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Tumor volume measured by micro CT scans. Tumor volume and associated 95% confidence intervals estimated from linear mixed model analysis are shown. Data for individual mice are shown. We found a significantly faster increase in tumor volume in the CIH versus Sham groups (p = 0.0003) and significant differences between the two groups across all timepoints (overall p<0.0001). In pairwise comparisons at each individual timepoint, the CIH group had trending or significantly greater tumor volume at day 26 (p = 0.055), day 33 (p = 0.004) and day 40 (p<0.0001). Sample size is as follows: for CIH at Day 12 (n = 11), Day 19 (n = 11), Day 26 (n = 11), Day 33 (n = 11), Day 40 (n = 10); for Sham at Day 12 (n = 13), Day 19 (n = 13), Day 26 (n = 13), Day 33 (n = 13), Day 40 (n = 13). https://doi.org/10.1371/journal.pone.0212930.g004
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Background
Epidemiological data suggests that obstructive sleep apnea (OSA) is associated with increased cancer incidence and mortality. We investigate the effects of cyclical intermittent hypoxia (CIH), akin to the underlying pathophysiology of OSA, on lung cancer progression and metastatic profile in a mouse model.
Methods
Intrathoracic injectio...
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Background:
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Citations
... The cause of SPN is complex, including smoking, long-term exposure to polluted environments or heavy dust work, lung infections or malignant tumors, and granulomas or fibrosis or inflammatory lesions caused by other diseases. An animal study showed that intermittent hypoxia was a contributing factor to lung cancer in mice and accelerated tumor growth [5]. However, there have been no clinical reports about it. ...
Background
Obstructive sleep apnea (OSA) has been shown to be an important risk factor for cardiovascular disease (CVD), and intermittent hypoxia is an important pathogenetic factor for it. In the clinic, it was found that most CVD patients combined with OSA were also combined with solitary pulmonary nodules (SPN) or thyroid nodules (TN). Are these disorders related to intermittent hypoxia? One study showed that intermittent hypoxia is a pathogenic factor for lung cancer in mice, but there have been no clinical reports. So we conducted a retrospective study to explore whether intermittent hypoxia caused by OSA increases the incidence of SPN, TN, and other disorders.
Methods
We selected 750 patients with cardiovascular disease (CVD), who were divided into the control group and the OSA group according to the result of portable sleep monitoring. Retrospectively analyzed the comorbidities that patients with OSA are prone to and explored the correlation between OSA and those comorbidities.
Results
The incidence of SPN, TN, cervical spondylosis, and carotid-artery plaques was higher in the OSA group than in the control group. These diseases are significantly associated with OSA (p < 0.05), and their incidence increased with an elevated apnea–hypopnea index. After excluding interference from age, gender, BMI, smoking history, history of lung disease, and history of tumors, OSA showed a significant correlation with SPN. After excluding age, gender, BMI, and thyroid disease, OSA was associated with TN. Patients with comorbidities have lower nocturnal oxygen saturation and more extended periods of apnea. Logistic multiple regression results revealed that male, advanced age, obesity, CS, and nasal septum deviation were independent risk factors for OSA.
Conclusions
Patients combined with OSA may further develop more comorbidities, such as SPN, TN, and carotid-artery plaques. It may be related to intermittent hypoxia caused by OSA.
... In addition, Cai et al. analyzed the methylation dataset of COVID-19 by utilizing the Monte Carlo feature selection method analyzed the methylation dataset of COVID-19 and found that EPSTI1, NACAP1, SHROOM3, C19ORF35 and MX1 as key features could [39][40][41][42]. Intriguingly, periodic intermittent hypoxia has been implicated as a causative factor for non-small cell lung cancer in TP53fl/ fl mice, thereby facilitating accelerated tumor growth [43]. Hence, we postulate that individuals afflicted with the concomitant presence of these two ailments are predisposed to a heightened risk of cancer or tumor development, ultimately resulting in diminished overall survival rates. ...
