Wiencke JK, Zheng S, Christiani DC, Wain JC, Mark EJ, Kelsey KT. 2001. p16(INK4a) and histology-specific methylation of CpG islands by exposure to tobacco smoke in non-small cell lung cancer. Cancer Research 61(8) 3419-3424. Lee BW, Wain JC, Kelsey KT, Wiencke JK, Christiani DC. 1998. Association between diet and lung cancer location. American Journal Respiratory and Critical Care Medicine 158(4) 1197-1203. Nelson HH, Kelsey KT. 2002. The molecular epidemiology of asbestos and tobacco in lung cancer. Oncogene 21(48) 7284-7288. Sekido Y, Pass HI, Bader S, Mew DJ, Christman MF, Gazdar AF, Minna JD. 1995. Neurofi-bromatosis type 2 (NF2) gene is somatically mutated in mesothelioma but not in lung cancer. Cancer Research 55(6) 1227-1231. Wong L, Zhou J, Anderson D, Kratzke RA. 2002. Inactivation of...

Committee Findings

The biologic effects of asbestos fibers depend on their physicochemical properties, dimensions, and deposition and persistence at target sites. On the basis of rodent models of lung cancer and malignant mesothelioma, fiber carcinogenicity is correlated with increased cell proliferation, inflammation, and fibrosis in the lungs and pleura. Several mechanisms have been proposed for the biologic activity of asbestos fibers observed in vitro and in animal models. Long asbestos fibers that are incompletely phagocytized stimulate production of reactive oxygen species that induce DNA damage, oxidant stress, and activation of cell-signaling pathways and lead to cell proliferation. Long asbestos fibers have been shown to interfere physically with the mitotic apparatus and produce chromosomal damage, especially deletions. Asbestos fibers may also directly produce physical injury of target cells and tissues that is repaired by compensatory hyperplasia. There is strong epidemiologic and...

Anxiety and depression

While a causal link between mood disorders and a dysfunction of the nicotinic cholinergic system has not been definitively established, compelling evidence exists suggesting a relationship 32-35 . A number of antidepressants in clinical use have been identified as antagonists at nicotinic receptors 32 . Nicotine and mecamyla-mine (9) have been shown to potentiate the effects of both imipramine and citalo-pram in the mouse tail-suspension test 36 . Mecamylamine also potentiates the effects of amitriptyline in the mouse forced swim test 37 . The novel 2, 7-diazaspiro 4.4 nonane TC-2216 (10) is a highly selective modulator for a4p2 (K 42nM, no affinity for a7, minimal interaction with a3p4) which exhibited preclinical activity in the forced swim test, a behavioral model predictive of clinical antidepressant effects 38,39 . The pyridyl ether A-85380 (11) was also active in the forced swim test it was suggested that nicotine and related agonists with antidepressant effects may be achieving...

Drug dependence and withdrawal

Withdrawal from nicotine, cocaine, opiates, and alcohol often leads to a negative emotional state and elevated levels of anxiety. These undesirable effects can sometimes be counteracted by increasing self-administration of the substance, which leads to relapse to the addicted state. External stressors can often lead to a relapse in abuse as well. Antagonists of CRF-R1 are increasingly being examined as potential treatments for addiction and the negative aspects of drug withdrawal 11 . The role of CRF-R2 in drug withdrawal and dependence is less well understood and will not be discussed here. 3.3.1 Nicotine withdrawal CRF receptor antagonists may be useful for treatment of the negative affective aspects of withdrawal from nicotine. Pretreatment of nicotine-dependent rats with CRF-R1 2 peptide antagonist D-Phe CRF(12_41) was shown to prevent the elevations in brain reward threshold associated with nicotine withdrawal 70 . D-Phe CRF(12_41) also caused a decrease in stress-induced...

Nicotinic receptor agonists

Evidence indicates that abnormal regulation of nicotine acetylcholine receptors (nAChRs) may contribute to the inattention and cognitive impairments associated with ADHD. Presynaptic nAChRs modulate the release of NE, DA, 5-HT, acetylcholine, glutamate and g-aminobutyric acid, neurotransmitters important to learning and memory 63 . nAChRs are comprised of a combination of 5a and b subunits which confer distinct pharmacologic properties. a4b2 and a7 antagonists were shown to disrupt working memory in rats 64 . In clinical trials, nicotine skin patches and the nicotine agoinist ABT-418 were shown to be effective in alleviating inattention in adults with ADHD 65,66 . The significantly higher occurrence of cigarette smoking (nearly twice the general population) in adolescents and adults with ADHD may represent a form of self-medication 67 .

Risk Factors For Psp And

The epidemiology of PD has been greatly aided by two natural experiments that generated important hypotheses regarding its etiology. The first was the encephalitis lethargica epidemic, which suggested a role for an infective agent (20). The second was the strange occurrence of MPTP-induced parkinsonism (21), which suggested the role of a neurotoxic agent and led to studies examining the role of pesticides because of its similarity with paraquat (22). The relevance of these models for the etiology of PSP and or MSA is far more questionable. However, in the absence of any other clues, most researchers have simply used risk factors that have been suggested to be important for PD, e.g., smoking behavior, head injury, pesticides, well water, etc., and tested them out in PSP and MSA as essentially a hypothesis-generating exercise.

Nicotinicmuscarinic Receptors

Nicotinic cholinergic receptors (nAChR) have been the target of PET radioligand development for several years, Early studies with 11C nicotine indicated that high levels of non-specific binding complicated image interpretation 41 , Several analogs of epibatidine, such as 18F norchlorofluoroepibatidine, have been radiolabeled as potential PET agents, However, concerns related to the extreme toxicity associated with these derivatives, even at microgram levels, have limited their use in human PET studies, Radiofluorinated derivatives of the a4p2-selective compound A85380 (2- 18F fluoro-A85380 (16) and 6- 18F fluoro-A8530 (17)) have facilitated quantitative imaging of the nAChR system in vivo 42,43 , For muscarinic cholinergic receptors (mAChR), a number of non-selective radioligands for the four receptor subtypes of mAChR have been prepared and evaluated, but the lack of subtype selectivity has limited their application, An M2-selective agonist, 18F FP-TZTP, has been radiolabeled and...

Periodic Health Checkups for

Those at risk Men who smoke or chew tobacco men with poor oral hygiene. Those at risk Men with a family history of high blood pressure, heart disease, kidney disease, or stroke men who are overweight or have diabetes men who smoke or use tobacco products. Those at risk Men with a family history of heart disease men who have diabetes men who smoke or use tobacco products.

