ILC2s: Unraveling the innate immune orchestrators in allergic inflammation.

The prevalence rate of allergic diseases including asthma, atopic rhinitis (AR) and atopic dermatitis (AD) has been significantly increasing in recent decades due to environmental changes and social developments. With the study of innate lymphoid cells, the crucial role played by type 2 innate lymphoid cells (ILC2s) have been progressively unveiled in allergic diseases. ILC2s, which are a subset of innate lymphocytes initiate allergic responses. They respond swiftly during the onset of allergic reactions and produce type 2 cytokines, working in conjunction with T helper type 2 (Th2) cells to induce and sustain type 2 immune responses. The role of ILC2s represents an intriguing frontier in immunology; however, the intricate immune mechanisms of ILC2s in allergic responses remain relatively poorly understood. To gain a comphrehensive understanding of the research progress of ILC2, we summarize recent advances in ILC2s biology in pathologic allergic inflammation to inspire novel approaches for managing allergic diseases.

Involvement and repair of epithelial barrier dysfunction in allergic diseases.

The epithelial barrier serves as a critical defense mechanism separating the human body from the external environment, fulfilling both physical and immune functions. This barrier plays a pivotal role in shielding the body from environmental risk factors such as allergens, pathogens, and pollutants. However, since the 19th century, the escalating threats posed by environmental pollution, global warming, heightened usage of industrial chemical products, and alterations in biodiversity have contributed to a noteworthy surge in allergic disease incidences. Notably, allergic diseases frequently exhibit dysfunction in the epithelial barrier. The proposed epithelial barrier hypothesis introduces a novel avenue for the prevention and treatment of allergic diseases. Despite increased attention to the role of barrier dysfunction in allergic disease development, numerous questions persist regarding the mechanisms underlying the disruption of normal barrier function. Consequently, this review aims to provide a comprehensive overview of the epithelial barrier's role in allergic diseases, encompassing influencing factors, assessment techniques, and repair methodologies. By doing so, it seeks to present innovative strategies for the prevention and treatment of allergic diseases.

Relationship between multi-slice computed tomography features and pathological risk stratification assessment in gastric gastrointestinal stromal tumors.

BACKGROUND: Computed tomography (CT) imaging features are associated with risk stratification of gastric gastrointestinal stromal tumors (GISTs). AIM: To determine the multi-slice CT imaging features for predicting risk stratification in patients with primary gastric GISTs. METHODS: The clinicopathological and CT imaging data for 147 patients with histologically confirmed primary gastric GISTs were retrospectively analyzed. All patients had received dynamic contrast-enhanced CT (CECT) followed by surgical resection. According to the modified National Institutes of Health criteria, 147 lesions were classified into the low malignant potential group (very low and low risk; 101 lesions) and high malignant potential group (medium and high-risk; 46 lesions). The association between malignant potential and CT characteristic features (including tumor location, size, growth pattern, contour, ulceration, cystic degeneration or necrosis, calcification within the tumor, lymphadenopathy, enhancement patterns, unenhanced CT and CECT attenuation value, and enhancement degree) was analyzed using univariate analysis. Multivariate logistic regression analysis was performed to identify significant predictors of high malignant potential. The receiver operating curve (ROC) was used to evaluate the predictive value of tumor size and the multinomial logistic regression model for risk classification. RESULTS: There were 46 patients with high malignant potential and 101 with low-malignant potential gastric GISTs. Univariate analysis showed no significant differences in age, gender, tumor location, calcification, unenhanced CT and CECT attenuation values, and enhancement degree between the two groups (P > 0.05). However, a significant difference was observed in tumor size (3.14 ± 0.94 vs 6.63 ± 3.26 cm, P < 0.001) between the low-grade and high-grade groups. The univariate analysis further revealed that CT imaging features, including tumor contours, lesion growth patterns, ulceration, cystic degeneration or necrosis, lymphadenopathy, and contrast enhancement patterns, were associated with risk stratification (P < 0.05). According to binary logistic regression analysis, tumor size [P < 0.001; odds ratio (OR) = 26.448; 95% confidence interval (CI): 4.854-144.099)], contours (P = 0.028; OR = 7.750; 95%CI: 1.253-47.955), and mixed growth pattern (P = 0.046; OR = 4.740; 95%CI: 1.029-21.828) were independent predictors for risk stratification of gastric GISTs. ROC curve analysis for the multinomial logistic regression model and tumor size to differentiate high-malignant potential from low-malignant potential GISTs achieved a maximum area under the curve of 0.919 (95%CI: 0.863-0.975) and 0.940 (95%CI: 0.893-0.986), respectively. The tumor size cutoff value between the low and high malignant potential groups was 4.05 cm, and the sensitivity and specificity were 93.5% and 84.2%, respectively. CONCLUSION: CT features, including tumor size, growth patterns, and lesion contours, were predictors of malignant potential for primary gastric GISTs.

