In silico analysis to identify miR-1271-5p/PLCB4 (phospholipase C Beta 4) axis mediated oxaliplatin resistance in metastatic colorectal cancer.

Oxaliplatin (OXA) is the first-line chemotherapy drug for metastatic colorectal cancer (mCRC), and the emergence of drug resistance is a major clinical challenge. Although there have been numerous studies on OXA resistance, but its underlying molecular mechanisms are still unclear. This study aims to identify key regulatory genes and pathways associated with OXA resistance. The Gene Expression Omnibus (GEO) GSE42387 dataset containing gene expression profiles of parental and OXA-resistant LoVo cells was applied to explore potential targets. GEO2R, STRING, CytoNCA (a plug-in of Cytoscape), and DAVID were used to analyze differentially expressed genes (DEGs), protein-protein interactions (PPIs), hub genes in PPIs, and gene ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. R2 online platform was used to run a survival analysis of validated hub genes enriched in KEGG pathways. The ENCORI database predicted microRNAs for candidate genes. A survival analysis of those genes was performed, and validated using the OncoLnc database. In addition, the 'clusterProfiler' package in R was used to perform gene set enrichment analysis (GSEA). We identified 395 DEGs, among which 155 were upregulated and 240 were downregulated. In total, 95 DEGs were screened as hub genes after constructing the PPI networks. Twelve GO terms and three KEGG pathways (steroid hormone biosynthesis, malaria, and pathways in cancer) were identified as being significant in the enrichment analysis of hub genes. Twenty-one hub genes enriched in KEGG pathways were defined as key genes. Among them AKT3, phospholipase C Beta 4 (PLCB4), and TGFB1 were identified as OXA-resistance genes through the survival analysis. High expressions of AKT3 and TGFB1 were each associated with a poor prognosis, and lower expression of PLCB4 was correlated with worse survival. Further, high levels of hsa-miR-1271-5p, which potentially targets PLCB4, were associated with poor overall survival in patients with CRC. Finally, we found that PLCB4 low expression was associated with MAPK signaling pathway and VEGF signaling pathway in CRC. Our results demonstrated that hsa-miR-1271-5p/PLCB4 in the pathway in cancer could be a new potential therapeutic target for mCRC with OXA resistance.

Associations between risk of Alzheimer's disease and obstructive sleep apnea, intermittent hypoxia, and arousal responses: A pilot study.

Objectives: Obstructive sleep apnea (OSA) may increase the risk of Alzheimer's disease (AD). However, potential associations among sleep-disordered breathing, hypoxia, and OSA-induced arousal responses should be investigated. This study determined differences in sleep parameters and investigated the relationship between such parameters and the risk of AD. Methods: Patients with suspected OSA were recruited and underwent in-lab polysomnography (PSG). Subsequently, blood samples were collected from participants. Patients' plasma levels of total tau (T-Tau) and amyloid beta-peptide 42 (Aß42) were measured using an ultrasensitive immunomagnetic reduction assay. Next, the participants were categorized into low- and high-risk groups on the basis of the computed product (Aß42 × T-Tau, the cutoff for AD risk). PSG parameters were analyzed and compared. Results: We included 36 patients in this study, of whom 18 and 18 were assigned to the low- and high-risk groups, respectively. The average apnea-hypopnea index (AHI), apnea, hypopnea index [during rapid eye movement (REM) and non-REM (NREM) sleep], and oxygen desaturation index (≥3%, ODI-3%) values of the high-risk group were significantly higher than those of the low-risk group. Similarly, the mean arousal index and respiratory arousal index (R-ArI) of the high-risk group were significantly higher than those of the low-risk group. Sleep-disordered breathing indices, oxygen desaturation, and arousal responses were significantly associated with an increased risk of AD. Positive associations were observed among the AHI, ODI-3%, R-ArI, and computed product. Conclusions: Recurrent sleep-disordered breathing, intermittent hypoxia, and arousal responses, including those occurring during the NREM stage, were associated with AD risk. However, a longitudinal study should be conducted to investigate the causal relationships among these factors.

Association between cyclic variation in the heart rate index and biomarkers of neurodegenerative diseases in obstructive sleep apnea syndrome: A pilot study.

PURPOSE: Obstructive sleep apnea syndrome (OSAS) has mostly been examined using in-laboratory polysomnography (Lab-PSG), which may overestimate severity. This study compared sleep parameters in different environments and investigated the association between the plasma levels of neurochemical biomarkers and sleep parameters. METHODS: Thirty Taiwanese participants underwent Lab-PSG while wearing a single-lead electrocardiogram patch. Participants' blood samples were obtained in the morning immediately after the recording. Participants wore the patch for the subsequent three nights at home. Sleep disorder indices were calculated, including the apnea-hypopnea index (AHI), chest effort index, and cyclic variation of heart rate index (CVHRI). The 23 eligible participants' derived data were divided into the normal-to-moderate (N-M) group and the severe group according to American Association of Sleep Medicine (AASM) guidelines (Lab-PSG) and the recommendations of a previous study (Rooti Rx). Spearman's correlation was used to examine the correlations between sleep parameters and neurochemical biomarker levels. RESULTS: The mean T-Tau protein level was positively correlated with the home-based CVHRI (r = 0.53, p < 0.05), whereas no significant correlation was noted between hospital-based CVHRI and the mean T-tau protein level (r = 0.25, p = 0.25). The home-based data revealed that the mean T-Tau protein level in the severe group was significantly higher than that in the N-M group (severe group: 24.75 ± 6.16 pg/mL, N-M group: 19.65 ± 3.90 pg/mL; p < 0.05). Furthermore, the mean in-hospital CVHRI was higher than the mean at-home values (12.16 ± 13.66 events/h). CONCLUSION: Severe OSAS patients classified by home-based CVHRI demonstrated the higher T-Tau protein level, and CVHRI varied in different sleep environments.

