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Background Artificial intelligence (AI) assistance has been considered as a promising way to improve colonoscopic polyp detection, but there are limited prospective studies on real‐time use of AI systems. Methods We conducted a prospective, multicenter, randomized controlled trial of patients undergoing colonoscopy at six centers. Eligible patients were randomly assigned to conventional colonoscopy (control group) or AI‐assisted colonoscopy (AI group). AI assistance was our newly developed AI system for real‐time colonoscopic polyp detection. Primary outcome is polyp detection rate (PDR). Secondary outcomes include polyps per positive patient (PPP), polyps per colonoscopy (PPC), and non‐first polyps per colonoscopy (PPC‐Plus). Results A total of 2352 patients were included in the final analysis. Compared with the control, AI group did not show significant increment in PDR (38.8% vs. 36.2%, p = 0.183), but its PPC‐Plus was significantly higher (0.5 vs. 0.4, p, Artificial intelligence (AI) assistance plays a limited role in overall polyp detection. AI system increases detection of easily missed polyps, including non‐first polyps, diminutive and flat polyps. The impact is greater for male operators, longer withdrawal time, and elderly obese patients.

There are significant risks of adverse events such as stricture, delayed bleeding and perforation following esophageal endoscopic submucosal dissection (ESD). So, it is necessary to protect the artificial ulcer and promote the healing process. This study was performed to investigate the protective role of a novel gel against esophageal ESD-associated wounds. It was a multicenter, randomized, single-blind, controlled trial, which recruited participants who underwent esophageal ESD in four hospitals in China. Participants were randomly assigned to the control or experimental group in a 1:1 ratio and the gel was used after ESD in the latter. Masking of the study group allocations was only attempted for participants. The participants were instructed to report any adverse events on post-ESD day 1, 14, and 30. Moreover, repeat endoscopy was performed at the two-week follow-up to confirm wound healing. Finally, of the 92 recruited patients, 81 completed the study. In the experimental group, the healing rates were significantly higher than the control group (83.89 ± 9.51% vs. 73.28 ± 17.81%, P = 0.0013). Participants reported no severe adverse events during the follow-up period. In conclusion, this novel gel could accelerate wound healing following esophageal ESD safely, effectively, and conveniently. Therefore, we recommend to apply this gel in daily clinical practice.

Background: Although associated with high en bloc and complete resection rates, endoscopic resection, which is widely performed for gastrointestinal mucosal and submucosal lesions, may cause bleeding and perforation. However, novel agents are being introduced to minimize these complications. Methods: In this multicenter, randomized, single blind, controlled trial, participants who underwent colonic endoscopic resection across four hospitals in China were randomly assigned to the control or experimental group(1:1 ratio); the gel was used after colonic endoscopic resection in the latter. Participants were instructed to report adverse events on the first day, 14th day, and one-month post-intervention. Repeat endoscopy was performed at two-week follow-up to confirm resection site healing. Results: Of the 92 screened participants, 73 completed the study. Each ulcer bed was successfully coated with the gel over an 87.4±13.4% area within approximately three minutes in the experimental group. The calculated healing rates were significantly higher in the experimental than in the control group (84.7±10.8% vs. 72.6±16.0%, P=0.0004). No severe relative adverse event occurred during follow-up. Conclusions: This novel gel is a safe, effective, and convenient agent that promotes wound healing after colonic endoscopic resection. And we recommend application of this gel to protect the ulcer bed in daily clinical practice. Trial registration This trial has been registered in Chinese Clinical Trial Registry (ChiCTR2100053692).

The Yes-associated protein-1 (YAP1) is an essential regulator of human Hippo signaling pathway and functions through interaction with TEA domain-4 (TEAD4) transcription factor involved in the tumorigenesis of nasopharyngeal cancer. Previously, a parallel helix-helix interaction (PHHI) was identified as the key hotspot at YAP1-TEAD4 complex interface and has been exploited as an attractive druggable target to disrupt the complex. In this study, we investigated a roughly orthogonal cation-π-π stacking system across the crystal PHHI packing interface by integrating computational modeling and binding assay, which forms between one YAP1 helical residue Phe69 and two TEAD4 helical residues Phe373/Lys376. A synergistic effect between cation-π and π-π interactions was observed; they separately represent two wings of the stacking system. The π-electron is primarily responsible for the synergistic effect. Combination between diverse aromatic/charged amino acids. as well as neutral alanine on the cation-π-π stacking, revealed that the presence of aromatic tryptophan and charged arginine at, respectively, the residues 373 and 376 of TEAD4 helix can considerably improve PHHI binding affinity by ~6-fold, whereas neutral alanine substitution on each residue and on both would reduce the affinity significantly, confirming a strong synergistic effect involved in the roughly orthogonal cation-π-π stacking system at YAP1-TEAD4 PHHI interface.