New Aneurysms And The Need For Followup

After adjustment for age and hypertension, female sex and cigarette smoking have been found to be independent risk factors for aneurysmal formation and growth (130). New formation of aneurysms at different sites have been reported up to 17 years after initial treatment for aneurysmal occlusion, implying a need for long-term follow-up by periodical cerebral angiography (58). In addition, 2 cases have been reported of de novo intracranial aneurysmal formation that developed quickly (131). One patient developed 2 new aneurysms within a 6-month period, whereas the other developed 2 new aneurysms within a 22-month period. Short screening intervals might be necessary in patients at high risk for new aneurysmal formation, including patients who are young, are female, are cigarette smokers, have a history of arterial hypertension, have first-degree relatives with intracranial aneurysms, or who have been previously treated for an intracranial aneurysm.

Box 23 Beyond Kochs Postulates

The importance of Koch's postulates is emphasized by the continuing effort to apply new technologies to the issue of causality. In 1965, Bradford Hill proposed nine criteria to assess the strength of association between a disease and an agent that is thought to cause the disease. (His work revealed the association between lung cancer and cigarette smoking.) None of his criteria, listed here, is absolute, but together they can make a strong case

Partial Agonists At Nicotinic Ach Receptors

''Partial agonists are ligands that produce a smaller than maximal response compared with the natural ligand at full receptor occupation'' 14 . Acetylcholine (4) is the natural full agonist at two known receptor subclasses important for neurotransmission the muscarinic (mAChRs) and nicotinic (nAChRs) receptors, which are distributed throughout the central nervous system (CNS) and the periphery. The nicotinic receptor subtypes are ligand-gated ion channels that mediate fast synaptic transmission upon acetylcholine binding and also mediate the full agonist effect of nicotine. These ion channels are formed from pentameric assemblies of subunits creating a central aqueous pore. There are 12 neuronal nAChR subunits divided into a and b subtypes (a2 a10, b2 b4) differentiated by the presence or absence of a key ''cys-cys loop'' near the acetylcholine-binding site respectively. The known combinations of subunits form a broad range of nAChR subtypes with significantly different...

Fused Bicyclic Benzazepines

As mentioned earlier, the dinitration reaction of TFA-protected benzaze-pine (56-62) led to a number of important fused heterocycles. SAR development in the 6,6-fused derivatives revealed the importance of the ''quinoline nitrogen'' (5-position) to affinity and functional activity (Figure 13). Quinoxaline derivatives (68), directly accessed from dinitro intermediates in two steps, displayed optimal partial agonist activity with hydrogen substitution (e.g., varenicline (1)). Small groups were well-tolerated at C-6 and 7 (H, CH3, OH, OCH3, etc.) but reduced the functional potency of these derivatives. Aryl appendages generally decreased binding affinities and reduced partial agonist efficacy. Both quinoline (69) and quinazoline (70) derivatives with small groups displayed high affinity, but were uniformly full agonists, being more efficacious at 10 mM compared with the effect of 10 mM nicotine in oocytes. 3-Substitutied quinolines with groups larger than methyl (7-position of 69, Figure...

Induction Of Aox Enzymes

However, it is important also to have an index of total DNA damage in the human body (i.e., the input side of the steady-state equation). The most common approach has been to assess the output side (i.e., trying to estimate the rate of repair of oxidized DNA). This is usually achieved by measuring urinary excretion of DNA base damage products. Several DNA base damage products are excreted in human urine, including 80HdG, 8-hydroxyguanine, 8-hydroxyadenine, and 7-methyl-8-hydroxy-guanine (39,41,42), but the one most exploited is 80HdG, usually measured by a method involving highperformance liquid chromatography (HPLC) with electrochemical detection (38). For example, in one study of 169 humans, the average 80HdG excretion was 200-300 pmol kg per 24 h, corresponding to 140-200 oxidative modifications of guanine per cell per day (42,43). Furthermore, smokers excrete 50 more 80HdG than nonsmokers on average, suggestive of a mean 50 increased rate of oxidative DNA damage from smoking (42)....

Avoiding Risky Behavior

There are risks associated with nearly every activity in which the consequences are unknown or uncertain. Risky behavior can include everything from adventurous activities such as skydiving or mountain climbing to routine activities such as driving to work. Some behaviors, such as gambling or gang activity, carry an identifiable risk of loss or harm that occurs each time they are performed. For other activities, such as cigarette smoking, the resulting harm often occurs in the longer term. Because of this delayed impact, people often ignore or deny the risk involved.

Alcohol and Other Drugs

Dependence on alcohol and other drugs, also called addiction, poses a triple threat to the dependent person and to society as a whole. It increases the probability that a person will do something potentially harmful, such as acting in a violent or careless manner. It leads to impaired judgment that affects certain everyday activities, such as driving a car, thereby increasing the risk of injury or death. And it creates chemical imbalances in the brain and the body that increase the risk of illness and death. Nicotine, the drug found in cigarettes and other tobacco products, is extremely addictive.

Potential Therapeutic Applications

The second therapeutic application for which clinical data are available is smoking cessation. Strong interaction between cannabinoids and brain reward function are well documented 84 . Several studies demonstrated that SR141716 was able to block the reinforcing effects of heroin 85 , morphine 86 , ethanol 87 and nicotine 88,89 . Cannabinoid antagonists were therefore suggested as potential treatment for nicotine and alcohol dependence. The STRATUS-US phase III clinical trial enrolled 787 tobacco smokers motivated to stop, who were randomized to placebo, or to 5 or 20 mg rimonabant once daily for 10 weeks. Among patients receiving 20mg rimonabant, 27.6 were able to stop smoking compared to 16.1 of those taking placebo. Moreover, among patients who were not obese at baseline, there was a 77 reduction in post-cessation weight gain compared to placebo 79 . These results are highly encouraging, considering the need for effective pharmacotherapies for the treatment of tobacco dependence 90...

Clinical Box 11 Why Doesnt Your Stomach Digest Itself

The weakening of these mucosal defense mechanisms results in ulcerations and eventually gastric ulcer disease. A variety of factors including excessive alcohol and tobacco consumption, stress, and nonsteroidal anti-inflammatory drugs such as aspirin can lead to erosion in the lining of the stomach. Additionally, there is also a positive correlation between Helicobacter pylori (H. pylori) bacterial infection and the incidence of gastric and ulcers of the small intestine. H. pylori produces large quantities of the enzyme urease, which hydrolyzes urea to produce ammonia. The ammonia neutralizes the gastric acid in the bacteria's immediate environment thus protecting the bacteria from the toxic effects of its normally toxic acid environment. It is remarkable how some cells find a way to survive even in the deadliest environment.

