Autologous transplantation of P63+ lung progenitor cells for chronic obstructive pulmonary disease therapy.

Adult lung resident stem/progenitor cells, including P63+ progenitor cells, have demonstrated the capacity for regeneration of lung epithelium in preclinical models. Here, we report a clinical trial of intrapulmonary P63+ progenitor cell transplantation in 28 participants with stage II to IV chronic obstructive pulmonary disease (COPD). Autologous P63+ progenitor cells were isolated from the airway basal layer of participants in the intervention group via bronchoscopic brushing, cultured for 3 to 5 weeks, and then transplanted back into the lungs via bronchoscopy at 0.7 × 106 to 5.2 × 106 cells per kilogram of body weight. Twenty patients were evaluable at the end of the study (intervention group, n = 17; control group, n = 3). No grade 3 to 5 adverse events (AEs) or serious AEs occurred. Although bronchoscopy-associated AEs were recorded in participants in the intervention group, other AEs were not substantial different between groups. Twenty-four weeks after transplantation, participants in the intervention group displayed improvement in gas transfer capacity [diffusing capacity of the lung for carbon monoxide (DLCO) change from baseline: +18.2%], whereas the control group experienced a decrease (DLCO change from baseline: -17.4%; P = 0.008). Furthermore, participants in the intervention group showed >30-meter increase in walking distance within 6 minutes. Transcriptomic analysis of progenitor cells isolated from responding and nonresponding individuals in the intervention group showed that higher expression of P63 was associated with treatment efficacy. In conclusion, transplantation of cultured P63+ lung progenitor cells was safe and might represent a potential therapeutic strategy for COPD.

EBUS-TBLC increase the diagnosis rate in different type of peripheral pulmonary lesions.

Background and objective: Recently, endobronchial ultrasonography with guide sheath-guided (EBUS-GS) has been increasingly used in the diagnosis of peripheral pulmonary lesions (PPLs) from human natural orifice. However, the diagnostic rate is still largely dependent on the location of the lesion and the probe. Here, we reported a new procedure to improve the diagnostic rate of EBUS-transbronchial lung cryobiopsy (EBUS-TBLC), which performed under general anesthesia with laryngeal mask airway (LMA) in all of the patients. This study retrospectively evaluated the diagnosis of PPLs with 'blind-ending' type (Type I) and 'pass-through' type procedures (Type II) of EBUS-GS-TBLB or EBUS-TBLC respectively. Methods: Retrospective review of 136 cases performed by EBUS-GS-TBLB or EBUS-TBLC for PPLs over 2 years. Results: A total of 126 cases EBUS-GS-TBLB or EBUS-TBLC were performed during the study period. Among them, 66 (52.4%) were performed Type I and 60 (47.6%) were performed Type II. Clinical baseline characteristics did not differ between two groups. The overall diagnosis rate of 126 patients with EBUS-GS-TBLB or EBUS-TBLC was 73% (92/126), and different method type have significant influence on the diagnostic yield (P = 0.012, x2 = 4.699). Among them, diagnostic yields for Type I with forceps biopsy (n=34), Type I with cryobiopsy (n=32), Type II with forceps biopsy (n=30), and Type II with cryobiopsy (n=30) were 72.5%, 64.5%, 70.4% and 74.2% respectively (Figure 2A). The study further compared the outcomes of different procedures in concentric and eccentric lesion. Diagnostic yields for Type I with eccentric (n=30), Type I with concentric (n=36), Type II with eccentric (n=34), and Type II with concentric (n=26) were 58.2%, 76.9%, 60.2% and 74.8%, respectively (P < 0.05). The incidence of complications in 126 patients was 2.6%. Conclusion: EBUS-GS-TBLB and EBUS-TBLC both are very safe and highly diagnostic technique; different method types have significant influence on the diagnostic yield. Moreover, Type II procedure has higher diagnostic yield. In addition, Type I with eccentric had the lowest diagnosis yield.

Up-to-date advance in the relationship between OSA and stroke: a narrative review.

PURPOSE: Obstructive sleep apnea (OSA) and stroke affect each other. In this review, we summarized the effect of OSA on the onset and recurrence of stroke, the prognosis, and the treatment of poststroke patients with OSA. METHODS: Pubmed/MEDLINE were searched through May 2023 to explore the relationship between OSA and stroke. The relevant papers included OSA and stroke, OSA and recurrent stroke, and the prognosis and treatment of poststroke patients with OSA. RESULTS: The results showed that OSA can promote the onset and recurrence of stroke and that OSA may adversely affect the prognosis of poststroke patients. The application of continuous positive airway pressure (CPAP) and other treatments may benefit poststroke patients with OSA, though the long term effects of treatment are not well documented. CONCLUSION: Both the onset and recurrence of stroke closely correlated with OSA, but the specific mechanisms remain unclear. Further studies should be carried out to explore effective treatments in patients with stroke and OSA.

