RBMS1 reflects a distinct microenvironment and promotes tumor progression in ocular melanoma.

Ocular melanoma, including uveal melanoma (UM) and conjunctival melanoma (CM), is the most common ocular cancer among adults with a high rate of recurrence and poor prognosis. Loss of epigenetic homeostasis disturbed gene expression patterns, resulting in oncogenesis. Herein, we comprehensively analyzed the DNA methylation, transcriptome profiles, and corresponding clinical information of UM patients through multiple machine-learning algorithms, finding that a methylation-driven gene RBMS1 was correlated with poor clinical outcomes of UM patients. RNA-seq and single-cell RNA-seq analyses revealed that RBMS1 reflected diverse tumor microenvironments, where high RBMS1 expression marked an immune active TME. Furthermore, we found that tumor cells were identified to have the higher communication probability in RBMS1+ state. The functional enrichment analysis revealed that RBMS1 was associated with pigment granule and melanosome, participating in cell proliferation as well as apoptotic signaling pathway. Biological experiments were performed and demonstrated that the silencing of RBMS1 inhibited ocular melanoma proliferation and promoted apoptosis. Our study highlighted that RBMS1 reflects a distinct microenvironment and promotes tumor progression in ocular melanoma, contributing to the therapeutic customization and clinical decision-making.

[Effect of total flavonoids of buckwheat flower and leaf on myocardial cell apoptosis and Wnt/ß-catenin/PPARγ pathway in arrhythmic rats].

This paper aimed to investigate the effect of total flavonoids of buckwheat flower and leaf on myocardial cell apoptosis and Wnt/ß-catenin/peroxisome proliferator-activated receptor γ(PPARγ) pathway in arrhythmic rats. SD rats were randomly divided into a control group, a model group, a low-dose(20 mg·kg~(-1)) group of total flavonoids of buckwheat flower and leaf, a medium-dose(40 mg·kg~(-1)) group of total flavonoids of buckwheat flower and leaf, a high-dose(80 mg·kg~(-1)) group of total flavonoids of buckwheat flower and leaf, a propranolol hydrochloride(2 mg·kg~(-1)) group, with 12 rats in each group. Except the control group, rats in other groups were prepared as models of arrhythmia by sublingual injection of 1 mL·kg~(-1) of 0.002% aconitine. After grouping and intervention with drugs, the arrhythmia, myocardial cells apoptosis, myocardial tissue glutathione peroxidase(GSH-Px), catalase(CAT), malondialdehyde(MDA), serum interleukin-6(IL-6), prostaglandin E2(PGE2) levels, myocardial tissue apoptosis, and Wnt/ß-catenin/PPARγ pathway-related protein expression of rats in each group were measured. As compared with the control group, the arrhythmia score, the number of ventricular premature beats, ventricular fibrillation duration, myocardial cell apoptosis rate, MDA levels in myocardial tissues, serum IL-6 and PGE2 levels, Bax in myocardial tissues, and Wnt1 and ß-catenin protein expression levels increased significantly in the model group, whereas the GSH-Px and CAT levels, and Bcl-2 and PPARγ protein expression levels in myocardial tissues reduced significantly. As compared with the model group, the arrhythmia score, the number of ventricular premature beats, ventricular fibrillation duration, myocardial cell apoptosis rate, MDA leve in myocardial tissues, serum IL-6 and PGE2 levels, Bax in myocardial tissues, and Wnt1 and ß-catenin protein expression levels reduced in the drug intervention groups, whereas the GSH-Px and CAT levels and Bcl-2 and PPARγ protein expression levels in myocardial tissues increased. The groups of total flavonoids of buckwheat flower and leaf were in a dose-dependent manner. There was no significant difference in the levels of each index in rats between the propranolol hydrochloride group and the high-dose group of total flavonoids of buckwheat flower and leaf. The total flavonoids of buckwheat flower and leaf inhibit the activation of Wnt/ß-catenin pathway, up-regulate the expression of PPARγ, reduce oxidative stress and inflammatory damage in myocardial tissues of arrhythmic rats, reduce myocardial cell apoptosis, and improve the symptoms of arrhythmia in rats.

Determination of surgical margins in laparoscopic parenchyma-sparing hepatectomy of neuroendocrine tumors liver metastases using indocyanine green fluorescence imaging.

