Capecitabine or Capecitabine Plus Oxaliplatin Versus Fluorouracil Plus Cisplatin in Definitive Concurrent Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma (CRTCOESC): A Multicenter, Randomized, Open-Label, Phase 3 Trial.

PURPOSE: This phase 3 trial aimed to compare the efficacy and safety of capecitabine or capecitabine plus oxaliplatin (XELOX) with those of fluorouracil plus cisplatin (PF) in definitive concurrent chemoradiotherapy (DCRT) for inoperable locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Patients were randomly assigned to receive two cycles of capecitabine, XELOX, or PF along with concurrent intensity-modulated radiation therapy. Patients in each arm were again randomly assigned to receive two cycles of consolidation chemotherapy or not. The primary end points were 2-year overall survival (OS) rate and incidence of grade ≥3 adverse events (AEs). RESULTS: A total of 246 patients were randomly assigned into the capecitabine (n = 80), XELOX (n = 85), and PF (n = 81) arms. In capecitabine, XELOX, and PF arms, the 2-year OS rate was 75%, 66.7%, and 70.9% (capecitabine v PF: hazard ratio [HR], 0.91 [95% CI, 0.61 to 1.35]; nominal P = .637; XELOX v PF: 0.86 [95% CI, 0.58 to 1.27]; P = .444); the median OS was 40.9 (95% CI, 34.4 to 49.9), 41.9 (95% CI, 28.6 to 52.1), and 35.4 (95% CI, 30.4 to 45.4) months. The incidence of grade ≥3 AEs during the entire treatment was 28.8%, 36.5%, and 45.7%, respectively. Comparing the consolidation chemotherapy with the nonconsolidation chemotherapy groups, the median OS was 41.9 (95% CI, 34.6 to 52.8) versus 36.9 (95% CI, 28.5 to 44) months (HR, 0.71 [95% CI, 0.52 to 0.99]; nominal P = .0403). CONCLUSION: Capecitabine or XELOX did not significantly improve the 2-year OS rate over PF in DCRT for inoperable locally advanced ESCC. Capecitabine showed a lower incidence of grade ≥3 AEs than PF did.

PHF5A promotes esophageal squamous cell carcinoma progression via stabilizing VEGFA.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the main subtype of esophageal cancer. Current therapeutic effect is far from satisfaction. Hence, identifying susceptible genes and potential targets is necessary for therapy of ESCC patients. METHODS: Plant homeodomain (PHD)-finger domain protein 5 A (PHF5A) expression in ESCC tissues was examined by immunohistochemistry. RNA interference was used for in vitro loss-of-function experiments. In vivo assay was performed using xenograft mice model by subcutaneous injection. Besides, microarray assay and co-immunoprecipitation experiments were used to study the potential downstream molecules of PHF5A in ESCC. The molecular mechanism between PHF5A and vascular endothelial growth factor A (VEGFA) was explored by a series of ubiquitination related assays. RESULTS: We found that PHF5A was highly expressed in ESCC tissues compared to normal tissues and that was correlated with poor prognosis of ESCC. Loss-of-function experiments revealed that PHF5A silence remarkably inhibited cell proliferation, migration, and induced apoptosis as well as cell cycle arrest. Consistently, in vivo assay demonstrated that PHF5A deficiency was able to attenuate tumor growth. Furthermore, molecular studies showed that PHF5A silencing promoted VEGFA ubiquitination by interacting with MDM2, thereby regulating VEGFA protein expression. Subsequently, in rescue experiments, our data suggested that ESCC cell viability and migration promoted by PHF5A were dependent on intact VEGFA. Finally, PI3K/AKT signaling rescue was able to alleviate shPHF5A-mediated cell apoptosis and cell cycle arrest. CONCLUSION: PHF5A is a tumor promoter in ESCC, which is dependent on VEGFA and PI3K/AKT signaling. PHF5A might serve as a potential therapeutic target for ESCC treatment.

NALCN is a potential biomarker and therapeutic target in human cancers.

