Polymeric nano-micelle of carbon monoxide donor SMA/CORM2 ameliorates acetaminophen-induced liver injury via suppressing HMGB1/TLR4 signaling pathway.

Acetaminophen (APAP) overdose-induced hepatotoxicity is the most common cause of acute liver failure. Excessive generation of reactive oxygen species (ROS) and inflammatory responses are the major causes of necrosis and/or necroptosis of the liver cells. Currently, the treatment options for APAP-induced liver injury are very limited, N-acetylcysteine (NAC) is the only approved drug to treat APAP overdose patients. It is of great necessity to develop new therapeutic strategies. In a previous study, we focused on the anti-oxidative, anti-inflammatory signal molecule carbon monoxide (CO), and developed a nano-micelle encapsulating CO donor, i.e., SMA/CORM2. Administration of SMA/CORM2 to the mice exposed to APAP significantly ameliorated the liver injury and inflammatory process, in which modulating macrophage reprogramming plays a critical role. Along this line, in this study, we investigated the potential effect of SMA/CORM2 on toll-like receptor 4 (TLR4) and high mobility group protein B1 (HMGB1) signaling pathways that are known to be closely involved in many inflammatory responses and necroptosis. In a mouse APAP-induced liver injury model, similar to the previous study, SMA/CORM2 at 10 mg/kg remarkably improved the condition of the liver after injury as evidenced by histological examination and liver function. During the process of liver injury triggered by APAP, TLR4 expression gradually increased over time, and it was significantly upregulated as early as 4 h after APAP exposure, whereas, an increase of HMGB1 was a late-stage event. Notably, SMA/CORM2 treatment suppressed significantly both TLR4 and HMGB1, consequently inhibiting the progression of inflammation and liver injury. Compared to CORM2 without SMA modification (native CORM2) of 1 mg/kg that is equivalent to 10 mg/kg of SMA/CORM2 (the amount of CORM2 in SMA/CORM2 is 10% [w/w]), SMA/CORM2 exhibited a much better therapeutic effect, indicating its superior therapeutic efficacy to native CORM2. These findings revealed that SMA/CORM2 protects against APAP-induced liver injury via mechanisms involving the suppression of TLR4 and HMGB1 signaling pathways. Taking together the results in this study and previous studies, SMA/CORM2 exhibits great therapeutic potential for APAP overdose-induced liver injury, we thus anticipate the clinical application of SMA/CORM2 for the treatment of APAP overdose, as well as other inflammatory diseases.

Gender difference in the associations between health literacy and problematic mobile phone use in Chinese middle school students.

BACKGROUND: Problematic mobile phone use (PMPU) is becoming increasingly popular and has serious harmful effects on physical and mental health among adolescents. Inadequate health literacy (HL) is related to some risky behaviors and mental health problems in adolescents. Nevertheless, few studies have explored the relationship between HL and PMPU and the gender difference in the relationship among Chinese adolescents. The aim of this study was to examine the associations between HL and PMPU and explore gender difference in the associations. METHODS: A total of 22,628 junior and senior high school students (10,990 males and 11,638 females) in 6 regions of China participated in this study. HL and PMPU were measured by self-report validated questionnaires. Chi-square tests and logistic regression analysis were conducted in the study. RESULTS: Logistic regression analysis showed that students with inadequate HL are likely to have PMPU (OR = 2.013, 95% CI: 1.840-2.202), and different degrees of association can be seen in six dimensions. Besides, in both males and females, students with inadequate HL had a higher risk of PMPU (OR male = 1.607, 95% CI: 1.428-1.807; OR female = 2.602, 95% CI: 2.261-2.994). Regarding the gender difference, the results showed that males had more PMPU than females, and the difference was more significant for students with adequate HL than those with inadequate HL (OR inadequate = 1.085, 95% CI: 1.016-1.159; OR adequate = 1.770, 95% CI: 1.490-2.101). Similarly, there were associations in the six dimensions. CONCLUSIONS: HL decreases PMPU, and males have a higher risk of PMPU than females. These findings suggest a reasonable strategy to reduce PMPU by improving the HL level of adolescents.

Prognostic importance of the preoperative New-Naples prognostic score for patients with gastric cancer.

