The monocyte to lymphocyte ratio not only at baseline but also at relapse predicts poor outcomes in patients with hepatocellular carcinoma receiving locoregional therapy.

BACKGROUND: Monocyte to lymphocyte ratio (MLR) represents a pro-inflammatory immune microenvironment. The aim of this study was to elucidate the effect of MLR and subsequent MLR when relapse occurred (R-MLR) on prognosis for hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE) combined with ablation. METHODS: A prospective analysis was conducted on 606 patients with HCC who were treated with TACE combined with local ablation in Beijing You'an Hospital affiliated to Capital Medical University from January 1, 2012 to December 31, 2016. MLR or R-MLR were stratified according to the optimal cut-off values. The cumulative recurrence-free survival (RFS), overall survival (OS) , and recurrence-death survival (RDS) rates were calculated by Kaplan-Meier method. The Cox proportion hazard model and logistic regression analysis was conducted to screen for independent predictive factors for indicating early relapse and long-term prognosis. RESULTS: High MLR was significantly associated with relapse, early recurrence, and overall survival. After a median follow-up of 59.4 months, The cumulative 1-, 3-, 5-year RFS rates of low MLR were 74.6%, 43.8%, and 34.0%; while 66.1%, 32.2%, and 22.6% for high group (P < 0.001). There were also significant differences in corresponding OS rates of the two groups (P = 0.003). The cumulative 1-, 3-, 5-year OS rates of low R-MLR were 99.5%, 87.2%, 75.5%; while 98.3%, 78.3%, 61.7% for high group (P < 0.001). There were also significant differences in corresponding RDS rates in the two groups (P = 0.008). 436 patients were divided into four groups on the base of cut-off values of MLR and R-MLR (low-low, low-high, high-low, and high-high). The low-low group has shown better outcomes including the cumulative 1-, 3-, 5-year OS, and RDS rates(P < 0.001). CONCLUSIONS: High MLR was related to unfavorable outcome. Subsequent change of MLR between baseline and HCC relapse could indicate poor long-term survival after relapse.

Effects of taurine against benzo[α]pyrene-induced cell cycle arrest and reactive oxygen species-mediated nuclear factor-kappa B apoptosis via reduction of mitochondrial stress in A549 cells.

Taurine is a free amino acid that prevents reactive oxygen species (ROS) formation. ROS production is associated with oxidative stress, cell proliferation, apoptosis, inflammation, and DNA alterations in benzo[α]pyrene (BaP)-induced lung cells. Here, we assessed the effect of adding of 25 mM taurine on human pulmonary alveolar epithelial A549 cells treated with different concentrations of BaP. After culturing for 24 h, the cells were tested for biomarkers including cell viability, cellular morphology, Annexin V-FITC/propidium iodide, cell cycle regulation, ROS accumulation, mitochondrial membrane potential (MMP), and expression of related signaling genes and proteins. BaP induced cell cycle arrest and decreased cell viability in a dose-dependent manner. In addition, 50 µM BaP induced a 52.2% increase in ROS levels and inhibited MMP by up to 80%; however, taurine decreased BaP-induced ROS production by 19.5% and restored MMP. The expression of nuclear factor-kappa B (NF-κB), B-cell lymphoma-2 (BCL-2) homologous antagonist killer (Bak), BCL-2-associated X protein (Bax), and cytochrome c at both the mRNA and protein levels were increased, and the expression of BCL-2 and BCL-x1 was decreased by BaP treatment. Furthermore, BaP activated caspase-3/7 expression by up to 25%. However, taurine decreased the expression of NF-κB, Bak, Bax and cytochrome c levels, reduced caspase-3/7 activities, and increased the expression of BCL-2 and BCL-x1. Hence, taurine attenuates BaP-induced oxidative stress and mitochondrial dysfunction by inhibiting the NF-κB-mediated intrinsic apoptosis pathway in A549 cells. Taurine can be considered as a preventive molecule to prevent lung damage.