Background: Sodium leak channel non-selective (NALCN), known as a voltage-independent Na+ channel, is increasingly considered to play vital roles in tumorigenesis and metastasis of human cancers. However, no comprehensive pan-cancer analysis of NALCN has been conducted. Our study aims to explore the potential diagnostic, prognostic and therapeutic value of NALCN in human cancers. Methods: Through comprehensive application of datasets from Human Protein Atlas (HPA), The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), Enhanced Version of Tumor Immune Estimation Resource (TIMER2.0), Tumor and Immune System Interaction Database (TISIDB), The University of Alabama at Birmingham Cancer data analysis Portal (UALCAN), cBioPortal, GeneMANIA and Search Tool for the Retrieval of Interaction Gene/Proteins (STRING) databases, we explored the potential roles of NALCN in different cancers. The differential expression, prognostic implications, pathological stages and grades, molecular and immune subtypes, diagnostic accuracy, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR) genes, immune checkpoint genes, chemokine genes, major histocompatibility complex (MHC)-related genes, tumor-infiltrating immune cells (TIICs), promoter methylation, mutations, copy number alteration (CNA), and functional enrichment related to NALCN were analyzed. Results: Most cancers lowly expressed NALCN. Upregulated NALCN expression was associated with poor or better prognosis in different cancers. Moreover, NALCN was correlated with clinicopathological features in multiple cancers. NALCN showed high diagnostic accuracy in 5 caner types. NALCN is highly linked with immune-related biomarkers, immune-related genes and TIICs. Significant methylation changes and genetic alteration of NALCN can be observed in many cancers. Enrichment analysis showed that NALCN is closely related to multiple tumor-related signaling pathways. Conclusion: Our study revealed the vital involvement of NALCN in cancer. NALCN can be used as a prognostic biomarker for immune infiltration and clinical outcomes, and has potential diagnostic and therapeutic implications.

PD-1/PD-L1 Inhibitor Plus Chemotherapy Versus PD-1/PD-L1 Inhibitor in Microsatellite Instability Gastrointestinal Cancers: A Multicenter Retrospective Study.

PURPOSE: To investigate the efficacy of PD-1/PD-L1 inhibitors plus chemotherapy versus anti-PD-1/PD-L1 monotherapy in advanced microsatellite instability (MSI)/mismatch repair-deficient (dMMR) gastrointestinal cancers. METHODS: We retrospectively recruited patients with MSI/dMMR gastrointestinal cancer who received anti-PD-1/PD-L1 with or without chemotherapy and compared objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) of PD-1/PD-L1 inhibitor plus chemotherapy (chemo-anti-PD-1/PD-L1 group) and PD-1/PD-L1 inhibitor alone (anti-PD-1/PD-L1 group). Propensity score-based overlap weighting analysis was conducted to adjust the baseline covariable imbalance. Sensitivity analysis was performed to confirm the stability of the results by propensity score matching and multivariable Cox and logistic regression models. RESULTS: A total of 256 patients were eligible, with 68 and 188 receiving chemo-anti-PD-1/PD-L1 and anti-PD-1/PD-L1, respectively. The chemo-anti-PD-1/PD-L1 group showed significant improvements versus the anti-PD-1/PD-L1 group in ORR (61.8% v 38.8%; P = .001), DCR (92.6% v 74.5%; P = .002), PFS (median PFS [mPFS], not reached [NR] v 27.9 months; P = .004), and OS (median OS [mOS], NR v NR; P = .014). After overlap weighting, the improvements tended to be more significant with chemo-anti-PD-1/PD-L1 versus anti-PD-1/PD-L1 in ORR (62.5% v. 38.3%; P < .001), DCR (93.8% v 74.2%; P < .001), PFS (mPFS, NR v 26.0 months; P = .004), and OS (mOS, NR v NR; P = .010). These results were solidified through sensitivity analysis. CONCLUSION: Chemo-anti-PD-1/PD-L1 is superior to anti-PD-1/PD-L1 in MSI/dMMR gastrointestinal cancers with improved efficacy.

Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Esophageal Squamous Cell Carcinoma.

