Correlation between tumor budding and the long-term follow-up outcomes after endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma.

BACKGROUND: The effect of tumor budding (TB) on the prognosis of patients with esophageal squamous cell carcinoma (ESCC) after endoscopic submucosal dissection (ESD) remains unclear. We evaluated the long-term outcomes of patients with superficial ESCC after ESD and the risk factors of TB for the long-term prognosis. METHODS: We conducted a retrospective study in a Chinese hospital. All patients with ESCC treated by ESD and reported TB were included consecutively. Comparative analyses were conducted in three parts: specimen analysis, follow-up analyses of unmatched patients, and propensity score-matched (PSM) patients. Cox proportional hazard regression models were constructed to identify risk factors for overall survival and recurrence-free survival (RFS). RESULTS: A total of 437 patients were enrolled [154 TB and 283 no tumor budding (NTB)], and 258 patients (52 TB and 206 NTB) were included in the follow-up analysis. Results showed that the invasion depth, differentiation type, and positive vascular invasion (all p < 0.001) of the TB group were significantly different from the NTB group. The all-cause mortality and the median RFS time between the two groups were comparable. RFS rate at 5 years were 84.6% and 80.6%, respectively (p = 0.43). Cox analyses identified that having other cancers but not TB, as a risk factor independently associated with overall survival and RFS after ESD. CONCLUSION: TB tends to be associated with invasion depth, differentiation type, and positive vascular invasion. However, it might not affect the long-term outcomes of patients with superficial ESCC after ESD when other high-risk factors are negative.

Bimetallic Intercalated Vanadium Oxide As a High-Performance Cathode for Aqueous Zinc Ion Batteries.

In this paper, a bimetallic Na0.13Mg0.02V2O5·0.98H2O (NMVO) material with an interlayer spacing of 11.67 Å was synthesized by a simple preintercalation method as a cathode for zinc ionic batteries (ZIBs). The large layer spacing provides a wide channel for the embedding of Zn2+, resulting in high reversible capacity and ion diffusion kinetics. In addition, by virtue of the high electronic conductivity of metal ions, NMVO exhibits excellent electronic conductivity under the combined action of Na+ and Mg2+ bimetallic intercalation. At the same time, preintercalation ions and structural water act as interlayer pillars to stabilize the layer structure of NMVO during the cycling process. The above reasonable structural design endows the NMVO with excellent electrochemical performance. The battery with NMVO cathode delivers a high initial capacity of 126 mAh g-1 at 10 A g-1, and still remains at 76% after 5000 cycles, providing 100 Wh kg-1 energy density and 9.5 kW kg-1 power density (based on the mass of cathode). This bimetallic intercalation structure provides a general feasible scheme for the design of vanadium-based electrode materials.

Low-Temperature and High-Performance Vanadium-Based Aqueous Zinc-Ion Batteries.

Aqueous zinc-ion batteries have attracted attention due to their low cost and high safety. Unfortunately, dendrite growth, hydrogen evolution reactions, cathodic dissolution, and other problems are more serious; not only that, but also the cathodic and anodic materials' lattices contract when the temperature drops, and charge transfer and solid phase diffusion become slow, seriously aggravating dendrite growth. At present, there are few studies on the low-temperature system, and studies on retaining high specific capacity are even more rare. Herein, ethylene glycol (EG) and manganese sulfate (MSO) are selected as additives, and the manganese vanadate (MVO) cathode is used to find a high-performance solution at low temperature. MVO can provide higher specific capacity and better structural stability than MnO2 to adapt to a low-temperature environment. At the same time, Mn2+ in MSO can produce a cationic shield covering the initial zinc tip at an appropriate concentration to avoid the tip effect and inhibit the dissolution of MVO. EG can not only reduce the freezing point of the electrolyte but also promote the desolvation of [Zn(H2O)6]2+. The synergistic effect of the three elements prevents the dissolution equilibrium of Mn2+ in MVO from fluctuating greatly due to the change of temperature. Therefore, when we use EG@0.2 M MnSO4 + 2 M ZnSO4 (EG + 0.2Mn/2ZSO) electrolyte at -30 °C, the Zn||Zn batteries which used this type of electrolyte can remain 350 h at 1 mA cm-2 without failure. The Zn||Cu batteries can retain 100% Coulombic efficiency after more than 2000 cycles at 0.2 mA cm-2. The Zn||MVO battery can reach 231.13 mA h g-1 at its first cycle, and the capacity retention rate is still above 85% after 1000 cycles, which is higher than that of the existing low-temperature research system.

