Predictive Value of Red Blood Cell Distribution Width in Chronic Obstructive Pulmonary Disease Patients with Pulmonary Embolism.

PURPOSE: This study is aimed at investigating the relationship between red cell distribution width (RDW) and chronic obstructive pulmonary disease (COPD) patients with pulmonary embolism (PE). METHODS: We conducted a retrospective study enrolling a total of 125 patients from January 2013 to December 2019. The study group consisted of 40 COPD patients with PE, and the control group had 85 COPD patients without PE. Clinical data including demographic characteristics, comorbidities, and results of imaging examinations and laboratory tests were recorded. Blood biomarkers, including red blood cell distribution width standard deviation (RDW-SD), red blood cell distribution width coefficient of variation (RDW-CV), and D-Dimer, were included. RESULTS: RDW-SD and RDW-CV were higher in the COPD patients with the PE group (p < 0.001). A higher RDW-SD led to a significantly increased risk of PE than a lower RDW-SD (adjusted odds ratio (OR): 1.188; 95% confidence interval (CI): 1.048-1.348). The area under the curve (AUC) of RDW-SD used for predicting PE was 0.737. Using 44.55 as the cutoff value of RDW-SD, the sensitivity was 80% and the specificity was 64.7%. The prediction accuracy of RDW-SD combined with D-Dimer (AUC = 0.897) was higher than that of RDW-SD or D-Dimer alone. The optimal cutoff value of RDW-SD+D-Dimer for predicting PE was 0.266, which generated a sensitivity of 87.5% and specificity of 83.5%. CONCLUSION: RDW is significantly increased in COPD patients with PE and may thus be useful in predicting the occurrence of PE in patients with COPD.

The T helper type 17/regulatory T cell imbalance was associated with Ras-GTPase overexpression in patients with pulmonary hypertension associated with chronic obstructive pulmonary disease.

Pulmonary hypertension (PH) is a common but dangerous complication in chronic obstructive pulmonary disease (COPD). We hypothesized that dysregulation in the T helper type 17 (Th17) compartment could contribute to the development of COPD-associated PH (COPD-PH). To investigate this hypothesis, patients with COPD-PH and age- and sex-matched healthy controls were recruited, and their circulating CD4+ T cells were activated using anti-CD3/CD28 antibodies. The frequency of interleukin-17 (IL-17) -secreting cells was significantly higher in COPD-PH patients than in healthy controls. The secretion of IL-17 was significantly higher from COPD-PH CD4+ T cells than from control CD4+ T cells, whereas the secretion of interferon-γ and IL-4 was not significantly different. The expression of transforming growth factor-ß, on the other hand, was significantly higher in healthy controls than in COPD-PH patients. Activated CD4+ T cells from COPD-PH patients also presented significantly lower forkhead box P3 (FOXP3) and higher retinoic acid receptor-related orphan C2 (RORC2) expression than CD4+ T cells from healthy controls. In both controls and patients, a negative correlation between RORC2 and FOXP3 was found, ex vivo and after CD3/CD28 activation. The serum IL-6 level was slightly higher in COPD-PH patients than in controls, but the IL-6 transcription by monocytes was comparable in COPD-PH patients and controls. Interestingly, CD4+ T cells from COPD-PH patients presented significantly higher levels of Kirsten rat sarcoma viral oncogene homolog and neuroblastoma RAS viral oncogene homolog than CD4+ T cells from healthy controls. Inhibiting Ras-GTPases using farnesylthiosalicylic acid significantly reduced the ratio of RORC2/FOXP3 expression in CD4+ T cells. Overall, we demonstrated that an imbalance of Th17/regulatory T cells was a hallmark of COPD-PH.

Expression and correlation of MALAT1 and SOX9 in non-small cell lung cancer.