New perspective on exploring the predictive factors of blood pressure reduction during CPAP treatment in people with severe OSA and hypertension: a prospective observational study.

BACKGROUND: The predictive factors of blood pressure (BP) response to continuous positive airway pressure (CPAP) in obstructive sleep apnoea (OSA) are still being explored. We aimed to assess the antihypertensive effect of CPAP considering the obstructive respiratory event-triggered BP surge profiles in 130 subjects with severe OSA and untreated hypertension. METHODS: Nocturnal BP was monitored continuously and synchronised with polysomnography. Event-triggered BP surge profiles were studied: BP surge as the value of event-related systolic BP (SBP) elevation; BP index as the number of BP surge events of ≥10 mm Hg per hour. Patients were then divided into two groups according to the median BP index (high and low BP surge groups) and assigned to 4 weeks of CPAP. Changes in BPs and plasma biomarkers were compared. After the initial evaluation, patients with a better BP response in the high BP surge group were then followed up for the second evaluation at 24 months. RESULTS: Overall, a modest decrease was observed in both office and asleep BPs at the 4-week follow-up; however, BPs dropped more markedly in patients in the high BP surge group than those in the low BP surge group, in both office SBP (5.3 mm Hg vs 2.2 mm Hg, p=0.003) and diastolic BP (4.0 mm Hg vs 1.2 mm Hg, p<0.001), especially the asleep SBP (9.0 mm Hg vs 2.1 mm Hg, p<0.001). For 30 cases in the high BP surge group, optimal BP control was achieved in 60.0% of patients and BP<140/90 mm Hg reached up to 83.3% after 24 months of CPAP. Linear regression revealed that BP index was significantly associated with BP decrease during CPAP treatment. CONCLUSIONS: Our results suggested that high event-triggered BP surge was a sensitive predictor of BP response to CPAP in patients with severe OSA and untreated hypertension. TRIAL REGISTRATION NUMBER: Clinical Trials.gov Identifier: NCT03246022; https://clinicaltrials.gov/ct2/show/NCT03246022?term=NCT+03246022&draw=2&rank=1.

Central nervous system efficacy of rezivertinib (BPI-7711) in advanced NSCLC patients with EGFR T790M mutation: A pooled analysis of two clinical studies.

BACKGROUND: Rezivertinib (BPI-7711) is a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) which revealed the systematic and central nervous system (CNS) antitumor activities for EGFR T790M-mutated advanced NSCLC in previous clinical studies and is further analyzed here. METHODS: Eligible patients from the previous phase I and phase IIb studies of rezivertinib were included for pooled analysis. Post-progressive patients who received a prescribed dosage (≥180 mg) of rezivertinib orally once daily were included in full analysis set (FAS), while those with stable, asymptomatic CNS lesions, including measurable and non-measurable ones at baseline were included in CNS full analysis set (cFAS). Patients with measurable CNS lesions were included in CNS evaluable for response set (cEFR). BICR-assessed CNS objective response rate (CNS-ORR), CNS disease control rate (CNS-DCR), CNS duration of response (CNS-DoR), CNS progression-free survival (CNS-PFS), and CNS depth of response (CNS-DepOR) were evaluated. RESULTS: 355 patients were included in FAS, among whom 150 and 45 patients were included in cFAS and cEFR. This pooled analysis showed the CNS-ORR was 32.0% (48/150; 95% CI: 24.6-40.1%) and the CNS-DCR was 42.0% (63/150; 95% CI: 34.0-50.3%) in cFAS, while that in cEFR were 68.9% (31/45; 95% CI: 53.4-81.8%) and 100% (45/45; 95% CI: 92.1-100.0%). In cEFR, the median CNS-DepOR and the mean of CNS-DepOR were -52.0% (range: -100.0 to 16.1%) and -46.8% (95% CI: -55.5 to -38.1%). In cFAS, the median CNS-DoR and CNS-PFS were 13.8 (95% CI: 9.6-not calculable [NC]) and 16.5 (95% CI: 13.7-NC) months. CONCLUSIONS: Rezivertinib demonstrated encouraging clinical CNS efficacy among advanced NSCLC patients with EGFR T790M mutation and CNS metastases.

Role of AIM2 Gene Knockdown Mechanism in Diabetic Cardiomyopathy: an In Vivo and Ex Vivo Study.