Processing mechanism synergizing surface and intercalation pseudocapacitance engineering fast-charging Li-based anode materials.

Pseudocapacitive material can achieve rapid charge and discharge response. In this study, a vanadium-based conductive network hydrate (Na0.13Mg0.02)V2O5·0.98H2O (NMVO) was designed. The Na+ and Mg2+ in NMVO are sandwiched between two layers of vacancy-ordered prisms and monoclinic nanonetwork V3O7 (VO2:V2O5 = 1:1) to form a conductive network with a layer spacing of up to 11.67 Å, this structure facilitates rapid interlayer diffusion of cations and enhanced conductivity. Reduction-NMVO (r-NMVO) with hierarchical heterostructures was prepared via an in-situ electrochemical process to generate interlayer vanadium-based active sites (LiV3O8, LiV2O5, Na3V3O8, MgVO3) with multi-electron reaction, which enhanced the generation of surface redox pseudocapacitance. The interlayer heterostructure is integrated with the core of the precursor V3O7 to form an active site-rich conductive network with strong pulse impact resistance, which promotes the generation of intercalated pseudocapacitance and increases the cycle stability of the electrode. This intercalation-surface redox pseudocapacitive mechanism was confirmed by first-principles, in-situ, and ex-situ characterization analysis. The r-NMVO|Li battery still maintains a capacity of 95.5 % after 65,500 cycles at a current density of 50 A g-1. These results contribute directly to the realization of stable, fast charge and discharge material design.

Compartmentalized PGRP expression along the dipteran Bactrocera dorsalis gut forms a zone of protection for symbiotic bacteria.

All metazoan guts are subject to opposing pressures wherein the immune system must eliminate pathogens while tolerating the presence of symbiotic microbiota. The Imd pathway is an essential defense against invading pathogens in insect guts, but tolerance mechanisms are less understood. Here, we find PGRP-LB and PGRP-SB express mainly in the anterior and middle midgut in a similar pattern to symbiotic Enterobacteriaceae bacteria along the Bactrocera dorsalis gut. Knockdown of PGRP-LB and PGRP-SB enhances the expression of antimicrobial peptide genes and reduces Enterobacteriaceae numbers while increasing abundance of opportunistic pathogens. Microbiota numbers recover to normal levels after the RNAi effect subsided. In contrast, high expression of PGRP-LC in the foregut allows increased antibacterial peptide production to efficiently filter the entry of pathogens, protecting the symbiotic bacteria. Our study describes a mechanism by which regional expression of PGRPs construct a protective zone for symbiotic microbiota while maintaining the ability to fight pathogens.

Artificial Intelligence for Detecting and Delineating Margins of Early ESCC Under WLI Endoscopy.

