SUMOylation-triggered ALIX activation modulates extracellular vesicles circTLCD4-RWDD3 to promote lymphatic metastasis of non-small cell lung cancer.

Lymph node (LN) metastasis is one of the predominant metastatic routes of non-small cell lung cancer (NSCLC) and is considered as a leading cause for the unsatisfactory prognosis of patients. Although lymphangiogenesis is well-recognized as a crucial process in mediating LN metastasis, the regulatory mechanism involving lymphangiogenesis and LN metastasis in NSCLC remains unclear. In this study, we employed high-throughput sequencing to identify a novel circular RNA (circRNA), circTLCD4-RWDD3, which was significantly upregulated in extracellular vesicles (EVs) from LN metastatic NSCLC and was positively associated with deteriorated OS and DFS of patients with NSCLC from multicenter clinical cohort. Downregulating the expression of EV-packaged circTLCD4-RWDD3 inhibited lymphangiogenesis and LN metastasis of NSCLC both in vitro and in vivo. Mechanically, circTLCD4-RWDD3 physically interacted with hnRNPA2B1 and mediated the SUMO2 modification at K108 residue of hnRNPA2B1 by upregulating UBC9. Subsequently, circTLCD4-RWDD3-induced SUMOylated hnRNPA2B1 was recognized by the SUMO interaction motif (SIM) of ALIX and activated ALIX to recruit ESCRT-III, thereby facilitating the sorting of circTLCD4-RWDD3 into NSCLC cell-derived EVs. Moreover, EV-packaged circTLCD4-RWDD3 was internalized by lymphatic endothelial cells to activate the transcription of PROX1, resulting in the lymphangiogenesis and LN metastasis of NSCLC. Importantly, blocking EV-mediated transmission of circTLCD4-RWDD3 via mutating SIM in ALIX or K108 residue of hnRNPA2B1 inhibited the lymphangiogenesis and LN metastasis of NSCLC in vivo. Our findings reveal a precise mechanism underlying SUMOylated hnRNPA2B1-induced EV packaging of circTLCD4-RWDD3 in facilitating LN metastasis of NSCLC, suggesting that EV-packaged circTLCD4-RWDD3 could be a potential therapeutic target against LN metastatic NSCLC.

Identification of predictors of long-term survival and prognostic outcomes in thymic squamous cell carcinoma: A real-world study.

BACKGROUND: Although thymic squamous cell carcinoma (TSCC) is among the most prevalent forms of thymic carcinoma, there are relatively few studies on this tumor type, and its staging, optimal treatment strategies, and relevant prognostic factors remain controversial. METHODS: The present study analyzed 79 patients diagnosed with TSCC between January 2008 and January 2021. Kaplan-Meier curves and Cox univariate and multivariate regression analyses were used to explore factors associated with overall survival (OS) and progression-free survival (PFS) in the overall patient cohort and patient subgroups stratified according to the TNM stage. Time-dependent receiver operating characteristic (ROC) analyses were used to compare the TNM and Masaoka systems as predictors of patient prognosis. RESULTS: The 5- and 10-year OS rates in this study were 65.5% and 49.4%, respectively, with corresponding 5- and 10-year PFS rates of 52.3% and 37.9%. Survival outcomes were better for patients with early-stage disease (p < 0.001) and patients that underwent surgical treatment (p < 0.001). Neither extent of resection (p = 0.820) nor the surgical approach (p = 0.444) influenced patient survival. In individuals with advanced disease, all forms of adjuvant therapy including radiotherapy (p = 0.021), chemotherapy (p = 0.035), and chemoradiation (p = 0.01) significantly improved patient PFS, but only adjuvant chemoradiotherapy improved patient OS (p = 0.035). When predicting the patient survival outcomes, the TNM system was slightly superior to the Masaoka system (area under the ROC curve [AUC] at 5 years: OS, 0.742 vs. 0.723; PFS, 0.846 vs. 0.816). CONCLUSION: TSCC is an orphan malignancy with a poor prognosis. TNM staging may be superior to Masaoka staging as a predictor of TSCC patient prognosis. Surgery is the mainstay of TSCC treatment. Video-assisted thoracoscopy (VATS) should be considered for selected patients. Multimodal therapy was associated with excellent results for patients with advanced TNM stage, particularly when surgery was accompanied by adjuvant chemoradiation.

A systematic review and meta-analysis of thymic mucosa-associated lymphoid tissue lymphoma.