Background
The prevalence of obstructive sleep apnea (OSA) was found to be higher in individuals following COVID-19 infection. However, the intricate mechanisms that underscore this concomitance remain partially elucidated. The aim of this study was to delve deeper into the molecular mechanisms that underpin this comorbidity.
Methods
We acquired gene expression profiles for COVID-19 (GSE157103) and OSA (GSE75097) from the Gene Expression Omnibus (GEO) database. Upon identifying shared feature genes between OSA and COVID-19 utilizing LASSO, Random forest and Support vector machines algorithms, we advanced to functional annotation, analysis of protein–protein interaction networks, module construction, and identification of pivotal genes. Furthermore, we established regulatory networks encompassing transcription factor (TF)-gene and TF-miRNA interactions, and searched for promising drug targets. Subsequently, the expression levels of pivotal genes were validated through proteomics data from COVID-19 cases.
Results
Fourteen feature genes shared between OSA and COVID-19 were selected for further investigation. Through functional annotation, it was indicated that metabolic pathways play a role in the pathogenesis of both disorders. Subsequently, employing the cytoHubba plugin, ten hub genes were recognized, namely TP53, CCND1, MDM2, RB1, HIF1A, EP300, STAT3, CDK2, HSP90AA1, and PPARG. The finding of proteomics unveiled a substantial augmentation in the expression level of HSP90AA1 in COVID-19 patient samples, especially in severe conditions.
Conclusions
Our investigation illuminate a mutual pathogenic mechanism that underlies both OSA and COVID-19, which may provide novel perspectives for future investigations into the underlying mechanisms.
... OSA is implicated in oncogenesis [11,12], tumor progression [13], and all-cause cancer mortality [14][15][16]. Preclinical [17,18] and epidemiological studies [14] have proposed that chronic intermittent hypoxia (IH), a pathophysiologic feature of OSA, contributes to tumor growth and metastasis. To date, clinical studies have been done to assess the prevalence of OSA in specific types of cancers [19,20], yet there has not been an established screening tool for OSA in patients with cancer. ...
Background
Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder associated with daytime sleepiness, fatigue, and increased all-cause mortality risk in patients with cancer. Existing screening tools for OSA do not account for the interaction of cancer-related features that may increase OSA risk.
Study Design and Methods
This is a retrospective study of patients with cancer at a single tertiary cancer institution who underwent a home sleep apnea test (HSAT) to evaluate for OSA. Unsupervised machine learning (ML) was used to reduce the dimensions and extract significant features associated with OSA. ML classifiers were applied to principal components and model hyperparameters were optimized using k-fold cross-validation. Training models for OSA were subsequently tested and compared with the STOP-Bang questionnaire on a prospective unseen test set of patients who underwent an HSAT.
Results
From a training dataset of 249 patients, kernel principal component analysis (PCA) extracted eight components through dimension reduction to explain the maximum variance with OSA at 98%. Predictors of OSA were smoking, asthma, chronic kidney disease, STOP-Bang score, race, diabetes, radiation to head/neck/thorax (RT-HNT), type of cancer, and cancer metastases. Of the ML models, PCA + RF had the highest sensitivity (96.8%), specificity (92.3%), negative predictive value (92%), F1 score (0.93), and ROC-AUC score (0.88). The PCA + RF screening algorithm also performed better than the STOP-Bang questionnaire alone when tested on a prospective unseen test set.
Conclusions
The PCA + RF ML model had the highest accuracy in screening for OSA in patients with cancer. History of RT-HNT, cancer metastases, and type of cancer were identified as cancer-related risk factors for OSA.
... Therefore, it is critical to determine the LN metastasis accurately. It has been shown that multiphase contrastenhanced micro-CT is feasible for the evaluation and monitoring of lung cancer metastases in small animal studies [92][93][94]. Another study indicates that micro-CT can be used as a method for diagnosing metastatic LNs with a clinical N0 status in mice [95]. ...