INTRODUCTION: Conventional white light imaging (WLI) endoscopy is the most common screening technique used for detecting early esophageal squamous cell carcinoma (ESCC). Nevertheless, it is difficult to detect and delineate margins of early ESCC using WLI endoscopy. This study aimed to develop an artificial intelligence (AI) model to detect and delineate margins of early ESCC under WLI endoscopy. METHODS: A total of 13,083 WLI images from 1,239 patients were used to train and test the AI model. To evaluate the detection performance of the model, 1,479 images and 563 images were used as internal and external validation data sets, respectively. For assessing the delineation performance of the model, 1,114 images and 211 images were used as internal and external validation data sets, respectively. In addition, 216 images were used to compare the delineation performance between the model and endoscopists. RESULTS: The model showed an accuracy of 85.7% and 84.5% in detecting lesions in internal and external validation, respectively. For delineating margins, the model achieved an accuracy of 93.4% and 95.7% in the internal and external validation, respectively, under an overlap ratio of 0.60. The accuracy of the model, senior endoscopists, and expert endoscopists in delineating margins were 98.1%, 78.6%, and 95.3%, respectively. The proposed model achieved similar delineating performance compared with that of expert endoscopists but superior to senior endoscopists. DISCUSSION: We successfully developed an AI model, which can be used to accurately detect early ESCC and delineate the margins of the lesions under WLI endoscopy.

The Negative Regulative Roles of BdPGRPs in the Imd Signaling Pathway of Bactrocera dorsalis.

Peptidoglycan recognition proteins (PGRPs) are key regulators in insects' immune response, functioning as sensors to detect invading pathogens and as scavengers of peptidoglycan (PGN) to reduce immune overreaction. However, the exact function of PGRPs in Bactrocera dorsalis is still unclear. In this study, we identified and functionally characterized the genes BdPGRP-LB, BdPGRP-SB1 and BdPGRP-SC2 in B. dorsalis. The results showed that BdPGRP-LB, BdPGRP-SB1 and BdPGRP-SC2 all have an amidase-2 domain, which has been shown to have N-Acetylmuramoyl-l-Alanine amidase activity. The transcriptional levels of BdPGRP-LB and BdPGRP-SC2 were both high in adult stages and midgut tissues; BdPGRP-SB1 was found most abundantly expressed in the 2nd instar larvae stage and adult fat body. The expression of BdPGRP-LB and BdPGRP-SB1 and AMPs were significantly up-regulated after injury infected with Escherichia coli at different time points; however, the expression of BdPGRP-SC2 was reduced at 9 h, 24 h and 48 h following inoculation with E. coli. By injection of dsRNA, BdPGRP-LB, BdPGRP-SB1 and BdPGRP-SC2 were knocked down by RNA-interference. Silencing of BdPGRP-LB, BdPGRP-SB1 and BdPGRP-SC2 separately in flies resulted in over-activation of the Imd signaling pathway after bacterial challenge. The survival rate of the ds-PGRPs group was significantly reduced compared with the ds-egfp group after bacterial infection. Taken together, our results demonstrated that three catalytic PGRPs family genes, BdPGRP-LB, BdPGRP-SB1 and BdPGRP-SC2, are important negative regulators of the Imd pathway in B. dorsalis.

Gut fungal community and its probiotic effect on Bactrocera dorsalis.

The oriental fruit fly, Bactrocera dorsalis (Diptera: Tephritidae) is a destructive horticultural pest which causes considerable economic losses every year. A collection of microorganisms live within the B. dorsalis gut, and they are involved in its development, physiology, and behavior. However, knowledge regarding the composition and function of the gut mycobiota in B. dorsalis are still limited. Here, we comprehensively characterized the gut mycobiota in B. dorsalis across different developmental stages. High-throughput sequencing results showed a significant difference in fungal species abundance and diversity among different developmental stages of B. dorsalis. Quantitative polymerase chain reaction and culture-dependent methods showed that yeast species was the dominant group in the larval stage. We isolated 13 strains of yeast from the larval gut, and found that GF (germ-free) larvae mono-associated with strain Hanseniaspora uvarum developed faster than those mono-associated with other tested fungal strains. Supplementing the larval diet with H. uvarum fully rescued B. dorsalis development, shortened the larval developmental time, and increased adult wing lengths, as well as the body sizes and weights of both pupae and adults. Thus, our study highlights the close interactions between gut fungi, especially H. uvarum, and B. dorsalis. These findings can be applied to the sterile insect technique program to promote host development during mass insect rearing.