Lymph node metastasis, the leading cause of mortality in esophageal squamous carcinoma (ESCC) with a highly complex tumor microenvironment, remains underexplored. Here, the transcriptomes of 85 263 single cells are analyzed from four ESCC patients with lymph node metastases. Strikingly, it is observed that the metastatic microenvironment undergoes the emergence or expansion of interferon induced IFIT3+ T, B cells, and immunosuppressive cells such as APOC1+ APOE+ macrophages and myofibroblasts with highly expression of immunoglobulin genes (IGKC) and extracellular matrix component and matrix metallopeptidase genes. A poor-prognostic epithelial-immune dual expression program regulating immune effector processes, whose activity is significantly enhanced in metastatic malignant epithelial cells and enriched in CD74+ CXCR4+ and major histocompatibility complex (MHC) class II genes upregulated malignant epithelia cells is discovered. Comparing with primary tumor, differential intercellular communications of metastatic ESCC microenvironment are revealed and furtherly validated via multiplexed immunofluorescence and immunohistochemistry staining, which mainly rely on the crosstalk of APOC1+ APOE+ macrophages with tumor and stromal cell. The data highlight potential molecular mechanisms that shape the lymph-node metastatic microenvironment and may inform drug discovery and the development of new strategies to target these prometastatic nontumor components for inhibiting tumor growth and overcoming metastasis to improve clinical outcomes.

Feasibility and tolerability of sintilimab plus anlotinib as the second-line therapy for patients with advanced biliary tract cancers: An open-label, single-arm, phase II clinical trial.

Patients with biliary tract cancer (BTC) were associated with poor prognosis and limited therapeutic options after first-line therapy currently. In this study, we sought to evaluate the feasibility and tolerability of sintilimab plus anlotinib as the second-line treatment for patients with advanced BTC. Eligible patients had histologically confirmed locally advanced unresectable or metastatic BTC and failed after the first-line treatment were recruited. The primary endpoint was overall survival (OS). Simultaneously, association between clinical outcomes and genomic profiling and gut microbiome were explored to identify the potential biomarkers for this regimen. Twenty patients were consecutively enrolled and received study therapy. The trail met its primary endpoint with a median OS of 12.3 months (95% CI: 10.1-14.5). Only four (20%) patients were observed of the grade 3 treatment-related adverse events (TRAEs) and no grade 4 or 5 TRAEs were detected. Mutation of AGO2 was correlated with a significantly longer OS. Abundance of Proteobacteria was associated with inferior clinical response. Therefore, sintilimab plus anlotinib demonstrated encouraging anti-tumor activity with a tolerable safety profile and deserved to be investigated in larger randomized trials for patients with advanced BTC subsequently.

Macrophage-derived exosomes regulate gastric cancer cell oxaliplatin resistance by wrapping circ 0008253.

Oxaliplatin (OXA) is a first-line chemotherapy drug for gastric cancer. We aimed to investigate the effect of circ 0008253, contained in M2 polarized macrophage-derived exosomes, on OXA resistance of gastric carcinoma cells. Flow cytometry was performed to detect the differentiation of macrophages and cell apoptosis. Cell Counting Kit-8 assay was conducted to examine the cell viability. Transmission electron microscopy, Nanoparticle Tracking Analysis, Western bolt, and Immunofluorescence were carried out. Cell proliferation was detected with a colony formation experiment. Levels of CD206, Arg1, IL-10, and TGF-ß were increased in M2 polarized macrophages. Cell viability was decreased gradually with the increase of time and OXA concentration. Apoptosis of gastric carcinoma cells was decreased after co-culture with M2-polarized macrophages. Exosomes isolated from M2-polarized macrophages (M2-Exos) could be co-located with gastric carcinoma cells. M2-Exos enhanced drug resistance, reduced apoptosis and OXA resistance. Bioinformatics analysis showed that circ 0008253 could be transferred from M2-Exos to gastric carcinoma cells. Overexpressing circ 0008253 increased cell viability, tumor size, and ABCG2 levels, decreased OXA sensitivity. Circ 0008253, contained in M2-Exos, was directly transferred from tumor-associated macrophage to gastric carcinoma cells, finally enhancing OXA resistance.

The Optimal Therapy after Progression on Immune Checkpoint Inhibitors in MSI Metastatic Gastrointestinal Cancer Patients: A Multicenter Retrospective Cohort Study.

