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.

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 promotes host resistance to low-temperature stress by stimulating its arginine and proline metabolism pathway in adult Bactrocera dorsalis.

Gut symbiotic bacteria have a substantial impact on host physiology and ecology. However, the contribution of gut microbes to host fitness during long-term low-temperature stress is still unclear. This study examined the role of gut microbiota in host low-temperature stress resistance at molecular and biochemical levels in the oriental fruit fly Bactrocera dorsalis. The results showed that after the gut bacteria of flies were removed via antibiotic treatment, the median survival time was significantly decreased to approximately 68% of that in conventional flies following exposure to a temperature stress of 10°C. Furthermore, we found that Klebsiella michiganensis BD177 is a key symbiotic bacterium, whose recolonization in antibiotic treated (ABX) flies significantly extended the median survival time to 160% of that in the ABX control, and restored their lifespan to the level of conventional flies. Notably, the relative levels of proline and arginine metabolites were significantly downregulated by 34- and 10-fold, respectively, in ABX flies compared with those in the hemolymph of conventional flies after exposure to a temperature stress of 10°C whereas recolonization of ABX flies by K. michiganensis BD177 significantly upregulated the levels of proline and arginine by 13- and 10- fold, respectively, compared with those found in the hemolymph of ABX flies. qPCR analysis also confirmed that K. michiganensis-recolonized flies significantly stimulated the expression of transcripts from the arginine and proline metabolism pathway compared with the ABX controls, and RNAi mediated silencing of two key genes Pro-C and ASS significantly reduced the survival time of conventional flies, postexposure low-temperature stress. We show that microinjection of L-arginine and L-proline into ABX flies significantly increased their survival time following exposure to temperature stress of 10°C. Transmission electron microscopy (TEM) analysis further revealed that low-temperature stress caused severe destruction in cristae structures and thus resulted in abnormal circular shapes of mitochondria in ABX flies gut, while the recolonization of live K. michiganensis helped the ABX flies to maintain mitochondrial functionality to a normal status, which is important for the arginine and proline induction. Our results suggest that gut microbiota plays a vital role in promoting the host resistance to low-temperature stress in B. dorsalis by stimulating its arginine and proline metabolism pathway.

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.

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.

Comparative genomics of Klebsiella michiganensis BD177 and related members of Klebsiella sp. reveal the symbiotic relationship with Bactrocera dorsalis.

BACKGROUND: Bactrocera dorsalis is a destructive polyphagous and highly invasive insect pest of tropical and subtropical species of fruit and vegetable crops. The sterile insect technique (SIT) has been used for decades to control insect pests of agricultural, veterinary, and human health importance. Irradiation of pupae in SIT can reduce the ecological fitness of the sterile insects. Our previous study has shown that a gut bacterial strain BD177 that could restore ecological fitness by promoting host food intake and metabolic activities. RESULTS: Using long-read sequence technologies, we assembled the complete genome of K. michiganensis BD177 strain. The complete genome of K. michiganensis BD177 comprises one circular chromosome and four plasmids with a GC content of 55.03%. The pan-genome analysis was performed on 119 genomes (strain BD177 genome and 118 out of 128 published Klebsiella sp. genomes since ten were discarded). The pan-genome includes a total of 49305 gene clusters, a small number of 858 core genes, and a high number of accessory (10566) genes. Pan-genome and average nucleotide identity (ANI) analysis showed that BD177 is more similar to the type strain K. michiganensis DSM2544, while away from the type strain K. oxytoca ATCC13182. Comparative genome analysis with 21 K. oxytoca and 12 K. michiganensis strains, identified 213 unique genes, several of them related to amino acid metabolism, metabolism of cofactors and vitamins, and xenobiotics biodegradation and metabolism in BD177 genome. CONCLUSIONS: Phylogenomics analysis reclassified strain BD177 as a member of the species K. michiganensis. Comparative genome analysis suggested that K. michiganensis BD177 has the strain-specific ability to provide three essential amino acids (phenylalanine, tryptophan and methionine) and two vitamins B (folate and riboflavin) to B. dorsalis. The clear classification status of BD177 strain and identification of unique genetic characteristics may contribute to expanding our understanding of the symbiotic relationship of gut microbiota and B. dorsalis.

Real-time automated diagnosis of precancerous lesions and early esophageal squamous cell carcinoma using a deep learning model (with videos).