Chronic hyperglycemia induces reactive oxygen species that have an essential function in tissue injuries in cases of diabetic cardiomyopathy. The mechanism of the absent in melanoma 2 (AIM2)-associated inflammasome response in diabetic cardiomyopathy is unknown. Therefore, this study was performed to investigate the role of AIM2 and its molecular mechanisms. Diabetic rats received 1 × 108 viral injections of 5'-GGTCACCAGTTCCTCAGTT-3' (n = 15) or 5'-TTCTCCGAACGTGTCACGT-3' (negative control group, n = 15). Normal rats (n = 15) and diabetic rats (n = 15) were also included in the experiment. Ex vivo study was performed on primary cardiomyocytes for different concentrations of glucose. AIM2 inhibition did not affect any of the metabolic parameters (p > 0.05 for all). AIM2 protein levels were significantly increased in rats with diabetes mellitus compared with those in the control group (p < 0.0001, q = 32.044). Also, viral injection (sequence: 5'-GGTCACCAGTTCCTCAGTT-3') decreased the diabetes mellitus-induced increase in expression of AIM2 protein levels (p < 0.0001, q = 27.129). Cardiac dysfunctions were reported in rats with diabetes mellitus characterized by several parameters (p < 0.01 for all). The diabetic myocardium of rats was reported to have higher deposits of extracellular matrix compared to the control rats (p < 0.001). These effects were downregulated by viral injection (sequence: 5'-GGTCACCAGTTCCTCAGTT-3'). Ex vivo research revealed that high glucose concentrations significantly increased AIM2 protein expression, reactive oxygen species, and cell death. AIM2 protein in diabetic cardiomyopathy is associated with reactive oxygen species production and cardiomyocyte death.

Efficacy and Safety of Rezivertinib (BPI-7711) in Patients With Locally Advanced or Metastatic/Recurrent EGFR T790M-Mutated NSCLC: A Phase 2b Study.

INTRODUCTION: Rezivertinib (BPI-7711) is a novel third-generation EGFR tyrosine kinase inhibitor (TKI) targeting both EGFR-sensitizing mutations and EGFR T790M mutation. This study aimed to evaluate the efficacy and safety of rezivertinib in patients with locally advanced or metastatic/recurrent EGFR T790M-mutated NSCLC. METHODS: Patients with locally advanced or metastatic/recurrent NSCLC with confirmed EGFR T790M mutation who progressed after first-/second-generation EGFR TKI therapy or primary EGFR T790M mutation were enrolled. Patients received rezivertinib at 180 mg orally once daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary end point was objective response rate (ORR) assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival, and safety. This study is registered with Clinical Trials.gov (NCT03812809). RESULTS: A total of 226 patients were enrolled from July 5, 2019, to January 22, 2020. By the data cutoff date on January 24, 2022, the median duration of follow-up was 23.3 months (95% confidence interval [CI]: 22.8-24.0). The ORR by blinded independent central review was 64.6% (95% CI: 58.0%-70.8%), and DCR was 89.8% (95% CI: 85.1%-93.4%). The median duration of response was 12.5 months (95% CI: 10.0-13.9), and median PFS was 12.2 months (95% CI: 9.6-13.9). The median overall survival was 23.9 months (95% CI: 20.0-not calculated [NC]). Among 91 (40.3%) patients with central nervous system (CNS) metastases, the median CNS PFS was 16.6 months (95% CI: 11.1-NC). In 29 patients with more than or equal to one brain target lesion at baseline, the CNS ORR and CNS DCR were 69.0% (95% CI: 49.2%-84.7%) and 100% (95% CI: 88.1%-100%), respectively. Time to progression of CNS was 16.5 months (95% CI: 9.7-NC). Of 226 patients, 188 (83.2%) had at least one treatment-related adverse event, whereas grade more than or equal to 3 occurred in 45 (19.9%) patients. No interstitial lung disease was reported. CONCLUSIONS: Rezivertinib was found to have promising efficacy and favorable safety profile for patients with locally advanced or metastatic/recurrent NSCLC with EGFR T790M mutation.

miR-211-5p Alleviates the Myocardial Ischemia Injury Induced by Ischemic Reperfusion Treatment via Targeting FBXW7.

Cardiovascular diseases, a class of the most common diseases, seriously threaten human health, which is a direct inducement of death in most countries. The restoration of blood supply is an impactful intervention way for cardiovascular disease treatments while the injury induced by oxygen-glucose deprivation and ischemic reperfusion (I/R) may further impact the tissues of the patients. Myocardial reperfusion is a precondition for saving ischemic myocardial tissues in acute myocardial infarction while the injury induced by immediate reperfusion takes a great challenge for cardiovascular disease treatment. Howbeit, the reperfusion of coronary blood could aggravate the injury triggered by ischemia. At present, several studies have focused on the etiopathogenesis and therapeutic strategies of ischemia-reperfusion injury of the myocardium. The report has verified that miR-211-5p was elevated in the pathological specimens, while the influence of miR-211-5p in I/R-mediated injury of myocardial cells remains unclear. This research is aimed at illustrating the role of miR-211-5p in the progression of I/R injury of myocardial cells, and qRT-PCR, western blot, CCK-8, and TUNEL assay were used to investigate the functions of miR-211-5p on I/R-mediated injury of myocardial cells. The result mirrored that miR-211-5p was distinctly reduced in the I/R-induced AC16, and reduced miR-211-5p could evidently improve the viability of I/R-induced AC16. miR-211-5p could directly target FBXW7, and FBXW7 upregulation could reverse the improvement of AC16 in viability and apoptosis level after suffering I/R. Moreover, it was also proved that miR-211-5p can mediate the activation of Wnt/ß-catenin via attenuating FBXW7. Consequently, this investigation identified miR-211-5p as a positive role to attenuate the injury of myocardial cells when suffering I/R treatment.