Micro-computed tomography (micro-CT) is a relatively new imaging modality and the three-dimensional (3D) images obtained via micro-CT allow researchers to collect both quantitative and qualitative information on various types of samples. Micro-CT could potentially be used to examine human diseases and several studies have been published on this topic in the last decade. In this study, the potential uses of micro-CT in understanding and evaluating lung carcinoma and the relevant studies conducted on lung and other tumors are summarized. Currently, the resolution of benchtop laboratory micro-CT units has not reached the levels that can be obtained with light microscopy, and it is not possible to detect the histopathological features (e.g., tumor type, adenocarcinoma pattern, spread through air spaces) required for lung cancer management. However, its ability to provide 3D images in any plane of section, without disturbing the integrity of the specimen, suggests that it can be used as an auxiliary technique, especially in surgical margin examination, the evaluation of tumor invasion in the entire specimen, and calculation of primary and metastatic tumor volume. Along with future developments in micro-CT technology, it can be expected that the image resolution will gradually improve, the examination time will decrease, and the relevant software will be more user friendly. As a result of these developments, micro-CT may enter pathology laboratories as an auxiliary method in the pathological evaluation of lung tumors. However, the safety, performance, and cost effectiveness of micro-CT in the areas of possible clinical application should be investigated. If micro-CT passes all these tests, it may lead to the convergence of radiology and pathology applications performed independently in separate units today, and the birth of a new type of diagnostician who has equal knowledge of the histological and radiological features of tumors.
... Lung cancer is responsible for the most deaths from malignancy, and NSCLC accounts for 80-85% of lung cancer of which about 50% are LUAD [46,47]. In addition, animal studies have shown that IH promotes LUAD progression [48], but the specific mechanism has not been studied. A great deal of research has shown that exosomes transfer a variety of miRNAs from releasing cells to recipient cells [49], thus promoting tumor development [50,51]. ...
Background
Intermittent hypoxia (IH) is a factor involved in the incidence and progression of lung adenocarcinoma (LUAD). Bone marrow-derived bone mesenchymal stem cells (BMSCs)-derived exosomes are related to the promotion of tumor development. The objective of this experiment was to clarify the mechanism of exosomes from BMSCs in promoting the progression of LUAD induced by IH.Methods
This study examined if IH BMSCS-derived exosomes affect the malignancy of LUAD cells in vitro. Dual-luciferase assays were conducted to confirm the target of miR-31-5p with WD repeat domain 5 (WDR5). We further investigated whether or not exosomal miR-31-5p or WDR5 could regulate epithelial–mesenchymal transition (EMT). We determined the effect of IH exosomes using a tumorigenesis model in vivo.ResultsmiR-31-5p entered into LUAD cells via exosomes. MiR-31-5p was greatly upregulated in IH BMSCs-derived exosomes compared with RA exosomes. Increased expression of exosomal miR-31-5p induced by IH was discovered to target WDR5 directly, increased activation of WDR5, and significantly facilitated EMT, thereby promoting LUAD progression.Conclusions
The promoting effect of IH on LUAD is achieved partly through BMSCs-derived exosomal miR-31-5p triggering WDR5 and promoting EMT.
... The IH is involved in tumor progression, including metabolism, proliferation, apoptosis, and angiogenesis via several mechanisms such as increasing gene mutation frequency (37), stimulating reactive free radical production (38) and promoting endothelial cell proliferation (37). Animal studies using lung cancer models have also shown that IH promotes cancer cell invasiveness (39,40) and increases melanoma cell growth, necrosis, and pulmonary metastasis (41). The earliest study in humans is the famous Wisconsin Sleep Cohort (42), where 1,522 patients from the community were followed up for an average of 22 years and the overall mortality rate for patients with OSA was 7.36%, with higher tumor mortality in patients with OSA (5.21%) than in those without OSA (2.68%). ...
Background:
The association between colorectal cancer (CRC) and obstructive sleep apnoea (OSA) has been attracting increasing attention. several studies had confirmed that OSA increases the risk of CRC onset. However, the findings of studies on the morbidity of OSA in patients with CRC were unclear. Therefore, this study aimed to investigate the morbidity of OSA in patients with CRC as well as the association between the clinicopathological characteristics of OSA and CRC.