BACKGROUND: Neuroendocrine tumors (NETs) are a group of heterogenous tumors originating from neuroendocrine system. Approximately, 40 percent will go through liver metastases, and liver-directed therapy was proved to improve the survival outcome. Parenchyma-sparing hepatectomy is advocated for the resection of NETs liver metastases while the possible relatively low negative margin rate is concerned. Indocyanine green (ICG) fluorescence imaging provides a real-time navigation on determination of surgical margins in colorectal cancer liver metastases. However, there was no previous study that reported the applications of ICG fluorescence imaging in NETs liver metastases. The present study aimed to evaluate the feasibility and security of using ICG fluorescence imaging to determine surgical margins of NETs liver metastases during operation. METHODS: A retrospective two-arm cohort study was performed on 25 consecutive patients with NETs liver metastases who underwent laparoscopic parenchyma-sparing hepatectomy (LPSH). Patients were divided into two groups according to whether or not the ICG fluorescence imaging was used. Data on sociodemographic characteristics, laboratory parameters, pathology results, and surgical outcomes were collected. RESULTS: A total of 145 tumors pathologically diagnosed with NETs liver metastases were resected from 25 patients. The pathological results indicated negative margins in all tumors (102/102) in LPSH with ICG fluorescence imaging group. The negative margin rate was significantly higher in LPSH using the ICG fluorescence imaging (100% v.s 88.4%, p = 0.002). Surgical outcomes, including operation time, estimated blood loss, intraoperative transfusion rate, and postoperative morbidity, were comparable between LPSH with and without ICG fluorescence imaging groups. CONCLUSION: ICG fluorescence imaging showed the potential to identify tumor boundaries and determine surgical margins. This technique may serve as a valuable intraoperative navigation in patients with NETs liver metastases.

Association between delta anion gap and hospital mortality for patients in cardiothoracic surgery recovery unit: a retrospective cohort study.

BACKGROUNDS: High level of anion gap (AG) was associated with organic acidosis. This study aimed to explore the relationship between delta AG (ΔAG = AGmax - AGmin) during first 3 days after intensive care unit (ICU) admission and hospital mortality for patients admitted in the cardiothoracic surgery recovery unit (CSRU). METHODS: In this retrospective cohort study, we identified patients from the open access database called Multiparameter Intelligent Monitoring in Intensive Care III (MIMIC III). A logistic regression model was established to predict hospital mortality by adjusting confounding factors using a stepwise backward elimination method. We conducted receiver operating characteristic (ROC) curves to compare the diagnostic performance of acid-base variables. Cox regression model and Kaplan Meier curve were applied to predict patients' 90-day overall survival (OS). RESULTS: A total of 2,860 patients were identified. ΔAG was an independent predictive factor of hospital mortality (OR = 1.24 per 1 mEq/L increase, 95% CI: 1.11-1.39, p < 0.001). The area under curve (AUC) values of ΔAG suggested a good diagnostic accuracy (AUC = 0.769). We established the following formula to estimate patients' hospital mortality: Logit(P) = - 15.69 + 0.21ΔAG + 0.13age-0.21BE + 2.69AKF. After calculating Youden index, patients with ΔAG ≥ 7 was considered at high risk (OR = 4.23, 95% CI: 1.22-14.63, p = 0.023). Kaplan Meier curve demonstrated that patients with ΔAG ≥ 7 had a poorer 90-day OS (Adjusted HR = 3.20, 95% CI: 1.81-5.65, p < 0.001). CONCLUSION: ΔAG is a prognostic factor of hospital mortality and 90-day OS. More prospective studies are needed to verify and update our findings.

The prognostic value of modified NUTRIC score for patients in cardiothoracic surgery recovery unit: A retrospective cohort study.

