Salvianolic acid B inhibits thrombosis and directly blocks the thrombin catalytic site.

Background: Salvianolic acid B (SAB) is a major component of Salvia miltiorrhiza root (Danshen), widely used in East/Southeast Asia for centuries to treat cardiovascular diseases. Danshen depside salt, 85% of which is made up of SAB, is approved in China to treat chronic angina. Although clinical observations suggest that Danshen extracts inhibited arterial and venous thrombosis, the exact mechanism has not been adequately elucidated. Objective: To delineate the antithrombotic mechanisms of SAB. Methods: We applied platelet aggregation and coagulation assays, perfusion chambers, and intravital microscopy models. The inhibition kinetics and binding affinity of SAB to thrombin are measured by thrombin enzymatic assays, intrinsic fluorescence spectrophotometry, and isothermal titration calorimetry. We used molecular in silico docking models to predict the interactions of SAB with thrombin. Results: SAB dose-dependently inhibited platelet activation and aggregation induced by thrombin. SAB also reduced platelet aggregation induced by adenosine diphosphate and collagen. SAB attenuated blood coagulation by modifying fibrin network structures and significantly decreased thrombus formation in mouse cremaster arterioles and perfusion chambers. The direct SAB-thrombin interaction was confirmed by enzymatic assays, intrinsic fluorescence spectrophotometry, and isothermal titration calorimetry. Interestingly, SAB shares key structural similarities with the trisubstituted benzimidazole class of thrombin inhibitors, such as dabigatran. Molecular docking models predicted the binding of SAB to the thrombin active site. Conclusion: Our data established SAB as the first herb-derived direct thrombin catalytic site inhibitor, suppressing thrombosis through both thrombin-dependent and thrombin-independent pathways. Purified SAB may be a cost-effective agent for treating arterial and deep vein thrombosis.

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In the context of rapid urbanization, metropolitan areas are facing the risk of supply-demand mismatches among ecosystem services. Investigating the patterns, relationships, and driving factors of multiple supply-demand risks is of great significance to support the efficient management of regional ecological risks. We quantified the single/comprehensive supply-demand risk rates of six ecosystem services in Wuhan Metropolitan Area at the township scale in 2000, 2010, and 2020. By applying the self-organizing feature map network and optimal parameter geo-detector, we identified supply-demand risks bundles of ecosystem services and influencing factors of comprehensive risks. The results showed significant spatial variations in the supply-demand risks of typical ecosystem services from 2000 to 2020. The supply-demand risk associated with grain production, water yield, carbon sequestration, and green space recreation increased, while soil conservation and water purification risks decreased. The comprehensive ecosystem services supply-demand risk increased from 0.41 to 0.45, indicating a 'core area increase and periphery decrease' trend. Throughout the study period, the area exhibited bundles of comprehensive extremely high-risk bundles (B1), comprehensive high-risk bundles (B2), water purification high-risk bundles (B3), and grain production-soil conservation risk bundles (B4). The transition of risk types from B3 to B2 and from B2 to B1 suggested an increase in the combination and intensity of supply-demand risk. Vegetation cover, nighttime light index, and population density were the main driving factors for spatial variations in comprehensive supply-demand risk. Ecologi-cal risk assessment based on ecosystem services supply-demand bundles could provide an effective and reliable way to regulate multiple regional risk issues.

Selenium Ameliorated Oxidized Fish Oil-Induced Lipotoxicity via the Inhibition of Mitochondrial Oxidative Stress, Remodeling of Usp4-Mediated Deubiquitination, and Stabilization of Pparα.