Limitations Of Animal Models

Human ICH usually occurs in the setting of longstanding comorbidities (e.g., tobacco use, diabetes, hypertension) and commonly in the presence of active drugs (e.g., antiplatelet, anticoagulant, statin). These conditions cannot be easily reproduced in animal models. For example, even spontaneously hypertensive rats are not likely to reproduce the decades-long effects in humans of elevated arterial pressure. Human ICH also varies by race, in incidence overall, and in incidence by age epoch, suggesting important and yet-to-be-discovered variations in genetic susceptibility. Inferences regarding treatment must also be drawn with caution. Findings have demonstrated significant benefits from mechanical and pharmacologic interventions that have not been reproduced in human trials, whether small and focused (51,119) or large and inclusive (120). Among the several potential explanations for these discrepancies, delay in treating ICH patients is the likeliest. However, toward improving the...

Discuss the important features of the preoperative evaluation

The anesthesiologist should review the surgical diagnosis, organ systems involved, and planned procedure. Important features include personal interview, physical examination, and review of medical records. Important questions involve medications, drug allergies, substance abuse (e.g., cigarettes, alcohol, illicit drugs), review of systems, and prior anesthetic experience (i.e., history of difficult intubation, delayed emergence, malignant hyperthermia, prolonged neuromuscular blockade, or postoperative nausea and vomiting). From this evaluation the anesthesiologist decides if any preoperative tests or consultations are indicated and then formulates an anesthetic care plan.

What benefits and risks are associated with preoperative cigarette cessation

All health care providers should take advantage of any opportunity to encourage patients to quit smoking. In years past various arguments were made to suggest that smoking cessation immediately before surgery increased certain perioperative risks such as increased airway irritability, diminished wound healing with nicotine replacement therapy, and increased patient anxiety associated with nicotine withdrawal. Most of these arguments have since been disproven and nonetheless pale in comparison to the overall health benefit of smoking cessation.

Vitamin E Primary Prevention Trials

Smokers aged The Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study was the first large-scale randomized trial of antioxidant vitamins in a well-nourished population. This 2 x 2 factorial trial tested the effect of synthetic vitamin E (50 mg d) and beta-carotene (20 mg d) in the prevention of lung cancer among 29,133 Finnish male smokers aged 50-69 years.29 After a median of 6.1 years, vitamin E supplementation did not reduce the risk of lung cancer (the primary endpoint). There was also no clear reduction in risk of death due to ischemic heart disease (RR 0.95 95 CI, 0.85-1.05) or ischemic stroke (RR 0.84 95 CI, 0.59-1.19) although the risk of developing angina was lower among those assigned to vitamin E (RR 0.91 95 CI, 0.83-0.99).30 It was initially thought that the lack of convincing beneficial effect may have been due to inadequate dosing of vitamin E or a short follow-up time, but post-trial results with 8 more years of follow-up found no effect of alpha-tocopherol on...

Vitamin E Secondary Prevention Trials

Studies of vitamin E for the prevention of angina pectoris have had mostly negative results. A placebo-controlled trial of 3,200 IU d of vitamin E in stable angina patients led to a nonsignificant trend toward an improved angina pain score in a 9-week placebo-controlled trial40 while a trial of large dose vitamin E (1,600 IU d) in 48 patients with angina found no benefit on exercise capacity, left ventricular function or angina symptoms.41 These small studies of short duration may not have been adequately powered to detect small-to-moderate benefits of antioxidant therapy, but even among 1,795 smokers with angina followed over 4 years in the ATBC trial there was no evidence of a beneficial effect with low-dose vitamin E supplementation (RR 1.06 95 CI, 0.85-1.33).42 I,862 male smokers aged 50-69 with prior MI Finland

Background Subtypes Of Nicotinic Acetylcholine Receptors

The nAChR in skeletal muscle has been known for many years and has been extensively studied.13 It is composed of five protein subunits two a, and one each of P, y (or s), and 5 arranged around a central pore that forms an ion channel. Agonist binding results in channel opening and ion flux through the cell membrane. A pharmacologically distinct nAChR subtype in autonomic ganglia also has been known for many years. Molecular biology techniques have led to identification of mRNA for numerous additional nAChR subunits in neuronal tissue (cc2-a8 and P2-P4), as well as a9 from rat cochlea. Heterologous expression studies have shown that numerous pairwise and or triplex combinations of a2-a6 and (32-P4 subunits form functioning ion channels, whereas only a7, a8, and a9 can form homomeric channels. Thus many different subtypes of nAChRs are theoretically possible. Efforts to elucidate which combinations exist in nature and what are their functional roles continue to be subjects of intense...

Historical Perspective Early Work On nAChR Modulators At Abbott Laboratories

In 1989, Mike Williams joined the Neuroscience Discovery group at Abbott with the challenge of refocusing research activities toward a more aggressive drug discovery mode. His initial effort involved redirection of an existing effort in Alzheimer's disease that was, like many others, focused on muscarinic agonists as a palliative therapy. Many other companies were targeting the same approach, and compounds active at muscarinic receptors are highly prone to unacceptable side-effect liabilities. Therefore, it was felt that Abbott could be more competitive by focusing in the area of nicotinic receptor agonists, whereby two acute, albeit limited, human trials had shown beneficial action of nicotine in improving cognitive function in Alzheimer's patients. The decision was somewhat risky, inasmuch as there were few programs of this type in the industry, inevitably raising questions regarding what others knew that we did not, and vice versa. Moreover, the word nicotine immediately conjured...

Pulmonary Pathophysiology

Emphysema is most often caused by cigarette smoking, although some genetic diseases can cause similar damage to the alveoli. Once this damage has occurred, it is not reversible. Chronic obstructive pulmonary disease (COPD) is a slowly progressive disease of the lung and airways. COPD can include asthma, chronic bronchitis, chronic emphysema, or some combination of these conditions. The disease is characterized by a gradual loss of lung function. The most significant risk factor for COPD is cigarette smoking. Other documented causes of COPD include occupational dusts and chemicals. Genetic factors can also play a significant role in some forms of this disease.