Water quality model parameter identification of an open channel in a long distance water transfer project based on finite difference, difference evolution and Monte Carlo.

A new method is proposed based on the finite difference method (FDM), differential evolution algorithm and Markov Chain Monte Carlo (MCMC) simulation to identify water quality model parameters of an open channel in a long distance water transfer project. Firstly, this parameter identification problem is considered as a Bayesian estimation problem and the forward numerical model is solved by FDM, and the posterior probability density function of the parameters is deduced. Then these parameters are estimated using a sampling method with differential evolution algorithm and MCMC simulation. Finally this proposed method is compared with FDM-MCMC by a twin experiment. The results show that the proposed method can be used to identify water quality model parameters of an open channel in a long distance water transfer project under different scenarios better with fewer iterations, higher reliability and anti-noise capability compared with FDM-MCMC. Therefore, it provides a new idea and method to solve the traceability problem in sudden water pollution accidents.

Role of TRPA1 and TRPV1 in the ROS-dependent sensory irritation of superior laryngeal capsaicin-sensitive afferents by cigarette smoke in anesthetized rats.

BACKGROUND: Laryngeal exposure to cigarette smoke (CS) evokes sensory irritation, but the mechanisms are largely unclear. The TRPA1 and TRPV1 receptors are two types of Ca(2+)-permeant channels located at the terminals of airway capsaicin-sensitive afferents. We investigated the mechanisms underlying the airway reflex evoked by laryngeal CS exposure in anesthetized rats. METHODS: CS (7 ml) was delivered into a functionally isolated larynx, while the animals (n = 201) breathed spontaneously. Respiratory parameters were measured. All use of pharmacological agents involved pretreatment by laryngeal application. RESULTS: Laryngeal CS exposure immediately evoked a concentration-dependant apneic response that was unrelated to the nicotine content of the CS. This inhibition of breathing was abolished by bilateral sectioning of the superior laryngeal nerves (SLNs) or by perineural capsaicin treatment of the SLNs (selective blocking of capsaicin-sensitive afferent neural conduction), suggesting the involvement of superior laryngeal capsaicin-sensitive afferents in the reflex. The reflex apnea was significantly attenuated by N-acetyl-l-cysteine (antioxidant), EGTA (extracellular Ca(2+) chelator) and BAPTA-AM (intracellular Ca(2+) chelator), indicating the importance of reactive oxygen species (ROS) and Ca(2+). This reflex apnea was also partially reduced by HC030031 (TRPA1 receptor antagonist) and capsazepine (TRPV1 receptor antagonist), and was nearly abolished by a combination of these two antagonists, suggesting a central role for the TRPA1 and TRPV1 receptors. Furthermore, the reflex apnea was attenuated by indomethacin (cyclooxygenase inhibitor); however, the attenuation by indomethacin was not increased by pretreatment with HC030031 or capsazepine, indicating that TRPA1 and TRPV1 receptor functionality is, at least in part, linked to cyclooxygenase metabolites. CONCLUSIONS: The reflex apnea evoked by laryngeal CS requires activation of both TRPA1 and TRPV1 receptors, which are likely to be located at the terminals of superior laryngeal capsaicin-sensitive afferents. Laryngeal sensory irritation by CS seems to depend on the actions of ROS and cyclooxygenase metabolites on these two types of receptors.

Effect of HBsAg expression in liver tissue on prognosis of hepatocellular carcinoma after minimally invasive interventional therapy.