The transcription factor XBP1 in dendritic cells promotes the TH2 cell response in airway allergy.

Dendritic cells (DCs) that express T cell immunoglobulin domain molecule-4 (TIM4), a cell surface receptor for phosphatidylserine, induce T helper 2 (TH2) cell responses and allergic reactions. We elucidated the role of the transcription factor X-box-binding protein-1 (XBP1) in the induction of the TH2 cell response through its role in generating TIM4+ DCs. We found that XBP1 was required for TIM4 mRNA and protein expression in airway DCs in response to the cytokine interleukin-2 (IL-2) and that this pathway was required for TIM4 expression on DCs in response to the allergens PM2.5 and Derf1. The IL-2-XBP1-TIM4 axis in DCs contributed to Derf1/PM2.5-induced, aberrant TH2 cell responses in vivo. An interaction between the guanine nucleotide exchange factor Son of sevenless-1 (SOS1) and the GTPase RAS promoted XBP1 and TIM4 production in DCs. Targeting the XBP1-TIM4 pathway in DCs prevented or alleviated experimental airway allergy. Together, these data suggest that XBP1 is required for TH2 cell responses by inducing the development of TIM4+ DCs, which depends on the IL-2-XBP1-SOS1 axis. This signaling pathway provides potential therapeutic targets for the treatment of TH2 cell-dependent inflammation or allergic diseases.

Comparing the effectiveness and safety of Sorafenib plus TACE with Apatinib plus TACE for treating patients with unresectable hepatocellular carcinoma: a multicentre propensity score matching study.

OBJECTIVE: Local combined systemic therapy has been an important method for the treatment of unresectable hepatocellular carcinoma (HCC).The purpose of this study was to compare the effectiveness and safety of transarterial chemoembolization (TACE) plus Sorafenib versus TACE plus Apatinib for treating patients with unresectable HCC. METHODS: The clinical data of patients with unresectable HCC who were treated with TACE plus Sorafenib or TACE plus Apatinib at 5 Chinese medical centers between January 2016 and December 2020 were retrospectively analyzed. Propensity score matching (PSM) was applied to reduce the bias from confounding factors. RESULTS: A total of 380 patients were enrolled, of whom 129 cases were treated with TACE plus Sorafenib and 251 cases with TACE plus Apatinib. After the 1:1 PSM, 116 pairs of patients were involved in this study. The results showed that the PFS and OS in the TACE-Sorafenib group were significantly longer than those in the TACE-Apatinib group (PFS: 16.79 ± 6.45 vs. 14.76 ± 6.98 months, P = 0.049; OS: 20.66 ± 6.98 vs. 17.69 ± 6.72 months, P = 0.013). However, the ORR in the TACE-Apatinib group was markedly higher than that in the TACE-Sorafenib group (70.69% vs. 56.03%, P = 0.021). There were more patients with adverse events (AEs) in the TACE-Apatinib group than those in the TACE-Sorafenib group before dose adjustment (87 vs. 63, P = 0.001); however, the number of patients who suffered from AEs was not significantly different between the two groups after the dose adjustment (62 vs. 55, P = 0.148). No treatment-related death was found in the two groups. Subgroup analysis revealed that patients with unresectable HCC could better benefit from regular doses than reduced doses (Sorafenib, 22.59 vs. 18.02, P < 0.001; Apatinib, 19.75 vs. 16.86, P = 0.005). CONCLUSION: TACE plus either Sorafenib or Apatinib could effectively treat patients with unresectable HCC, the safety of TACE plus Sorafenib was better. and the ORR of TACE plus Apatinib was higher.

Effectiveness of lenvatinib plus immune checkpoint inhibitors in primary advanced hepatocellular carcinoma beyond oligometastasis.