Aims: Studies demonstrated that oxidized fish oil (OFO) promoted oxidative stress and induced mitochondrial dysfunction and lipotoxicity, which attenuated beneficial effects of fish oil supplements in the treatment of nonalcoholic fatty liver disease (NAFLD). The current study was performed on yellow catfish, a good model to study NAFLD, and its hepatocytes to explore whether selenium (Se) could alleviate OFO-induced lipotoxicity via the inhibition of oxidative stress and determine its potential mechanism. Results: The analysis of triglycerides content, oxidative stress parameters, and histological and transmission electronic microscopy observation showed that high dietary Se supplementation alleviated OFO-induced lipotoxicity, oxidative stress, and mitochondrial injury and dysfunction. RNA-sequencing and immunoblotting analysis indicated that high dietary Se reduced OFO-induced decline of peroxisome-proliferator-activated receptor alpha (Pparα) and ubiquitin-specific protease 4 (Usp4) protein expression. High Se supplementation also alleviated OFO-induced reduction of thioredoxin reductase 2 (txnrd2) messenger RNA (mRNA) expression level and activity. The txnrd2 knockdown experiments revealed that txnrd2 mediated Se- and oxidized eicosapentaenoic acid (oxEPA)-induced changes of mitochondrial reactive oxygen species (mtROS) and further altered Usp4 mediated-deubiquitination and stabilization of Pparα, which, in turn, modulated mitochondrial fatty acid ß-oxidation and metabolism. Mechanistically, Usp4 deubiquitinated Pparα and ubiquitin-proteasome-mediated Pparα degradation contributed to oxidative stress-induced mitochondrial dysfunction. Innovation: These findings uncovered a previously unknown mechanism by which Se and OFO interacted to affect lipid metabolism via the Txnrd2-mtROS-Usp4-Pparα pathway, which provides the new target for NAFLD prevention and treatment. Conclusion: Se ameliorated OFO-induced lipotoxicity via the inhibition of mitochondrial oxidative stress, remodeling of Usp4-mediated deubiquitination, and stabilization of Pparα. Antioxid. Redox Signal. 40, 433-452.

Lobe-specific analysis of perioperative chemotherapy for non-small cell lung cancer patients.

OBJECTIVES: Perioperative cisplatin-based chemotherapy decreases the risk of death over surgery alone and is a standard of care. Here, we examined perioperative chemotherapy indications for stage IB-III non-small cell lung cancer (NSCLC) patients according to lobe-specific analysis. METHODS: Resectable NSCLC patients with stage IB-III who received perioperative chemotherapy with and without radiotherapy after lung resection were identified from the SEER database. Propensity score matching (PSM) analysis was performed to reduce the inherent bias of retrospective studies. The Kaplan-Meier method and log-rank tests were used to assess the differences in overall survival (OS). RESULTS: The study enrolled 23,844 patients before PSM. The perioperative chemotherapy group had better OS than the nonperioperative chemotherapy group in stage IB-III NSCLC patients before and after PSM. However, subgroup analysis according to stage demonstrated that perioperative chemotherapy did not markedly benefit patients with stage IB. Furthermore, lobar subgroup analysis did not show survival advantages in primary tumors located in either the right middle lobe in stages II and III NSCLC or the right lower lobe in stage III NSCLC. CONCLUSIONS: Lobe-specific perioperative chemotherapy is recommended in NSCLC patients. For stage IB NSCLC, right middle lobe NSCLC from stage IB-III and right lower lobe NSCLC from stage III, perioperative chemotherapy might not confer survival benefits.

Characterization and tissue expression of twelve selenoproteins in yellow catfish Pelteobagrus fulvidraco fed diets varying in oxidized fish oil and selenium levels.

BACKGROUND: Selenium (Se) functions through selenoproteins and is essential to growth and metabolism of vertebrates. The present study was conducted to identify twelve selenoproteins genes (selenoe, selenof, selenoh, selneoi, selenom, selenok, selneon, selenoo, selenot, selenos, selenou and msrb1) from yellow catfish. Their mRNA expression patterns, as well as their response to dietary oxidized fish oils and Se addition were explored. METHODS: We use 3'and 5' RACE PCR to clone full-length cDNA sequence of twelve selenoprotein genes from yellow catfish. Their mRNA expression patterns were assessed via quantitative real-time PCR. Yellow catfish were fed diet adequate Se+ fresh fish oil, adequate Se+ oxidized fish oil, high Se+ fresh fish oil and high Se+ oxidized fish oil, respectively, for 10 weeks. Their kidney, heart, brain and testis were used to assess the mRNA expression of twelve selenoprotein. RESULTS: Twelve selenoprotein genes had similar domains with mammals and the other fish. Their mRNAs were expressed widely in eleven tissues but varied with the tissues. Dietary oxidized fish oils and Se addition influenced their mRNA abundances of twelve selenoproteins in a tissue-dependent manner. CONCLUSION: Our study demonstrated the characterization and expression of twelve selenoproteins, and elucidated their responses in yellow catfish fed diets varying in oxidized fish oils and Se addition, which increased our knowledge into the biological function and regulatory mechanism of Se and selenoproteins in fish.