Background: The aim of this study was to investigate the association between pathologic markers and prognosis in patients with hepatocellular carcinoma who received transcatheter chemoembolization combined with locoregional ablation therapy. Methods: This retrospective study included 111 hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). All patients underwent transcatheter arterial chemoembolization (TACE) combined with locoregional ablation therapy, and received core needle biopsy before therapy in Beijing You 'an Hospital affiliated to Capital Medical University from January 1, 2013 to December 31, 2016. Demographic, pathological indicators and clinical laboratory data were collected. The cumulative recurrence-free survival (RFS) and overall survival (OS) were calculated and compared by Kaplan-Meier method and Log-rank test, and Cox proportional risk model was used to screen for independent predictors of recurrence and long-term prognosis in HCC patients. Results: There was a correlation between HBsAg expression in liver tissue and prognosis of HCC patients. Patients with negative HBsAg expression had longer 1-,3- and 5-year RFS rates than positive HBsAg expression (78.3%, 43.5%, 30.4% and 58.5%, 24.5%, 17.0%, P=0.018). Meanwhile,the postoperative 1-,3-and 5-year OS rates of HCC patients in the negative HBsAg expression group were significantly higher than those of HCC patients in the positive HBsAg expression group (100%, 89.1%, 80.4% and 100%, 75.5%, 58.5%, P=0.008). Conclusions: The prognosis of patients with hepatocellular carcinoma with negative HBsAg expression was better than that with positive HBsAg expression. Accordingly, the expression of the liver HBsAg before combined therapy was a prognostic indicator for OS and RFS. For patients with liver HBsAg positive, follow-up should be strengthened and corresponding intervention measures should be taken to improve prognosis.

Dynamic Changes of Cytokine Profiles and Their Correlation With Tumor Recurrence Following Thermal Ablation in Hepatocellular Carcinoma.

The 5-year recurrence rate of thermal ablation for hepatocellular carcinoma (HCC) is high, and whether this treatment strategy induces systemic immune response remains elusive. This study aimed to investigate the effects of thermal ablation on HCC patients' cytokine profiles and to explore the correlation of cytokine profiles with tumor recurrence after ablation. A total of 22 HCC patients were included in this prospective study. The levels of 27 cytokines in the peripheral blood of HCC patients were measured before ablation (baseline), week 1, and week 4 after ablation using a Bio-Plex Pro Human Cytokine 27-plex Assay kit. Cytokines showed different dynamic changing trends after ablation treatment. It was found that the level of IL-6 was significantly elevated at week 1 and returned to the baseline level at week 4 after ablation. The level of IL-10 was slightly reduced at week 1 and significantly decreased at week 4. The levels of MCP-1, macrophage inflammatory protein-1ß (MIP-1ß), and TNF-α were similarly reduced at week 1 and increased at week 4. The levels of IL-17, platelet-derived growth factor-BB (PDGF-BB), and regulated upon activation, normal T cell expressed and secreted (RANTES) showed little to no change at week 1 while an observable increase at week 4. Patients with a high IL-10 level (2.99 pg/ml) at baseline and low levels of TNF-α (20.4 pg/ml), PDGF-BB (107.78 pg/ml), and RANTES (2303.94 pg/ml) at week 4 were at risk of tumor recurrence during 1-year follow-up. The results suggested that thermal ablation activated systemic immune responses by changing the levels of cytokines. The results also demonstrated that measurement of IL-10 at baseline, TNF-α, PDGF-BB, and RANTES at week 4 after ablation might predict the risk of tumor recurrence.

Prognostic significance of globulin/low-density lipoprotein ratio in patients with hepatocellular carcinoma after local ablative therapy: a retrospective cohort study.