BACKGROUND: In microsatellite instability (MSI)/mismatch repair-deficient (dMMR) gastrointestinal cancers, the optimum therapy after the progression of immune checkpoint inhibitors (ICIs) is yet unknown. Here, we compared the efficacy of programmed death 1 (PD1)/programmed death ligand-1 (PD-L1) inhibitors plus other therapy and chemotherapy with or without targeted therapy in MSI/dMMR gastrointestinal cancer patients after progression on anti-PD1/PD-L1 monotherapy. METHODS: We retrospectively recruited MSI/dMMR gastrointestinal cancer patients who had progressed on anti-PD1/PD-L1 monotherapy. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and PFS ratio (PFSr) were compared between patients who received anti-PD1/PD-L1 plus other therapy (ICI-plus group) and patients who received chemotherapy with or without targeted therapy (chemo-targeted group). RESULTS: In total, 26 and 25 patients were recruited in the ICI-plus group and chemo-targeted group, respectively. Significantly better DCR (80.8% vs. 44.0%, p = 0.007), PFS (median PFS 6.9 months vs. 3.0 months, p = 0.001), OS (median OS NR vs. 14.1 months, p = 0.043), and PFSr (2.4 vs. 0.9, p = 0.021), along with a numerically higher ORR (23.1% vs. 12.0%, p = 0.503) were observed in the ICI-plus group compared with the chemo-targeted group. Multivariate analyses identified the therapy regimen as an important prognostic factor in gastrointestinal cancers. CONCLUSIONS: Compared to conventional chemotherapy with or without targeted therapy, continuing anti-PD1/PD-L1 in combination with other treatments showed better clinical outcomes in MSI/dMMR gastrointestinal cancer patients who progressed on PD1/PD-L1 blockade, which should be validated prospectively in clinical trials.

Long non-coding RNA NEAT1 mediated RPRD1B stability facilitates fatty acid metabolism and lymph node metastasis via c-Jun/c-Fos/SREBP1 axis in gastric cancer.

BACKGROUND: Lymph node metastasis is one of most common determinants of the stage and prognosis of gastric cancer (GC). However, the key molecular events and mechanisms mediating lymph node metastasis remain elusive. METHODS: RNA sequencing was used to identify driver genes responsible for lymph node metastasis in four cases of gastric primary tumors, metastatic lesions of lymph nodes and matched normal gastric epithelial tissue. qRT-PCR and IHC were applied to examine RPRD1B expression. Metastatic functions were evaluated in vitro and in vivo. RNA-seq was used to identify target genes. ChIP, EMSA and dual luciferase reporter assays were conducted to identify the binding sites of target genes. Co-IP, RIP, MeRIP, RNA-FISH and ubiquitin assays were applied to explore the underlying mechanisms. RESULTS: The top 8 target genes (RPRD1B, MAP4K4, MCM2, TOPBP1, FRMD8, KBTBD2, ADAM10 and CXCR4) that were significantly upregulated in metastatic lymph nodes of individuals with GC were screened. The transcriptional cofactor RPRD1B (regulation of nuclear pre-mRNA domain containing 1B) was selected for further characterization. The clinical analysis showed that RPRD1B was significantly overexpressed in metastatic lymph nodes and associated with poor outcomes in patients with GC. The Mettl3-induced m6A modification was involved in the upregulation of RPRD1B. Functionally, RPRD1B promoted lymph node metastasis capabilities in vitro and in vivo. Mechanistic studies indicated that RPRD1B increased fatty acid uptake and synthesis by transcriptionally upregulating c-Jun/c-Fos and activating the c-Jun/c-Fos/SREBP1 axis. In addition, NEAT1 was upregulated significantly by c-Jun/c-Fos in RPRD1B-overexpressing cells. NEAT1, in turn, increased the stability of the RPRD1B mRNA by recruiting the m6A "reader" protein hnRNPA2B1 and reduced the degradation of the RPRD1B protein by inhibiting TRIM25-mediated ubiquitination. Notably, this functional circuitry was disrupted by an inhibitor of c-Jun/c-Fos/AP1 proteins (SR11302) and small interfering RNAs targeting NEAT1, leading to a preferential impairment of lymph node metastasis. CONCLUSIONS: Based on these findings, RPRD1B facilitated FA metabolism and assisted primary tumor implantation in lymph nodes via the c-Jun/c-Fos/SREBP1 axis, which was enhanced by a NEAT1-mediated positive feedback loop, serving as a potential therapeutic target for GC treatment.

Hyaluronic Acid-Stabilized Fe3O4 Nanoparticles for Promoting In Vivo Magnetic Resonance Imaging of Tumors.