BACKGROUND: Targeted therapy combined with immune checkpoint inhibitors is considered a promising treatment for primary advanced hepatocellular carcinoma (HCC). Nevertheless, the difference between synchronous and asynchronous treatment of lenvatinib with programmed death receptor-1 (PD-1) inhibitor in advanced HCC is still unclear. The aim of this investigation is to evaluate the effectiveness of synchronous and asynchronous of lenvatinib and PD-1 inhibitor on the advanced HCC beyond oligometastasis. METHODS: In this study, 213 patients from four institutions in China were involved. Patients were split into two collections: (1) lenvatinib plus PD-1 inhibitor were used synchronously (synchronous treatment group); (2) patients in asynchronous treatment group received PD-1 inhibitor after 3 months of lenvatinib treatment prior to tumour progression. To analyse progression-free survival (PFS), overall survival (OS), efficacy and safety of patients in both groups, we employed propensity score matching (PSM). RESULTS: The 6-, 12- and 24-month OS rates were 100%, 93.4% and 58.1% in the synchronous treatment group and 100%, 71.5% and 25.3% in the asynchronous treatment group, respectively. In contrast to the asynchronous treatment group, the group treated synchronously exhibited a substantially enhanced OS (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.30-0.66; p < .001). The 6-, 12- and 18-month PFS rates were 82.6%, 42.6% and 10.8% in the synchronous treatment group and 63.3%, 14.2% and 0% in the asynchronous treatment group, respectively. A significant difference was observed in the PFS rate (HR, 0.46; 95% CI, 0.33-0.63; p < .001) between the two collections. CONCLUSIONS: Patients with advanced HCC beyond oligometastasis, simultaneous administration of lenvatinib and PD-1 inhibitor led to significant improvements in survival.

The Role of Purine Metabolism-Related Genes PPAT and IMPDH1 in the Carcinogenesis of Intrahepatic Cholangiocarcinoma Based on Metabonomic and Bioinformatic Analyses.

In this study, we investigated the role of tumor microenvironment and serum differential metabolites in intrahepatic cholangiocarcinoma (ICC) carcinogenesis, providing new evidence for ICC treatment. Serum samples from healthy individuals and ICC patients were collected for metabolomic analysis. The purine metabolites such as inosine, guanosine, hypoxanthine, and xanthine were increased in patient serum. TCGA database samples were collected, and the correlation between purine metabolism-related genes and ICC clinical features was analyzed using R language to obtain the differential genes including PPAT, PFAS, ATIC, and IMPDH2. High PPAT expression was associated with poor ICC prognosis. A PPAT silencing model in HCCC-9810 cells was constructed. The cell phenotype was examined by qRT-PCR, CCK-8, transwell, and flow cytometry, showing a decrease in IMPDH1 expression, colony and invasive cells numbers, and an increase in apoptosis. Guanosine reversed IMPDH1 expression in HCCC-9810 cells, promoting the secretion of inflammatory factors IL-6, IL-8, OPN, VEGF, and VCAM-1 and intensifying epithelial-mesenchymal transition (EMT) progression in the cells. In nude mice, the IMPDH1 inhibitory drug MMF inhibited tumor growth and reduced the expression of tumor stem cell characteristic markers CD133 and SOX2. Guanosine accelerated the malignant progression of ICC inhibition of purine metabolism-related genes, PPAT and IMPDH2, suppressed the malignant phenotype in HCCC-9810 cells, and inhibited tumor growth.

Efficacy of radiofrequency ablation following transarterial chemoembolisation combined with sorafenib for intermediate stage recurrent hepatocellular carcinoma: a retrospective, multicentre, cohort study.

Background: The evidence of radiofrequency ablation (RFA) following transarterial chemoembolisation (TACE) combined with sorafenib for intermediate-stage recurrent hepatocellular carcinoma (RHCC) is limited. Patient responses to this treatment vary because of the heterogeneous nature of RHCC, making it important to identify patients who are most likely to benefit from this combination therapy. The aim of this study was to evaluate the efficacy of RFA following TACE and sorafenib for the intermediate-stage RHCC. Methods: This retrospective, multicentre, cohort study included 363 patients with intermediate-stage RHCC underwent TACE combined with sorafenib (TACE-sorafenib group) or RFA following TACE and sorafenib (TACE-sorafenib + RFA group) between January 01, 2009 to December 31, 2015 from four institutions in China. Overall survival (OS), progression-free survival (PFS) and efficacy of patients were compared between the two groups by propensity score-matching (PSM). Findings: The 1-, 3-, and 5-year OS rates were 97.7%, 83.7%, 54.7% in TACE-sorafenib + RFA group, and 93.3%, 57.0%, 32.7% in TACE-sorafenib group. The 1-, 2-, and 3-year PFS rates were 85.3%, 58.0%, 26.9% in TACE-sorafenib + RFA group, and 55.3%, 30.7%, 15.3% in TACE-sorafenib group. Compared with the TACE-sorafenib group, the TACE-sorafenib + RFA group had significantly longer OS (HR, 0.54; 95%CI, 0.40-0.73; P < 0.001) and PFS (HR, 0.52; 95% CI, 0.41-0.66; P < 0.001). Subgroup analysis was conducted to precisely screen out the beneficial population from RFA treatment. Interpretation: Our findings suggest that addition of RFA following TACE and sorafenib combination was superior to TACE combined with sorafenib for intermediate-stage RHCC, resulting in longer OS and PFS. Patients who had good response to TACE and achieved downstaging successfully could not benefit from the RFA therapy. Funding: This research was funded by National Natural Science Foundation of China (No. 81627803), Chen Xiao-Ping Science and Technology Development Fund (CXPJJH1200009-06).