Betacarotene Primary Prevention Trials

Results from large-scale randomized trials of beta-carotene in the primary prevention of CVD have been disappointing. These trials are summarized in Table 3.4. In the previously described ATBC trial among Finnish male smokers, participants assigned to 20 mg d of beta-carotene had an increased risk of ischemic heart disease mortality (RR 1.12 95 CI, 1.00-1.25) and no reduction in the risk of angina (RR 1.06 95 CI, 0.97-1.16). For the primary endpoint of lung cancer, an increased risk was noted after 4 years (RR 1.18 95 CI 1.03-1.36), but this association disappeared after 6 years of post-trial follow-up (RR 1.06 95 CI 0.94-1.20).31 There were no late preventive effects of beta-carotene. The Physicians' Health Study (PHS I) was a randomized, double-blind, placebo-controlled trial of beta-carotene (50 mg every other day) and low-dose aspirin among 22,071 U.S. male physicians aged 40-84 years, of whom 11 were current smokers and 39 were former smokers.53 After 12 years of follow-up, those...

The Pyridyl Ether Series

Meanwhile, compounds prepared previously during the muscarinic program were screened for nicotinic activity. This approach yielded notable success when compound 8 (Figure 1), a pyridazinyl ether, was found to have affinity for the rat brain 3H cytisine nAChR binding site in the nanomolar range ( 46 nM, Table 2).10 Prepared in 1989 by John Chung, compound 8 had been found to be a weak ligand for muscarinic receptors (K, > 10,000 nM at both M, and M2 subtypes). Melwyn Abreo, noting the presence of the 2-pyrrolidinyl moiety in nicotine, prepared the corresponding 2-pyrrolidinyl analogue 9 (Figure 2), which was shown to possess similar affinity to that of 8 Kx 29 nM). Borrowing again from the structure of nicotine, the heteroaryl moieties of 8 and 9 were replaced with 3-pyridyl (Figure 3), yielding compounds 10 and 11, respectively. Whereas compound 10 showed an impressive 10-fold improvement in binding affinity 3 nM), the impact of this result was overshadowed by the enthusiasm...

Susceptibility To Transitional Cell Carcinoma

In a cohort study on urinary bladder cancer, mainly transitional cell carcinoma (TCC), in the BFD-endemic area, an increased risk was observed among patients affected with BFD as compared with the unaffected (Chiou et al., 1995). The odds ratio of developing urinary bladder cancer was around four-fold after adjustment for age, sex, cigarette smoking and cumulative arsenic exposure. In our most recent cohort study on TCC in the BFD-endemic and non-endemic areas, an increased risk of developing TCC was observed among patients affected with skin cancer than the unaffected. The odds ratio was around five-fold after adjustment for age, sex, cigarette smoking and cumulative arsenic exposure.

Synthetic And Small Molecular Weight Inhibitors

A third compound which was in Phase ill clinical trials, BAY12-9566 (Tanomastat) 3, has recently been withdrawn, due to a higher rate of disease progression in the treated group in a small cell lung cancer trial (18). Recent data from the Phase III trial of 1_in gastric cancer showed that although the trial did not meet its primary endpoint of a survival benefit, there was a trend towards efficacy,

Combination Antioxidant Primary Prevention Trials

Who were smokers The Beta-Carotene and Retinol Efficacy Trial (CARET) evaluated a combined treatment of beta-carotene (30 mg daily) and retinol (25,000 IU daily) in 18,314 men and women at elevated risk of lung cancer due to cigarette smoking and or occupational exposure to asbestos.61 The trial was stopped early due to lack of benefit and an increased incidence of lung cancer in the active treatment group (RR 1.28 95 CI, 1.04-1.57). After 4 years, the group assigned to the antioxidant combination had an increased risk of total mortality (RR 1.17 95 CI, 1.03-1.33) and a trend toward increased CVD mortality (RR 1.26 95 CI, 0.99-1.61).

Cholinergic mechanisms in the striatum

Nicotine increases the release of dopamine (Wonnacott et al., 2000 Dani, 2001), and so must acetylcholine, by acting on nicotinic receptors. (6) The striatum regulates movement, which is easier to study than memory in animals (Chase et al., 1998). (7) Direct and indirect striatal projection pathways have opposite feedback effects in the cortex (Fig. 1). Anything that produces a direct > indirect imbalance (including loss of indirect projection neurons early in Huntington's disease, excessive use of levodopa or dopamine agonists for Parkinson's disease, upregulation of dopamine receptors in tardive dyskinesia, and loss of one subthalamic nucleus in hemiballismus) can yield excessive movement. Anything that produces an indirect> direct imbalance (including loss of nigros-triatal dopaminergic neurons in Parkinson's disease, blockade of dopamine receptors by anti-schizophrenic drugs, and depletion of dopamine by reserpine) can yield inadequate movement. (8) Unilateral...

Properties of the Coronary Microcirculation

A particularly important aspect of endothelial regulation of vasomo-tion is that endothelial-mediated vasodilation is abnormal in a variety of pathological conditions. These include atherosclerosis, hypercholester-olemia, diabetes, hypertension, cigarette smoking, and aging. The mechanisms underlying these abnormal endothelium-dependent responses have been the subject of substantial debate. Deficiencies of the substrate for eNOS, l-arginine, and the co-factor tetrahydrobiopterin have all been implicated, as well as the endogenous competitor of l-

Confocal microscopy of muscarinic receptors on dendritic spines

It is clear that most of the M1 receptors in the brain are co-localized with glutamate receptors at the tips of dendritic spines in the cortex, hippocampus and striatum, that M1-activation potentiates excitatory NMDA currents, and that M1-knockout causes severe cortical-hippocampal memory deficits and hyperactivity. Thus M1-rich spines are crucial for normal cognition and movement. We have begun to examine the specific characteristics of these spines in the rat hippocampus and striatum with fluorescent m1-toxin1 and confocal microscopy (McCollum et al., 2003). So far it is clear that the fluorescent toxin saturates M1 receptors in vivo, that toxin-receptor complexes are stable in perfusion-fixed tissue, and that M1-rich dendritic spines are beautifully imaged by confocal microscopy. We intend to use this approach to address the following questions. How does the administration of donepezil (an esterase inhibitor used to treat dementia) (Barnes et al., 2000), or atropine (a common...

Interview And Clinical Examination

Patients diagnosed with liver enlargement were further interrogated regarding any past history of jaundice, parasite expulsion, history of taking alcohol or other hepato-toxic drugs. In regard to the respiratory system, if the participant did not volunteer any information concerning the presence of a respiratory problem, they were then specifically asked whether they had any cough or breathing difficulty. Crepitations were determined by auscultation and were defined as the presence of any chest sounds including rals or rhonchi. Participants were also asked if they were current or past smokers.