The use of iron oxide (Fe3O4) nanoparticles as novel contrast agents for magnetic resonance imaging (MRI) has attracted great interest due to their high r 2 relaxivity. However, both poor colloidal stability and lack of effective targeting ability have impeded their further expansion in the clinics. Here, we reported the creation of hyaluronic acid (HA)-stabilized Fe3O4 nanoparticles prepared by a hydrothermal co-precipitation method and followed by electrostatic adsorption of HA onto the nanoparticle surface. The water-soluble HA functions not only as a stabilizer but also as a targeting ligand with high affinity for the CD44 receptor overexpressed in many tumors. The resulting HA-stabilized Fe3O4 nanoparticles have an estimated size of sub-20 nm as observed by transmission electron microscopy (TEM) imaging and exhibited long-term colloidal stability in aqueous solution. We found that the nanoparticles are hemocompatible and cytocompatible under certain concentrations. As verified by quantifying the cellular uptake, the Fe3O4@HA nanoparticles were able to target a model cell line (HeLa cells) overexpressing the CD44 receptor through an active pathway. In addition, we showed that the nanoparticles can be used as effective contrast agents for MRI both in vitro in HeLa cells and in vivo in a xenografted HeLa tumor model in rodents. We believe that our findings shed important light on the use of active targeting ligands to improve the contrast of lesion for tumor-specific MRI in the nano-based diagnosis systems.

Long-term effect of hospital volume on the postoperative prognosis of 158,618 patients with esophageal squamous cell carcinoma in China.

Background: The impact of hospital volume on the long-term survival of esophageal squamous cell carcinoma (ESCC) has not been well assessed in China, especially for stage I-III stage ESCC. We performed a large sample size study to assess the relationships between hospital volume and the effectiveness of ESCC treatment and the hospital volume value at the lowest risk of all-cause mortality after esophagectomy in China. Aim: To investigate the prognostic value of hospital volume for assessing postoperative long-term survival of ESCC patients in China. Methods: The date of 158,618 patients with ESCC were collected from a database (1973-2020) established by the State Key Laboratory for Esophageal Cancer Prevention and Treatment, the database includes 500,000 patients with detailed clinical information of pathological diagnosis and staging, treatment approaches and survival follow-up for esophageal and gastric cardia cancers. Intergroup comparisons of patient and treatment characteristics were conducted with the X2 test and analysis of variance. The Kaplan-Meier method with the log-rank test was used to draw the survival curves for the variables tested. A Multivariate Cox proportional hazards regression model was used to analyze the independent prognostic factors for overall survival. The relationship between hospital volume and all-cause mortality was assessed using restricted cubic splines from Cox proportional hazards models. The primary outcome was all-cause mortality. Results: In both 1973-1996 and 1997-2020, patients with stage I-III stage ESCC who underwent surgery in high volume hospitals had better survival than those who underwent surgery in low volume hospitals (both P<0.05). And high volume hospital was an independent factor for better prognosis in ESCC patients. The relationship between hospital volume and the risk of all-cause mortality was half-U-shaped, but overall, hospital volume was a protective factor for esophageal cancer patients after surgery (HR<1). The concentration of hospital volume associated with the lowest risk of all-cause mortality was 1027 cases/year in the overall enrolled patients. Conclusion: Hospital volume can be used as an indicator to predict the postoperative survival of ESCC patients. Our results suggest that the centralized management of esophageal cancer surgery is meaningful to improve the survival of ESCC patients in China, but the hospital volume should preferably not be higher than 1027 cases/year. Core tip: Hospital volume is considered to be a prognostic factor for many complex diseases. However, the impact of hospital volume on long-term survival after esophagectomy has not been well evaluated in China. Based on a large sample size of 158,618 ESCC patients in China spanning 47 years (1973-2020), We found that hospital volume can be used as a predictor of postoperative survival in patients with ESCC, and identified hospital volume thresholds with the lowest risk of death from all causes. This may provide an important basis for patients to choose hospitals and have a significant impact on the centralized management of hospital surgery.

Circ-SFMBT2 drives the malignant phenotypes of esophageal cancer by the miR-107-dependent regulation of SLC1A5.