BACKGROUND AND AIMS: We developed a system for computer-assisted diagnosis (CAD) for real-time automated diagnosis of precancerous lesions and early esophageal squamous cell carcinomas (ESCCs) to assist the diagnosis of esophageal cancer. METHODS: A total of 6473 narrow-band imaging (NBI) images, including precancerous lesions, early ESCCs, and noncancerous lesions, were used to train the CAD system. We validated the CAD system using both endoscopic images and video datasets. The receiver operating characteristic curve of the CAD system was generated based on image datasets. An artificial intelligence probability heat map was generated for each input of endoscopic images. The yellow color indicated high possibility of cancerous lesion, and the blue color indicated noncancerous lesions on the probability heat map. When the CAD system detected any precancerous lesion or early ESCCs, the lesion of interest was masked with color. RESULTS: The image datasets contained 1480 malignant NBI images from 59 consecutive cancerous cases (sensitivity, 98.04%) and 5191 noncancerous NBI images from 2004 cases (specificity, 95.03%). The area under curve was 0.989. The video datasets of precancerous lesions or early ESCCs included 27 nonmagnifying videos (per-frame sensitivity 60.8%, per-lesion sensitivity, 100%) and 20 magnifying videos (per-frame sensitivity 96.1%, per-lesion sensitivity, 100%). Unaltered full-range normal esophagus videos included 33 videos (per-frame specificity 99.9%, per-case specificity, 90.9%). CONCLUSIONS: A deep learning model demonstrated high sensitivity and specificity for both endoscopic images and video datasets. The real-time CAD system has a promising potential in the near future to assist endoscopists in diagnosing precancerous lesions and ESCCs.

Tephritidae fruit fly gut microbiome diversity, function and potential for applications.

The family Tephritidae (order: Diptera), commonly known as fruit flies, comprises a widely distributed group of agricultural pests. The tephritid pests infest multiple species of fruits and vegetables, resulting in huge crop losses. Here, we summarize the composition and diversity of tephritid gut-associated bacteria communities and host intrinsic and environmental factors that influence the microbiome structures. Diverse members of Enterobacteriaceae, most commonly Klebsiella and Enterobacter bacteria, are prevalent in fruit flies guts. Roles played by gut bacteria in host nutrition, development, physiology and resistance to insecticides and pathogens are also addressed. This review provides an overview of fruit fly microbiome structure and points to diverse roles that it can play in fly physiology and survival. It also considers potential use of this knowledge for the control of economically important fruit flies, including the sterile insect technique and cue-lure baiting.

Calcium sensing receptor mediated the excessive generation of ß-amyloid peptide induced by hypoxia in vivo and in vitro.

Hypoxia played an important role in the pathogenesis of AD. Hypoxia increased Aß formation, then caused Alzheimer's disease. Calcium sensing receptor (CaSR) was involved in the regulation of cell growth, differentiation, hormonal secretion and other physiological function. Increasing evidence supported CaSR might play a more prominent role in susceptibility to AD, but the role of CaSR in Aß overproduction induced by hypoxia and its mechanisms remain unclear. To investigate whether CaSR mediated the overproduction of Aß induced by hypoxia, immunoblot and immunochemistry were employed to determine the expression of CaSR and BACE1 in hippocampal neurons and tissue and Ca(2+) image system was used to measure [Ca(2+)]i in hippocampal neurons. The content of Aß was detected with ELISA kits. Our research found that hypoxia increased the expression of CaSR in hippocampal neurons and tissue and [Ca(2+)]i in hippocampal neurons. Calhex 231, a selective blocher of CaSR, inhibited the increase in [Ca(2+)]i induced by hypoxia. Hypoxia or GdCl3, an agonist of CaSR, increased the expression of BACE1 in hippocampal neurons and tissue, but Calhex 231 or Xesto C (a selective inhibitor of IP3 receptor) partly prevented hypoxia-induced BACE1 overexpression. Hypoxia or GdCl3 increased the content of Aß42 and Aß40 in hippocampal tissue, however Calhex 231 or Xesto C prevented hypoxia-induced the overproduction of Aß42 and Aß40 partly. Based on the above data, we suggested that hypoxia increased [Ca(2+)]i by elevated CaSR expression to promote BACE1 expression, thereby resulting in the overproduction of Aß42 and Aß40.

Optimization of spatial acquisition systems for low-light-level robustness in space optical communications.

The channel establishment in space optical communications relies on the Acquisition, Tracking, and Pointing (ATP) systems to initially acquire and then stably track the beacon beam. However, insufficient optical power may lead to unstable acquisition or even acquisition failure. In this Letter, we describe the mechanisms causing the instability, and then propose an approach to constrain the acquisition velocity. The approach is based on velocity prediction obtained from the light spot centroids and angle measurement data. Theoretical and experimental results show that the acceptable minimum optical power for acquisition decreases by 5.5 dB after optimization, which effectively enhances the acquisition system's robustness under low-light-level conditions. This approach improves the adaptability of satellite-ground optical communications and also has practical value for deep-space optical communications.

Predictive filtering-based fast reacquisition approach for space-borne acquisition, tracking, and pointing systems.

We propose a novel approach for recapturing targets as quickly as possible after the space-borne ATP (Acquisition, Tracking, and Pointing) system target loss in free-space laser communication. The approach uses past angular information to predict the target trajectory. An optimized finite memory filter is designed as the prediction algorithm. To obtain optimal prediction performance, the designed filter determines the filter parameters of different curve parts during offline training, and the parameters are adjusted according to the curve characteristics during predictive filtering. Simulation results indicate prediction accuracy above 0.1 degrees within 5 seconds. An experimental system was constructed in the lab to simulate the reacquisition process using a dynamic target and a real ATP system. Experimental results show that, compared with the classical orbit prediction method, this approach can effectively yield shorter acquisition times.

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.

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.

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.

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.