How will my clinician use my test results to determine whether I have osteoporosis

A Z-score is usually not helpful in making the diagnosis of osteoporosis. However, if it is particularly low (lower than -1.5), it is important for your clinician to evaluate you for conditions and illnesses that may be causing your bone loss associated with secondary osteoporosis. Such causes of secondary osteoporosis might include thyroid or parathyroid disease, cigarette smoking, excessive alcohol intake, problems with absorption from your gastrointestinal tract, or the use of medications known to be harmful to bone. Cigarette smoking

From Alzheimers Disease To Analgesia Opportunity Knocks

In the mid-1970s, Daly and coworkers reported isolation of a new substance from the skin of an Ecuadoran frog Epipedobates tricolor that showed potency several hundred fold greater than morphine in a screen for analgesic activity. The structure epibatidine (40) was first elucidated in the early 1990s, once improved analytical techniques became available,27 and found to have a number of structural features in common with nicotine. Shortly thereafter, it was reported that the analgesic actions of epibatidine involved activation of neuronal nAChRs.28,29 Epibatidine is a highly toxic substance, causing death in mice at only about six times the effective dose for analgesia,30 and eliciting profound cardiovascular effects in dogs at low doses (< 5 nmol kg iv).31 Although it was far from certain that a compound could be identified that would achieve a useful separation between analgesic and toxic effects, the potential to develop a novel, nonopioid, non-NSAID treatment for pain suggested...

The Effect Modification Of Alcohol By Smoking

There are only two epidemiologic studies on the effect modification of alcohol by smoking and neither of them examines it in relation to the risk of stroke. In a Japanese cohort of 19,231 men, alcohol consumption and all-cause mortality had a J-shaped association in nonsmokers but not in smokers 78 , In a cross-sectional study of 5,312 German men and women, the rise in blood pressure associated with drinking was higher in smokers than in nonsmokers 79 , Some studies have instead examined the effect modification of smoking by alcohol. In a cohort of 22,071 US male physicians, alcohol attenuated the linear effect of smoking on the risk of total stroke 38 , In a Japanese cohort of 1,775 men, a dose-dependent decrease in diastolic blood pressure and serum HDL cholesterol by increasing cigarette smoking was evident in nondrinkers but not in drinkers The effects of both alcohol and tobacco are manifold, which makes them complicated to examine and understand. The effects may be additive or...

Protecting Your Lungs

Lung cancer is the leading cause of cancer death among both men and women in the United States. Twice as many men as women die of chronic obstructive pulmonary disease (such as emphysema), and pneumonia is a more common cause of death among men than among women. Lung disease is directly related to specific risk factors such as cigarette smoking and working in occupations that carry risks for developing lung disease. Plastics, wood, metal, and textile workers bakers millers farmers poultry handlers miners grain elevator workers laboratory technicians drug manufacturers dry cleaners and detergent manufacturers are all exposed to airborne agents that can cause occupational asthma, lung cancer, and other respiratory disorders. smoking and avoiding exposure to tobacco smoke are critical to protecting your lungs. Cigarette smoke is the major cause of lung cancer, chronic bronchitis, and emphysema. Exposure to cigarette smoke also increases your risk of respiratory infection, including...

Carcinogenic Interactions For Smoking And Occupational Inhaled Arsenic

Table 3 provides three examples of carcinogenicity from arsenic and smoking (Pershagen et al., 1981 Enterline, 1983 Pershagen, 1985). The first shows that the relative risk for lung cancer, comparing retired arsenic smelter workers to the male population in the state where the study was conducted, among nonsmokers is 5.1. If we compare smokers to nonsmokers among the general population of males, the relative risk is 7.2. If the effects were multiplicative then we would expect the arsenic-exposed workers who were smokers to have a relative risk of about 35. The actual relative risk is 20.7, indicating that there is interaction on the multiplicative scale the effects of smoking and arsenic exposure are less than multiplicative. If we express these numbers on the additive scale, we obtain an excess relative risk (ERR) for arsenic exposure among nonsmokers of 4.1, an ERR for smoking in the general population of males of 6.2, and an expected ERR, under an additive model, of 11.3 (...

Discussion And Conclusions

While it is known that for those exposed to arsenic occupationally through inhalation, smoking increases the arsenic-associated risk for developing lung cancer, it is unclear whether smoking has a similar modifying effect in relation to carcinogenicity of ingested arsenic. Several studies do suggest that smoking influences methylation, but findings require confirmation in different populations, and the impact on cancer risk and attributable cases is unclear. Similarly, genetic factors also appear to influence methylation capacity, but the data are sparse. Liver disease or infections that alter liver function are also suspect modifying factors. Attention should be paid to those who are taking medications that may compromise liver function.

Results And Discussion

Preliminary analysis of the database (Tables 1 and 2) collected during 15 years (three 5-year intervals) of 844 lung cancer cases suggests a permanent increase of lung cancer incidence in both the most polluted part of the district and the rest of it. The incidence of lung cancer is markedly influenced by exposure to arsenic in occupational settings as can been seen from Table 3.

Antioxidant nutrients

C and E would reduce the recurrence of adenomas in patients who had undergone polypectomy showed no evidence of a protective effect.31 Similarly, a prolonged placebo-controlled intervention with vitamin E or vitamin E and beta-carotene failed to prevent the development of lung cancer in smokers.30 There is good epidemiological evidence for an inverse association between intake of carotenoids and lung cancer, and weaker evidence for protective effects against cancers of the alimentary tract.37 The possibility that carotenoids might express antioxidant activity in human tissues, thereby protecting cell membranes, proteins and DNA against damage by free radicals, provides a plausible rationale for these associations, but once again the causal link has not been proven and the possibility remains that carotenoids are acting as markers for fruit and vegetable intake which may be beneficial for other reasons.36 Intervention trials with beta-carotene have proved disappointing. The...