Background: Mucosa-associated lymphoid tissue (MALT) lymphoma of the thymus is a rare disease. The present meta-analysis aims at accumulating current evidence to explore the clinical characteristics, treatments, and prognoses of thymic MALT lymphoma. Methods: We searched seven databases for studies published between the start date of database establishment and September 15, 2021. We included studies of patients with histological diagnoses and excluded those without data specifically on thymic MALT lymphoma. The quality was analyzed using an assessment tool. All data were tabulated. Pooled proportion was obtained using random-effects model. Statistical analysis was performed on R statistic software. Results: Overall, 52 case reports and 13 case series were eligible. The quality of case reports was inferior to that of case series in terms of selection (P<0.001). Based on the analysis of patients in the case reports, age, gender, concurrent diseases, and tumor size did not differ between limited-stage and advanced-stage cases. Surgery is the mainstay to treat thymic MALT lymphoma. The surgical approach and extent did not influence the occurrence of events. Patients at Ann Arbor stage I were prone to not receiving postoperative therapy (P=0.011), though it may not reduce the occurrence of events (P=0.637). The five-year overall survival (OS) rate and five-year progression-free survival (PFS) rate were 97.2% and 88.4%, respectively. Patients with advanced-stage disease were more likely to suffer events (P=0.009). Conclusions: Thymic MALT lymphoma is an extremely rare disease with a favorable prognosis. Currently available evidence is insufficient to draw solid judgments about treatment and prognosis. However, patients may benefit if thymectomy is chosen as the primary treatment. In some patients, lymph node sampling or dissection should be considered. In addition, if the patient is at an advanced-stage, postoperative therapy should be considered.

Comparative analysis of the long-term outcomes of segmentectomy and lobectomy for stage IA1 lung adenocarcinoma in patients with or without previous malignancy of other organs: a population-based study.

BACKGROUND: For early stage non-small cell lung cancer, whether limited resection can yield comparable outcomes to those of lobectomy hasn't been established. We compared Overall survival (OS) and lung cancer-specific survival (LCSS) after segmentectomy or lobectomy in stage IA1 (≤10 mm) lung adenocarcinoma (LUAD) patients. RESEARCH DESIGN AND METHODS: We retrospectively recruited patients who'd been diagnosed with lung cancer for the first time and treated with segmentectomy or lobectomy, with or without previous other malignancy. RESULTS: 1788 patients were included. After propensity score matching: 5-year OS were 85.6% for segmentectomy and 84.7% for lobectomy (p=0.951); 5-year LCSS were 93.5% for segmentectomy; and 93.0% for lobectomy (p=0.726). Cox regression analysis revealed segmentectomy was comparable to lobectomy in OS and LCSS. Having a second lung cancer later in life was associated with a worse LCSS for lobectomy (p<0.05) rather than segmentectomy. After patients were stratified according to malignancy history, subgroup analyses showed no significant prognosis differences between two surgeries. CONCLUSIONS: For stage IA1 LUAD patients who were diagnosed with lung cancer for the first time, with or without previous other malignancy, segmentectomy yields comparable outcomes to those of lobectomy. It may provide better outcomes for patients with multiple suspicious nodules.

Identification of Resectable N2 in NSCLC: A Single Center Experience and Review of the SEER Database.

BACKGROUND: Non-small cell lung carcinoma (NSCLC) with ipsilateral and/or subcarinal mediastinal lymphatic spread (N2) is a heterogeneous disease. The role of surgical resection in patients with N2 NSCLC remains controversial and no survival-based definition of "resectable N2" exists. The purpose of this study is to evaluate the factors that potentially affect the survival of N2 NSCLC patients who receive surgical resection and to define "resectable N2" based on the survival benefits. METHODS: Data from the open Surveillance, Epidemiology, and End Results (SEER) database from the National Cancer Institute in the United States were used to construct a nomogram. Patients who received surgery between 2010 and 2015 for N2 NSCLC were included. Independent prognostic factors for survival identified through Cox regression analysis were used to create the nomogram. The C-index, receiver operating characteristics (ROC) analyses, calibration curves, and risk stratification were used to evaluate the nomogram. The nomogram was also validated using data from 222 patients from Peking Union Medical College Hospital (PUMCH). Furthermore, lung cancer-related deaths were compared using competitive risk analysis. RESULTS: In total, 4267 patients were included in the SEER cohort. Male gender, old age, high T stage and grade, adenosquamous and squamous cell carcinoma, lower lobe and overlapping lesions, extended lobe or bilobectomy and pneumonectomy, no chemotherapy, radiation before and after surgery, positive number of lymph nodes, and lymph node ratio (LNR) were identified as independent risk factors for higher mortality. The nomogram was created using these parameters. The C-index was 0.665 (95% confidence interval (CI), 0.651-0.679) and 0.722 (95% CI, 0.620-0.824) in the SEER and PUMCH cohorts, respectively. The calibration curves showed satisfactory consistency between the predicted and actual survival status in both the SEER and PUMCH cohorts. Competitive risk analysis confirmed that the variables in the nomogram, except radiation, are risk factors for prognosis. CONCLUSIONS: "Resectable N2" should be assessed by a multidisciplinary team. The novel nomogram developed in this study may help with clinical decision-making for this patient population.