BACKGROUND: Malnutrition is highly prevalent in critically ill patients. The modified Nutrition Risk in the Critically ill (mNUTRIC) score has been introduced to evaluate the nutritional risk of patients in an intensive care unit (ICU). The mNUTRIC score is a predictive factor of mortality for patients in a medical or mixed ICU, whereas the relationship between mNUTRIC and prognosis of patients in a cardiothoracic surgery recovery unit (CSRU) is unclear and related researches are limited. METHODS: We conducted this retrospective cohort study to explore the value of mNUTRIC score in CSRU patients. We identified totally 4059 patients from the Multiparameter Intelligent Monitoring in Intensive Care III (MIMIC III) database. RESULTS: The optimal cut-off value of mNUTRIC score was 4 and a total of 1498 (36.9%) patients were considered to be at high nutritional risk (mNUTRIC ≥ 4). A multivariate logistic regression model indicated that patients at high nutritional risk have higher hospital mortality compared to those at low nutritional risk (odds ratio = 2.49, 95% confidence interval (CI) = 1.32-4.70, p = 0.005]. Furthermore, a Cox regression model was established adjusted for age, white blood cell and body mass index. The Kaplan-Meier curve indicated that patients at high nutritional risk have poorer 365-days [hazard ratio (HR) = 1.76, 95% CI = 1.30-2.37, p < 0.001] and 1000-days (HR = 2.30, 95% CI = 1.87-2.83, p < 0.001) overall survival. CONCLUSIONS: The mNUTRIC score could not only predict hospital mortality, but also be an independent prognostic factor for long-term survival in CSRU patients. More well-designed clinical trials are needed to verify and update our findings.

Metastatic pancreatic adenocarcinomas could be classified into M1a and M1b category by the number of metastatic organs.

BACKGROUND: With the improvement of treatment and prognosis for patients with late malignant diseases, certain malignancies with distant metastasis (M1 category) have been further classified into M1a (single metastatic site) and M1b (multiple metastatic sites) category in the staging system. We aimed to assess the feasibility of sub-classifying metastatic pancreatic adenocarcinoma (mPA) into M1a and M1b category depending on the number of metastatic organs. METHODS: Patient records were collected from the Surveillance, Epidemiology, and End Results (SEER) database (2010-2015). Univariable and multivariable analyses were performed using the Cox regression model. Then survival analysis was determined using the Kaplan-Meier method. RESULTS: A total of 11,885 patients were included in this analysis, including 9425 patients with single metastasis and 2460 patients with multiple metastases. Multivariable analysis showed that gender, age, marital status, grade, surgery, chemotherapy, and radiotherapy were independent prognostic factors for patients with single metastasis; gender, age, marital status, grade, chemotherapy and radiotherapy were independent prognostic factors for patients with multiple metastases. Notably, surgery was an independent prognostic factor for patients with single metastasis (P < 0.001) but not for patients with multiple metastases (P = 0.134). Kaplan-Meier analysis showed that patients with single metastasis (M1a) had better survival outcomes than patients with multiple metastases (M1b) (P < 0.001). CONCLUSIONS: PA patients with M1 diseases could be divided into M1a (single metastasis) category and M1b (multiple metastases) category by the number of metastatic organs. The subclassification would facilitate individualized treatment for late PA patients. Surgery was associated with lower mortality in M1a patients but not significantly in M1b patients.

The value of lung function assessment and Testin expression detection in clinicopathological features and prognosis of NSCLC patients.

OBJECTIVE: The aim of this study is to investigate the clinical value and potential prognostic significance of lung function assessment and Testin expression in non-small cell lung cancer (NSCLC) patients. METHODS: The NSCLC patients were classified into three groups according to lung function: group of normal lung function, group of PRISm (preserved ratio impaired spirometry) (FEV1, forced expiratory volume during the first second < 80% predicted and FEV1/FVC (forced vital capacity) ≥ 70%) and group of COPD (chronic obstructive pulmonary disease) (FEV1/FVC < 70%). The pre-operational clinicopathological characteristics of these patients were recorded and the markers of systemic inflammatory response, including neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), platelet to lymphocyte ratio (PLR) and eosinophils (EOS), were compared between three groups. The expression of Testin in NSCLC samples was detected by IHC and we further explored the correlation between Testin expression and clinicopathological characteristics and prognosis of NSCLC patients. Finally, Cox regression analysis was conducted to study the prognostic factors of NSCLC patients. RESULTS: Of the 158 NSCLC patients, percentages of normal lung function, PRISm and COPD were 41.4%, 22.8% and 36.1%, respectively. Patients with tumor in the left lung were more likely to have pulmonary dysfunction (PRISm and COPD) than the right lung. The markers of systemic inflammatory response showed differences to various degree in the three groups and NSCLC patients with PRISm or COPD presented more unfavorable prognosis than patients with normal function. The expression of Testin correlated with lymph node metastasis, TNM stage and tumor invasion of NSCLC patients. Moreover, patients with low Testin expression exhibited poorer disease-free survival and overall survival than those with high Testin expression. In Cox regression analysis, we found that PRISm, COPD and Testin expression served as prognostic factors in NSCLC patients. CONCLUSIONS: The presence of COPD or PRISm influenced systemic inflammatory response and prognosis of NSCLC patients. Testin expression correlated with clinicopathological features and could be potentially used as a prognostic marker in NSCLC.