Materials And Methods

The standardized personal interview was used based on a structured questionnaire and was carried out by four public health nurses who were well-trained in the interview technique and questionnaire details. Information obtained from the interview included the duration of well water consumption, residential history, sociodemographic characteristics, cigarette smoking, alcohol consumption, physical activities, history of sunlight exposure, as well as personal and family history of hypertension, diabetes, cerebrovascular disease, heart disease, and cancers. Well water samples were collected during the interviews at home, acidified with hydrochloric acid immediately and then stored at 20 C until sub

Proteomic Applications in Cancer

Lung Cancer Proteomic studies in lung cancer, the most common cancer worldwide, have been reviewed 37 . Initial studies on lung cancer proteomics were first published in the early 1990s. These early studies focused on the relationship between histopathological characteristics and 2D-PAGE reproducibility 38 . A few years later, the first differentially expressed proteins in lung cancer were identified in small cell lung cancer (SCLC), including -tubulin, heat-shock proteins 73 and 90, lamin B, and proliferating cell nuclear antigen (PCNA). This report demonstrated for the first time that 2D-PAGE combined with protein identification was an effective approach to identify biomarkers in cancer 39 . Later on, with improvements in MS technology, it was possible to identify about 20 potential biomarkers in lung cancer tissue 40 . Recently, a SELDI study in early lung cancer stages and premalignant bronchial lesions analyzed LCM specimens of normal lung, atypical adenomatous...

Fetal Undernutrition Pathway

There is a considerable body of epidemiological data relating an impaired intra-uterine environment to the development of later central adiposity. For instance, studies of elderly populations show greater visceral adiposity among individuals who were born small (22). Children of smokers, who experience prenatal hypoxia and are likely to be born small, are more likely to develop obesity (23). Studies of the Dutch winter famine of 1944-1945, where previously well-nourished women were exposed to Nazi-imposed severe rationing, show that those who were pregnant during the famine gave birth to offspring who subsequently became obese (24).

Oxidized Lipoproteins

Cigarette smoking was demonstrated to render LDL more susceptible to oxidative modification by incubation with cultured SMC as compared to LDL from nonsmokers. LDL which was isolated from smokers was metabolized by cultured peritoneal macrophages twice as avidly as LDL of nonsmokers (68). This was in agreement with the findings that treatment of LDL with cigarette smoke extract leads to cholesteryl ester accumulation in cultured macrophages (69).

Cardioprotective Effect Of Moderate Wine Drinking

Supply phytochemical isoflavenoids, vitamins which have powerful antioxidant effects. These effects include inhibition oflow-density lipoprotein oxidation as well as reduction in coagulation and improved thrombolysis. Most importantly, the beneficial protective effects of a moderate alcohol intake are found only in non-smokers 20 .

Alcohol Abuse And Cardiovascular Disease

Although there is considerable evidence that moderate drinking protects against mortality and morbidity from coronary heart disease 21,22 , heavy consumption is shown to have deleterious cardiovascular effects. It exerts its adverse effects by increasing the risks of cardiomyopathy, hypertension, and stroke 23 , Chronic ethanol consumption has been linked to the prevalence of hypertension, which contributes to an increased incidence of stroke. Heavy drinkers have alO mmHg higher systolic blood pressure than non-drinkers even though the relationship may differ between men and women 24 , Stroke is a leading cause of death and morbidity. Alcohol may increase the risk of stroke through various mechanisms that include hypertension, hypercoagulable states, cardiac arrhythmias, and cerebral blood flow reductions 25 , Hypertension, including borderline hypertension, is probably the most important stroke risk factor based on degree of risk and prevalence. Furthermore, cardiac morbidity,...

The Coeffect Of Alcohol And Tobacco Smoking

Alcoholics are commonly heavy smokers. There is a synergistic effect of alcohol consumption and smoking on cancer development, with long term ethanol consumption enhancing the mutagenicity of tobacco-derived product 24 , The combined ingestion of ethanol resulted in a significant formation of smoke-related DNA adducts in the esophagus and in their further, dramatic increase in the heart. Thus ethanol consumption increases the bioavailability of DNA binding of smoke components in the upper digestive tract and favors their systemic distribution. Formation ofDNA adducts in the organs examined may be relevant in the pathogenesis oflung and esophageal cancers as well as in the pathogenesis of other types of chronic degenerative diseases, such as chronic obstructive pulmonary diseases and cardiomyopathies 29 , Numerous studies have indicated a correlation between ethanol intake and cigarette smoking in heavy drinkers 30 , On a pharmacological basis, an ethanol-induced potentiation of...

PNS of the Peripheral Nervous System

Paraneoplastic autonomic neuropathy is primarily seen with SCLC 103 . Lymphoma, non-small cell lung cancer, and ovarian cancer are also associated with autonomic disturbances 104 . Autonomic dysfunction affects 23-30 of Hu antibody positive patients 36, 98 and is the predominant symptom at presentation in up to 9 of the patients 90 . The onset of symptoms is usually subacute. A prominent clinical manifestation in patients with paraneo-plastic autonomic neuropathy is gastrointestinal dysmotility and intestinal pseudo-obstruction, which can occur as part of the PEM SN syndrome or as the sole symptom of Hu antibody related PNS. Ortostatic hypotension and erectile dysfunction are other common features 37, 105, 106 . Autonomic neuropathy is also commonly associated with the CRMP-5 antibody and have been detected in more than 30 of CRMP-5 antibody positive patients 30 .

Criteria For Causation

This is that chemicals are often produced by a variety of sources. For instance, although municipal waste incineration produces at least 25 noxious groups of chemicals antimony, arsenic, beryllium, cadmium, carbon monoxide, chromium, cobalt, copper, dioxins and furans, hydrogen chloride, hydrogen fluoride, lead, magnesium, mercury, nickel, nitrogen oxides, particulates, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, selenium, sulphur dioxide, thallium, tin, vanadium and zinc, these chemicals are produced also by a variety of other sources. Nineteen of these 25 chemicals are constituents of tobacco smoke, 10 of the 25 are liberated through burning coal, and 6 of the 25 are found in exhaust emissions from motor vehicles. Municipal waste incineration is the major contributor of 9 of the 25 chemicals. All of these chemicals occur at background levels in the environment. Confirmation of an unequivocal association between incineration and an adverse environmental or human...

Cytokines and muscle protein degradation in cachexia

Chronic overproduction of cytokines may lead to cachexia in various animal chronic illness models. Cytokines such as interleukin (IL)-1 P, IL-6, and tumor necrosis factor (TNF)-a are upregulated in various animal cachexia models. The pathogenetic role of the cytokine network in upregulating muscle protein degradation has been documented as the result of a complex interplay among TNF-a, IL-6, IL-1 , interferon (IFN)-y, and a variety of humoral mediators. Neutralization of these factors by genetic or pharmacological methods leads to attenuation of cachexia. Chronic infusion of IL-1 or TNF-a causes anorexia, rapid weight loss, and catabolism of body protein stores, analogous to the state observed with chronic illness (31-34). Anticytokine approaches have been proven at least partially effective in attenuating muscle weight loss in cancer. Mice bearing the Lewis lung carcinoma are protected from cachexia when treated with antibodies against IFN-y (35). Implantation of the Lewis lung...