BACKGROUND: Increasing studies focused on the regulatory roles of circular RNAs (circRNAs) in diverse cancers. This study was to evaluate the function and mechanism of circRNA Scm-like with four malignant brain tumor domains 2 (circ-SFMBT2) in esophageal cancer (EC). METHODS: The circ-SFMBT2, microRNA-107 (miR-107) and solute-linked carrier family A1 member 5 (SLC1A5) levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was evaluated by 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT) assay, colony formation assay and EdU assay. Cell apoptosis and invasion were detected by flow cytometry and transwell assay. Glutamine metabolism was assessed by the corresponding kits for glutamine consumption, α-ketoglutarate production and glutamate production. Western blot was used for protein quantification. The binding analysis was performed using dual-luciferase reporter assay, RNA immunoprecipitation (RIP) and pull-down assays. The functional research of circ-SFMBT2 in vivo was performed by xenograft tumor assay. Exosomes were identified by morphological observation and protein detection. RESULTS: Circ-SFMBT2 was overexpressed in EC samples and cells. Circ-SFMBT2 downregulation inhibited EC cell proliferation, invasion and glutamine metabolism. Circ-SFMBT2 targeted miR-107 and the regulation of circ-SFMBT2 was achieved by sponging miR-107. SLC1A5 was a target of miR-107, and it worked as an oncogene in EC cells. MiR-107 retarded the EC progression by downregulating SLC1A5. Circ-SFMBT2 could affect the SLC1A5 expression by targeting miR-107. Circ-SFMBT2 regulated EC progression in vivo by miR-107/SLC1A5 axis. Circ-SFMBT2 was transferred by exosomes in EC cells. CONCLUSION: These results suggested that circ-SFMBT2 upregulated the SLC1A5 expression to promote the malignant development of EC by serving as a miR-107 sponge.

LncRNA HCP5 Induces Gastric Cancer Cell Proliferation, Invasion, and EMT Processes Through the miR-186-5p/WNT5A Axis Under Hypoxia.

OBJECTIVE: To experimentally determine the involvement and mechanism of long non-coding RNA (lncRNA) HCP5 in the development of gastric cancer (GC). METHODS: Detection of HCP5, miR-186-5p, and WNT5A expression in clinical GC tissues and adjacent healthy tissues was performed, followed by Pearson correlation analysis. BGC-823 and AGS cells, with interferences of HCP5, miR-186-5p, and WNT5A, were cultured under hypoxia. MTT, colony formation assay, Caspase-3 activity assay, and transwell assay were applied for the determination of cell proliferation, viability, apoptosis, and invasion, respectively. Expressions of WNT5A and protein markers of epithelial-mesenchymal transition (EMT) in cells were detected by western blotting. And the binding of HCP5 and WNT5A to miR-186-5p was validated using dual-luciferase reporter assay. RESULTS: In GC tissues, an increase in HCP5 and WNT5A expressions and a reduction in miR-186-5p expression were found, and the negative correlation between miR-186-5p and HCP5/WNT5A was proven. Subsequently, under hypoxia, an increase in HCP5 and WNT5A expressions and a decrease in miR-186-5p expression in GC cells were confirmed. In addition, in GC cells under hypoxia, the inhibition of HCP5 suppressed cell biological activity and EMT, while the inhibition of miR-186-5p or the overexpression of WNT5A led to the opposite changes. CONCLUSION: An upregulation of WNT5A expression by HCP5 competitively binding to miR-186-5p promotes GC cell development.

Long Non-Coding RNA NEAT1 Serves as Sponge for miR-365a-3p to Promote Gastric Cancer Progression via Regulating ABCC4.

INTRODUCTION: Long non-coding RNA (lncRNA) was reported to be a crucial regulator in cancer. In this work, our purpose is to explore the biological roles of nuclear paraspeckle assembly transcript 1 (NEAT1) in gastric cancer (GC). METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect NEAT1 expression in GC cells and normal cells. GC cell behaviors after NEAT1 overexpression or downregulation were analyzed by Cell Counting Kit-8 assay, colony formation assay, wound-healing assay, and flow cytometry assay. Bioinformatic tools were used to analyze the significance of NEAT1 in GC. The involvement of microRNA-365a-3p (miR-365a-3p) and ATP-binding cassette subfamily C member 4 (ABCC4) in the biological roles of NEAT1 in GC progression was validated by luciferase activity reporter assay and rescue experiments. RESULTS: We found NEAT1 increased expression in both GC tissues and cells and correlated with poorer overall survival of cancer patients. We found NEAT1 overexpression promotes, while its knockdown inhibits GC cell proliferation, colony formation, invasion, and cell cycle progression in vitro. Mechanism analyses showed that NEAT1 serves as a ceRNA to upregulate ABCC4 expression via sponging miR-365a-3p. CONCLUSION: In this study, we revealed a NEAT1/miR-365a-3p/ABCC4 triplet in GC progression, which may provide novel targeted therapy markers for GC.