A nomogram for preoperative prediction of lymph node metastasis in patients with intrahepatic cholangiocarcinoma based on inflammation-related markers / 中华外科杂志

Objectives: To construct a nomogram for prediction of intrahepatic cholangiocarcinoma (ICC) lymph node metastasis based on inflammation-related markers,and to conduct its clinical verification. Methods: Clinical and pathological data of 858 ICC patients who underwent radical resection were retrospectively collected at 10 domestic tertiary hospitals in China from January 2010 to December 2018. Among the 508 patients who underwent lymph node dissection,207 cases had complete variable clinical data for constructing the nomogram,including 84 males,123 females,109 patients≥60 years old,98 patients<60 years old and 69 patients were pathologically diagnosed with positive lymph nodes after surgery. Receiver operating characteristic curve was drawn to calculate the accuracy of preoperative imaging examinations to determine lymph node status,and the difference in overall survival time was compared by Log-rank test. Partial regression squares and statistically significant preoperative variables were screened by backward stepwise regression analysis. R software was applied to construct a nomogram,clinical decision curve and clinical influence curve,and Bootstrap method was used for internal verification. Moreover,retrospectively collecting clinical information of 107 ICC patients with intraoperative lymph node dissection admitted to 9 tertiary hospitals in China from January 2019 to June 2021 was for external verification to verify the accuracy of the nomogram. 80 patients with complete clinical data but without lymph node dissection were divided into lymph node metastasis high-risk group and low-risk group according to the score of the nomogram among the 858 patients. Log-rank test was used to compare the overall survival of patients with or without lymph node metastasis diagnosed by pathology. Results: The area under the curve of preoperative imaging examinations for lymph node status assessment of 440 patients was 0.615,with a false negative rate of 62.8% (113/180) and a false positive rate of 14.2% (37/260). The median survival time of 207 patients used to construct a nomogram with positive or negative postoperative pathological lymph node metastases was 18.5 months and 27.1 months,respectively (P<0.05). Five variables related to lymph node metastasis were screened out by backward stepwise regression analysis,which were combined calculi,neutrophil/lymphocyte ratio,albumin,liver capsule invasion and systemic immune inflammation index,according to which a nomogram was constructed with concordance index(C-index) of 0.737 (95%CI: 0.667 to 0.806). The C-index of external verification was 0.674 (95%CI:0.569 to 0.779). The calibration prediction curve was in good agreement with the reference curve. The results of the clinical decision curve showed that when the risk threshold of high lymph node metastasis in the nomogram was set to about 0.32,the maximum net benefit could be obtained by 0.11,and the cost/benefit ratio was 1∶2. The results of clinical influence curve showed that when the risk threshold of high lymph node metastasis in the nomogram was set to about 0.6,the probability of correctly predicting lymph node metastasis could reach more than 90%. There was no significant difference in overall survival time between patients with high/low risk of lymph node metastasis assessed by the nomogram and those with pathologically confirmed lymph node metastasis or without lymph node metastasis (Log-rank test:P=0.082 and 0.510,respectively). Conclusion: The prediction accuracy of preoperative nomogram for ICC lymph node metastasis based on inflammation-related markers is satisfactory,which can be used as a supplementary method for preoperative diagnosis of lymph node metastasis and is helpful for clinicians to make personalized decision of lymph node dissection for patients with ICC.

Survival analysis of patients with intrahepatic cholangiocarcinoma treated with adjuvant chemotherapy after radical resection based on CoxPH model and deep learning algorithm / 中华外科杂志

Objective: To establish a predictive model for survival benefit of patients with intrahepatic cholangiocarcinoma (ICC) who received adjuvant chemotherapy after radical resection. Methods: The clinical and pathological data of 249 patients with ICC who underwent radical resection and adjuvant chemotherapy at 8 hospitals in China from January 2010 to December 2018 were retrospectively collected. There were 121 males and 128 females,with 88 cases>60 years old and 161 cases≤60 years old. Feature selection was performed by univariate and multivariate Cox regression analysis. Overall survival time and survival status were used as outcome indicators,then target clinical features were selected. Patients were stratified into high-risk group and low-risk group,survival differences between the two groups were analyzed. Using the selected clinical features, the traditional CoxPH model and deep learning DeepSurv survival prediction model were constructed, and the performance of the models were evaluated according to concordance index(C-index). Results: Portal vein invasion, carcinoembryonic antigen>5 μg/L,abnormal lymphocyte count, low grade tumor pathological differentiation and positive lymph nodes>0 were independent adverse prognostic factors for overall survival in 249 patients with adjuvant chemotherapy after radical resection (all P<0.05). The survival benefit of adjuvant chemotherapy in the high-risk group was significantly lower than that in the low-risk group (P<0.05). Using the above five features, the traditional CoxPH model and the deep learning DeepSurv survival prediction model were constructed. The C-index values of the training set were 0.687 and 0.770, and the C-index values of the test set were 0.606 and 0.763,respectively. Conclusion: Compared with the traditional Cox model, the DeepSurv model can more accurately predict the survival probability of patients with ICC undergoing adjuvant chemotherapy at a certain time point, and more accurately judge the survival benefit of adjuvant chemotherapy.