Case report: Catecholamine cardiomyopathy in children with neuroblastoma.

Introduction: Many endocrine diseases, such as neuroblastoma (NB), can be linked with acquired cardiomyopathy and heart failure. Neuroblastoma's cardiovascular manifestations are typically hypertension, electrocardiogram (ECG) changes, and conduction disturbances. Case Presentation: A 5-year-old 8-month-old girl was admitted to the hospital with ventricular hypertrophy and hypertension (HT) and heart failure. She had no previous history of HT. On color doppler echocardiography, the left atrium and left ventricle were enlarged. The left ventricular ejection fraction (EF) was as low as 40%, and the ventricular septum and left ventricular free wall were thickened. The internal diameters of both coronary arteries were widened. Abdominal computed tomography scan (CT) demonstrated an 8.7 cm × 7.1 cm × 9.5 cm tumor behind the left peritoneum. In urine catecholamines analysis, free-norepinephrine (f-NE), free-dopamine (f-DA), free-normetanephrine (f-NMN), free-3-methoxytyramine (f-3MT), vanillylmandelic acid (VMA), and homovanillic acid (HVA) levels were all greater than the normal range for 24 h except free-metanephrine (f-MN) and free-epinephrine (f-E). Based on these findings, we diagnosed her as NB complicated by catecholamine cardiomyopathy manifested by hypertrophic cardiomyopathy (HCM). Oral metoprolol, spironolactone, captopril and amlodipine furosemide, and intravenously injected sodium nitroprusside and phentolamine were employed for treating HT. After the tumor resection, the blood pressure (BP) and urinary catecholamine levels were all restored. After a follow-up of 7 months, echocardiography indicated normalization of ventricular hypertrophy and function. Conclusion: This is a rare report showing catecholamine cardiomyopathy in NB children. Tumor resection leads to a return to normal of the catecholamine cardiomyopathy manifested as HCM.

Clinical significance of preoperative neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in the prognosis of resected early-stage patients with non-small cell lung cancer: A meta-analysis.

BACKGROUND: Poor prognosis is linked to peripheral blood levels of preoperative platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR) in many advanced cancers. Nevertheless, whether the correlation exists in resected early-stage cases with non-small cell lung cancer (NSCLC) stays controversial. Consequently, we performed a meta-analysis to explore the preoperative NLR and PLR's prognostic significance in early-stage patients with NSCLC undergoing curative surgery. METHODS: Relevant studies that validated the link between preoperative NLR or PLR and survival results were found via the proceeding databases: PubMed, Embase, Cochrane Library, and Web of Science. The merged 95% confidence interval (CI) and hazard ratio (HR) was employed to validate the link between the NLR or PLR's index and overall survival (OS) and disease-free survival (DFS) in resected NSCLC cases. We used sensitivity and subgroup analyses to assess the studies' heterogeneity. RESULTS: An overall of 21 studies were attributed to the meta-analysis. The findings indicated that great preoperative NLR was considerably correlated with poor DFS (HR = 1.58, 95% CI: 1.37-1.82, p < 0.001) and poor OS (HR = 1.51, 95% CI: 1.33-1.72, p < 0.001), respectively. Subgroup analyses were in line with the pooled findings. In aspect of PLR, raised PLR was indicative of inferior DFS (HR = 1.28, 95% CI: 1.04-1.58, p = 0.021) and OS (HR = 1.37, 95% CI: 1.18-1.60, p < 0.001). In the subgroup analyses between PLR and DFS, only subgroups with a sample size <300 (HR = 1.67, 95% CI: 1.15-2.43, p = 0.008) and TNM staging of mixed (I-II) (HR = 1.47, 95% CI: 1.04-2.07, p = 0.028) showed that the link between high PLR and poor DFS was significant. CONCLUSIONS: Preoperative elevated NLR and PLR may act as prognostic biomarkers in resected early-stage NSCLC cases and are therefore valuable for guiding postoperative adjuvant treatment.