BACKGROUND: The wide applicability of the Naples prognostic score (NPS) is still worthy of further study in gastric cancer (GC). This study aimed to construct a New-NPS based on the differences in immunity and nutrition in patients with upper and lower gastrointestinal tumors to help obtain an individualized prediction of prognosis. METHODS: This study retrospectively analyzed patients who underwent radical gastrectomy from April 2014 to September 2016. The cutoff values of the preoperative neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), serum albumin (Alb), and total cholesterol (TC) were calculated by ROC curve analysis. ROC and t-ROC were used to evaluate the accuracy of the prognostic markers. The Kaplan-Meier method and log-rank test were used to analyze the overall survival probability. Univariate and multivariate analyses based on Cox risk regression were used to show the independent predictors. The nomogram was made by R studio. The predictive accuracy of nomogram was assessed using a calibration plot, concordance index (C-index), and decision curve. RESULTS: A total of 737 patients were included in training cohort, 411 patients were included in validation cohort. ROC showed that the New-NPS was more suitable for predicting the prognosis of GC patients. NPS = 2 indicated a poor prognosis. Multivariate analysis showed that CEA (P = 0.026), Borrmann type (P = 0.001), pTNM (P < 0.001), New-NPS (P < 0.001), and nerve infiltration (P = 0.035) were independent risk factors for prognosis. CONCLUSION: The New-NPS based on the cutoff values of NLR, LMR, Alb, and TC is not only suitable for predicting prognosis but can also be combined with clinicopathological characteristics to construct a nomogram model for GC patients.

Metastatic lymph nodes and prognosis assessed by the number of retrieved lymph nodes in gastric cancer.

BACKGROUND: The prognostic value of quantitative assessments of the number of retrieved lymph nodes (RLNs) in gastric cancer (GC) patients needs further study. AIM: To discuss how to obtain a more accurate count of metastatic lymph nodes (MLNs) based on RLNs in different pT stages and then to evaluate patient prognosis. METHODS: This study retrospectively analyzed patients who underwent GC radical surgery and D2/D2+ LN dissection at the Cancer Hospital of Harbin Medical University from January 2011 to May 2017. Locally weighted smoothing was used to analyze the relationship between RLNs and the number of MLNs. Restricted cubic splines were used to analyze the relationship between RLNs and hazard ratios (HRs), and X-tile was used to determine the optimal cutoff value for RLNs. Patient survival was analyzed with the Kaplan-Meier method and log-rank test. Finally, HRs and 95% confidence intervals were calculated using Cox proportional hazards models to analyze independent risk factors associated with patient outcomes. RESULTS: A total of 4968 patients were included in the training cohort, and 11154 patients were included in the validation cohort. The smooth curve showed that the number of MLNs increased with an increasing number of RLNs, and a nonlinear relationship between RLNs and HRs was observed. X-tile analysis showed that the optimal number of RLNs for pT1-pT4 stage GC patients was 26, 31, 39, and 45, respectively. A greater number of RLNs can reduce the risk of death in patients with pT1, pT2, and pT4 stage cancers but may not reduce the risk of death in patients with pT3 stage cancer. Multivariate analysis showed that RLNs were an independent risk factor associated with the prognosis of patients with pT1-pT4 stage cancer (P = 0.044, P = 0.037, P = 0.003, P < 0.001). CONCLUSION: A greater number of RLNs may not benefit the survival of patients with pT3 stage disease but can benefit the survival of patients with pT1, pT2, and pT4 stage disease. For the pT1, pT2, and pT4 stages, it is recommended to retrieve 26, 31 and 45 LNs, respectively.

Development and Validation of an Age-Related Gastric Cancer-Specific Immune Index.

Background: Aging has a negative impact on the immune function of patients. The purpose of this study was to construct an age-related specific immune index according to the immune aging phenomenon of gastric cancer (GC) and explore its prognostic value. Methods: This study retrospectively analyzed patients who underwent radical GC surgery in the Department of Gastrointestinal Surgery, Affiliated Cancer Hospital of Harbin Medical University, from August 2014 to December 2016 and divided them into a training cohort and a validation cohort. A new immune score, the GC-specific immune index (GSII), was developed as a series of lymphocyte subsets associated with the prognosis of patients with GC. Then, the receiver operating characteristic (ROC) curve was used to compare the prediction performance. The Kaplan‒Meier method and Log rank test were used to analyze the overall survival of patients. Cox hazard regression models were used to identify independent risk factors associated with prognosis. Finally, a nomogram model was constructed by combining the GSII and clinicopathological characteristics, and the calibration chart, consistency index, and decision curve were used to test the performance of the model. Results: Aging did not significantly affect CD8 cell counts but decreased CD4 and CD19 cell counts. Based on the Cox analysis, the GSII of patients ≤60 years old was 0.079×lg CD4+0.348×lg CD19, and the GSII of patients >60 years old was 0.058×lg CD4. A decreased GSII was indicative of a poor prognosis and was an independent risk factor associated with patient outcomes. The nomogram constructed based on the GSII and clinicopathological features accurately predicted patient prognosis. Furthermore, the GSII was well validated in the validation cohort. Conclusion: The GSII constructed for the special immune aging phenomenon of GC can accurately predict patient prognosis.