Efficacy of Zidovudine-Amikacin Combination Therapy In Vitro and in a Rat Tissue Cage Infection Model against Amikacin-Resistant, Multidrug-Resistant Enterobacteriales.

Multidrug-resistant (MDR) Enterobacteriales infections have become an urgent global threat to public health. The aim of this study was to evaluate the efficacy of zidovudine-amikacin combination therapy in vitro and in vivo. Molecular characteristics and antibiotic resistance profiles of 53 amikacin-resistant MDR, extensively drug-resistant (XDR), or pan-drug-resistant (PDR) clinical isolates were examined via PCR and susceptibility testing. Checkerboard assays were performed for these 53 isolates to assess in vitro synergistic effects of the zidovudine-amikacin combination, and static time-kill experiments were performed for four XDR or PDR Enterobacteriales isolates. A Galleria mellonella model and a rat tissue cage infection model were established to assess in vivo synergistic effects. The aac(6')-Ib gene was detected in 25 (47.2%) isolates, followed by armA in 5 (9.4%) isolates, rmtB in 27 (50.9%) isolates, and rmtC in 3 (5.8%) isolates. Checkerboard assays showed the synergy of this combination against 38 (71.7%) isolates. The time-kill assays further confirmed that zidovudine strongly synergized with amikacin against four XDR or PDR Enterobacteriales isolates. The Galleria mellonella model study showed that the survival benefit of zidovudine-amikacin combination therapy was significantly better than that of monotherapy for those four Enterobacteriales isolates. Furthermore, the rat tissue cage infection model study showed that zidovudine-amikacin combination therapy displayed more potent bactericidal activity than monotherapy after 3 and 7 days of treatment for the above four isolates. Our data support the idea that the zidovudine-amikacin combination could be a plausible alternative therapy against infections with amikacin-resistant MDR Enterobacteriales, especially with XDR and PDR Enterobacteriales. IMPORTANCE Our study revealed for the first time that the zidovudine-amikacin combination shows a significant bactericidal effect against amikacin-resistant MDR, XDR, and PDR Enterobacteriales. Second, using in vitro and in vivo approaches, our study showed that zidovudine strongly synergized with amikacin against amikacin-resistant MDR Enterobacteriales isolates. Most importantly, with regard to survival benefit, pharmacokinetics, and bactericidal effects, our in vivo experiment demonstrated the effectiveness of zidovudine-amikacin.

The Progress of the Prevention and Treatment of Vitamin D to Tuberculosis.

The progressions of a number of lung diseases, including acute lung injury, cystic fibrosis, asthma, chronic obstructive pulmonary disease, pneumonia and tuberculosis (TB) are found to be highly associated with inflammatory responses. As a signaling nutrient, Vitamin D modulates the activities of dendritic cells, monocytes/macrophages, T and B cells, and tissue epithelial cells in the body to induce inflammatory responses and boost immune functions. Given the high prevalence of vitamin D deficiency among pulmonary insufficiency and inflammation-related cases, researchers indicated vitamin D supplementation could have a potential role in the prevention and treatment of lung disease, especially tuberculosis. In this paper, we reviewed published studies on the role of vitamin D in the prevention and treatment of tuberculosis. The paper identified vitamin D's potential as an adjunctive therapy and demonstrated its safety so as to provide an impetus for further studies and clinical applications.

Methylation-driven gene DLL3 is a potential prognostic biomarker in ocular melanoma correlating with metastasis.