Long noncoding RNA ZNFX1-AS1 promotes the invasion and proliferation of gastric cancer cells by regulating LIN28 and CAPR1N1.

BACKGROUND: Long noncoding RNA (lncRNA) ZNFX1-AS1 (ZFAS1) is a newly discovered lncRNA, but its diagnostic value in gastric cancer is unclear. AIM: To investigate the potential role of ZFAS1 in gastric cancer and to evaluate the clinical significance of ZFAS1 as a biomarker for gastric cancer screening. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to screen for gastric cancer-associated lncRNAs in gastric cancer patients, gastric stromal tumor patients, gastritis or gastric ulcer patients, and healthy controls. Correlations between ZFAS1 expression and clinicopathological features were analyzed. The biological effects of ZFAS1 on the proliferation, migration, and invasion of gastric cancer cells were studied by MTT, colony formation, and transwell mi-gration assays. The potential mechanism of ZFAS1 was demonstrated using enzyme-linked immunosorbent assay and qRT-PCR. The relationship between ZFAS1 and tumorigenesis was demonstrated using in vivo tumor formation assays. RESULTS: The plasma level of lncRNA ZFAS1 was significantly higher in preoperative patients with gastric cancer than in individuals in the other 4 groups. Increased expression of ZFAS1 was significantly associated with lymph node metastasis, advanced TNM stage, and poor prognosis. ZFAS1 regulated the proliferation, migration, and invasion of gastric cancer cells and regulated the growth of gastric cancer cells in vivo. LIN28 and CAPRIN1 were identified as key downstream mediators of ZFAS1 in gastric cancer cells. CONCLUSION: LncRNA ZFAS1 promoted the invasion and proliferation of gastric cancer cells by modulating LIN28 and CAPRIN1 expression, suggesting that ZFAS1 can be used as a potential diagnostic and prognostic biomarker in gastric cancer.

An eosinophil-Sos1-RAS axis licenses corticosteroid resistance in patients with allergic rhinitis.

BACKGROUND: Corticosteroid resistance (CR) is a serious disadvantage in treating many chronic inflammatory conditions. Eosinophils are the main inflammation cells in allergic reactions. Environmental pollution, such as PM2.5, is associated with the pathogenesis of allergic disorders. The objective of this study is to elucidate the mechanism by which the exposure to PM2.5 confers eosinophil CR status. METHODS: Patients with allergic rhinitis were recruited and assigned to corticosteroid sensitive (CS) and CR groups. Eosinophils were purified from nasal lavage fluids collected from patients with allergic rhinitis. A murine AR mouse model was developed with dust mite allergens and PM2.5 as the sensitization reagents. RESULTS: CR status was detected in about 60% eosinophil collected in patients with AR. Upon exposure to eosinophil activators, CS eosinophils released a large quantity of mediators, which was suppressed by the presence of steroids in the culture. CR eosinophils demonstrated resistance to steroidal therapy. RAS activation levels in eosinophils were higher in CR eosinophils than in CS eosinophils. Higher expression of the Son of sevenless-1 (Sos1) was detected in CR eosinophils, which formed a complex with RAS and glucocorticoidreceptor-α in CR eosinophils to prevent the binding between steroids and glucocorticoidreceptor-α. The presence of an Sos1 inhibitor dissociated glucocorticoid receptor-α from RAS/Sos1 complex, that restored the sensitivity to steroids in eosinophils. Administering the Sos1 inhibitor effectively attenuated the experimental allergic rhinitis. CONCLUSIONS: CR status was detected in approximately 1/3 eosinophils sampled from patients with allergic rhinitis. Sos1 was instrumental in the development and perseverance of CR in eosinophils. Sos1 inhibition restored sensitivity to steroids in CR eosinophils, which effectively reduced experimental allergic rhinitis.

Kinase inhibitor-induced cardiotoxicity assessed in vitro with human pluripotent stem cell derived cardiomyocytes.