Impact of AADAC gene expression on prognosis in patients with Borrmann type III advanced gastric cancer.

BACKGROUND: The prognosis of Borrmann type III advanced gastric cancer (AGC) is known to vary significantly among patients. This study aimed to determine which differentially expressed genes (DEGs) are directly related to the survival time of Borrmann type III AGC patients and to construct a prognostic model. METHODS: We selected 25 patients with Borrmann type III AGC who underwent radical gastrectomy. According to the difference in overall survival (OS), the patients were divided into group A (OS<1 year, n=11) and group B (OS>3 years, n=14). DEGs related to survival time in patients with Borrmann type III AGC were determined by mRNA sequencing. The prognosis and functional differences of DEGs in different populations were determined by The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) public databases. The expression of mRNA and protein in cell lines was detected by quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) and Western blot (WB). Immunohistochemical (IHC) staining was used to detect protein expression in the paraffin-embedded tissues of 152 patients with Borrmann type III AGC who underwent radical gastrectomy. After survival analysis, nomograms were constructed to predict the prognosis of patients with Borrmann type III AGC. RESULTS: Arylacetamide deacetylase (AADAC) is a survival-related DEG in patients with Borrmann type III AGC. The higher the expression level of its mRNA and protein is, the better the prognosis of patients. Bioinformatics analysis found that AADAC showed significant differences in prognosis and function in European and American populations and Asian populations. In addition, the mRNA and protein expression levels of AADAC were high in differentiated gastric cancer (GC) cells. We also found that AADAC was an independent prognostic factor for patients with Borrmann type III AGC, and its high expression was significantly correlated with better OS and disease-free survival (DFS). Nomogram models of AADAC expression level combined with clinicopathological features can be used to predict the OS and DFS of Borrmann type III AGC. CONCLUSION: AADAC can be used as a biomarker to predict the prognosis of Borrmann type III AGC and has the potential to become a new therapeutic target for GC.

Prognostic significance of serum inflammation indices for different tumor infiltrative pattern types of gastric cancer.

BACKGROUND: Inflammatory indices are considered to be potential prognostic biomarkers for patients with gastric cancer (GC). However, there is no evidence defining the prognostic significance of inflammatory indices for GC with different tumor infiltrative pattern (INF) types. AIM: To evaluate the significance of inflammatory indices and INF types in predicting the prognosis of patients with GC. METHODS: A total of 962 patients who underwent radical gastrectomy were retrospectively selected for this study. Patients were categorized into the expansive growth type (INFa), the intermediate type (INFb), and the infiltrative growth type (INFc) groups. The cutoff values of inflammatory indices were analyzed by receiver operating characteristic curves. The Kaplan-Meier method and log-rank test were used to analyze overall survival (OS). The chi-square test was used to analyze the association between inflammatory indices and clinical characteristics. The independent risk factors for prognosis in each group were analyzed by univariate and multivariate analyses based on logistic regression. Nomogram models were constructed by R studio. RESULTS: The INFc group had the worst OS (P < 0.001). The systemic immune-inflammation index (P = 0.039) and metastatic lymph node ratio (mLNR) (P = 0.003) were independent risk factors for prognosis in the INFa group. The platelet-lymphocyte ratio (PLR) (P = 0.018), age (P = 0.026), body mass index (P = 0.003), and postsurgical tumor node metastasis (pTNM) stage (P < 0.001) were independent risk factors for prognosis in the INFb group. The PLR (P = 0.021), pTNM stage (P = 0.028), age (P = 0.021), and mLNR (P = 0.002) were independent risk factors for prognosis in the INFc group. The area under the curve of the nomogram model for predicting 5-year survival in the INFa group, INFb group, and INFc group was 0.787, 0.823, and 0.781, respectively. CONCLUSION: The outcome of different INF types GC patients could be assessed by nomograms based on different inflammatory indices and clinicopathologic features.

Nomograms predicting prognosis of patients with pathological stages T1N2-3 and T3N0 gastric cancer.