Background: Ocular melanoma is an aggressive malignancy with a high rate of metastasis and poor prognosis. Increasing evidence indicated that DNA methylation plays an important role in the occurrence and development of ocular melanoma. Hence, exploring new diagnostic and prognostic biomarkers at the genetic level may be beneficial to the prognosis of patients with ocular melanoma. Methods: We collected DNA methylation and gene expression profiles of human UM (uveal melanoma) and CM (conjunctival melanoma) samples from various datasets. We conducted differential methylation and expression analyses to screen the potential biomarkers. Correlation analysis was performed to investigate the relationships between the expression level of DLL3 (delta-like protein 3) and the methylation level of its corresponding CpGs. We explored the prognostic and diagnostic value of DLL3 in UM and CM. Functional annotation and GSEA (gene set enrichment analysis) were applied to get insight into the possible biological roles of DLL3. A cohort of 60 ocular melanoma patients as well as UM and CM cell lines were used to validate our findings in bioinformatic analyses. Results: We found that DLL3 was a methylation-driven gene correlating with UM metastasis. The CpGs of DLL3 are mainly located in the gene body and their methylation level positively correlated to DLL3 expression. Multivariate Cox regression analysis revealed that DLL3 was an independent protective factor for UM patients. High DLL3 expression significantly prolonged the overall survival and disease-free survival of UM patients. DLL3 also showed a promising power to distinguish CM from normal tissues. Functional annotation exhibited that DLL3 may suppress UM progression through modulating immune activities and down-regulating various signaling pathways. External datasets, biospecimens, and cell lines further validated the aberrant expression and prognostic role of DLL3 in ocular melanoma. Conclusion: Methylation-driven gene DLL3 could serve as a new potential diagnostic and prognostic biomarker in ocular melanoma. Our findings may contribute to improving the clinical outcomes of patients with UM or CM.

Distinguishing optimal esophagectomy candidates in elderly patients: A nomogram based on propensity score matching.

BACKGROUND: A survival benefit from esophagectomy was observed in elderly patients. But it's unclear how to identify specific patients who can benefit. Thus, we aimed to establish a predictive model to identify optimal candidates for esophagectomy. METHODS: Patients (age ≥75 years) with esophageal cancer in Surveillance, Epidemiology and End Results (SEER) database were used to establish the predictive model. Propensity-score matching (PSM) was applied to eliminate the imbalance between esophagectomy group and non-esophagectomy group. We hypothesized that elderly patients could benefit from esophagectomy with longer cancer specific survival (CSS) time than those who did not receive esophagectomy. Patients received surgery were divided into beneficial group and non-beneficial group according to the median CSS time of non-esophagectomy group. Prognostic factors affecting patients' long-term survival were identified. Among esophagectomy group, a logistic regression model based on these factors was established to build a nomogram. RESULTS: A total of 7,025 eligible patients were extracted from the SEER database, with 831 patients received esophagectomy. Surgery was independently associated with better long-term survival (median CSS time in the matched population: 35 vs. 8 months, p < 0.001). As a result, 361 (68.6%) patients were divided into beneficial group (CSS >8 months). Factors including age, tumor site, histology, differentiation grade, TNM stage, and tumor size were used to formulate the nomogram, which was named as esophagectomy candidates screening score (ECSS). The validation from two aspects showed the model a useful and stable one. CONCLUSION: A predictive model was established to distinguish optimal candidates for esophagectomy among elderly patients with EC.

Mechanistic Understanding of the Palmitoylation of Go Protein in the Allosteric Regulation of Adhesion Receptor GPR97.

Adhesion G-protein-coupled receptors (aGPCRs)-a major family of GPCRs-play critical roles in the regulation of tissue development and cancer progression. The orphan receptor GPR97, activated by glucocorticoid stress hormones, is a prototypical aGPCR. Although it has been established that the palmitoylation of the C-terminal Go protein is essential for Go's efficient engagement with the active GPR97, the detailed allosteric mechanism remains to be clarified. Hence, we performed extensive large-scale molecular dynamics (MD) simulations of the GPR97-Go complex in the presence or absence of Go palmitoylation. The conformational landscapes analyzed by Markov state models revealed that the overall conformation of GPR97 is preferred to be fully active when interacting with palmitoylated Go protein. Structural and energetic analyses indicated that the palmitoylation of Go can allosterically stabilize the critical residues in the ligand-binding pocket of GPR97 and increase the affinity of the ligand for GPR97. Furthermore, the community network analysis suggests that the palmitoylation of Go not only allosterically strengthens the internal interactions between Gαo and Gßγ, but also enhances the coupling between Go and GPR97. Our study provides mechanistic insights into the regulation of aGPCRs via post-translational modifications of the Go protein, and offers guidance for future drug design of aGPCRs.