Interleukin-17A mediates tobacco smoke-induced lung cancer epithelial-mesenchymal transition through transcriptional regulation of ΔNp63α on miR-19.

Interleukin-17A (IL-17A) is an essential inflammatory cytokine in the progress of carcinogenesis. Tobacco smoke (TS) is a major risk factor of lung cancer that influences epithelial-mesenchymal transition (EMT) process. However, the potential mechanism by which IL-17A mediates the progression of lung cancer in TS-induced EMT remains elusive. In the present study, it was revealed that the IL-17A level was elevated in lung cancer tissues, especially in tumor tissues of cases with experience of smoking, and a higher IL-17A level was correlated with induction of EMT in those specimens. Moreover, the expression of ΔNp63α was increased in IL-17A-stimulated lung cancer cells. ΔNp63α functioned as a key oncogene that bound to the miR-17-92 cluster promoter and transcriptionally increased the expression of miR-19 in lung cancer cells. Overexpression of miR-19 promoted EMT in lung cancer with downregulation of E-cadherin and upregulation of N-cadherin, while its inhibition suppressed EMT. Finally, the upregulated levels of IL-17A, ΔNp63α, and miR-19 along with the alteration of EMT-associated biomarkers were found in lung tissues of TS-exposed mice. Taken together, the abovementioned results suggest that IL-17A increases ΔNp63α expression, transcriptionally elevates miR-19 expression, and promotes TS-induced EMT in lung cancer. These findings may provide a new insight for the identification of therapeutic targets for lung cancer.

Depression of Non-Neuronal Cholinergic System May Play a Role in Co-Occurrence of Subjective Daytime Sleepiness and Hypertension in Patients with Obstructive Sleep Apnea Syndrome.

PURPOSE: Simultaneous occurrence of hypertension and excessive daytime sleepiness (EDS) is very common in obstructive sleep apnea syndrome (OSAS), although no study has specifically addressed this issue. The present study explored the risk factors for co-occurrence of OSAS-related EDS and hypertension. PATIENTS AND METHODS: A total of 161 OSAS patients were studied after undergoing an eight-hour in-laboratory polysomnography for one night. The OSAS severity assessment depends on the number of breathing disturbances per hour of sleep. EDS was defined using the Epworth Sleepiness Scale (ESS) scores of ≥13. Hypertension was defined according to direct cuff blood pressure (BP) measurements. Beat-to-beat R-R interval data were incorporated in polysomnography for heart rate variability analysis. The low-frequency/high-frequency band ratio was used to reflect sympathovagal balance. The study participants were divided into four groups based on the presence of EDS and/or hypertension: EDS with hypertension (n = 53), EDS without hypertension (n = 27), no EDS with hypertension (n = 38), and no EDS or hypertension (n = 43). Clinical, polysomnographic and heart rate data were compared and studied among the four groups. Plasma acetylcholine (ACh) levels were assessed to explore the effects of the non-neuronal cholinergic system and the co-occurrence of EDS and hypertension. RESULTS: Patients with EDS and hypertension had more severe OSAS severity indices compared to control patients. Increased cardiac sympathovagal imbalance and nocturnal hypoxemia regulated the presence of EDS and hypertension. Further plasma biomarker analysis revealed that both ESS scores and BP levels were associated with significantly elevated plasma norepinephrine, interleukin-6 and superoxide dismutase levels and significantly decreased ACh levels. Logistic regression analyses showed that ACh was the only factor significantly associated with co-occurrence of EDS and hypertension after controlling for confounders using odds ratio of 0.932, with a 95% confidence interval of 0.868 to 1.000 (P = 0.049). CONCLUSION: The results suggested that OSAS coupled with both EDS and hypertension is a more severe phenotype of the respiratory disorder. The presence of EDS and hypertension was accompanied by sympathovagal imbalance, and co-occurrence of these two conditions may be related to decreased plasma ACh levels.

TAp63α Is Involved in Tobacco Smoke-Induced Lung Cancer EMT and the Anti-cancer Activity of Curcumin via miR-19 Transcriptional Suppression.