Background: Low-density lipoprotein (LDL) and globulin (GLOB) have been found to be predictors for some malignant tumors, but their predictive value in hepatocellular carcinoma (HCC) has hardly been elucidated. This study assessed the prognostic significance of GLOB to LDL ratio (GLR) in HCC patients before ablation. Methods: This study analyzed 312 early-stage HCC patients who were hospitalized and underwent ablative treatment in Beijing You'an Hospital, Capital Medical University, from 1 January 2014 to 1 January 2019. The primary endpoint was the recurrence-free survival (RFS), calculated from treatment initiation to cancer recurrence, whereas the overall survival (OS) was measured from treatment initiation to death or last follow-up. Cox regression analysis was used to assess the GLR independently associated with recurrence and survival. OS and RFS were calculated by Kaplan-Meier analysis and compared between groups using the log rank test. The optimal cut-off value and prognostic role of GLR and other markers were evaluated via the receiver operating characteristic (ROC) curves and the Youden index. Results: Univariate and multivariate analysis found that the tumor number, tumor size, and GLR were independent risk factors of relapse, whereas etiology, tumor number, tumor size, fibrinogen (Fib), and GLR were related to OS. We classified the patients into groups with high and low levels of GLR based on the optimal cut-off value of GLR identified by ROC curve. The cumulative 1-, 3-, and 5-year RFS rates in the low GLR group were 76.4%, 53.8%, and 43.4% respectively, whereas those in the high GLR group were 71%, 31%, and 22%, respectively (P<0.001). In terms of OS, the low GLR group showed a 1-, 3-, and 5-year OS of 99.5%, 92.0%, and 80.2% respectively, and 98%, 73%, and 63% respectively for the high GLR group (P<0.001). Finally, patients were stratified by GLR and tumor size. The outcomes revealed that patients in group A (GLR <16.54 and tumor size ≤30 mm) showed better prognosis than those in group B (GLR ≥16.54 and tumor size ≤30 mm or GLR <16.54 and tumor size >30 mm) and group C (GLR ≥16.54 and tumor size >30 mm) (P<0.001). Conclusions: Preoperative GLR ratio has predictive value for patients with HCC who have undergone complete ablation.

Interim efficacy and safety of PD-1 inhibitors in preventing recurrence of hepatocellular carcinoma after interventional therapy.

Introduction: Locoregional interventional therapy including transcatheter arterial chemoembolization (TACE) and ablation are the current standard of treatment for early-to-mid-stage hepatocellular carcinoma (HCC). However, questions remain unanswered regarding the management of recurrence after locoregional treatment. PD-1 inhibitors can block inhibitory signals of T-cell activation and proliferation to reduce the recurrence. We conducted a single-arm phase 2 trial to evaluate the efficacy and safety of PD-1 inhibitors following locoregional interventional therapy in HCC patients with high recurrence risk guided by our novel scoring system. Methods: Patients enrolled initially treated by TACE combined with ablation, then willingly joined the experimental group. One month later, they received the anti-PD-1 adjuvant therapy (intravenous injection of 200 mg), which was repeated every 3 weeks for a total of 4 or 8 cycles. Within this same period, other patients were screened into the control group to match the experimental group by 1:1 based on the propensity score matching method (PSM). The primary endpoint was relapse-free survival (RFS). Secondary endpoints included overall survival (OS) recurrence modality, safety, and quality of life. Result: At the time of data cutoff, the median RFS of the control group was 7.0 months while the experimental group had not reached it. Moreover, the 1-year RFS rate was 73.3% in the experimental group and 46.7% in the control group, showing a significant difference (P =0.02). The rate of local tumor progression in the experimental group was clearly lower than that in the control group (P = 0.027). Benefits associated with anti-PD-1 adjuvant therapy were observed in patients with multiple tumors and tumor size ≤2cm. Univariate and multivariate analyses demonstrated that anti-PD-1 adjuvant therapy was an independent favorable prognostic factor for RFS in HCC patients. The most frequent AE observed in this study was RCCEP, and other AEs included diarrhea, hepatotoxicity, rash, pruritus, and fatigue. The incidence of GRADE ≥3 AE and withdrawal in this study was low with no deaths recorded. Conclusions: Interim analysis from the study suggest the addition of anti-PD-1 adjuvant therapy after TACE combined with ablation could significantly prolong RFS with controllable safety for early-to-mid-stage HCC patients with high recurrence risk.

Nomogram established on account of Lasso-Cox regression for predicting recurrence in patients with early-stage hepatocellular carcinoma.