Characterization of Immune-Related Molecular Subtypes and a Prognostic Signature Correlating With the Response to Immunotherapy in Patients With Gastric Cancer.

Gastric cancer (GC) is a disease characterized by high molecular and phenotypic heterogeneity and represents a leading cause of cancer-related death worldwide. The tumor immune microenvironment (TIME) affects the response to immunotherapy and the prognosis of patients with GC. Explorations of the TIME in GC and characterization of molecular subtypes might enhance personalized treatment and facilitate clinical decision-making. In this study, two molecular subtypes were defined through unsupervised consensus clustering based on immune-related dysregulated genes. Then, patients with different molecular subtypes of GC were shown to have distinct differences in sensitivity to immune checkpoint blockers (ICBs). The immune-related prognostic signature was established utilizing least absolute shrinkage and selection operator (LASSO)-Cox regression analysis. Three independent external cohorts and the IMvigor210 cohort were introduced to validate the robustness of IPRS. scRNA-seq data of GC samples were used to decipher the underlying mechanisms of how IPRS contributes to the TIME. GC biospecimens were collected for RT-qPCR to further validate our findings. In summary, we characterized the abnormal TIME of GC and constructed a reliable immune-related prognostic signature correlating with the response to immunotherapy. This study may provide new strategies for developing individualized treatments for patients with GC.

Surgical Apgar score could predict complications after esophagectomy: a systematic review and meta-analysis.

OBJECTIVES: Esophagectomy is the most effective treatment for oesophageal cancer, although the incidence of postoperative complications remains high. Severe major complications, such as intrathoracic anastomotic leakage, are costly and life-threatening to patients. Therefore, early identification of postoperative complications is essential. The surgical Apgar score (SAS) was introduced by Gawande and colleagues to predict major complications after oesophagectomy. Several studies were carried out with inconsistent results. METHODS: PubMed, Embase, Web of Science, ClinicalTrials.gov and the Cochrane Library were searched for studies regarding SAS and oesophagectomy. Forest plots were generated using a random-effects model to investigate the actual predictive value of SAS in identifying major complications after oesophagectomy. RESULTS: Nine retrospective cohort studies were finally identified from selected electronic databases. The meta-analysis demonstrated that SAS could forecast the incidence of postoperative complications (odds ratio = 1.82, 95% confidence interval: 1.43-2.33, P < 0.001). Subgroup analysis validated the predictive value of SAS whether as continuous or discrete variables. In addition, a meta-analysis of 4 studies demonstrated that SAS could predict the incidence of pulmonary complications (odds ratio = 2.32, 95% confidence interval: 1.61-3.36, P < 0.001). Significant heterogeneity but no publication bias was found. CONCLUSIONS: Lower SAS scores could predict the incidence of major morbidities and pulmonary complications after oesophagectomy. Significant heterogeneity limits the reliability of the results, even if publication bias is not observed. More high-quality prospective research should be conducted to verify the findings. PROSPERO registration ID: CRD42020209004.

A RASSF8-AS1 based exosomal lncRNAs panel used for diagnostic and prognostic biomarkers for esophageal squamous cell carcinoma.

BACKGROUND: Exosomal long non-coding RNA (lncRNA) has been shown to be potential biomarker for cancer diagnosis and follow up. However, little is known about its application in esophageal squamous cell carcinoma (ESCC) detection. Here, we sought to develop a novel diagnostic model based on serum exosomal lncRNAs to improve ESCC screening efficiency. METHODS: A multiphase, case-control study was conducted among 140 ESCC patients and 140 healthy controls. Microarray screening was performed to acquire differentially expressed exosomal lncRNAs in the discovery phase. The diagnostic model Index I was constructed based on a panel of three lncRNAs using logistic regression in the training phase, and were confirmed in a subsequent validation phase. A receiver operating characteristic (ROC) curve was generated to calculate the diagnostic value. The effects of the selected lncRNAs level on ESCC mortality were evaluated using a Cox hazard regression model and Kaplan-Meier curve analysis, and the expression level with clinicopathological features was also calculated. Finally, we explored the oncogenic potential of candidate lncRNA RASSF8-AS1 in vitro and by target mRNA sequencing. RESULTS: Index I was able to discriminate ESCC patients from healthy controls, and showed superiority to classic tumor biomarkers. Moreover, serum levels of the exosomal lncRNAs correlated with clinicopathological features and prognosis. The in vitro assays showed that RASSF8-AS1 played an oncogenic role in ESCC. Target mRNA scanning results suggested involvement of RASSF8-AS1 in tumor immunity and metabolism. CONCLUSION: The newly identified serum exosomal lncRNAs could be used as new biomarkers for ESCC, and showed oncogenic potential in ESCC.