Many small molecule kinase inhibitors (SMKIs), used predominantly in cancer therapy, have been implicated in serious clinical cardiac adverse events, which means that traditional preclinical drug development assays were not sufficient for identifying these cardiac liabilities. To improve clinical cardiac safety predictions, the effects of SMKIs targeting many different signaling pathways were studied using human pluripotent stem cell derived cardiomyocytes (hPSC-CMs) in combined assays designed for the detection of both electrophysiological (proarrhythmic) and non-electrophysiological (non-proarrhythmic) drug-induced cardiotoxicity. Several microplate-based assays were used to quantitate cell death, apoptosis, mitochondrial damage, energy depletion, and oxidative stress as mechanism-based non-electrophysiological cardiomyocyte toxicities. Microelectrode arrays (MEA) were used to quantitate in vitro arrhythmic events (iAEs), field potential duration (FPD) prolongation, and spike amplitude suppression (SAS) as electrophysiological effects. To enhance the clinical relevance, SMKI-induced cardiotoxicities were compared by converting drug concentrations into multiples of reported clinical maximum therapeutic plasma concentration, "FoldCmax", for each assay. The results support the conclusion that the combination of the hPSC-CM based electrophysiological and non-electrophysiological assays have significantly more predictive value than either assay alone and significantly more than the current FDA-recommended hERG assay. In addition, the combination of these assays provided mechanistic information relevant to cardiomyocyte toxicities, thus providing valuable information on potential drug-induced cardiotoxicities early in drug development prior to animal and clinical testing. We believe that this early information will be helpful to guide the development of safer and more cost-effective drugs.

Impact of adjuvant chemotherapy on prognosis in intrahepatic cholangiocarcinoma patients underwent radical resection / 中华外科杂志

Objectives: To investigate the clinical value of adjuvant chemotherapy(ACT) in patients with intrahepatic cholangiocarcinoma(ICC) who underwent radical resection and to explore the optimal population that can benefit from ACT. Methods: A retrospective cohort study method was adopted. The clinical and pathological data of 685 patients with ICC who underwent curative intent resection in 10 Chinese hepatobiliary surgery centers from January 2010 to December 2018 were collected;There were 355 males and 330 females. The age(M(IQR)) was 58(14) years (range: 22 to 83 years). Propensity score matching(PSM) was applied to balance the differences between the adjuvant and non-adjuvant chemotherapy groups. Log-rank test was used to compare the prognosis of the two groups of patients. A Bayesian network recurrence-free survival(RFS) prediction model was constructed using the median RFS time (14 months) as the target variable, and the importance of the relevant prognostic factors was ranked according to the multistate Birnbaum importance calculation. A survival prognostic prediction table was established to analyze the population benefiting from adjuvant chemotherapy. Results: Among 685 patients,214 received ACT and 471 did not receive ACT. A total of 124 pairs of patients were included after PSM, and patients in the ACT group had better overall survival (OS) and RFS than those in the non-ACT group(OS: 32.2 months vs. 18.0 months,P=0.003;RFS:18.0 months vs. 10.0 months,P=0.001). The area under the curve of the Bayesian network RFS prediction model was 0.7124. The results of the prognostic factors in order of importance were microvascular invasion (0.158 2),perineural invasion (0.158 2),N stage (0.155 8),T stage (0.120 9), hepatic envelope invasion (0.090 3),adjuvant chemotherapy (0.072 1), tumor location (0.057 5), age (0.042 3), pathological differentiation (0.034 0), sex (0.029 3), alpha-fetoprotein (0.028 9) and preoperative jaundice (0.008 5). A survival prediction table based on the variables with importance greater than 0.1 (microvascular invasion,perineural invasion,N stage,T staging) and ACT showed that all patients benefited from ACT (increase in the probability of RFS≥14 months from 2.21% to 7.68%), with a more significant increase in the probability of RFS≥14 months after ACT in early-stage patients. Conclusion: ACT after radical resection in patients with ICC significantly prolongs the OS and RFS of patients, and the benefit of ACT is greater in early patients.