Associations among sleep-disordered breathing, arousal response, and risk of mild cognitive impairment in a northern Taiwan population.

STUDY OBJECTIVES: Dementia is associated with sleep disorders. However, the relationship between dementia and sleep arousal remains unclear. This study explored the associations among sleep parameters, arousal responses, and risk of mild cognitive impairment (MCI). METHODS: Participants with the chief complaints of memory problems and sleep disorders, from the sleep center database of Taipei Medical University Shuang-Ho Hospital, were screened, and the parameters related to the Cognitive Abilities Screening Instrument, Clinical Dementia Rating, and polysomnography were determined. All examinations were conducted within 6 months and without a particular order. The participants were divided into those without cognitive impairment (Clinical Dementia Rating = 0) and those with MCI (Clinical Dementia Rating = 0.5). Mean comparison, linear regression models, and logistic regression models were employed to investigate the associations among obtained variables. RESULTS: This study included 31 participants without MCI and 37 with MCI (17 with amnestic MCI, 20 with multidomain MCI). Patients with MCI had significantly higher mean values of the spontaneous arousal index and spontaneous arousal index in the non-rapid eye movement stage than those without MCI. An increased risk of MCI was significantly associated with increased spontaneous arousal index and spontaneous arousal index in the non-rapid eye movement stage with various adjustments. Significant associations between the Cognitive Abilities Screening Instrument scores and the oximetry parameters and sleep disorder indexes were observed. CONCLUSIONS: Repetitive respiratory events with hypoxia were associated with cognitive dysfunction. Spontaneous arousal, especially in non-rapid eye movement sleep, was related to the risk of MCI. However, additional longitudinal studies are required to confirm their causality. CITATION: Tsai C-Y, Hsu W-H, Lin Y-T, et al. Associations among sleep-disordered breathing, arousal response, and risk of mild cognitive impairment in a northern Taiwan population. J Clin Sleep Med. 2022;18(4): 1003-1012.

Comparison of Hospital-Based and Home-Based Obstructive Sleep Apnoea Severity Measurements with a Single-Lead Electrocardiogram Patch.

Obstructive sleep apnoea (OSA) is a global health concern, and polysomnography (PSG) is the gold standard for assessing OSA severity. However, the sleep parameters of home-based and in-laboratory PSG vary because of environmental factors, and the magnitude of these discrepancies remains unclear. We enrolled 125 Taiwanese patients who underwent PSG while wearing a single-lead electrocardiogram patch (RootiRx). After the PSG, all participants were instructed to continue wearing the RootiRx over three subsequent nights. Scores on OSA indices-namely, the apnoea-hypopnea index, chest effort index (CEI), cyclic variation of heart rate index (CVHRI), and combined CVHRI and CEI (Rx index), were determined. The patients were divided into three groups based on PSG-determined OSA severity. The variables (various severity groups and environmental measurements) were subjected to mean comparisons, and their correlations were examined by Pearson's correlation coefficient. The hospital-based CVHRI, CEI, and Rx index differed significantly among the severity groups. All three groups exhibited a significantly lower percentage of supine sleep time in the home-based assessment, compared with the hospital-based assessment. The percentage of supine sleep time (∆Supine%) exhibited a significant but weak to moderate positive correlation with each of the OSA indices. A significant but weak-to-moderate correlation between the ∆Supine% and ∆Rx index was still observed among the patients with high sleep efficiency (≥80%), who could reduce the effect of short sleep duration, leading to underestimation of the patients' OSA severity. The high supine percentage of sleep may cause OSA indices' overestimation in the hospital-based examination. Sleep recording at home with patch-type wearable devices may aid in accurate OSA diagnosis.

Differentiation Model for Insomnia Disorder and the Respiratory Arousal Threshold Phenotype in Obstructive Sleep Apnea in the Taiwanese Population Based on Oximetry and Anthropometric Features.

Insomnia disorder (ID) and obstructive sleep apnea (OSA) with respiratory arousal threshold (ArTH) phenotypes often coexist in patients, presenting similar symptoms. However, the typical diagnosis examinations (in-laboratory polysomnography (lab-PSG) and other alternatives methods may therefore have limited differentiation capacities. Hence, this study established novel models to assist in the classification of ID and low- and high-ArTH OSA. Participants reporting insomnia as their chief complaint were enrolled. Their sleep parameters and body profile were accessed from the lab-PSG database. Based on the definition of low-ArTH OSA and ID, patients were divided into three groups, namely, the ID, low- and high-ArTH OSA groups. Various machine learning approaches, including logistic regression, k-nearest neighbors, naive Bayes, random forest (RF), and support vector machine, were trained using two types of features (Oximetry model, trained with oximetry parameters only; Combined model, trained with oximetry and anthropometric parameters). In the training stage, RF presented the highest cross-validation accuracy in both models compared with the other approaches. In the testing stage, the RF accuracy was 77.53% and 80.06% for the oximetry and combined models, respectively. The established models can be used to differentiate ID, low- and high-ArTH OSA in the population of Taiwan and those with similar craniofacial features.