INTRODUCTION: Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related deaths in the world. MALAT1 and SOX9 have important roles in tumour formation and development in several types of cancers. However, little is known about the function and co-relationship of these 2 factors in NSCLC in vivo. OBJECTIVES: To explore the role of MALAT1 and SOX9 expression relationship, their clinical pathological characteristics and OS on NSCLC patients. METHODS: Paired of primary lung cancer tissues and the matched tumour adjacent tissues were collected in 121 NSCLC patients. MALAT1 and SOX9 mRNA expression was measured by SYBR green q RT-PCR assay. SOX-9 protein expression was measured by streptavidin-peroxidase (SP) staining method. RESULTS: MALAT1and SOX9 expression was higher in NSCLC tissues than the adjacent tissues, and they have positive correlation. Moreover, SOX9 protein expression was higher in NSCLC tissues, especially in MALAT1 mRNA higher expressed NSCLC tissues. MALAT1 and SOX9 mRNA expression were associated with age (x2 =11.474, P = .009), tumour size (x2 =26.839, P = .000), TNM stage (x2 =8.010, P = .046) and LEL. (x2 =53.908, P = .000). NSCLC patients with higher MALAT1 and SOX9 mRNA expression had poorer OS rates. CONCLUSIONS: MALAT1 and SOX9 could be used as prognostic co-biomarker in NSCLC.

Factors Associated With Prolonged Viral Shedding in Patients With Avian Influenza A(H7N9) Virus Infection.

Background: Data are limited on the impact of neuraminidase inhibitor (NAI) treatment on avian influenza A(H7N9) virus RNA shedding. Methods: In this multicenter, retrospective study, data were collected from adults hospitalized with A(H7N9) infection during 2013-2017 in China. We compared clinical features and A(H7N9) shedding among patients with different NAI doses and combination therapies and evaluated factors associated with A(H7N9) shedding, using Cox proportional hazards regression. Results: Among 478 patients, the median age was 56 years, 71% were male, and 37% died. The median time from illness onset to NAI treatment initiation was 8 days (interquartile range [IQR], 6-10 days), and the median duration of A(H7N9) RNA detection from onset was 15.5 days (IQR, 12-20 days). A(H7N9) RNA shedding was shorter in survivors than in patients who died (P < .001). Corticosteroid administration (hazard ratio [HR], 0.62 [95% confidence interval {CI}, .50-.77]) and delayed NAI treatment (HR, 0.90 [95% CI, .91-.96]) were independent risk factors for prolonged A(H7N9) shedding. There was no significant difference in A(H7N9) shedding duration between NAI combination treatment and monotherapy (P = .65) or between standard-dose and double-dose oseltamivir treatment (P = .70). Conclusions: Corticosteroid therapy and delayed NAI treatment were associated with prolonged A(H7N9) RNA shedding. NAI combination therapy and double-dose oseltamivir treatment were not associated with a reduced A(H7N9) shedding duration as compared to standard-dose oseltamivir.

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.

Direct bilirubin levels are prognostic in non-small cell lung cancer.

We investigated the prognostic value of serum bilirubin levels in stage I-II non-small cell lung cancer (NSCLC) patients and evaluated the relationship between bilirubin levels and response to first-line platinum-based chemotherapy. We divided 634 NSCLC patients from a single hospital in China into retrospective training (n = 307) and prospective validation (n = 327) cohorts. X-tile was used to identify the optimal serum bilirubin cutoff value for sorting retrospective cohort patients into low and high overall survival (OS) groups. TNM stage and serum bilirubin levels were associated with OS on univariate analysis. Direct bilirubin (DBIL) levels were correlated with tumor progression and response to first-line platinum-based chemotherapy, and were associated with OS after adjusting for TNM stage. Our findings indicate a DBIL-based prognostic nomogram is more accurate than the TNM staging system in predicting clinical outcomes, and that the DBIL level is an independent predictor of OS in NSCLC. Thus, an index that combines DBIL with TNM stage may better predict patient outcomes than TNM stage alone.

Juglanin inhibits lung cancer by regulation of apoptosis, ROS and autophagy induction.