Characterization of 500 Chinese patients with cervical esophageal cancer by clinicopathological and treatment outcomes.

Objective: There are no comprehensive studies on survival outcomes and optimal treatment protocols for cervical esophageal cancer (CEC), due to its rare clinical prevalence. Our objective was to determine the relationship between pathological characteristics, treatment protocols, and survival outcomes in Chinese CEC patients. Methods: A total of 500 Chinese CEC patients were selected from our 500,000 esophageal and gastric cardia carcinoma database (1973-2018). There were two main groups: patients treated with surgery, and patients receiving non-surgical treatments (radiotherapy, radiochemotherapy, and chemotherapy). The Chi-square test and Kaplan-Meier method were used to compare the continuous variables and survival. Results: Among the 500 CEC patients, 278 (55.6%) were male, and the median age was 60.9 ± 9.4 years. A total of 496 patients (99.2%) were diagnosed with squamous cell carcinoma. In 171 (34.2%) patients who received surgery, 22 (12.9%) had undergone laryngectomy. In 322 (64.4%) patients who received non-surgical treatments, 245 (76.1%) received radiotherapy. Stratified survival analysis showed that only T stage was related with survival outcomes for CEC patients in the surgical group, and the outcomes between laryngectomy and non-laryngectomy patients were similar. It was noteworthy that the 5-year survival rate was similar in CEC patients among the different groups treated with surgery, radiotherapy, chemotherapy, or radiochemotherapy (P = 0.244). Conclusions: The CEC patients had similar survival outcomes after curative esophagectomy and radiotherapy, including those with or without total laryngectomy. These findings suggest that radiotherapy could be the initial choice for treatment of Chinese CEC patients.

New Strategy toward Household Coal Combustion by Remarkably Reducing SO2 Emission.

A large amount of sulfur dioxide (SO2) will be released during rural household coal combustion, causing serious environmental pollution. Therefore, it is very urgent to develop a clean and efficient fuel to substitute rural household coal controlling SO2 emission. In this paper, a new strategy toward scattered coal combustion with remarkably reducing SO2 emission was proposed. Coal and compound additive of Al2O3 and CaCO3 were blended and then copyrolysis at 1050 °C was performed to produce clean coke. First, the sulfur content of clean coke was reduced, meanwhile, generating sulfur fixation precursor during pyrolysis. Then, clean coke is used for efficient sulfur fixation during the subsequent combustion process to reduce SO2 emissions. The effects of combustion temperature, Al/S molar ratio, and the mechanism of sulfur retention during clean coke combustion were studied in the tube furnace and muffle furnace. The mechanism can be attributed the following reason: (a) CaS produced during pyrolysis and CaO decomposed by complex additives were oxidized during combustion, and CaO captured the SO2 released from clean coke combustion, which formed CaSO4. (b) CaSO4 reacts with Al2O3 to produce calcium sulfoaluminate at high temperatures, which improves the sulfur fixation efficiency of clean coke combustion at high temperatures. In a word, this new strategy can greatly reduce the emission of SO2, thus helping to solve rural household coal pollution problems.

Down-Regulation of CIDEA Promoted Tumor Growth and Contributed to Cisplatin Resistance by Regulating the JNK-p21/Bad Signaling Pathways in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies with poor prognosis and lack of effective targeted therapies. In this study, we investigated the tumor suppressive role of the cell death inducing DFF like effector A (CIDEA) in ESCC. Firstly, public datasets and ESCC tissue microarray analysis showed that CIDEA was frequently down-regulated at both the mRNA and protein level. This was significantly associated with low differentiation and TNM stage in ESCC, and indicated poor prognosis for ESCC patients. Bisulfite genomic sequencing (BGS) and methylation-specific PCR (MSP) analysis revealed that the down-regulation of CIDEA was associated with hypermethylation of its promoter, which was also correlated with the poor prognosis in ESCC patients. In vitro and in vivo functional studies demonstrated that CIDEA decreased cell growth, foci formation, DNA replication, and tumorigenesis in nude mice. Further study revealed that, during starvation or cisplatin induced DNA damage, CIDEA facilitated the G1-phase arrest or caspase-dependent mitochondrial apoptosis through the JNK-p21/Bad pathway. Therefore, CIDEA is a novel tumor suppressor gene that plays an important role in the development and progression of ESCC, and may provide a potential therapeutic target for patients with ESCC.