Methods:
A total of 414 patients with a pathological diagnosis of CRC from 1 January, 2020 to 30 December, 2020 were included in this study. Demographic characteristics, clinical information, and tumor characteristics of participants were collected; sleep was monitored using a wearable oximeter and via sleep quality questionnaire. The oxygen desaturation index (ODI) was used to classify OSA severity so that the diagnostic criteria for OSA were set based on the ODI as 0-5 (normal) and ≥5 (abnormal). After correcting for confounding factors, a logistic regression analysis was performed to calculate the odds ratio (OR) and 95% confidence interval (CI) for the factors affecting the tumor lymph node stage (N stage).
Results:
A total of 402 patients with CRC were included in this study, including 225 (55.97%) men and 177 (44.03%) women. The mean ODI value of participants was 3.40±8.17. The morbidity of OSA among the patients with CRC having ODI ≥5 was 16.17%. A comparison between the normal and abnormal ODI value groups revealed that the high proportion of abnormal ODI was related to higher N stage (P<0.05). Logistic regression analysis revealed a correlation of ODI values and age to the N stage. Specifically, CRC patients with an abnormal ODI had a higher risk of lymph node metastasis compared to those with normal ODI (OR =1.915, 95% CI: 1.025 to 3.579). Moreover, patients with CRC aged ≥65 years had a higher risk of lymph node metastasis compared to those aged <65 years (OR =2.190, 95% CI: 1.163 to 4.125).
Conclusions:
CRC patients with abnormal ODI are susceptible to OSA. Additionally, abnormal ODI and age ≥65 years are relevant factors for the N2 stage.
... (B) Experimental application of the obstructive sleep apnoea (OSA) challenges (IH: intermittent hypoxia, SF: sleep fragmentation) and control normoxia to cancer models of tumorigenesis (spontaneous by ageing or induced by virus/chemicals) and tumours induced by subcutaneous, intravenous, or orthotopic cancer cell application. [13,17,20,22,[25][26][27][29][30][31][32]43,44] 3 [16,24,28] ↑ 13/13 ↑ 13/13 Despite the rather compelling findings summarized in Table 1, some important issues must be pointed out. First, most data from animal models came from experiments carried out in two types of murine cancer (lung and melanoma) that only included a very restricted number of cancer cell types, such that the transferability of these findings to human cancers remains uncertain. ...
Obstructive sleep apnoea (OSA) is a prevalent disorder associated with increased cardiovascular, metabolic and neurocognitive morbidity. Recently, an increasing number of basic, clinical and epidemiological reports have suggested that OSA may also increase the risk of cancer, and adversely impact cancer progression and outcomes. This hypothesis is convincingly supported by biological evidence linking certain solid tumours and hypoxia, as well as by experimental studies involving cell and animal models testing the effects of intermittent hypoxia and sleep fragmentation that characterize OSA. However, the clinical and epidemiological studies do not conclusively confirm that OSA adversely affects cancer, even if they hold true for specific cancers such as melanoma. It is likely that the inconclusive studies reflect that they were not specifically designed to test the hypothesis or because of the heterogeneity of the relationship of OSA with different cancer types or even sub-types. This review critically focusses on the extant basic, clinical, and epidemiological evidence while formulating proposed directions on how the field may move forward.
... Prior animal studies and in vitro models demonstrate the potential of intermittent hypoxia to contribute to cancer progression. Intermittent hypoxia promotes tumor growth and metastasis in melanoma-injected mice as well as other murine tumor models 28,29 and is associated with altered immunomodulation 30 and resistance to radiation in cancer cell lines. 11,31 However, it has recently been shown that not all tumors within a particular site exhibit similar susceptibility to intermittent hypoxia. ...
Background:
In vitro and animal studies suggest that intermittent hypoxia characterizing sleep apnea contributes to accelerated cancer progression. However, the impact of sleep apnea on survival subsequent to cancer diagnosis is unknown.