Juglanin (Jug) is obtained from the crude extract of Polygonum aviculare, exerting suppressive activity against cancer cell progression in vitro and in vivo. Juglanin administration causes apoptosis and reactive oxygen species (ROS) in different types of cells through regulating various signaling pathways. In our study, the effects of juglanin on non-small cell lung cancer were investigated. A significant role of juglanin in suppressing lung cancer growth was observed. Juglanin promoted apoptosis in lung cancer cells through increasing Caspase-3 and poly ADP-ribose polymerase (PARP) cleavage, which is regulated by TNF-related apoptosis-inducing ligand/Death receptors (TRAIL/DRs) relied on p53 activation. Anti-apoptotic members Bcl-2 and Bcl-xl were reduced, and pro-apoptotic members Bax and Bad were enhanced in cells and animals receiving juglanin. Additionally, nuclear factor-κB (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinases (MAPKs) activation were inhibited by juglanin. Further, juglanin improved ROS and induced autophagy. ROS inhibitor N-acetyl-l-cysteine (NAC) reversed apoptosis induced by juglanin in cancer cells. The formation of autophagic vacoules and LC3/autophagy gene7 (ATG7)/Beclin1 (ATG6) over-expression were observed in juglanin-treated cells. Also, juglanin administration to mouse xenograft models inhibited lung cancer progression. Our study demonstrated that juglanin could be a promising candidate against human lung cancer progression.

MALAT1-miR-101-SOX9 feedback loop modulates the chemo-resistance of lung cancer cell to DDP via Wnt signaling pathway.

Cisplatin (DDP)-based chemotherapy is a standard strategy for lung cancer, while chemoresistance remains a major therapeutic challenge. Recent evidence highlights the crucial regulatory roles of long non-coding RNAs (lncRNA) in tumor biology. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has important roles in regulating the proliferation, invasion and migration of lung cancer cell. High MALAT1 expression in lung cancer was related to poorer clinicopathologic features in this study. MALAT1 knockdown alone was sufficient to amplify DDP-induced repression of cell viability. MALAT1 knockdown could also sensitized DDP-resistant lung cancer cells (A549/DDP and H1299/DDP) to DDP. Further assays indicated that MALAT1 acted as a competing endogenous RNA to upregulate SOX9 expression by sponging miR-101 in DDP-resistant cancer cells, through Wnt signaling pathway. Moreover, SOX9 could bind to the promoter of MALAT1 to activate its transcription. Taken together, MALAT1, miR-101 and SOX9 form a feedback loop to enhance the chemo-resistance of lung cancer cell to DDP; this MALAT1-miR-101-SOX9 feedback loop plays an important role in the chemo-resistance of lung cancer cell to DDP and may serve as a potential target for cancer treatment.

An upregulation of CD8+CD25+Foxp3+ T cells with suppressive function through interleukin 2 pathway in pulmonary arterial hypertension.

Accumulating evidence suggests that abnormal inflammation plays a critical role in the pathogenesis of pulmonary arterial hypertension (PAH). CD8+CD25+Foxp3+ T cell is a novel cell subtype, and its role in PAH is not yet investigated. Here, we observed that PAH patients presented a significant upregulation of CD8+CD25+Foxp3+ T cells and a downregulation of CD4+CD25+Foxp3+ T cells compared to healthy controls. Regardless, the total number of CD25+Foxp3+ T cells in PAH patients was still smaller than that in healthy controls. Compared to CD8+CD25- T cells, CD8+CD25+ T cells presented higher Foxp3 expression, lower interferon (IFN)-γ expression and higher transforming growth factor (TGF)-ß expression, in both healthy and PAH individuals. The CD8+CD25+ T cells in PAH patients also demonstrated regulatory function by suppressing the proliferation of CD4+CD25- and CD8+CD25- effector T cells, albeit at lower efficiency than CD4+CD25+ T cells from PAH patients and healthy volunteers. CD8+CD25+ T cells from PAH responded to interleukin (IL)-2 supplement by expansion and upregulating Foxp3 expression. In PAH patients, IL-2-treated CD8+CD25+ T cells were more potent at inhibiting CD4+CD25- effector T cell proliferation than IL-2-untreated CD8+CD25+ T cells. Together, we found an upregulation of CD8+CD25+Foxp3+ T cells in PAH patients, and this T cell population presented suppressive activity that could be enhanced by IL-2 treatment.