Reinforcement of Bonding Strength and Water Resistance of Soybean Meal-Based Adhesive via Construction of an Interactive Network from Biomass Residues.

Soybean meal-based adhesives are attractive potential environmentally friendly replacements for formaldehyde-based adhesives. However, the low strength and poor water resistance of soybean meal-based adhesives limit their practical application. This study was conducted to develop a natural fiber-reinforced soybean meal-based adhesive with enhanced water resistance and bonding strength. Pulp fiber (PF), poplar wood fiber (WF), and bagasse fiber (BF) were added as fillers into the soybean meal-based adhesive to enhance its performance via hydrogen bonding between the PF and the soybean meal system. The enhanced adhesive exhibited a strong crosslinking structure characterized by multi-interfacial interactions wherein PF served as a bridging ligament and released residual stress into the crosslinking network. The crosslinked structure and improved interfacial interactions were confirmed by Fourier transform infrared (FTIR) spectrophotometry, thermogravimetric analysis (TGA), and scanning electron microscopy (SEM) measurements. Plywood bonded with 4 wt % PF-containing soybean meal-based adhesive exhibited a wet shear strength (1.14 MPa) exceeding that of plywood bonded with the control group by 75.4% due to the stable crosslinking network having efficiently transformed stress and prevented the permeation of water molecules.

Clinical efficacy and survival analysis of apatinib combined with docetaxel in advanced esophageal cancer.

BACKGROUND AND AIM: Standard chemotherapy has limited clinical efficacy in patients with esophageal cancer and there is a significant and unmet clinical need for effective treatment options for these patients. The aim of this study was to compare the clinical efficacy of the novel, targeted drug apatinib combined with docetaxel, and docetaxel combined with S-1 as second- or further-line treatment for patients with advanced esophageal cancer. METHODS: We enrolled 33 patients with advanced esophageal cancer in chemotherapy group or apatinib combined with chemotherapy group in this retrospective study. Apatinib (500 mg) was taken orally once daily; docetaxel was administered at a dose of 75 mg/m2; and S-1 was optional at a dose of 40-60 mg, based on body surface area. The primary endpoint of this study was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and the incidence and severity of adverse events (AEs). RESULTS: No complete response was observed in the two groups. However, two and five patients achieved partial response in the chemotherapy group and the apatinib combined with chemotherapy group, respectively. The ORR and DCR for the chemotherapy group was 11.1% and 33.3%, respectively. In the apatinib combination group, ORR and DCR was 88.9% and 93.3%, respectively. Anemia (11.1%) and neutropenia (5.6%) were the most frequent grade III/IV AEs observed in the chemotherapy group. In the apatinib combination group, the most frequent grade III/IV AEs were anemia (13.3%), hypertension (6.7%), and proteinuria (6.7%). Median PFS was significantly longer in the apatinib combination group than in the chemotherapy group (175 days vs 85 days, P=0.01). CONCLUSION: The combination of apatinib and docetaxel has a manageable toxicity profile and may prolong survival. Therefore, this combination may be used as as second- or further-line treatment for patients with advanced esophageal cancer.

Prognostic implications of MYBL2 in resected Chinese gastric adenocarcinoma patients.

BACKGROUND AND AIM: Gastric cancer (GC), a malignant tumor worldwide, is mostly diagnosed at an advanced stage. We selected the oncogene encoding transcription factors MYBL2 to investigate the connection between MYBL2 expression and GC prognosis. MATERIALS AND METHODS: MYBL2 mRNA and protein expression were measured by real-time PCR and immunohistochemistry, respectively. The relationship between MYBL2 protein expression and survival time was estimated by the Kaplan-Meier analysis. Cox proportional hazards model was used to evaluate the prognostic impact of MYBL2 expression. RESULTS: The overexpression of MYBL2 was related to tumor cell differentiation, Lauren type, and metastasis of lymph nodes (P<0.05). In the MYBL2 overexpression group, the median disease free survival was even poorer (P=0.000) and it comes to median overall survival (P=0.000). The study showed that MYBL2 expression was an independent hazard for disease free survival (P=0.004). CONCLUSION: The results of this study suggest that MYBL2 could indicate a promisingly prognostic biomarker for GC patients.