Transcriptome Analysis of the Anti-Proliferative Effects of Ginsenoside Rh3 on HCT116 Colorectal Cancer Cells.

The mechanism of ginsenoside Rh3 activity against cancer remains unclear. This study aimed to investigate the underlying mechanism. The effects of Rh3 on the cell proliferation, migration and invasion, and cycle and apoptosis were analyzed using CCK-8 assay, transwell migration assay and flow cytometry, respectively. The RNA transcriptome was sequenced and data were analyzed by R software. Protein expression and protein-protein interactions were determined by Western blotting and co-immunoprecipitation, respectively. The results showed Rh3 inhibited HCT116 cell proliferation, invasion, and migration, arrested cells at G1 phase; and increased apoptosis. Rh3 downregulated 314 genes and upregulated 371 genes. Gene Set Enrichment Analysis (GSEA) using The Kyoto Encyclopedia of Genes Genomics ranked DNA replication first, while GSEA using Gene Ontology ranked the initiation of DNA replication first. Compared with tumor data from The Cancer Genome Atlas (TCGA), most of genes related to DNA replication were oppositely regulated by Rh3. Furthermore, Rh3 down-regulated key protein expression related to DNA replication (Orc6, Cdt1, and Mcm2), but did not affect the loading of Mcm complexes onto ORC complexes nor the phosphorylation at ser139 of Mcm2. Therefore, Rh3 may inhibit colorectal cancer HCT116 cells by downregulation of genes related to DNA replication.

Metastatic pulmonary carcinoids with EML4-ALK fusion response to ALK inhibitors: two case reports and review of literature.

Background: Pulmonary carcinoids (PC), including typical (TC) and atypical carcinoids (AC), are low-grade neuroendocrine tumors (NETs) which account for 1-5% of all lung tumors. Due to the low prevalence of PC and extreme rarity of anaplastic lymphoma kinase (ALK) rearrangements in patients with PC, the advances in targeted therapy development in PC are still limited and there is no standard treatment. Even though in patients with PC harboring ALK rearrangements there is a room for a success in targeted therapy. To our knowledge, case 1 was the first report to detect ALK gene p.I1171N mutation after taking alectinib and sensitive to ceritinib in patients with atypical carcinoid. Case Description: Herein, we report the cases of 2 non-smoking patients, 51 year-old female with tumor in left lower lobe and 49 year-old female with tumor in right upper lobe, both with metastatic PC who harbored EML4-ALK fusion and were sensitive to small-molecule ALK inhibitors. The first patient initially received alectinib, then therapy was switched to ceritinib after developing drug resistance due to the missense mutation of ALK gene p.I1171N mutation in exon 22 detected by next-generation sequencing (NGS), and finally died of intracranial disease progression. The second patient also received alectinib, and her treatment is currently ongoing with good effect and tolerance. After conducting comprehensive review of literature, we found that 14 lung NETs with ALK rearrangements have been reported to date. The clinical outcome was partial response for 6 NETs patients and 5 patients exhibited stable disease after treatment with ALK inhibitors. Conclusions: According to the effectiveness of ALK inhibitors in our cases and previous articles, we recommend alectinib for the first-line treatment of metastatic PC with EML4-ALK fusion and highlight the need for molecular profiling of metastatic lung NETs patients and that ALK inhibitors are feasible in the treatment for metastatic lung NETs patients with ALK rearrangements. Finally, further studies to assess the real prevalence of ALK gene fusions and their spectrum of sensitivity to different ALK inhibitors are needed in larger cohorts.

Lobe-Specific Analysis of Sublobar Lung Resection for NSCLC Patients with Tumors ≤ 2 cm.