Purpose: To investigate the risk factors for recurrence in patients with early-stage hepatocellular carcinoma (HCC) after minimally invasive treatment with curative intent, then to construct a prediction model based on Lasso-Cox regression and visualize the model built. Methods: Clinical data were collected from 547 patients that received minimally invasive treatment in our hospital from January 1, 2012, to December 31, 2016. Lasso regression was used to screen risk factors for recurrence. Then we established Cox proportional hazard regression model and random survival forest model including several parameters screened by Lasso regression. An optimal model was selected by comparing the values of C-index, then the model was visualized and the nomogram was finally plotted. Results: The variables screened by Lasso regression including age, gender, cirrhosis, tumor number, tumor size, platelet-albumin-bilirubin index (PALBI), and viral load were incorporated in the Cox model and random survival forest model (P<0.05). The C-index of these two models in the training sets was 0.729 and 0.708, and was 0.726 and 0.700 in the validation sets, respectively. So we finally chose Lasso-Cox regression model, and the calibration curve in the validation set performed well, indicating that the model built has a better predictive ability. And then a nomogram was plotted based on the model chosen to visualize the results. Conclusions: The present study established a nomogram for predicting recurrence in patients with early-stage HCC based on the Lasso-Cox regression model. This nomogram was of some guiding significance for screening populations at high risk of recurrence after treatment, by which doctors can formulate individualized follow-up strategies or treatment protocols according to the predicted risk of relapse for patients to improve the long-term prognosis.

Identification of source information for sudden hazardous chemical leakage accidents in surface water on the basis of particle swarm optimisation, differential evolution and Metropolis-Hastings sampling.

A quick and accurate identification of source information on sudden hazardous chemical leakage accident is crucial for early accident warning and emergency response. This study firstly regards source identification problem of sudden hazardous chemical leakage accidents as an inverse problem and presents a source identification model based on the Bayesian framework. Secondly, a new identification method is designed on the basis of particle swarm optimisation (PSO), differential evolution (DE) and the Metropolis-Hastings (M-H) sampling method. Lastly, the designed method, i.e. PSO-DE-MH, is verified by an outdoor experiment analyses in a section of the South-North Water Transfer Project. Results show that the number of iterations, the average absolute error, the average relative error and the average standard deviations of the identification results obtained by PSO-DE-MH are less than those of PSO-DE and DE-MH. Moreover, the relative error and the sampling relative error of the identification results under five different measurement errors (MEs) (σ = 0.01, 0.05, 0.1, 0.15, 0.2) are less than 9.5% and 0.2%, respectively. The designed method is effective even when the standard deviation of the ME increases to 0.2. Therefore, the designed method can effectively and accurately obtain the source information of sudden hazardous chemical leakage accidents. This study provides a new idea and method to solve the difficult problems of emergency management.

The Dynamic Changes of AFP From Baseline to Recurrence as an Excellent Prognostic Factor of Hepatocellular Carcinoma After Locoregional Therapy: A 5-Year Prospective Cohort Study.

BACKGROUND: Although many studies have confirmed the prognostic value of preoperative alpha-fetoprotein (AFP) in patients with hepatocellular carcinoma (HCC), the association between AFP at baseline (b-AFP), subsequent AFP at relapse (r-AFP), and AFP alteration and overall survival in HCC patients receiving locoregional therapy has rarely been systematically elucidated. PATIENTS AND METHODS: A total of 583 subjects with newly diagnosis of virus-related HCC who were admitted to Beijing You 'an Hospital, Capital Medical University from January 1, 2012 to December 31, 2016 were prospectively enrolled. The influence of b-AFP, subsequent r-AFP, and AFP alteration on relapse and post-recurrence survival were analyzed. RESULTS: By the end of follow-up, a total of 431 (73.9%) patients relapsed and 200 (34.3%) died. Patients with positive b-AFP had a 24% increased risk of recurrence compared with those who were negative. Patients with positive r-AFP had a 68% increased risk of death after relapse compared with those who were negative. The cumulative recurrence-death survival (RDS) rates for 1, 3, 5 years in patients with negative r-AFP were 85.6% (184/215), 70.2%(151/215), and 67.4%(145/215), while the corresponding rates were 75.1% (154/205), 51.2% (105/205), and 48.8% (100/205) in those with positive AFP (P<0.001). 35 (21.6%) of the 162 patients with negative b-AFP turned positive at the time of recurrence, and of this subset, only 12 (34.3%) survived. Of the 255 patients with positive b-AFP, 86 (33.7%) turned negative at the time of relapse, and of this subset, only 30 (34.9%) died. The 1-, 3-, and 5-year cumulative RDS rates were also compared among groups stratified by AFP at baseline and relapse. The present study found that patients with positive AFP at baseline and relapse, as well as those who were negative turned positive, had the shortest RDS and OS. CONCLUSIONS: Not only AFP at baseline but also subsequent AFP at relapse can be used to predict a post-recurrence survival, which can help evaluate mortality risk stratification of patients after relapse.