As a key risk factor for lung cancer, tobacco smoke (TS) influences several cellular processes, including epithelial-mesenchymal transition (EMT). TAp63α is a crucial transcription factor involved in tumor progression. The present study was designed to investigate the potential role and underlying mechanisms of TAp63α in TS-induced lung cancer EMT. We found that compared to normal tissues, the tumor tissues collected from lung cancer patients showed a lower level of TAp63α expression, along with downregulated E-cadherin expression and upregulated Vimentin expression. Results of treatment with TAp63α and TAp63α siRNA as well as with tumor growth factor-ß (TGF-ß) showed that TAp63α acted as a tumor suppressor gene, and its upregulated expression suppressed lung cancer EMT. Significantly, TS exposure altered expression of EMT-related markers, enhanced cell migratory and invasive capacities, and decreased the TAp63α expression level in lung cancer cells. Overexpression of TAp63α significantly alleviated TS-stimulated lung cancer EMT. Mechanistically, TAp63α expression transcriptionally reduced the miR-19 level, which resulted in the suppression of lung cancer EMT. Additionally, as a natural compound possessing anti-cancer effects, curcumin inhibited TS-induced lung cancer EMT by increasing TAp63α expression and reducing miR-19 expression. Collectively, our results indicate that TAp63α inhibits TS-induced lung cancer EMT via transcriptionally suppressing miR-19 and the inhibitory effect of TAp63α on miR-19 mediates the anti-cancer action of curcumin. These findings provide new insights into novel targets for lung cancer prevention.

The rate of decrease in oxygen desaturation during severe obstructive sleep apnea syndrome is correlated with subjective excessive daytime sleepiness.

PURPOSE: To explore factors that influence subjective excessive daytime sleepiness (EDS) in patients with severe obstructive sleep apnea syndrome (OSAS). METHODS: Patients with snoring seen at the Sleep Medicine Center of The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University between October 2018 and November 2019 were included in this study. All patients underwent polysomnography (PSG). Noninvasive frequency-domain analysis was used to assess the autonomic nervous system regulation of the heart, with the low frequency (LF)/high frequency (HF) power ratio used to represent the sympathetic-parasympathetic balance. Daytime sleepiness was evaluated by the Epworth sleepiness scale (ESS). Overnight apnea episodes were included for analyses. The rate of pulse oxyhemoglobin saturation (SpO2) decrease was measured as the change in the percentage of SpO2 per second after obstructive apnea and was expressed as the oxygen desaturation rate (ODR). RESULTS: A total of 101 patients with severe OSAS were enrolled in this study and were further divided into two groups: the EDS group (ESS > 10, n = 52) and the non-EDS group (ESS ≤ 10, n = 49). The apnea-hypopnea index (AHI), respiratory effort-related arousals (RERAs), and LF/HF power ratio were significantly higher in the EDS group than in the non-EDS group (AHI: 69.9 ± 14.5 vs. 57.9 ± 16.1 events/h; RERAs: 42.2 ± 16.7 vs. 30.4 ± 13.7 events/h; LF/HF power ratio: 2.9 ± 0.8% vs. 2.4 ± 0.9%, all p < 0.001). Multiple linear regression analyses revealed that after adjusting for covariates expected to affect this relationship, ESS scores were correlated with ODR (ß = 0.520, p < 0.001) and LF/HF power ratio (ß = 0.155, p = 0.028), rather than with the traditional sleep-disordered breathing parameters. CONCLUSIONS: Compared with the traditional PSG parameters, both ODR and an increased LF/HF power ratio were more closely related to daytime sleepiness, especially ODR.

Integrative Analysis of Three Novel Competing Endogenous RNA Biomarkers with a Prognostic Value in Lung Adenocarcinoma.

Increasing evidence has shown competitive endogenous RNAs (ceRNAs) play key roles in numerous cancers. Nevertheless, the ceRNA network that can predict the prognosis of lung adenocarcinoma (LUAD) is still lacking. The aim of the present study was to identify the prognostic value of key ceRNAs in lung tumorigenesis. Differentially expressed (DE) RNAs were identified between LUAD and adjacent normal samples by limma package in R using The Cancer Genome Atlas database (TCGA). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway function enrichment analysis was performed using the clusterProfiler package in R. Subsequently, the LUAD ceRNA network was established in three steps based on ceRNA hypothesis. Hub RNAs were identified using degree analysis methods based on Cytoscape plugin cytoHubba. Multivariate Cox regression analysis was implemented to calculate the risk score using the candidate ceRNAs and overall survival information. The survival differences between the high-risk and low-risk ceRNA groups were determined by the Kaplan-Meier and log-rank test using survival and survminer package in R. A total of 2,989 mRNAs, 185 lncRNAs, and 153 miRNAs were identified. GO and KEGG pathway function enrichment analysis showed that DE mRNAs were mainly associated with "sister chromatid segregation," "regulation of angiogenesis," "cell adhesion molecules (CAMs)," "cell cycle," and "ECM-receptor interaction." LUAD-related ceRNA network was constructed, which comprised of 54 nodes and 78 edges. Top ten hub RNAs (hsa-miR-374a-5p, hsa-miR-374b-5p, hsa-miR-340-5p, hsa-miR-377-3p, hsa-miR-21-5p, hsa-miR-326, SNHG1, RALGPS2, and PITX2) were identified according to their degree. Kaplan-Meier survival analyses demonstrated that hsa-miR-21-5p and RALGPS2 had a significant prognostic value. Finally, we found that a high risk of three novel ceRNA interactions (SNHG1-hsa-miR-21-5p-RALGPS2, SNHG1-hsa-miR-326-RALGPS2, and SNHG1-hsa-miR-377-3p-RALGPS2) was positively associated with worse prognosis. Three novel ceRNAs (SNHG1-hsa-miR-21-5p-RALGPS2, SNHG1-hsa-miR-326-RALGPS2, and SNHG1-hsa-miR-377-3p-RALGPS2) might be potential biomarkers for the prognosis and treatment of LUAD.