Methylated Metabolites of Chicoric Acid Ameliorate Hydrogen Peroxide (H2O2)-Induced Oxidative Stress in HepG2 Cells.

Chicoric acid (CA) can display health benefits as a dietary polyphenol. However, as CA is widely metabolized in vivo, the actual compounds responsible for its bioactivities are not entirely known. Herein, the major methylated metabolites of CA were isolated from an in vitro co-incubation system, and their structures were elucidated. The antioxidant activities of the monomethylated metabolites (M1) and dimethylated metabolites (M2) of CA were evaluated against H2O2-induced oxidative stress damage in HepG2 cells and compared to CA. The results indicated that both M1 and M2 had better antioxidant capacities than CA by increasing cell viability, improving mitochondrial function, and balancing cellular redox status. These compounds also prevented oxidative stress by mediating the Keap1/Nrf2 transcriptional pathway and downregulating enzyme activity. The current research indicates that the methylated metabolites of CA could potentially be the candidates that are responsible for the biological efficacies attributed to CA.

Prognosis of segmentectomy in the treatment of stage IA non-small cell lung cancer.

With improvements in detection technology, increasing numbers of patients with non-small cell lung cancer (NSCLC) are being diagnosed at an early stage. In order to treat the illness with minimal invasion and preserve lung function to the greatest possible extent, there has been an increasing tendency towards treating early-stage NSCLC by segmentectomy. However, questions remain regarding whether patients may benefit from this procedure considering the surgical and oncological outcomes. Whether adequate margin distance and lymph node dissection may be achieved is one of the most important issues associated with this procedure. The present study reviews the prognosis of segmentectomy in the treatment of stage IA NSCLC.

Postoperative Short-term Outcomes Between Sublobar Resection and Lobectomy in Patients with Lung Adenocarcinoma.

BACKGROUND: To investigate postoperative temporary consequences of the enrolled patients with lung adenocarcinoma. PATIENTS AND METHODS: We analyzed the clinical data of patients with lung adenocarcinoma admitted by the same surgical team of Peking Union Medical College Hospital (PUMCH) from July 2019 to December 2019. Statistical methods including propensity score matching (PSM) analysis was used to analyze the differences among them. RESULTS: A total of 108 patients were enrolled, including 50 patients with sublobar resection and 58 patients with lobectomy. Before PSM, there were statistically significant differences in age (p=0.015), hospitalization costs (p=0.042), lymphadenectomy (p=0.000), pathological staging (p=0.000), number of lymph nodes removed (p=0.000), number of positive lymph nodes (p=0.034), chest drainage duration (p=0.000), total chest drainage (p=0.000), length of postoperative hospital stays (p=0.000), postoperative D-dimer level (p=0.030) and perioperative lymphocyte margin (LM) (p=0.003) between sublobar resection and lobectomy. After PSM, there were statistical differences in number of lymph nodes removed (p=0.000), chest drainage duration (p=0.031) and total chest drainage (p=0.002) between sublobar resection and lobectomy. Whether with PSM analysis or not, there were no significant differences in other blood test results, such as inflammation indicators, postoperative neutrophil-lymphocyte ratio (NLR), albumin level, perioperative activity of daily living (ADL) scale scoring margin, complications, postoperative admission to intensive care unit (ICU) and readmission within 30 days. NLR was associated with total chest drainage (p=0.000), length of postoperative hospital stays (p=0.000), postoperative D-dimer level (p=0.050) and ADL scale scoring margin (p=0.003) between sublobar resection and lobectomy. CONCLUSION: Sublobar resection, including wedge resection and segmentectomy, was as safe and feasible as lobectomy in our study, and they shared similar short-term outcomes. Postoperative NLR could be used to detect the clinical outcomes of patients. Secondary resectability of pulmonary function (SRPF) should be the main purpose of sublobar resection.

Metabolic and transcriptional regulation of phenolic conversion and tocopherol biosynthesis during germination of sesame (Sesamum indicum L.) seeds.