The effects of TNF-α/TNFR2 in regulatory T cells on the microenvironment and progression of gastric cancer.

TNFR2+ regulatory T cells preferentially accumulate in the tumor microenvironment, express high levels of immunosuppressive molecules and possess strong suppressive activity. Our study aimed to explore the characteristics and role of TNFR2+ Tregs in the microenvironment and progression of gastric cancer via polychromatic immunofluorescence, single-cell RNA sequencing and flow cytometry assays. The TNFR2+ Treg infiltration level in the tumor microenvironment increased significantly as gastric cancer progressed and was demonstrated to be a prognostic marker. Single-cell RNA sequencing revealed high levels of TNFR2 in tumor-infiltrating Tregs. The TNF-α/TNFR2 signaling pathway was activated, accompanied by the upregulation of costimulatory molecules. Unlike blood Tregs, tumor-infiltrating Tregs existed in activated and effector states. In addition to expressing costimulatory molecules such as TNFR2, 4-1BB, OX40 and GITR, tumor-infiltrating Tregs were also characterized by high expression levels of immune checkpoints such as CTLA-4 and TIGIT and chemokines such as CCR6. In vitro studies showed that the TNF-α/TNFR2 pathway increased the Foxp3 expression in CD4+ CD25+ T cells and the latent TGF-ß production in Tregs as well as enhanced the immunosuppressive function of Tregs. In summary, our study revealed high infiltration levels of TNFR2+ Tregs that were in activated and effector states in the tumor microenvironment. The infiltration level of TNFR2+ Tregs is a prognostic marker and an independent risk factor for gastric cancer. Activation of the TNF-α/TNFR2 pathway promotes the immunosuppressive phenotype and function of Tregs. Our study provides a new theoretical basis for TNFR2+ Tregs as a therapeutic target in gastric cancer.

Gut microbiota therapy for nonalcoholic fatty liver disease: Evidence from randomized clinical trials.

Nonalcoholic fatty liver disease (NAFLD) has a high prevalence worldwide, but there are no medications approved for treatment. Gut microbiota would be a novel and promising therapeutic target based on the concept of the gut-liver axis in liver disease. We reviewed randomized controlled trials on gut microbiota therapy in NAFLD in this study to evaluate its efficacy and plausibility in NAFLD.

Artificial intelligence for detecting superficial esophageal squamous cell carcinoma under multiple endoscopic imaging modalities: A multicenter study.

BACKGROUND AND AIM: Diagnosis of esophageal squamous cell carcinoma (ESCC) is complicated and requires substantial expertise and experience. This study aimed to develop an artificial intelligence (AI) system for detecting superficial ESCC under multiple endoscopic imaging modalities. METHODS: Endoscopic images were retrospectively collected from West China Hospital, Sichuan University as a training dataset and an independent internal validation dataset. Images from other four hospitals were used as an external validation dataset. The AI system was compared with 11 experienced endoscopists. Furthermore, videos were collected to assess the performance of the AI system. RESULTS: A total of 53 933 images from 2621 patients and 142 videos from 19 patients were used to develop and validate the AI system. In the internal and external validation datasets, the performance of the AI system under all or different endoscopic imaging modalities was satisfactory, with sensitivity of 92.5-99.7%, specificity of 78.5-89.0%, and area under the receiver operating characteristic curves of 0.906-0.989. The AI system achieved comparable performance with experienced endoscopists. Regarding superficial ESCC confined to the epithelium, the AI system was more sensitive than experienced endoscopists on white-light imaging (90.8% vs 82.5%, P = 0.022). Moreover, the AI system exhibited good performance in videos, with sensitivity of 89.5-100% and specificity of 73.7-89.5%. CONCLUSIONS: We developed an AI system that showed comparable performance with experienced endoscopists in detecting superficial ESCC under multiple endoscopic imaging modalities and might provide valuable support for inexperienced endoscopists, despite requiring further evaluation.