Oxygen desaturation rate as a novel intermittent hypoxemia parameter in severe obstructive sleep apnea is strongly associated with hypertension.

STUDY OBJECTIVES: To investigate the effects of different intermittent hypoxemia properties on blood pressure (BP) and short-term blood pressure variability (BPV) in severe obstructive sleep apnea (OSA) patients. METHODS: Nocturnal BP was continuously monitored by measuring pulse transmit time. Apnea-related systolic BP elevation values were used to reflect BPV. Beat-to-beat R-R interval data were incorporated in polysomnography for heart rate variability analysis. The low-frequency/high-frequency band ratio was used to reflect sympathovagal balance. The rate of pulse oxyhemoglobin saturation (SpO2) decrease was counted as the change in the percentage of SpO2 per second after obstructive apnea and expressed as the oxygen desaturation rate (ODR). Patients with severe OSA (n = 102) were divided into 2 groups according to the median ODR: faster ODR (FODR group: ODR > 0.37, n = 50) and slower ODR (ODR ≤ 0.37, n = 52). RESULTS: Comparisons between the 2 groups showed significantly higher systolic BP (SBP) values in the FODR group than in the slower ODR group (awake SBP 149.9 ± 18.3 vs 131.8 ± 15.6 mm Hg; asleep SBP: 149.6 ± 19.9 vs 128.7 ± 15.6 mm Hg; both P < .001), as well as short-term BPV (15.0 ± 4.8 vs 11.6 ± 3.6 mm Hg; P < .001), and the prevalence of hypertension (74.0% vs 26.9%; P < .001). Multiple linear regression analyses revealed that after adjusting for body mass index, functional residual capacity, expiratory reserve volume, and baseline SpO2, ODR, as assessed by ΔSpO2/Δt, had the strongest association with both BP and short-term BPV. Correlation analysis showed that ODR was positively correlated with the low-frequency/high-frequency band ratio (r = .288, P = .003). CONCLUSIONS: ODR, as a novel hypoxemia profile, was more closely associated with the elevation of BP and BPV in patients with severe OSA. FODR might be associated with enhanced sympathetic activity. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Characteristics of Obstructive Sleep Apnea Syndrome Related Hypertension and the Effect of Continuous Positive Airway Pressure Treatment on Blood Pressure; URL: https://clinicaltrials.gov/ct2/show/NCT03246022; Identifier: NCT03246022.

QTL mapping for grain yield-related traits in bread wheat via SNP-based selective genotyping.

KEY MESSAGE: We identified four chromosome regions harboring QTL for grain yield-related traits, and breeder-friendly KASP markers were developed and validated for marker-assisted selection. Identification of major stable quantitative trait loci (QTL) for grain yield-related traits is important for yield potential improvement in wheat breeding. In the present study, 266 recombinant inbred lines (RILs) derived from a cross between Zhongmai 871 (ZM871) and its sister line Zhongmai 895 (ZM895) were evaluated for thousand grain weight (TGW), grain length (GL), grain width (GW), and grain number per spike (GNS) in 10 environments and for grain filling rate in six environments. Sixty RILs, with 30 higher and 30 lower TGW, respectively, were genotyped using the wheat 660 K SNP array for preliminary QTL mapping. Four genetic regions on chromosomes 1AL, 2BS, 3AL, and 5B were identified to have a significant effect on TGW-related traits. A set of Kompetitive Allele Specific PCR markers were converted from the SNP markers on the above target chromosomes and used to genotype all 266 RILs. The mapping results confirmed the QTL named Qgw.caas-1AL, Qgl.caas-3AL, Qtgw.caas-5B, and Qgl.caas-5BS on the targeted chromosomes, explaining 5.0-20.6%, 5.7-15.7%, 5.5-17.3%, and 12.5-20.5% of the phenotypic variation for GW, GL, TGW, and GL, respectively. A novel major QTL for GNS on chromosome 5BS, explaining 5.2-15.2% of the phenotypic variation, was identified across eight environments. These QTL were further validated using BC1F4 populations derived from backcrosses ZM871/ZM895//ZM871 (121 lines) and ZM871/ZM895//ZM895 (175 lines) and 186 advanced breeding lines. Collectively, selective genotyping is a simple, economic, and effective approach for rapid QTL mapping and can be generally applied to genetic mapping studies for important agronomic traits.