(1) Background: Sublobar resection can be used as an alternative surgical strategy for early-stage non-small-cell lung cancer (NSCLC) patients. However, the choice between wedge resection and segmentectomy remains contentious. In this study, we investigated the optimal surgical procedure for sublobar resection in patients with NSCLC ≤ 2 cm with a lobe-specific analysis; (2) Methods: Data for patients with T1N0M0 with a diameter of ≤2 cm who had undergone sublobar resection were retrieved. Propensity score matching (PSM) was used to reduce the inherent bias, and the Kaplan-Meier method and log-rank tests were used to assess the differences in survival; (3) Results: A total of 1882 patients were identified after the PSM. Patients with NSCLC ≤ 2 cm who had undergone segmentectomy showed better survival than those who had undergone wedge resection. However, when NSCLC was ≤1 cm, there was no significant difference in OS between the two groups. This demonstrated an OS advantage of segmentectomy over wedge resection for patients with NSCLC tumors of 1-2 cm (p = 0.024). Further analysis indicated that this survival benefit was only observed in patients with right upper NSCLC of 1-2 cm, but not with NSCLC in the other four lobes; (4) Conclusions: Segmentectomy showed a greater survival benefit than wedge resection only in patients with NSCLC of 1-2 cm, particularly those with primary tumors in the right upper lobe. Therefore, we propose a lobe-specific sublobar resection strategy for early-stage NSCLC patients (tumors of 1-2 cm) who cannot tolerate lobectomy.

Sublobar Resection Versus Lobectomy for Early-Stage Pulmonary Carcinoid Tumors ≤3 cm in Size: A SEER Population-Based Study.

OBJECTIVE: This study aimed to determine the optimal surgical procedure for early-stage pulmonary carcinoids (PCs). BACKGROUND: PCs, comprising typical carcinoids (TCs) and atypical carcinoids (ACs), are rare low-grade malignant tumors. We determine the optimal surgical management for early-stage PCs using data from the Surveillance, Epidemiology, and End Results registry. METHODS: Clinical and survival data of patients with early-stage PC tumors with a diameter ≤3 cm were retrieved. The Kaplan-Meier method and logrank tests were used to assess the differences in overall survival (OS). Subgroup analyses were also performed. To reduce the inherent bias of retrospective studies, two propensity score matching (PSM) analysis with (PSM2) or without (PSM1) consideration of lymph node assessment were performed. RESULTS: In total, 2934 patients with PCs, including 2741 (93.42%) with TCs and 193 (6.58%) with ACs, were recruited. After PSM1 analysis, TC patients in the lobectomy group had a significantly better OS than those in the sublobar resection group ( P = 0.0067), which is more remarkable for patients with a tumor diameter of 2 cm

Use of crizotinib as neoadjuvant therapy for non-small cell lung cancers patient with ROS1 rearrangement: A case report.

Crizotinib showed significant antitumor effect in patients with advanced ROS1-rearranged non-small cell lung cancers (NSCLC). Most recently, many studies have explored the feasibility and efficacy of target therapy for perioperative application in NSCLC. Here, we describe a female patient who was diagnosed with stage IIIB lung adenocarcinoma exhibiting a CCDC6-ROS1 rearrangement by high-throughput sequencing. The tumor and lymph nodes showed durable response after the treatment of crizotinib. Given that a radiological downstaging was indicated, a right lower lobectomy and systemic lymphadenectomy were successfully performed. The pathological response was 60% and the tumor, nodes, and metastases (TNM) stage was ypT2bN0M0. The PD-L1 expression and activity of immunological cells were also investigated.

Frequent Genetic Alterations and Their Clinical Significance in Patients With Thymic Epithelial Tumors.

PURPOSE: Thymic epithelial tumors (TETs) are relatively rare neoplasms, including thymomas (types A, AB, B1, B2, and B3) and thymic carcinomas (TCs). The current knowledge about the biological properties of TETs is limited due to their low incidence. This study aimed to detect genetic alterations in TETs using next-generation sequencing(NGS) and explore their clinical significance in survival. METHODS: Tumor tissues and clinical data were collected from 34 patients with resected TETs in the Tianjin Medical University General Hospital between January 2011 and January 2019, and 56 cancer-associated genes were analyzed. The data of 123 TETs were retrieved from TCGA, and the information on their clinical and somatic mutations was explored. RESULTS: The cohort comprised 34 TETs including 17 thymomas and 17 TCs. The NGS results indicated that 73.08% of TCs+type B3 TETs and 37.50% of non-TCs+type B3 TETs each exhibited gene mutations. For patients with type B3/C, TP53 was the most frequent mutation (19.23%), followed by CDKN2A (11.54%). Similarly, in 123 TETs from the TCGA cohort, TP53 mutations were more frequent in patients with type B3/C than in patients with non-type B3/C (11.53% vs 3.09%). Further, patients with TET with TP53 mutations in the present cohort and the TCGA cohort had a worse prognosis compared with those without TP53 mutations. CONCLUSIONS: Gene mutation profiles between TCs+type B3 TETs and non-TCs+type B3 TETs were significantly different. The presence of TP53 mutations was more frequent in TCs+type B3 TETs than in non-TCs+type B3 TETs, which was associated with a worse prognosis.