BACKGROUND: Patients with pathological stages T1N2-3 (pT1N2-3) and pT3N0 gastric cancer (GC) have not been routinely included in the target population for postoperative chemotherapy according to the Japanese Gastric Cancer Treatment Guideline, and their prognosis is significantly different. AIM: To identify the high-risk patients after radical surgery by analyzing biomarkers and clinicopathological features and construct prognostic models for them. METHODS: A total of 459 patients with pT1N2-3/pT3N0 GC were retrospectively selected for the study. The Chi-square test was used to analyze the differences in the clinicopathological features between the pT1N2-3 and pT3N0 groups. The Kaplan-Meier analysis and log-rank test were used to analyze overall survival (OS). The independent risk factors for patient prognosis were analyzed by univariate and multivariate analyses based on the Cox proportional hazards regression model. The cutoff values of continuous variables were identified by receiver operating characteristic curve. The nomogram models were constructed with R studio. RESULTS: There was no statistically significant difference in OS between the pT1N2-3 and pT3N0 groups (P = 0.374). Prealbumin (P = 0.040), carcino-embryonic antigen (CEA) (P = 0.021), and metastatic lymph node ratio (mLNR) (P = 0.035) were independent risk factors for prognosis in the pT1N2-3 group. Age (P = 0.039), body mass index (BMI) (P = 0.002), and gastrectomy (P < 0.001) were independent risk factors for prognosis in the pT3N0 group. The area under the curve values of the nomogram models for predicting the 5-year prognosis of the pT1N2-3 group and pT3N0 group were 0.765 and 0.699, respectively. CONCLUSION: Nomogram model combining prealbumin, CEA, and mLNR levels can be used to predict the prognosis of pT1N2-3 GC. Nomogram model combining age, BMI, and gastrectomy can be used to predict the prognosis of pT3N0 GC.

Prognostic significance of serum inflammation indexes in different Lauren classification of gastric cancer.

BACKGROUND: Inflammatory indexes are considered to be potential prognostic biomarkers for patients with gastric cancer (GC). However, little evidence has defined the prognostic significance of inflammatory indexes for GC with different Lauren classification. METHODS: A total of 852 patients with GC were randomly selected consecutively into intestinal type and diffuse/mixed type groups. Group bias was reduced by propensity score matching. The cutoff values of inflammatory indexes were analyzed by receiver operating characteristic curve. The Kaplan-Meier method and log-rank test were used to analyze the overall survival (OS). The chi-square test was used to analyze the association between inflammatory indexes and clinical characteristics. The independent risk factor for prognosis in each group was analyzed by univariate and multivariate analyses based on logistic regression. The nomogram models were constructed by R studio. RESULTS: Intestinal type GC patients (p < 0.05) had a lower percentage of neutrophils in stage I, higher percentage of neutrophils and higher platelet count in stage Ⅲ (p < 0.05). Systemic immune-inflammation index (SII) (p < 0.001), pTNM stage (p < 0.001), and postoperative chemotherapy (p = 0.002) were independent risk factors for prognosis in the intestinal type group. Platelet-lymphocyte ratio (PLR) (p < 0.001) and pTNM stage (p = 0.001) were independent risk factors for prognosis in the diffuse/mixed type group. The area under the curve of the nomogram model in predicting 5-year prognosis in the intestinal type group and diffuse/mixed type group were 0.807 and 0.788, respectively. CONCLUSION: SII combined with postoperative chemotherapy and pTNM stage were used to construct a nomogram model to predict the prognosis of intestinal type GC. PLR combined with pTNM stage can be used to construct a nomogram model for diffuse/mixed type GC patients.

Efficacy of Postoperative FOLFOX Versus XELOX Chemotherapy for Gastric Cancer and Prognostic Value of Platelet-Lymphocyte Ratio in Patients Receiving XELOX.

BACKGROUND: Surgery combined with postoperative chemotherapy is an effective method for treating patients with gastric cancer (GC) in Asia. The important roles of systemic inflammatory response in chemotherapy have been gradually verified. The purpose of this study was to assess the difference in clinical effectiveness of FOLFOX (oxaliplatin + leucovorin + 5-fluorouracil) and XELOX (oxaliplatin + capecitabine), and the prognostic value of postoperative platelet-lymphocyte ratio (PLR) in the XELOX group. METHODS: Patients who received radical gastrectomy combined with postoperative chemotherapy between 2004 and 2014 were consecutively selected into the FOLFOX and XELOX groups. Group bias was reduced through propensity score matching, which resulted in 278 patients in each group. Cut-off values of systemic immune inflammation (SII) score and PLR were obtained by receiver operating characteristic curve. Kaplan-Meier and Log-rank tests were used to analyze overall survival. The chi-square test was used to analyze the association between clinical characteristics and inflammatory indexes. Univariate and multivariate analyses based on Cox regression analysis showed independent risk factors for prognosis. The nomogram was made by R studio. RESULTS: Patients receiving XELOX postoperative chemotherapy had better survival than those receiving FOLFOX (P < 0.001), especially for stage III GC (P = 0.002). Preoperative SII was an independent risk factor for prognosis in the FOLFOX group, and PLR of the second postoperative chemotherapy regimen in the XELOX group, combined with tumor size and pTNM stage, could construct a nomogram for evaluating recurrence and prognosis. CONCLUSION: XELOX is better than FOLFOX for treatment of GC in Chinese patients, and a nomogram constructed by PLR, tumor size and pTNM stage can predict recurrence and prognosis.