Sulforaphane Inhibits the Acquisition of Tobacco Smoke-Induced Lung Cancer Stem Cell-Like Properties via the IL-6/ΔNp63α/Notch Axis.

Background: Tobacco smoke (TS) critically contributes to the development of lung cancer; however, the underlying molecular mechanisms remain unclear. The induction of cancer stem cells (CSCs) by TS represents an early event in tumor initiation. The lung cancer-related gene ΔNp63α is highly expressed in epithelial tissues and drives tumor formation and cancer stem cell properties. This study investigated the role of ΔNp63α in the long-term acquisition of TS-induced lung CSC-like properties. Methods: The expression levels of ΔNp63α, lung CSC markers, and interleukin (IL)-6 in lung carcinoma specimens were determined by western blotting and enzyme linked immunosorbent assays. Human bronchial epithelial (HBE) cells were chronically exposed to 2 % cigarette smoke extract for 55 passages, following which colony formation capacity, expression of proteins associated with malignant transformation, lung CSC markers, and tumor incidence were investigated. The effects of ΔNp63α on long-term TS exposure-induced lung CSC-like properties and Notch activation were analyzed using tumorsphere formation ability, immunofluorescence assays, luciferase reporter assays, and western blotting. The roles of IL-6 on chronic TS exposure-induced lung CSC-like properties and ΔNp63α expression were also examined. Moreover, the effects of sulforaphane (SFN) on TS-transformed lung CSC-like properties, IL-6 and ΔNp63α expression, and Notch signaling were investigated in vitro and in vivo. Results: Higher levels of ΔNp63α were observed in the lung cancer tissues of smokers than in those of non-smokers, whereas ΔNp63α was positively correlated with CD133 and Oct4 expression in lung cancer tissues. Data from the in vivo and in vitro experiments demonstrated that long-term TS exposure-transformed HBE (THBE) cells acquired lung CSC-like properties. Furthermore, ΔNp63α transcriptionally activated the Notch signaling pathway to promote the acquisition of CSC-like properties by the THBE cells. TS upregulated IL-6, which increased ΔNp63α expression in THBE sphere-forming cells. Finally, SFN inhibited the TS-induced CSC-like properties of THBE cells via the IL-6/ΔNp63α/Notch axis. Conclusion: Our data suggest that the IL-6/ΔNp63α/Notch axis plays an important role in the long-term TS exposure-induced acquisition of lung CSC-like properties and SFN intervention.

Study on the Isolation of Two Atrazine-Degrading Bacteria and the Development of a Microbial Agent.

Two bacteria capable of efficiently degrading atrazine were isolated from soil, and named ATLJ-5 and ATLJ-11. ATLJ-5 and ATLJ-11 were identified as Bacillus licheniformis and Bacillus megaterium, respectively. The degradation efficiency of atrazine (50 mg/L) by strain ATLJ-5 can reach about 98.6% after 7 days, and strain ATLJ-11 can reach 99.6% under the same conditions. The degradation of atrazine is faster when two strains are used in combination. Adding the proper amount of fresh soil during the degradation of atrazine by these two strains can also increase the degradation efficiency. The strains ATLJ-5 and ATLJ-11 have high tolerance to atrazine, and can tolerate at least 1000 mg/L of atrazine. In addition, the strains ATLJ-5 and ATLJ-11 have been successfully made into a microbial agent that can be used to treat atrazine residues in soil. The degradation efficiency of atrazine (50 mg/kg) could reach 99.0% by this microbial agent after 7 days. These results suggest that the strains ATLJ-5 and ATLJ-11 can be used for the treatment of atrazine pollution.

Inducers of post-apneic blood pressure fluctuation monitored by pulse transfer time measurement in obstructive sleep apnea varied with syndrome severity.