Complete disease remission in a TP53 and KRAS co-mutated brain oligometastatic lung cancer patient after immuno-chemotherapy and surgical resection: a case report.

Lung cancer is the most common primary malignancy and tends to metastasize to the brain. A multimodal approach, including systematic therapy (targeted therapy, chemotherapy, immunotherapy) and local consolidative therapy (surgical intervention, radiation therapy, ablation therapy), is essential for treatment of oligometastatic lung cancer. The systemic immunotherapy has been shown to increase response rate and survival, which then has the potential benefit of making localized treatment more feasible for some cases of oligometastatic cancer. We present a 62-year-old male with stage IVB lung adenocarcinoma with five metastases in the brain. Molecular testing exhibited KRAS and TP53 co-mutation, with negative PD-L1 expression. The patient received six cycles of platinum-based chemotherapy plus pembrolizumab and minimally invasive lobectomy, followed by maintenance therapy with pemetrexed and pembrolizumab. The patient achieved complete disease remission, with no sign of recurrence for 22 months post-treatment. Moreover, we investigated PD-L1 expression and infiltration of immunological cells in biopsy tissue and surgical specimen prior to and after immuno-chemotherapy using multiple immunohistochemistry stains. The different infiltration levels of immune cells for TP53 and KRAS co-mutation were also explored using The Cancer Genome Atlas (TCGA) database and Cell type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT). To our knowledge, this is the first reported case in which a brain oligometastatic non-small cell lung carcinoma (NSCLC) patient has achieved a complete response after immuno-chemotherapy plus local surgical resection.

Prognostic value of ferroptosis-related genes in patients with lung adenocarcinoma.

BACKGROUND: The prevalence of lung adenocarcinomas (LUADs) has dramatically increased in recent decades. Ferroptosis is a process of iron-dependent regulatory cell death. It is still unclear whether the expression of ferroptosis-related genes (FRGs) is involved in the pathogenesis and survival of patients with LUAD. METHODS: We retrieved LUAD data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and used LASSO Cox regression analysis to select the gene signature suitable for modeling. The risk score was calculated according to the model, and the patients were divided into high- and low-risk groups according to the median risk score. Functional enrichment analysis was carried out by this group, and a model for predicting clinical prognosis was established by combining this group with clinical factors. RESULTS: Gene set enrichment analysis (GSEA) and single-sample gene set enrichment analysis (ssGSEA) analysis showed that there were several immune-related pathways and immune infiltration differences between high- and low-risk groups. A prognostic model integrating 10 ferroptosis-related genes (FR-DEGs), and clinical factors were constructed and validated in an external cohort. CONCLUSIONS: The FR-DEGs signature was related to immune infiltration, and a model based on FR-DEGs and clinical factors was established to predict the prognosis of patients with LUAD.

Mutations Associated with No Durable Clinical Benefit to Immune Checkpoint Blockade in Non-S-Cell Lung Cancer.

