Obstructive sleep apnea and the prevalence and incidence of cancer

Background:

A link between obstructive sleep apnea and cancer development or progression has been suggested, possibly through chronic hypoxemia, but supporting evidence is limited. We examined the association between the severity of obstructive sleep apnea and prevalent and incident cancer, controlling for known risk factors for cancer development.

Methods:

We included all adults referred with possible obstructive sleep apnea who underwent a first diagnostic sleep study at a single large academic hospital between 1994 and 2010. We linked patient data with data from Ontario health administrative databases from 1991 to 2013. Cancer diagnosis was derived from the Ontario Cancer Registry. We assessed the cross-sectional association between obstructive sleep apnea and prevalent cancer at the time of the sleep study (baseline) using logistic regression analysis. Cox regression models were used to investigate the association between obstructive sleep apnea and incident cancer among patients free of cancer at baseline.

Results:

Of 10 149 patients who underwent a sleep study, 520 (5.1%) had a cancer diagnosis at baseline. Over a median follow-up of 7.8 years, 627 (6.5%) of the 9629 patients who were free of cancer at baseline had incident cancer. In multivariable regression models, the severity of sleep apnea was not significantly associated with either prevalent or incident cancer after adjustment for age, sex, body mass index and smoking status at baseline (apnea–hypopnea index > 30 v. < 5: adjusted odds ratio [OR] 0.96, 95% confidence interval [CI] 0.71–1.30, for prevalent cancer, and adjusted hazard ratio [HR] 1.02, 95% CI 0.80–1.31, for incident cancer; sleep time spent with oxygen saturation < 90%, per 10-minute increase: adjusted OR 1.01, 95% CI 1.00–1.03, for prevalent cancer, and adjusted HR 1.00, 95% CI 0.99–1.02, for incident cancer).

Interpretation:

In a large cohort, the severity of obstructive sleep apnea was not independently associated with either prevalent or incident cancer. Additional studies are needed to elucidate whether there is an independent association with specific types of cancer.Obstructive sleep apnea is a sleep-related breathing disorder characterized by repetitive episodes of upper-airway obstruction during sleep. Through sleep fragmentation, hypoxemia, hypercapnia, swings in intrathoracic pressure and increased sympathetic activity, these episodes lead to symptoms and health consequences.¹ In 2009, 23% of Canadian adults reported risk factors for obstructive sleep apnea, and 5% of the population 45 years and older reported being told by a health professional that they had the condition.²Obstructive sleep apnea has been postulated to cause cancer^3,4 or cancer progression,⁵ possibly through chronic intermittent hypoxemia,⁶ thus making it a potential modifiable risk factor for cancer development.⁷ However, the longitudinal evidence on this association is limited. Four cohort studies evaluated the longitudinal association between obstructive sleep apnea (expressed by the apnea–hypopnea index, oxygen desaturation or symptoms) and cancer development or cancer-related mortality (Appendix 1, available at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.140238/-/DC1).^3–5,8 All had limitations. Of the 3 that reported a positive association,^3,5,8 2 studies included a small number of participants with severe obstructive sleep apnea, had a relatively small number of events and did not consider competing risk of death from other causes;^5,8 and 2 used less reliable sleep-testing devices to define obstructive sleep apnea,^3,8 which may have introduced measurement bias. In the only study that did not show an association between obstructive sleep apnea and cancer,⁴ the former was diagnosed on the basis of self-reported symptoms, which could have resulted in misclassification of exposure.There is a need for a sufficiently large cohort study with a long enough follow-up to allow for the potential development of cancer that adjusts for important potential confounders, examines common cancer subtypes and has a rigorous assessment of both obstructive sleep apnea and cancer.^7,9,10 Our study was designed to improve upon the methods of published studies. We examined the association between the severity of obstructive sleep apnea (expressed by the apnea–hypopnea index or oxygen desaturation) and prevalent or incident cancer after controlling for known cancer risk factors.     

Early-Life Socioeconomic Status and the Prevalence of Breast Cancer in Later Life

Knowledge of mechanisms linking early-life social environment and breast cancer remains limited. We explore direct and indirect effects of early-life socioeconomic status (SES) on breast cancer prevalence in later life. Using 50-year data from the Wisconsin Longitudinal Study (N = 4,275) and structural equation modeling, we found a negative direct effect of early-life SES, indicating that women from higher-SES family background had lower breast cancer prevalence than women from lower-SES families. Additionally, early-life SES has a positive indirect effect on breast cancer via women's adult SES and age at first birth. Were it not for their higher SES in adulthood and delayed childbearing, women from higher-SES families of origin would have had lower breast cancer prevalence than women from lower-SES families. Yet, early-life SES is associated positively with adult SES and age at first birth, and women's higher adult SES and delayed childbearing are related to higher breast cancer prevalence.     