PURPOSE: This study investigated the properties of blood pressure (BP) fluctuation and sympathovagal imbalance with the severity of OSAS. METHODS: Nocturnal BP was continuously monitored by polysomnography for mild (n = 33), moderate (n = 34), and severe (n = 37) OSAS patients. Apnea-related systolic BP elevation (△SBP) indicated the amplitude of BP fluctuation. The SBP index, number of △SBP > 10 mmHg/h of sleep, indicated the frequency of significant BP fluctuations. The low frequency/high frequency (LF/HF) ratios indicated heart rate variability and sympathovagal imbalance. RESULTS: △SBP and the SBP index were the highest in severe OSAS (12.9 ± 2.3 mmHg and 33.7 ± 14.7/h), followed by moderate OSAS (9.5 ± 2.6 mmHg and 7.1 ± 4.4/h), and mild OSAS (8.3 ± 1.6 mmHg and 3.4 ± 2.1/h). The LF/HF ratios in severe OSAS were significantly higher than that in moderate and mild OSAS. In mild OSAS, arousal played a more important role in BP fluctuation. In moderate OSAS, the oxygen desaturation index (ODI) and the SBP index were correlated. The difference in △SBP induced by hypoxia or by arousal was not significant. In severe OSAS, the apnea-hypopnea index (AHI) and LF/HF ratio were correlated with the SBP index, and △SBP was larger with hypoxia than arousal. CONCLUSIONS: BP fluctuation and sympathovagal imbalance were both related to obstructive sleep apnea severity. The influence of arousal and hypoxia on BP fluctuation varied with OSAS severity. TRIAL REGISTRATION: NCT02876471.

Nocturnal blood pressure fluctuation and associated influential factors in severe obstructive sleep apnea patients with hypertension.

PURPOSE: Obstructive sleep apnea syndrome (OSAS) can induce dramatic blood pressure (BP) fluctuations during sleep and it can be associated with hypertension. We investigated the properties and associated influential factors of BP fluctuation in severe OSAS with and without hypertension. METHODS: Two hundred one severe OSAS subjects were divided into hypertensive and normotensive groups. BP was continuously monitored via measurement of pulse transmit time (PTT). The value of apnea-related systolic BP elevation (ΔSBP) was used to reflect the amplitude of BP fluctuation, and the SBP index (the number of ΔSBP > 10 mmHg per hour of sleep time) was used to stand for the frequency of significant BP fluctuations. RESULTS: Compared with the normotensive group, △SBP and SBP index were higher in the hypertensive group (13.8 ± 4.4 mmHg vs 10.9 ± 3.1 mmHg; 44.8 ± 21.3 events/h vs 26.8 ± 15.8 events/h, all p < 0.001). Multiple regression analysis showed that percentage of sleep time with oxygen saturation < 90% (TST90) and SBP index correlated more with mean level of awakeness and sleep SBP than with apnea-hypopnea index (AHI). Analysis of all apnea events demonstrated that △SBP and the frequency of BP fluctuations were more remarkable following hypoxia than following arousal; △SBP correlated more with oxygen desaturation degree (r = 0.388, p < 0.01) and minimal SpO2 (r = 0.392, p < 0.01) than with apnea length and desaturation duration. CONCLUSIONS: In severe OSAS, nocturnal and awake BP levels are associated more with the nocturnal hypoxic duration and BP fluctuation than with AHI. Nocturnal BP fluctuation can be induced by both hypoxia and arousal, and especially by hypoxia. TRIAL REGISTRATION: NCT02876471.

Multicenter study of diagnostic procedures, genetic aberration analysis, and first-line treatment of lung cancer in Jiangsu Province, China.

BACKGROUND: Jiangsu Province, China, is highly developed economically and culturally, and has a high prevalence of lung cancer. We aimed to evaluate the diagnostic procedures, genetic aberration analysis status, and first-line treatment models of lung cancer in Jiangsu Province. METHODS: Lung cancer patients diagnosed in 2016 at 22 tertiary care hospitals were evaluated. Demographic characteristics, tumor histology, staging, family history of lung cancer, auxiliary examinations, genetic testing, and first-line treatment were collected on discharge. Diagnostic and treatment data were analyzed by descriptive statistics. RESULTS: A total of 928 patients were enrolled. Chest computed tomography was the most frequently used diagnostic method; pathology diagnosis was carried out by transbronchial lung biopsy and transthoracic needle aspiration. Stage T1-2N0M0 small-cell lung cancer patients experienced surgical resection, and others received cisplatin and etoposide chemotherapy. Stage I and stage II non-small cell lung cancer patients experienced surgical resection; stage III and stage IV patients received cisplatin and pemetrexed chemotherapy as first-line treatment. Detection of epidermal growth factor receptor (EGFR) mutations occurred in 29.9% of non-selective, 36.5% of locally advanced or metastatic, and 42.1% of advanced non-squamous non-small cell lung cancer. The overall EGFR-positive rates were 49.0%, 52.5%, and 53.9%. A total 72.0% of patients with EGFR mutations were treated with tyrosine kinase inhibitors. CONCLUSION: Chest computed tomography was the most commonly performed diagnostic method for lung cancer. First-line treatment was primarily determined by disease stages and EGFR mutation status, with few expectations.