(1) Background: The immune checkpoint blockade (ICB) has shown promising efficacy in non-small-cell lung cancer (NSCLC) patients with significant clinical benefits and durable responses, but the overall response rate to ICBs is only 20%. The lack of responsiveness to ICBs is currently a central problem in cancer immunotherapy. (2) Methods: Four public cohorts comprising 2986 patients with NSCLC were included in the study. We screened 158 patients with NSCLC with no durable clinical benefit (NDB) to ICBs in the Rizvi cohort and identified NDB-related gene mutations in these patients using univariate and multivariate Cox regression analyses. Programmed death-ligand 1 (PD-L1) expression, tumor mutation burden (TMB), neoantigen load, tumor-infiltrating lymphocytes, and immune-related gene expression were analyzed for identifying gene mutations. A comprehensive predictive classifier model was also built to evaluate the efficacy of ICB therapy. (3) Results: Mutations in FAT1 and KEAP1 were found to correlate with NDB in patients with NSCLC to ICBs; however, the analysis suggested that only mutation in FAT1 was valuable in predicting the efficacy of ICB therapy, and that mutation in KEAP1 acted as a prognostic but not a predictive biomarker for NSCLC. Mutations in FAT1 were associated with a higher TMB and lower multiple lymphocyte infiltration, including CD8 (T-Cell Surface Glycoprotein CD8)+ T cells. We established a prognostic model according to PD-L1 expression, TMB, smoking status, treatment regimen, treatment type, and FAT1 mutation, which indicated good accuracy by receiver operating characteristic (ROC) analysis (area under the curve (AUC) for 6-months survival: 0.763; AUC for 12-months survival: 0.871). (4) Conclusions: Mutation in FAT1 may be a predictive biomarker in patients with NSCLC who exhibit NDB to ICBs. We proposed an FAT1 mutation-based model for screening more suitable NSCLC patients to receive ICBs that may contribute to individualized immunotherapy.

The Impact of Programmed Death-Ligand 1 Expression on the Prognosis of Early Stage Resected Non-Small Cell Lung Cancer: A Meta-Analysis of Literatures.

INTRODUCTION: Previous studies have demonstrated that programmed cell death-ligand 1 (PD-L1) serves as biomarker for poor prognosis and survival in advanced-stage non-small cell lung cancer (NSCLC) patients. However, the merit of PD-L1 expression to predict the prognosis of early stage NSCLC patients who underwent complete resection remains controversial. In the present study, we performed a meta-analysis to investigate the relationship between PD-L1 expression and prognosis in patients with early stage resected NSCLC. METHODS: Electronic databases, including PubMed, EMBASE, and the Cochrane Library, were searched until July 23 2020 for studies evaluating the expression of PD-L1 and the prognosis of resected NSCLCs. Hazard ratios (HRs) with 95% confidence intervals (CIs) of overall survival (OS) and disease-free survival (DFS) were pooled and analyzed. Heterogeneity and publication bias analyses were also assessed. RESULTS: A total of 15 studies involving 3,790 patients were considered in the present meta-analysis. The pooled HR indicated that PD-L1 expression related to a much shorter DFS (HR = 1.56, 95% CI: 1.18-2.05, p < 0.01), as well a significantly worse OS (HR = 1.68, 95% CI: 1.29-2.18, p < 0.01). Furthermore, our analysis indicated that PD-L1 expression was significantly associated with gender (male vs. female: OR = 1.27, 95% CI:1.01-1.59, p = 0.038), histology (ADC vs. SCC: OR = 0.54, 95% CI:0.38-0.77, p = 0.001), TNM stage (I vs. II-III: OR = 0.45, 95% CI:0.34-0.60, p = 0.000), smoking status (Yes vs No: OR = 1.43, 95% CI:1.14-1.80, p = 0.002) and lymph node metastasis (N+ vs N-: OR = 1.97, 95% CI:1.26-3.08, p = 0.003). CONCLUSIONS: The results of this meta-analysis suggest that PD-L1 expression predicts an unfavorable prognosis in early stage resected NSCLCs. The role of personalized anti-PD-L1/PD-1 immunotherapy in the adjuvant settings of resected NSCLC warrants further investigation.

Circular RNA Signature in Lung Adenocarcinoma: A MiOncoCirc Database-Based Study and Literature Review.

Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs (ncRNAs) with a structure of covalently closed continuous loops, which can regulate gene expression by acting as a microRNA sponge or through other mechanisms. Recent studies have identified that the expression of candidate circRNAs are dysregulated in various tumors and hence are considered as promising diagnostic or therapeutic targets across cancer types. However, the expression and function of circRNAs in lung adenocarcinoma (LUAD) remains unclear. In this article, we investigated the expression of circRNAs in LUAD via MiOncoCirc, which is the first and comprehensive database characterizing circRNAs across >2,000 cancer samples using an exome capture RNA sequencing. We identified seven abnormally expressed circRNAs in LUAD, including circCDR1-AS, circHIPK3, circFNDC3B, circPCMTD1, circRHOBTB3, circFAM13B, and circMAN1A2, as well as conducted a literature review about the function and features of these circRNAs. Previous studies have demonstrated that circCDR1-AS, circMAN1A2, and circHIPK3 were upregulated and significantly correlated with a poor survival, or promoted the tumor progression in lung cancer, whereas other circRNAs have not been fully explored. Besides, we reviewed all the publications regarding circRNAs and LUAD, and noticed that the dysregulation of these circRNAs impacts the development of LUAD through a variety of regulatory mechanisms. In conclusion, the underlying mechanisms of aberrant expression and functions of circRNAs in LUAD are worthy of being further investigated.

Ginsenoside Rh3 Inhibits Proliferation and Induces Apoptosis of Colorectal Cancer Cells.

BACKGROUND: Colorectal cancer is a common malignant tumor of the digestive tract, the morbidity rate of which is rising in recent years. Ginsenoside Rh3 was reported to have anticancer activity; however, the underlying mechanism still needs to be explored in depth. METHODS: Rabbit blood was used to test hemolytic effects of ginsenoside protopanaxadiol (PPD), Rh2, Rh3, and Rg3. Human colorectal cancer SW1116 cells were treated with different concentration of ginsenoside PPD, Rh2, Rh3, and Rg3 in vitro. MTT and TUNEL assay were used to examine cell proliferation and apoptosis. Semi quantitative RT-PCR, immunocytochemistry assay and flow cytometry assay were used to detect the expression of caspase3. RESULTS: The results showed that the inhibiting effects on SW1116 cells of PPD and Rh2 were stronger than those of Rh3 (p < 0.01), but Rh3 had better solubility and slighter hemolytic effects on blood cells than those ginsenosides. Ginsenoside Rh3 inhibited the proliferation of SW1116 cells at 60 µg/mL (p < 0.01), the inhibition effect was increased sharply when the dose of Rh3 was increased from 60 to 120 µg/mL, the inhibition rate was 62.1% at 120 µg/mL, the inhibition appeared at 9 h, and the peak activity occurred at 12 h and maintained until 48 h (p < 0.01). Compared to the control group, the ratio of apoptotic cells, the expression level of mRNA and protein of caspase3 increased in 120 µg/mL Rh3 treated group. CONCLUSION: As a potential anticancer medicine, ginsenoside Rh3 could inhibit the proliferation of colorectal cancer cells in a dose- and time-dependent manner and induce cell apoptosis through upregulating the expression of caspase3.

Critical role for PI3Kγ-dependent neutrophil reactive oxygen species in WKYMVm-induced microvascular hyperpermeability.

PI3K has been indicated in regulating microvascular permeability changes during inflammation. However, its role in neutrophil-driven microvascular leakage in acute inflammation remains unclear. Using intravital microscopy in mice, we examined the role of PI3Kγ and PI3Kδ in formyl peptide WKYMVm- and chemokine CXCL2-induced permeability changes and assessed simultaneously neutrophil adhesion and emigration in post-capillary venules of murine cremaster muscle. We found a PI3Kγ-specific mechanism in WKYMVm-induced but not CXCL2-induced microvascular hyperpermeability. The increased microvascular permeability triggered by WKYMVm was not entirely due to neutrophil adhesion and emigration in cremasteric microvasculature in different PI3K transgenic mouse strains. The PI3Kγ-specific hyperpermeability was neutrophil-mediated as this was reduced after depletion of neutrophils in mouse circulation. Chimeric mice with PI3Kγ-deficient neutrophils but wild-type endothelium also showed reduced hyperpermeability. Furthermore, we found that the catalytic function of PI3Kγ was required for reactive oxygen species (ROS) generation in neutrophils stimulated with WKYMVm. Pharmacological scavenging PI3Kγ-dependent ROS in the tissue eliminated the discrepancy in hyperpermeability between different PI3K transgenic mice and alleviated WKYMVm-induced microvascular leakage in all mouse strains tested. In conclusion, our study uncovers the critical role for PI3Kγ-dependent ROS generation by neutrophils in formyl peptide-induced microvascular hyperpermeability during neutrophil recruitment.