Effect of Three Microbial Fertilizers on Growth，Yield，Quality and Cadmium Accumulation of Chuanxiong Rhizoma / 中国实验方剂学杂志

ObjectiveTo explore the effects of three kinds of microbial fertilizers on the growth， yield， quality， and cadmium （Cd） accumulation of Chuanxiong Rhizoma （CX）. MethodTaking CX seeds as materials， field experiments were carried out in the main producing areas， Pengzhou and Meishan. The samples were collected during the harvesting period， and the agronomic characters and yield were determined. The contents of extract， volatile oil， and ferulic acid were analyzed by the collection method of Chinese Pharmacopoeia （2020 edition）. The content of Cd was determined by inductively coupled plasma-mass spectrometry （ICP-MS）. Data were processed by difference significance analysis， correlation analysis and cluster analysis. ResultThree kinds of microbial fertilizers with appropriate concentrations could promote the growth of CX. In terms of yield and quality， the treatment of Jinwuzong （1.50 ton/hm2， 1 ton=1 000 kg， the same below） and Cuijingyuan （1.5 L·hm-2） could increase the yield of medicinal materials by 0.92%-46.34%， while Cuijingyuan （1.8 L·hm-2） and Shenchu （15， 30 kg·hm-2） could increase the water-soluble extract of CX by 0.06%-18.79%， of which Cuijingyuan （1.8 L·hm-2） was significantly increased （P<0.01）. The alcohol-soluble extract of CX treated with Jinwuzong （0.75， 1.50， 2.25 ton/hm2）， Shenchu （15， 45 kg·hm-2）， and Cuijingyuan （1.2 L·hm-2） decreased significantly by 3.51%-22.94% （P<0.01）. The content of ferulic acid in CX treated with Jinwuzong （1.50 ton/hm2） and Shenchu （30 kg·hm-2） decreased by 2.14%-30.56%. Three kinds of microbial fertilizers had little effect on the content of volatile oil in CX. In the aspect of Cd enrichment， the concentration of Cd in rhizosphere soil of CX was increased by 11.33%-76.36% （P<0.01） after the treatment of Jinwuzong （0.75， 1.50， 2.25 ton/hm2）， Shenchu （15， 30， 45 kg·hm-2） and Cuijingyuan （1.2 L·hm-2）. However， the Cd enrichment coefficient of CX reduced by 2.58%-48.38%， the Cd content and Cd accumulation of CX decreased respectively by 9.54%-25.96% and 9.34%-18.88% via Jinwuzong （0.75 ton/hm2） and Cuijingyuan （1.8 L·hm-2）. ConclusionThree kinds of microbial fertilizers have a certain positive effect on the growth， substance accumulation， and reduction of Cd content in medicinal parts of CX， and the changes of each index are affected by the producing area and treatment method. Based on the comprehensive analysis of various indicators， Jinwuzong （0.75， 1.50 ton/hm2） can better adapt to the rhizosphere soil micro-ecological environment of CX， it can effectively reduce the content of Cd on the premise of guaranteeing the yield and quality of CX.

Early and late recurrences in lymph node-negative gastric cancer: a retrospective cohort study.

BACKGROUND: Predictors of recurrence in patients with lymph node-negative gastric cancer (GC) who have undergone curative resection have been widely investigated, but not the effects of predictors on timing of recurrence. OBJECTIVE: Determine the factors associated with early and late recurrence in patients with node-negative GC. DESIGN: Retrospective cohort. SETTING: Academic tertiary care center. PATIENTS AND METHODS: The study included patients with node-negative GC after curative resection between 2008 and 2018 at two institutions. Early and late recurrences were determined using a minimum P value approach to evaluate the optimal cutoff for recurrence-free survival (RFS). A competing risk model and landmark analysis were used to analyze factors associated with early and late recurrences. MAIN OUTCOME MEASURES: Recurrence-free survival and factors associated with survival. SAMPLE SIZE: 606. RESULTS: After a median follow-up of 70 months, 50 (8.3%) patients experienced recurrent disease. The optimal length of RFS for distinguishing between early (n=26) and late recurrence (n=24) was 24 months (P=.0013). The median RFS in the early and late recurrence groups was 11 and 32 months, respectively. Diffuse tumors (hazard ratio 3.358, P=.014), advanced T stage (HR 8.804, P=.003), perineural invasion (HR 10.955, P<.001), and anemia (HR 2.351, P=.018) were independent predictors of early recurrence. Mixed tumor location (HR 5.586, P=.002), advanced T stage (HR 5.066, P<.001), lymphovascular invasion (HR 5.902, P<.001), and elevated CA19-9 levels (HR 5.227, P<.001) were independent predictors of late recurrence. Similar results were obtained in the landmark analysis. CONCLUSIONS: Individualized therapeutic and follow-up strategies should be considered in future studies because of distinct patterns in predictors of early and late recurrence. LIMITATIONS: Retrospective design, small sample size. CONFLICT OF INTEREST: None.

The Efficacy and Prognostic Factors of the Combination of TACE and Apatinib for the Treatment of BCLC Stage C Hepatocellular Carcinoma.