Obesity And Abdominal Adiposity

Large decreases in life expectancy, even among patients who were non-smokers (Figure 7.8)22. Another recent study investigated the impact of BMI and measures of abdominal adiposity including waist circumference and waist-to-hip ratio on the prognosis of patients with stable cardiovascular disease who had been enrolled in the Heart Outcomes Prevention Evaluation (HOPE) study23. When compared with the first tertile, the third tertile of BMI was associated with a 20 increase in the relative risk of myocardial infarction23. The third tertile of waist circumference was associated with a 23 increase in the relative risk of myocardial infarction, a 38 increase in the relative risk of heart failure, and a 17 relative increase in total mortality when compared with the first tertile23. Patients within the third tertile of waist-to-hip ratio demonstrated a 24 increased relative risk of cardiovascular death, a 20 increased relative risk of

Clinical Box 42 Marijuana Antagonist Blocks Munchies

Recently, researchers have described cannabinoid (CB) receptors, which are the GPCRs that recognize tetrahydrocannabinol found in marijuana. The CB1 receptor is found in areas of the brain that control appetite and addiction to smoking (tobacco), and this receptor may be responsible for the munchies experienced by marijuana smokers. The munchie connection led researchers to develop CBi-receptor antagonists in hopes that they would be useful as aids for weight loss. One antagonist (rimonabant from Sanofi-Aventis) may soon be available as a diet pill and as an antismoking aid.

Have early menopause What does this mean for my bones and will I need treatment

Surgically-induced menopause (removal of both ovaries) will cause you to lose bone fairly rapidly. It is important for you to prevent bone loss by getting the appropriate amounts of calcium (1,200 to 1,500 mg), Vitamin D (400-800 IU), other necessary nutrients (see Table 6 in Question 54), and exercise. You should also be sure to make lifestyle changes that could improve your bone health, like avoiding heavy alcohol use and stopping smoking. In addition, you and your clinician may want to discuss medications for preventing bone loss. As long as your surgery did not result from cancer and you do not have any contraindications to taking them, you may take any of the medications that are approved for prevention of osteoporosis. If you are experiencing significant symptoms resulting from your induced menopause, a good option for you may be MHT (see Questions 64 and 66). Your clinician may also want to send you for bone mineral density testing to get a baseline reading of your bones. Women...

Pathogenesis of Paraneoplastic Nervous System Syndromes

With the exception of the Tr antigen, onconeural antigens are invariably expressed in the tumors of patients with antibody-verified PNS, and failure to find the relevant antigen expressed in a tumor from such patients should prompt investigation for a second tumor 14 . However, onconeural antigens are also expressed in tumors from patients without onconeural antibodies and with no signs of nervous system disease. in particular, tumors derived from neuroendocrine cells express the Hu antigen. Thus, 100 of SCLC tumors 170 and 50-78 of neuroblastomas 170, 171 express the Hu antigen. Tumors of non-neuroendocrine origin can also express the Hu antigen, as demonstrated by a study of extrathoracic non-small cell lung cancer associated with PEM SN 32 . Cdr2 is expressed in 60 of ovarian tumors and 25 of breast tumors 172, 173 .

Scope of clinical problem

Although the primary pathophysiology of PAD is impaired perfusion to the lower extremity, all conventional PAD treatments such as antiplatelet therapy, angiotensin-cascade antagonists, HMG-CoA-reduc-tase inhibitors, and smoking cessation target general atherosclerotic risk factor reduction (especially smoking cessation). In selected patients, structured exercise (in IC) and limb hygiene (in CLI) are of benefit. At present, pharmacological therapies used in PAD do not improve perfusion. Pentoxifylline, although widely prescribed in the United States, has little or no clinical benefit (6). Cilostazol, a phosphodiesterase inhibitor, offers some clinical efficacy, but its safety in patients with ventricular dysfunction remains in question, and the US Food and Drug

Pi3kakt Kinase Pathway Inhibitors In Clinical Trials

Perifosine (27) is a synthetic, orally available alkylphospholipid, derived from alkylphosphocholine, which targets the PI3 AKT survival pathway. Although the molecular mechanism underlying the antineoplastic activity of 27 is not fully elucidated, studies suggest that 27 interferes with turnover and synthesis of natural phospholipids. This disrupts membrane signaling at several sites resulting in the inhibition of the PI3K AKT survival pathway 42,43 . Recent preclinical evaluation in cultured human Jurkat T-leukemia cells has shown that adding low concentrations of 27 (5 mM) after treatment with the commonly used chemotherapy drug etoposide, induced cell death in a synergistic fashion. The observed increase in cell death is attributed to an inactivation of the AKT survival pathway, as treated cells showed a complete dephosphorylation of AKT 44 . Compound 27 also inhibited baseline phosphorylation of AKT in multiple myeloma cells in a time- and dose-dependent fashion 45 . Reduced...

Sequestration For Defense And Communication

Specialists feeding on either plants or animals that are fortified with toxic alkaloids are unpredictable in terms of how these natural products are processed. For example, nicotine, as previously mentioned, is degraded or rapidly eliminated by larvae of the tobacco hornworm, Manduca sexta37 Nicotine is not known to be stored by any tobacco-feeding insects and may simply be too reactive to be easily sequestered in tissues. Of course, the inability of these larvae to accumulate nicotine internally deprives them of a powerful defense, a development that must reflect the nonadaptive nature of this alkaloid for sequestration. Similarly, a tropane alkaloid, cocaine, is only sequestered in trace amounts after moth larvae, Elor a noyse , have fed on coca plants.5 The larvae of E. noyse excrete the alkaloid very rapidly, and the feces contains most of the ingested compound. Significantly, the adults are cryptically colored, which is consistent with a species that lacks protective defensive...

The role of nAChRs in normal and pathological behavioral and cognitive states

Nicotinic transmission has been proposed to participate in many cognitive processes. Not only can nicotine improve performance in various tasks involving spatial and associative learning, working memory and attention, but mecamylamine, a general nicotinic antagonist, has been demonstrated to impair memory performance (Levin, 1992). Furthermore, lesions of the cholinergic forebrain system result in cognitive deficits reverted by nicotine (Tilson et al., 1988 Decker et al., 1992 but see Gallagher and Colombo, 1995 Chappell et al., 1998). These findings, together with the observation that choliner-gic function is impaired in the brains of Alzheimer's disease patients have contributed to the formulation of a cholinergic hypothesis to explain the cognitive impairments observed in Alzheimer's disease (Robbins et al., 1997). Prompted by epidemiological studies suggesting that the incidence of Alzheimer's and Parkinson's disease is significantly reduced in smokers (reviewed in Fratiglioni and...