Lymphocyte to monocyte ratio is associated with response to first-line platinum-based chemotherapy and prognosis of early-stage non-small cell lung cancer patients.

Lymphocyte to monocyte ratio (LMR) has shown prognostic value in different types of cancer. This study assessed the prognostic performance of LMR in early-stage non-small cell lung cancer (NSCLC) patients and investigated the influence of LMR on the treatment response in patients receiving first-line platinum-based chemotherapy. Four hundred eighty-eight NSCLC patients and 500 healthy donors were enrolled in this study. The cutoff value for LMR was chosen by receiver operating characteristic curve analysis. The prognostic significance of markers was assessed by univariate and multivariate Cox regression models. The median overall survival was 43 months, and the median progression-free survival was 38 months. LMR was associated with disease status and the treatment response of first-line platinum-based chemotherapy. Multivariate analysis showed that LMR was an independent prognostic factor for both overall survival (hazard ratio = 1.53, 95 % confidence interval = 1.09-2.14, P = 0.015) and progression-free survival (hazard ratio = 1.20, 95 % confidence interval = 1.02-1.67, P = 0.028). Furthermore, integration of LMR into a prognostic model including TNM stage, tumor status, chemotherapy, and histological type generated a nomogram, which predicted accurately overall survival for NSCLC patients. Decreased LMR may be a potential biomarker of disease status, worse response to first-line platinum-based chemotherapy, and worse survival for NSCLC patients. A prospective study is warranted for further validation of our findings.

Complete mitochondrial genome sequence and mutations of the cardiac hypertrophy model inbred rat strain (Muridae; Rattus).

In the present work we undertook the complete mitochondrial genome sequencing of a important cardiac hypertrophy model inbred rat strain for the first time. The total length of the mitogenome was 16,308 bp. It harbored 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and 1 non-coding control region (D-loop region). The mutation events were also reported.

Ruscogenin exerts beneficial effects on monocrotaline-induced pulmonary hypertension by inhibiting NF-κB expression.

This study aims to examine the effect of ruscogenin on pulmonary arterial hypertension (PAH) and to determine the mechanism underlying this effect. We isolated pulmonary vascular smooth muscle cells (PVSMCs) from the pulmonary artery of the rats; the PVSMCs were cultured in vitro and then were treated with platelet-derived growth factor (PDGF), PDGF + ruscogenin, or PDGF + ruscogenin + parthenolide. We randomized Sprague-Dawley rats into five groups as follows: control group, PAH group, low-dose group, medium-dose group, and high-dose group; the rats in the low-, medium-, and high-dose groups received the vehicle and ruscogenin 0.1, 0.4, and 0.7 mg/kg, respectively, from day 1 to day 21 after injection of monocrotaline (MCT). We measured the mean pulmonary arterial pressure (mPAP), right ventricular systolic pressure (RVSP), and medial wall thickness of the pulmonary artery (PAWT). We examined the levels of the nuclear factor kappa B (NF-κB) protein by using immunohistochemistry and western blot analysis, and the mRNA levels of NF-κB in PVSMCs were evaluated using real-time polymerase chain reaction (PCR). The mPAP, RVSP, and PAWT and the protein and mRNA levels of NF-κB were significantly higher in the PAH model group than in the control group (P < 0.05). Ruscogenin induced a significant dose-dependent decrease in the mPAP, RVSP, and PAWT and in the NF-κB expression in the PAH group (P < 0.05), which suggests that ruscogenin will also exert dose-dependent effects on MCT-induced PAH through the inhibition of NF-κB.