Methods:
We identified a cohort of 1,575 adults diagnosed with sleep apnea between 2005-2014 with a subsequent cancer diagnosis via linkage of University of Washington Medicine system and a population-based cancer registry serving the same Seattle-Puget Sound region. We computed age-standardized 5-year relative survival after cancer diagnosis for all cancers combined, and for specific cancer sites, for both the sleep apnea cohort (SAC) and the general Seattle-Puget Sound population and used US life tables as the reference population. Relative survival was estimated by sex, cancer stage and healthcare engagement.
Results:
Five-year overall relative survival for cancer was more favorable in the SAC than in the general population (83.6%; 95% CI: 79.8-86.8% vs 71.6%; 95% CI: 71.3-71.9%); this pattern was applicable to most specific cancer sites. However, 5-year relative survival was slightly less favorable in the SAC among patients with melanoma (97.7%; 95% CI: 84.6-99.7% vs 99.2%; 95% CI: 98.8-99.5%) and cancer of the corpus uteri (84.0%; 95% CI: 58.2-94.5% vs 84.6%; 95% CI: 83.1-86.0%).
Conclusion:
The fact that survival after cancer, overall and for most cancer sites, was more favorable in sleep apnea patients warrants larger community-based studies to further tease out effects of sleep apnea and treatment on site-specific survival for different cancer types, particularly in patients with melanoma or uterine cancer.
Despite undeniable advances in modern medicine, lung cancer still has high morbidity and mortality rates. Lung cancer is preventable and treatable, and it is important to identify new risk factors for lung cancer, especially those that can be treated or reversed. Obstructive sleep apnea (OSA) is a very common sleep-breathing disorder that is grossly underestimated in clinical practice. It can cause, exacerbate, and worsen adverse outcomes, including death and various diseases, but its relationship with lung cancer is unclear. A possible causal relationship between OSA and the onset and progression of lung cancer has been established biologically. The pathophysiological processes associated with OSA, such as sleep fragmentation, intermittent hypoxia, and increased sympathetic nervous excitation, may affect normal neuroendocrine regulation, impair immune function (especially innate and cellular immunity), and ultimately contribute to the occurrence of lung cancer, accelerate progression, and induce treatment resistance. OSA may be a contributor to but a preventable cause of the progression of lung cancer. However, whether this effect exists independently of other risk factors is unclear. Therefore, by reviewing the literature on the epidemiology, pathogenesis, and treatment of lung cancer and OSA, we hope to understand the relationships between the two and promote the interdisciplinary exchange of ideas between basic medicine, clinical medicine, respiratory medicine, sleep medicine, and oncology.
Background
The association between obstructive sleep apnea syndrome (OSAS) and mortality has not been extensively researched among individuals with varying diabetic status. This study aimed to compare the relationship of OSAS with all‐cause and cause‐specific mortality in US individuals with or without diabetes based on data from the National Health and Nutrition Examination Survey (NHANES).
Methods
The study included participants from the NHANES 2005–2008 and 2015–2018 cycles with follow‐up information. OSAS data (OSAS.MAP10) was estimated from the questionnaire. Hazard ratios (HRs) and the 95% confidence interval (CI) of OSAS for mortality were calculated by Cox regression analysis in populations with different diabetes status. The relationships between OSAS and mortality risk were examined using survival curves and restricted cubic spline curves.
Results
A total of 13 761 participants with 7.68 ± 0.042 follow‐up years were included. In the nondiabetic group, OSAS.MAP10 was positively associated with all‐cause, cardiovascular, and cancer mortality. In individuals with prediabetes, OSAS.MAP10 was positively related to all‐cause mortality (HR 1.11 [95% CI: 1.03–1.20]) and cardiovascular mortality (HR 1.17 [95% CI: 1.03–1.33]). The relationship between OSAS.MAP10 and the risk of all‐cause mortality and cancer mortality exhibited L‐shaped curves in diabetes patients (both with nonlinear p values <.01). Further threshold effect analysis revealed that OSAS was positively related to death risk when OSAS.MAP10 exceeded the threshold scores.
Conclusion
The relationship between OSAS and mortality differed among participants with or without diabetes. Individualized clinical treatment plans should be developed in clinical practice to reduce the risk of death for patients with different metabolic conditions.
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