This study aims to evaluate the changes in phenolic acids, lignans and tocopherols of sesame seeds during 0-6 days of germination by monitoring the activities of phenolic metabolism-related enzymes and the expression of key genes in the tocopherol synthesis pathway. Sesamol, which is the most active lignan antioxidant, greatly increased, and most of the phenolic acid contents increased to varying degrees after germination. Correspondingly, the related enzymes, including phenylalanine ammonia-lyase (PAL), cinnamate-4-hydroxylase (C4H), and 4-coumarate:coenzyme A ligase (4CL), were activated. Germination also promoted the conversion of γ-tocopherol to α-tocopherol with the expression of related genes changed. Additionally, there was a high correlation between the tocopherol content and the relative expression levels of key genes. The germination process also increased the bio-accessibility of lignans and tocopherols. Therefore, germination can be utilized to improve the nutritional value of sesame-related products.

LncRNA HCG11 Suppresses Cell Proliferation and Promotes Apoptosis via Sponging miR-224-3p in Non-Small-Cell Lung Cancer Cells.

INTRODUCTION: Studies have found that Lnc-HCG11 is an important regulator of cancer. However, the function of Lnc-HCG11 in NSCLC is not known. Therefore, this experimental design was based on Lnc-HCG11 to explore the pathogenesis of NSCLC. METHODS: RT-qPCR was used to detect the expression of Lnc-HCG11 and miR-224-3p in NSCLC. The effects of Lnc-HCG11 and miR-224-3p on proliferation and apoptosis of NSCLC cells were detected by CCK-8 assay, Edu assay and Annexin V-FITC/PI assay. Target gene prediction and screening, luciferase reporter assays were used to verify downstream target genes for lnc-HCG11 and miR-224-3p. Western blotting was used to detect the protein expression of caspase-3. The tumor changes in mice were detected by in vivo. RESULTS: Lnc-HCG11 was significantly reduced in NSCLC. Lnc-HCG11 significantly inhibited cell proliferation of NSCLC cells and induced apoptosis. miR-224-3p was significantly elevated in the NSCLC cell line. Moreover, miR-224-3p significantly increased cell proliferation and inhibited apoptosis of NSCLC cells. Furthermore, Lnc-HCG11 was negatively correlated with miR-224-3p expression. Lnc-HCG11 over-expression was up-regulated the expression levels of c-caspase-3 and caspase-3. Finally, the results of in vivo animal models confirmed that Lnc-HCG11 inhibited tumor growth by modulating the miR-224-3p/c-caspase-3 axis. CONCLUSION: Lnc-HCG11 could inhibit the progression of NSCLC by modulating the miR-224-3p/caspase-3 axis, and Lnc-HCG11 may be a potential therapeutic target for NSCLC.

A geographical discrimination of Shanxi extra aged vinegars using polyalcohols as the discriminators.

A discrimination method based on polyalcohol determination was developed for authenticity of protected geographical indication (PGI) vinegars-Shanxi extra aged vinegar (SVs) in China. Six polyalcohols in vinegars including erythritol, arabitol, xylitol, inositol, mannitol, and sorbitol were selected as the PGI discriminators. GC/MS was used to analyze the polyalcohols in the SVs, Zhenjiang vinegars (ZVs), Kazuo aged vinegars (KVs), and other non-geographical indication protected vinegars (NVs). SVs can be distinguished from KVs by the chemical markers mannitol and sorbitol, although the production processes for both types of vinegars are similar. Principal component analysis (PCA) was used to distinguish SVs from ZVs and NVs. The differences among the three kinds of vinegars shown by PCA results may be due to the higher erythritol content in SVs, and the inositol and mannitol in ZVs. This study also found that the amount of polyalcohols in Chinese vinegars increases with the acidity value only, regardless of the aging time. The overall results indicated that the polyalcohols can be practicable discriminators for SV discrimination.

A similarity measure for two-dimensional fluorescent spectra.

A similarity measure was developed that can differentiate between two-dimensional fluorescent spectra based on their similarities and differences. The two-dimensional fluorescent spectra are digitalized into matrices. The difference between the two spectra is defined by a difference matrix, whose elements contain the difference of one two-dimensional fluorescent spectrum minus the other. The similarity measure is transformed into hypothesis tests of the similarity and difference between the two spectra. The scalar mean of the difference matrix is used as the statistical variable for the hypothesis test. The Bayesian prior odds ratio was estimated from multiple spectra of the same reference sample. A threshold for the hypothesis test that the spectra are different is proposed. The posterior odds ratio was used to quantify the similarity measure of the two spectra. Two-dimensional fluorescent spectra of Changyu red wine samples were used to demonstrate this method. The results show that this new method can detect differences between the spectra.