Objective: Apatinib is a inhibitor of vascular endothelial growth factor receptor-2. To explore the efficacy and prognostic factors of transarterial chemoembolization (TACE) combined with apatinib in the treatment of Barcelona Clinic Liver Cancer stage C (BCLC C) hepatocellular carcinoma (HCC). Methods: Clinical data of 146 HCC patients with BCLC stage C admitted to our hospital were collected and analyzed retrospectively, of which 76 cases were treated with TACE combined with apatinib (TACE-apatinib) and 70 with TACE alone. The tumor response, survival time, and adverse events were compared between the two groups, and the factors affecting the prognosis were analyzed. Results: The objective response rate (ORR) and disease control rate (DCR) in the TACE-apatinib group were higher than in the TACE-alone group (ORR: 42.10 vs. 25.71%, P = 0.03; DCR: 84.21 vs. 55.71%, P = 0.001). The median time to progression (TTP) and overall survival (OS) in the TACE-apatinib group were longer than in the TACE-alone group (TTP: 5.5 vs. 3.7 months, P = 0.02; OS: 10.0 vs. 6.2 months, P = 0.01). Univariate and multivariate Cox regression analysis showed that tumor size, Child-Pugh class, and the presence of the portal vein tumor thrombus affect the prognosis of patients. Subgroup analysis revealed that TACE-apatinib therapy resulted in a higher OS in patients with tumor size <10 cm, without portal vein tumor thrombus, and with Child-Pugh class A (P < 0.05). The likelihood of adverse events (hand-foot syndrome, hypertension, oral ulcer) was significantly higher in the increased in the TACE-apatinib group than in the TACE alone group (P < 0.05). Conclusion: TACE-apatinib is an effective and safe method for the treatment of BCLC stage C HCC. Tumor size, Child-Pugh class, and portal vein tumor thrombus affect survival time in HCC patients with BCLC stage C.

Cellulase production and efficient saccharification of biomass by a new mutant Trichoderma afroharzianum MEA-12.

BACKGROUND: Cellulase plays a key role in converting cellulosic biomass into fermentable sugar to produce chemicals and fuels, which is generally produced by filamentous fungi. However, most of the filamentous fungi obtained by natural breeding have low secretory capacity in cellulase production, which are far from meeting the requirements of industrial production. Random mutagenesis combined with adaptive laboratory evolution (ALE) strategy is an effective method to increase the production of fungal enzymes. RESULTS: This study obtained a mutant of Trichoderma afroharzianum by exposures to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), Ethyl Methanesulfonate (EMS), Atmospheric and Room Temperature Plasma (ARTP) and ALE with high sugar stress. The T. afroharzianum mutant MEA-12 produced 0.60, 5.47, 0.31 and 2.17 IU/mL FPase, CMCase, pNPCase and pNPGase, respectively. These levels were 4.33, 6.37, 4.92 and 4.15 times higher than those of the parental strain, respectively. Also, it was found that T. afroharzianum had the same carbon catabolite repression (CCR) effect as other Trichoderma in liquid submerged fermentation. In contrast, the mutant MEA-12 can tolerate the inhibition of glucose (up to 20 mM) without affecting enzyme production under inducing conditions. Interestingly, crude enzyme from MEA-12 showed high enzymatic hydrolysis efficiency against three different biomasses (cornstalk, bamboo and reed), when combined with cellulase from T. reesei Rut-C30. In addition, the factors that improved cellulase production by MEA-12 were clarified. CONCLUSIONS: Overall, compound mutagenesis combined with ALE effectively increased the production of fungal cellulase. A super-producing mutant MEA-12 was obtained, and its cellulase could hydrolyze common biomasses efficiently, in combination with enzymes derived from model strain T. reesei, which provides a new choice for processing of bioresources in the future.

Multiple Mutation Detection for Risk Assessment in Patients with Breast Cancer by Using Next-Generation Sequencing.

OBJECTIVE: Breast cancer is recognized as the most common cause of malignancy and cancer death worldwide; however, mutations in the cancer-related BRCA genes are detected in only 2-3% of patients with breast cancer. Because next-generation sequencing technology allows concurrent sequencing of numerous target genes, diverse cancer-susceptibility genes are now being evaluated, although their significance in clinical practice remains unclear. METHODS: In this study, we developed a sequencing panel containing the genes BRCA1, BRCA2, TP53, PIK3CA, ERBB2 (Her2), and PTEN, which are all associated with cancer risk in patients, and we enrolled 60 patients with breast cancer. RESULTS: Germline mutations were found to be carried by nine patients (15%): 3 in BRCA1, 5 in BRCA2, and 1 in TP53. The patients harboring these mutations are considered to face a high risk of developing malignant tumors, and cancer screening is thus recommended for the patients. CONCLUSION: This study demonstrates the feasibility of using Ion Torrent sequencing technology for reliably detecting gene mutations in clinical practice for guiding individualized drug therapy or combination therapies for breast cancer.