Identification of Candidate Biomarker ASXL2 and Its Predictive Value in Pancreatic Carcinoma.

Pancreatic adenocarcinoma is one of the most lethal diseases with a 5-year survival rate of about 8%. ASXL2 is an epigenetic regulator associated with various tumors including colorectal cancer, breast cancer, and myeloid leukemia. However, the role of ASXL2 in pancreatic cancer remains unclear. This is the first research focusing on the prognostic value of ASXL2 in pancreatic cancer. In this research, we aimed to explore the correlation between ASXL2 and the prognosis, as well as other features in PAAD. We obtained gene expression profiles of PAAD and normal tissues from TCGA, GEO, and Xena databases. TIMER and CIBERSORT algorithms were employed to investigate the effect of ASXL2 on tumor microenvironment. GSEA along with GO and KEGG enrichment analyses were conducted to uncover the biological functions of ASXL2. The response to various chemotherapeutic drugs was estimated by algorithms in R package "pRRophetic", while the sensitivity to immunotherapy was quantified by TIDE score. We found that ASXL2 was upregulated in the PAAD samples and elevated expression of ASXL2 was linked to poor overall survival. ASXL2 DNA methylation contributed to ASXL2 expression. Functional annotation indicated that ASXL2 was mainly involved in inflammatory response and epithelial mesenchymal transition. Patients with high ASXL2 expression were more likely to benefit from immune checkpoint blockade, gemcitabine, and mitomycin-C. Finally, external datasets and biospecimens were used and the results further validated the aberrant expression of ASXL2 in PAAD samples. In summary, our results highlight that ASXL2 is a potential prognostic and predictive biomarker in pancreatic cancer.

FAM83A and FAM83A-AS1 both play oncogenic roles in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. Nevertheless, the detailed molecular mechanisms of the progression of LUAD remain largely unknown. The present bioinformatics analysis reported that FAM83A and FAM83A-AS1 were upregulated in LUAD tissues and associated with prognosis in patients with LUAD. The purpose of the current study was to investigate the role of FAM83A and its antisense long non-coding (lnc)RNA FAM83A-AS1 in LUAD. Gene Expression Profiling Interactive Analysis was used to screen for potential oncogenes in LUAD and to analyze the clinical significance of FAM83A and FAM83A-AS1. Small interfering RNAs were constructed and transfected into LUAD cells to knock down the expression of FAM83A and FAM83A-AS1. EdU, Cell Counting Kit-8, Transwell and Matrigel assays were performed to detect the proliferation, migration and invasion of LUAD cells. The interaction between FAM83A-AS1, microRNA (miR)-495-3p and FAM83A was explored using a luciferase reporter assay. FAM83A and FAM83A-AS1 were both overexpressed in LUAD tissues compared with adjacent normal tissues. High expression of FAM83A and FAM83A-AS1 predicted worse survival and more advanced clinical stage. Knockdown of FAM83A or FAM83A-AS1 could inhibit the proliferation, migration and invasion of LUAD cells. Moreover, lncRNA FAM83A-AS1 regulated the expression of FAM83A by functioning as competing endogenous RNA for miR-495-3p. These results implicated that FAM83A and FAM83A-AS1 both played oncogenic roles in LUAD and FAM83A-AS1 could regulate the expression of FAM83A by sponging miR-495-3p. The study revealed a novel regulatory mechanism of tumor development in LUAD and FAM83A and FAM83A-AS1 may be novel biomarkers and therapeutic targets for LUAD.

lncRNA GAS6-AS1 inhibits progression and glucose metabolism reprogramming in LUAD via repressing E2F1-mediated transcription of GLUT1.