Immune-related adverse event profile of combination treatment of PD-(L)1 checkpoint inhibitors and bevacizumab in non-small cell lung cancer patients: data from the FDA adverse event reporting system.

BACKGROUND: Immune checkpoint inhibitors (ICIs) and bevacizumab-based therapy are a promising treatment approach to significantly improving overall survival (OS) of non-small cell lung cancer (NSCLC) patients. However, the incidence of adverse events induced by a combination treatment with programmed cell death-1 or programmed death ligand 1 [PD-(L)1] inhibitor and bevacizumab remains unknown. The current evidence from prospective studies is limited. Thus, efforts using real-world data to further improve our understanding of the potential adverse events will be necessary. METHODS: The present study included 15,872 participants with NSCLC in the FDA Adverse Event Reporting System (FAERS) database from April 2013 to September 2019. The definition of adverse events (AEs) relied on the Medical Dictionary for Regulatory Activities (MedDRA). Statistical analysis was performed, and odds ratio (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: Of the 15,872 participants with NSCLC, 15,463 cases were treated with the PD-(L)1 inhibitor monotherapy, while 409 cases were treated with both PD-(L)1 inhibitor and bevacizumab. Compared with monotherapy, combination therapy had lower risks of pneumonitis, respiratory failure, edema, disease progression, and death; however, combination therapy was also associated with significantly higher risks of pyrexia, general physical health deterioration, stomatitis, dehydration, thrombocytopenia, peripheral neuropathy, nephritis, bone marrow failure, immune thrombocytopenic purpura, neutropenia, and serious AEs. The results of the multivariate analysis suggested that combination therapy was the independent risk factor for pyrexia, neutropenia, nephritis, ITP, and the independent protective factor for respiratory failure. CONCLUSIONS: We observed that the spectrum and risk of irAEs differed widely between therapeutic regimens, and irAEs involved multiple organ systems both in monotherapy or combination therapy. Deepening our understanding of irAEs has a great clinical value for improving individualized clinical patient management and the safety of medication use.

Prophylactic transcatheter angiographic embolization reduces Forrest IIa ulcer rebleeding: A retrospective study.

ABSTRACT: The application of transcatheter angiographic embolization (TAE) is controversial in the treatment of ulcer bleeding. This study aims to determine rebleeding risk factors and evaluate the efficacy of prophylactic TAE (p-TAE) following endoscopic hemostasis in rebleeding prevention of Forrest lla ulcers.The medical records of Forrest lla ulcer patients who underwent endoscopic hemostasis (E group) and endoscopic hemostasis plus p-TAE (E + p-TAE group) in West China Hospital from May 2009 to May 2018 were retrospectively reviewed. Baseline characteristics, clinical efficacy, and rebleeding risk factors were analyzed.As a result, a total of 102 patients were included, with 75 and 27 patients in E and E + p-TAE group, respectively. Most of the baseline data in E and E + p-TAE group were similar except for the proportion of protruded non-bleeding visible vessel (NBVV) (E group vs E + p-TAE group, 50.7% vs 74.1%, P = .035). The rebleeding rate of E + p-TAE group (3.7%) was significantly lower than E group (24.0%) (P = .02). The protruded NBVV (OR: 6.896, 95% confidence interval [CI]: 1.532-30.642, P = .01) and employment of p-TAE (OR: 0.038, 95% CI: 0.003-0.448, P = .009) were identified as independent risk factors for Forrest IIa ulcer rebleeding. Additionally, log-rank test indicated the rebleeding occurrence was greatly reduced by p-TAE in patients with protruded NBVVs (P = .006).In conclusion, the protruded NBVV and employment of p-TAE were the independent risk factors tightly associated with rebleeding of Forrest IIa ulcer. P-TAE following endoscopic hemostasis could effectively prevent Forrest IIa ulcer from rebleeding.