Menthol suppresses laryngeal C-fiber hypersensitivity to cigarette smoke in a rat model of gastroesophageal reflux disease: the role of TRPM8.

Patients with gastroesophageal reflux disease (GERD) display enhanced laryngeal reflex reactivity to stimuli that may be due to sensitization of the laryngeal C-fibers by acid and pepsin. Menthol, a ligand of transient receptor potential melastatin-8 (TRPM8), relieves throat irritation. However, the possibility that GERD induces laryngeal C-fiber hypersensitivity to cigarette smoke (CS) and that menthol suppresses this event has not been investigated. We delivered CS into functionally isolated larynxes of 160 anesthetized rats. Laryngeal pH 5-pepsin treatment, but not pH 5-denatured pepsin, augmented the apneic response to CS, which was blocked by denervation or perineural capsaicin treatment (a procedure that blocks the conduction of C fibers) of the superior laryngeal nerves. This augmented apnea was partially attenuated by capsazepine [an transient receptor potential vanilloid 1 (TRPV1) antagonist], SB-366791 (a TRPV1 antagonist), and HC030031 [a transient receptor potential ankyrin 1 (TRPA1) antagonist] and was completely prevented by a combination of TRPV1 and TRPA1 antagonists. Local application of menthol significantly suppressed the augmented apnea and this effect was reversed by pretreatment with AMTB (a TRPM8 antagonist). Our electrophysiological studies consistently revealed that laryngeal pH 5-pepsin treatment increased the sensitivity of laryngeal C-fibers to CS. Likewise, menthol suppressed this laryngeal C-fiber hypersensitivity and its effect could be reversed by pretreatment with AMTB. Our results suggest that laryngeal pH 5-pepsin treatment increases sensitivity to CS of both TRPV1 and TRPA1, which are presumably located at the terminals of laryngeal C-fibers. This sensory sensitization leads to enhanced laryngeal reflex reactivity and augmentation of the laryngeal C-fiber responses to CS, which can be suppressed by menthol acting via TRPM8.

Suppressing cardiac vagal modulation and changing sleep patterns in rats after chronic ischemic stroke injury.

Chronic autonomic function and sleep architecture changes in patients post-stroke are not well understood. Using wireless polysomnographic recordings, this study aimed to investigate the long-term effects on sleep patterns and autonomic function in free moving rats after middle cerebral artery occlusion (MCAO). The sleep pattern and heart rate variability (HRV) of Wistar-Kyoto rats (WKY) were analyzed. After 7-10days, the rats were divided into two groups: an MCAO group (n=8) and a sham surgery group (n=8). Compared with shams, MCAO rats showed decreased accumulated quiet sleep (QS) time over 24h during the 3rd week. The time percentage, duration and delta power of QS were also significantly decreased in the MCAO group during the dark period. Compared with baseline, there were significant increases in the parasympathetic-associated HRV measures in the sham group, including the total power (TP), high frequency power (HF) and lower frequency power (LF), throughout the post-operative weeks (primarily the 2nd and 3rd weeks), reflecting a developmental increase of parasympathetic modulation; the normalized LF and the LF-HF ratio were unaffected. In great contrast, however, most of the HRV measures in the MCAO group were not significantly changed. Therefore, this study showed that the long-term effects of ischemic stroke injury involve retardation of the establishment of parasympathetic enhancement and disturbance of the normal sleep-wake cycle.