Examination of behavioral impairments in 02 and a 7 Ko animals

In a passive avoidance test, p2 Ko animals exhibited longer latencies than their wild-type (Wt) controls to enter a dark (preferred) compartment previously paired with an aversive stimulus. While nicotine reliably improved performance in Wt animals, it did not influence p2 Ko mice behavior (Picciotto et al., 1995). This result demonstrates the involvement of endogenous nicotinic transmission in the regulation of the cognitive mechanisms recruited in the passive avoidance paradigm. It further establishes that nicotinic agents modulate passive avoidance performance through b2-containing (b2*) nAChRs. On the other hand, young adult p2 as well as al Ko animals, performed normally in spatial learning (Morris Water Maze) and pavlovian fear conditioning tasks (Picciotto et al., 1995 Paylor et al., 1998 Caldarone et al., 2000). The interpretation of these data requires a clear distinction between the cognitive enhancing properties of nicotine, which seem to be dependent on b2* nAChR...

Attentional deficits in a7 and 02 Ko mice

Another way to reveal deficits in attentional processes is to measure the extent of latent inhibition. This term refers to a phenomenon by which noncon-tingent preexposure to a stimulus retards subsequent conditioning to that stimulus. In schizophrenic patients, latent inhibition is greatly impaired, but only a few studies have addressed the influence of nicotine on this process in humans (Thornton et al., 1996 Della Casa et al., 1999). In b2 Ko mice, latent inhibition levels measured in a fear conditioning paradigm were found to be normal (Caldarone et al., 2000). In rats however, nicotine has been demonstrated to either increase or decrease latent inhibition depending on the preexposure phase parameters (number and duration of the stimulus presentations) (Rochford et al., 1996). Therefore, the data on p2 Ko animals, that were generated using a single set of preconditioning parameters, are still too incomplete to be conclusive. However, in the study on rats, the potency of cytisine,...

Animal Models of Human Prostate Cancer

After lung cancer, cancer of the prostate (CaP) is the second most common cause of cancer death in American males. A latent disease, many men have prostate cancer cells long before overt signs of the disease are apparent. The annual incidence of CaP is over 100,000 in the United States, of which over 40,000 will die of the disease. Nearly a third of patients present with locally advanced or metastatic disease, and androgen deprivation therapy forms the basis of conventional therapy for the majority of these patients. However, currently available approaches for advanced CaP are not curative 137 , primarily because the cells lose their dependence on androgenic stimulation. The mechanisms of progression of CaP cells to hormone independence under androgen ablation therapy remain unclear. To investigate the factors and mechanisms that underlie the development of androgen resistance and metastasis, reliable in vivo models that mimic human CaP progression are essential. Moreover, it is...

Contribution of Ko mice to the study of nAChRs in brain reinforcement systems

Recent theoretical models for cognitive learning have underlined the importance of reinforcement mechanisms in the organization and selection of brain representations (Dehaene and Changeux, 2000). Although the precise role of the ascending DA system is still debated (Koob, 1996 Schultz, 1997 Berridge and Robinson, 1998 Di Chiara, 1998), most authors agree that its integrity is crucial to the expression of motivated behaviors. By modulating the activity of the main reward pathway, nicotinic transmission is thought to play a role in reinforcement. First, nicotine acts as a positive reinforcer, as shown by place preference and self-administration studies (see Di Chiara, 2000 and references there in). Second, lesions of the peduncu-lopontine nucleus, the major cholinergic input to mesencephalic DA neurons, have been reported to impair learning and expression of behaviors reinforced by non-nicotinic addictive drugs (Olmstead and Franklin, 1994), brain stimulation (Lepore and Franklin,...

Summary and Discussion

We have presented for discussion a broad-based review of the utility of adenoviral vectors in animal models of lung cancer. Since this entire compilation is devoted to Ad-gene therapy, we have particularly embellished the sections on animal models of disease, especially as they pertain to lung and prostate cancer. These examples illustrate that the development of our approaches may need to be disease specific, especially with respect to targeting and mode of delivery. From this review, it is evident that to realize the full potential of cancer gene therapy, advances need to be made on a number of fronts. Not only do we need to construct better Ad-vectors or more relevant animal models, we also need to incorporate emerging technologies to a useful purpose within the experimental design. For example, the pathway to human clinical trials may be better paved by an improved ability to gather interim surrogate measures of gene transfer and expression in animal models.

New Therapies From Existing Drugs

History is replete with examples of compounds that were originally developed for one disease and subsequently found to be beneficial in another. In contrast to the hypothesis-driven philosophy of modern drug discovery, many highly successful new treatments have been discovered by serendipity 3,5,12-14 . The phosphodiesterase (PDE-5) inhibitor, sildenafil for example was originally developed as a potential anti-angina therapy but was observed during early clinical trials to be efficacious for male erectile dysfunction, for which it was subsequently first approved. Further studies on sildenafil have expanded its label to include approval for pulmonary arterial hypertension. The alpha-2 adrenergic agonist, brimonidine, was originally synthesized as an anti-hypertensive and later discovered and marketed as an anti-glaucoma agent. Further examples of drugs with unexpected benefits beyond their initially approved indications include bupropion, which is approved as a smoking cessation drug,...

Aging reveals cognitive impairment in p2 Ko animals

Work on Ko animals has significantly contributed to research on the neuroprotective action of nicotine in various models of neurodegeneration, both in vitro and in vivo (see references in Belluardo et al., 2000). In an experimental model of parkinsonism (Ryan et al., 2001), acute nicotine treatment protected against metamphetamine-induced neurodegeneration of dopaminergic (DA) terminals in Wt mice. In mice lacking the a4 subunit, the extent of the lesion was similar to what was observed in Wt controls, and it could not be prevented by nicotine. The role of b2* nAChR in nicotine's neuroprotective actions has also been examined in an experimental model of excitotoxic brain injury, in neonates (Laudenbach et al., 2002). In this study, nicotine protected against the toxic effects of intracerebral ibotenate injections in Wt but not in b2 Ko animals. It should be noted, however, that in the absence of pharmacological treatment, the size of the lesion was significantly smaller in b2 Ko...

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