Glucose metabolism reprogramming is one of the hallmarks of cancer cells, although functional and regulatory mechanisms of long noncoding RNA (lncRNA) in the contribution of glucose metabolism in lung adenocarcinoma (LUAD) remain incompletely understood. The aim of this study was to uncover the role of GAS6-AS1 in the regulation of progression and glucose metabolism in LUAD. We discovered that overexpression of GAS6-AS1 suppressed tumor progression of LUAD both in vitro and in vivo. Metabolism-related assays revealed that GAS6-AS1 inhibited glucose metabolism reprogramming. Mechanically, GAS6-AS1 was found to repress the expression of glucose transporter GLUT1, a key regulator of glucose metabolism. Ectopic expression of GLUT1 restored the inhibition effect of GAS6-AS1 on cancer progression and glucose metabolism reprogramming. Further investigation identified that GAS6-AS1 directly interacted with transcription factor E2F1 and suppressed E2F1-mediated transcription of GLUT1, and GAS6-AS1 was downregulated in LUAD tissues and correlated with clinicopathological characteristics and survival of patients. Taken together, our results identified GAS6-AS1 as a novel tumor suppressor in LUAD and unraveled its underlying molecular mechanism in reprogramming glucose metabolism. GAS6-AS1 potentially may serve as a prognostic marker and therapeutic target in LUAD.

Comprehensive Analysis of the Prognostic Significance of Hsa-miR-100-5p and Its Related Gene Signature in Stomach Adenocarcinoma.

Stomach adenocarcinoma (STAD) is one of the most common cancers in the world. However, the prognosis of STAD remains poor, and the therapeutic effect of chemotherapy and immunotherapy varies from person to person. MicroRNAs (miRNAs) play vital roles in tumor development and metastasis and can be used for cancer diagnosis and prognosis. In this study, hsa-miR-100-5p was identified as the only dysregulated miRNA in STAD samples through an analysis of three miRNA expression matrices. A weighted gene co-expression network analysis (WGCNA) was performed to select hsa-miR-100-5p-related genes. A least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to establish a miR-100-5p-related prognostic signature. Kaplan-Meier analyses, nomograms, and univariate and multivariate Cox regression analyses were used to evaluate the prognostic signature, which was subsequently identified as an independent risk factor for STAD patients. We investigated the tumor immune environment between low- and high-risk groups and found that, among component types, M2 macrophages contributed the most to the difference between these groups. A drug sensitivity analysis suggested that patients with high-risk scores may be more sensitive to docetaxel and cisplatin chemotherapy and that patients in the low-risk group may be more likely to benefit from immunotherapy. Finally, external cohorts were evaluated to validate the robustness of the prognostic signature. In summary, this study may provide new ideas for developing more individualized therapeutic strategies for STAD patients.

The ratio of gastric tube length to thorax length: a vital factor affecting leak after esophageal cervical anastomosis.

BACKGROUND: Esophagogastric anastomotic leak (AL) is a severe complication following esophageal resection. This study aims to explore preliminarily whether the ratio of the gastric conduit length to the thorax length can be regarded as a potential prognostic variable for AL, and if so, a cut-off value can be found to divide the patients into distinct risk groups. METHODS: We retrospectively reviewed the clinical data of 273 patients who underwent esophagectomy. The gastric conduit length, the thorax length, and other covariates were collected. Logistic regression was first conducted to probe the rationality of the ratio as a risk indicator of AL. Then the dichotomizing analysis was applied to find the optimal cut-off value. RESULTS: The incidence of AL was 12.5% (34/273). The coefficient of the ratio in the logistic regression equation was -7.901 with P<0.001, which indicated that the larger the ratio, the smaller the risk of AL. Further smoothed scatter plots revealed that a potential step function of the ratio of AL incidence exists, of which the steep part ranges from 1.74 to 1.90. Results of the accurate cut-off value search through a minimum P value approach give the optimal dichotomization point of 1.79. CONCLUSIONS: The ratio of the gastric conduit length to the thorax length can reflect the tension in the anastomosis. The research proposes that surgeons can control the length of the gastric conduit during reconstruction to reduce the tension in the anastomosis and thus lead to a decrease in the incidence of AL.