Analysis of the Airway Microbiota of Healthy Individuals and Patients with Chronic Obstructive Pulmonary Disease by T-RFLP and Clone Sequencing

Chronic obstructive pulmonary disease (COPD) is a progressive, inflammatory lung disease that affects a large number of patients and has significant impact. One hallmark of the disease is the presence of bacteria in the lower airways. Objective: The aim of this study was to analyze the detailed structure of microbial communities found in the lungs of healthy individuals and patients with COPD. Nine COPD patients as compared and 9 healthy individuals underwent flexible bronchoscopy and BAL was performed. Bacterial nucleic acids were subjected to terminal restriction fragment (TRF) length polymorphism and clone library analysis. Overall, we identified 326 T-RFLP band, 159 in patients and 167 in healthy controls. The results of the TRF analysis correlated partly with the data obtained from clone sequencing. Although the results of the sequencing showed high diversity, the genera Prevotella, Sphingomonas, Pseudomonas, Acinetobacter, Fusobacterium, Megasphaera, Veillonella, Staphylococcus, and Streptococcus constituted the major part of the core microbiome found in both groups. A TRF band possibly representing Pseudomonas sp. monoinfection was associated with a reduction of the microbial diversity. Non-cultural methods reveal the complexity of the pulmonary microbiome in healthy individuals and in patients with COPD. Alterations of the microbiome in pulmonary diseases are correlated with disease.     

Role of anti-angiogenic factor endostatin in the pathogenesis of experimental ulcerative colitis

AimsVascular endothelial growth factor (VEGF) and pathologic angiogenesis have been demonstrated to play a pathogenic role in the development and progression of inflammatory bowel disease. Thus, we hypothesized that the potent anti-angiogenic factor endostatin might play a beneficial role in experimental ulcerative colitis (UC).Main methodsWe used three animal models of UC: (1) induced by 6% iodoacetamide (IA) in rats, or (2) by 3% dextran sulfate sodium (DSS) in matrix metalloproteinase-9 (MMP-9) knockout (KO) and wild-type mice, and (3) interleukin-10 (IL-10) KO mice. Groups of MMP-9 KO mice with DSS-induced UC were treated with endostatin or water for 5 days.Key findingsWe found concomitant upregulation of VEGF, PDGF, MMP-9 and endostatin in both rat and mouse models of UC. A positive correlation between the levels of endostatin or VEGF and the sizes of colonic lesions was seen in IA-induced UC. The levels and activities of MMP-9 were also significantly increased during UC induced by IA and IL-10 KO. Deletion of MMP-9 decreased the levels of endostatin in both water- and DSS-treated MMP-9 KO mice. Treatment with endostatin significantly improved DSS-induced UC in MMP-9 KO mice.Significance1) Concomitantly increased endostatin is a defensive response to the increased VEGF in UC, 2) MMP-9 is a key enzyme to generate endostatin which may modulate the balance between VEGF and endostatin during experimental UC, and 3) endostatin treatment plays a beneficial role in UC. Thus, anti-angiogenesis seems to be a new therapeutic option for UC.     

Antimutagenic effect of lectin and <Emphasis Type="Italic">N</Emphasis>-methyl-<Emphasis Type="Italic">N’</Emphasis>-nitro-<Emphasis Type="Italic">N</Emphasis>-nitrosoguanidine on induced mutagenesis in mammalian cells in vitro

Factors and ways in which macromolecules influence the mutation process are considered. An antimutagenic effect is demonstrated in a study of the combined influence of lectins and the alkylating agent N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) on mutagenesis in Chinese hamster cells. Thus, in different schemes of treatment of cells with albumin and MNNG, the experimental frequency of mutations induced by the two agents was statistically reliably lower than the theoretically expected level for their independent combined action. The possibility that there exist common targets and mechanisms through which different types of mutagenic agents act on the cell DNA is discussed.     

Expression of humanized anti-Her2/neu single-chain IgG1-like antibody in mammary glands of transgenic mice

A system for production of single-chain antibody in mammary glands of mice was developed on the basis of a hybrid gene constructed from the coding sequence of anti-Her2/neu single-chain antibody inserted into the first exon of the sheep beta-lactoglobulin gene. Lines of transgenic mice were obtained that expressed humanized single-chain anti-Her2/neu IgG1-like antibody in their milk. These antibodies interact with Her2/neu antigen with high affinity (K_d = 0.4 nM). The expression level of the transgene depended on its integration site in the genome but not on the copy number. The transgene had no toxic effect on the mice and was stably inherited, at least for two generations. The results reveal new opportunities of producing single-chain antibodies in the milk of animals.     

gamma-Tubulin in Leishmania: cell cycle-dependent changes in subcellular localization and heterogeneity of its isoforms

A panel of six anti-peptide antibodies recognizing epitopes in different regions of the gamma-tubulin molecule was used for the characterization and localization of gamma-tubulin during cell cycle in Leishmania promastigotes. Immunofluorescence microscopy revealed the presence of gamma-tubulin in the basal bodies, posterior pole of the cell, and in the flagellum. Furthermore, the antibodies showed punctuate staining in the subpellicular microtubule. This complex localization pattern was observed in both interphase and dividing cells, where staining of posterior poles and the subpellicular corset was more prominent. In posterior poles, gamma-tubulin co-distributed with the 210-kDa microtubule-interacting protein and the 57-kDa protein immunodetected with anti-vimentin antibody. Immunogold electron microscopy on thin sections of isolated flagella showed that gamma-tubulin was associated with the paraflagellar rod (PFR) that runs adjacent to the axonemal microtubules. Under different extraction conditions, gamma-tubulin in Leishmania was found only in insoluble cytoskeletal fractions, in contrast to tubulin dimers that were both in soluble and cytoskeletal pool. Two-dimensional electrophoresis revealed multiple charge variants of gamma-tubulin. Posttranslational modifications of Leishmania gamma-tubulin might therefore have an important role in the regulation of microtubule nucleation and interaction with other proteins. The complex pattern of gamma-tubulin localization and its properties indicate that gamma-tubulin in Leishmania might have other function(s) besides microtubule nucleation.