Romidepsin (FK228) regulates the expression of the immune checkpoint ligand PD-L1 and suppresses cellular immune functions in colon cancer.

Romidepsin (FK228), a histone deacetylase inhibitor (HDACi), has anti-tumor effects against several types of solid tumors. Studies have suggested that HDACi could upregulate PD-L1 expression in tumor cells and change the state of anti-tumor immune responses in vivo. However, the influence of enhanced PD-L1 expression in tumor cells induced by romidepsin on anti-tumor immune responses is still under debate. So, the purpose of this study was to explore the anti-tumor effects and influence on immune responses of romidepsin in colon cancer. The results indicated that romidepsin inhibited proliferation, induced G0/G1 cell cycle arrest and increased apoptosis in CT26 and MC38 cells. Romidepsin treatment increased PD-L1 expression in vivo and in vitro via increasing the acetylation levels of histones H3 and H4 and regulating the transcription factor BRD4. In subcutaneous transplant tumor mice and colitis-associated cancer (CAC) mice, romidepsin increased the percentage of FOXP3+ regulatory T cells (Tregs), decreased the ratio of Th1/Th2 cells and the percentage of IFN-γ+ CD8+ T cells in the peripheral blood and the tumor microenvironment. Upon combination with an anti-PD-1 antibody, the anti-tumor effects of romidepsin were enhanced and the influence on CD4+ and CD8+ T cells was partially reversed. Therefore, the combination of romidepsin and anti-PD-1 immunotherapy provides a more potential treatment for colon cancer.

Peroral endoscopic myotomy for the treatment of esophageal diverticulum: an experience in China.

BACKGROUND: With the development of minimally invasive endoscopic approaches for the esophagus in recent years, peroral endoscopic myotomy (POEM) in the treatment of esophageal diverticulum has been described recently in some reports due to its successful outcomes. The aim of this study is to report our experience with the use of diverticular POEM (D-POEM) technique in the management of esophageal diverticulum. METHODS: This retrospective study included consecutive patients with symptomatic esophageal diverticulum who visited our endoscopy center between April 2014 and January 2019. D-POEM was performed based on the principles of submucosal endoscopy. A new symptomatic scoring system was introduced to evaluate the severity of diverticular symptoms. RESULTS: A total of 10 patients with esophageal diverticulum (Zenker's 2, mid-esophagus 5, and epiphrenic 3) were included. The overall technical success rate of D-POEM was 100%, with a mean procedure time of 38.9 ± 20.5 (range 16-70) min. No serious complications occurred. Clinical improvement was achieved in 90% (9/10) of patients. The symptomatic score was significantly decreased from 2.5 (IQR 2.00-3.25) to 1.0 (IQR 0-1.25) (P = 0.007) during a median follow-up period of 11.0 (IQR 10.25-17.25) months. CONCLUSION: These findings suggested complete septotomy by D-POEM. Our preliminary data and experience put forwarded D-POEM as a safe and effective technique for esophageal diverticulum.

Regulatory mechanisms of microbial homeostasis in insect gut.

Insects live in incredibly complex environments. The intestinal epithelium of insects is in constant contact with microorganisms, some of which are beneficial and some harmful to the host. Insect gut health and function are maintained through multidimensional mechanisms that can proficiently remove foreign pathogenic microorganisms while effectively maintaining local symbiotic microbial homeostasis. The basic immune mechanisms of the insect gut, such as the dual oxidase-reactive oxygen species (Duox-ROS) system and the immune deficiency (Imd)-signaling pathway, are involved in the maintenance of microbial homeostasis. This paper reviews the role of physical defenses, the Duox-ROS and Imd signaling pathways, the Janus kinase/signal transducers and activators of transcription signaling pathway, and intestinal symbiotic flora in the homeostatic maintenance of the insect gut microbiome.