Esophageal and gastric cancers are common diseases with high morbidity and mortality; thus, early detection and treatment are beneficial to improve prognosis. Confocal laser endomicroscopy (CLE) is a novel imaging technique that permits the histological analysis of tissues during endoscopy. CLE has been shown to uniquely affect the diagnosis of early upper gastrointestinal cancers. Relevant literature was searched using PubMed and Google Scholar databases. Despite inherent flaws, CLE can reduce tissue damage and improve diagnostic accuracy to a certain extent. CLE in combination with other imaging methods can help enhance the detection rate and avoid unnecessary biopsies in the management of esophageal or gastric cancer and precancerous lesions. CLE is of great significance in the diagnosis and surveillance of early cancers of the upper gastrointestinal tract. Further technical innovations and the standardisation of CLE will make it more responsive to the needs of routine clinical applications.

Colorectal cancer (CRC) is the third most prevalent malignancy globally. Capecitabine is an important form of chemotherapy for colorectal cancer. The present study aims to investigate the underlying mechanism of action of the drug in CRC cells. In the present study, 50 pairs of CRC and adjacent normal tissues were collected, and CRC cell lines (SW480, SW620, HT29, LOVO and HCT116) and NCM460 colonic epithelial cells were also purchased and used. Western blotting was used to measure the expression levels of proteins involved in the receptor activator of nuclear factor-κB (RANK)/receptor activator of nuclear factor-κB ligand (RANKL) pathway and epithelial-to-mesenchymal transition (EMT), including RANK, RANKL, osteoprotegerin (OPG), E-cadherin, vimentin and N-cadherin. Proliferation and migration were measured using MTT, Cell Counting Kit-8, EdU, Transwell and wound healing assays, respectively. In the present study, it was found that the RANK/RANKL pathway was activated in cancer tissues and cells. Additionally, it was observed that capecitabine treatment reduced the protein expression of RANK, RANKL and OPG in HT29 cells, suggesting that capecitabine has a repressive effect on the RANK/RANKL pathway. Furthermore, functional experiments revealed that the proliferative ability and the EMT process observed in HT29 cells were inhibited after they were treated with capecitabine or transfected with si-RANK. Rescue assays were then performed, which revealed that the promotion of RANK via transfection of cells with 50 nM pcDNA3.1-RANK reversed the inhibitory effects of capecitabine on HT29 cell proliferation and EMT. These findings suggest that the regulatory role of capecitabine is at least partially mediated through the RANK/RANKL pathway in colorectal cancer. The present study demonstrated that capecitabine-induced repression of CRC is exerted by inhibiting the RANK/RANKL pathway, where this new mechanism potentially provides a novel therapeutic target.

Background: The immunotherapy for different types of cancers that targeting programmed death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) has highlighted the importance of suppressing specific T cell responses. Recently, several studies have shown that the expression level of PD-L1 in tumor cells is positively correlated with tumor metastasis as well as recurrence rate. The potent effects of post-translational modifications (PTMs) for PD-L1, such as ubiquitination, glycosylation, phosphorylation and palmitoylation, have been reported to be related to immunosuppression. However, the regulation of PD-L1 degradation in cancers is still not well understood. In this paper, we mainly investigate the deubiquitination regulation of PD-L1. Methods: The protein levels of PD-L1 and USP21 were detected by Immunoblotting and immunohistochemistry. The interaction between PD-L1 and USP21 was determined by co-immunoprecipitation. The deubiquitination of PD-L1 was determined by in vitro deubiquitination assay. The deubiquitination sites of PD-L1 were identified by mass spectrometry analysis. The expression of mRNA in target tissues was presented by bioinformatics analysis.Results: Overexpression of USP21 significantly increased PD-L1 abundance and knockdown of USP21 induced degradation of PD-L1. In vitro deubiquitination assay showed that USP21-WT reduced polyubiquitin chains from PD-L1 while USP21-C221A did not. Furthermore, five lysines in intracellular segment of PD-L1 are potential deubiquitin sites and cancer-derived mutations of PD-L1 in Asp276 have the ability to enhance the deubiquitination of PD-L1 mediated by USP21. Finally, we found that USP21 is the frequently amplified deubiquitinase in lung cancer, especially in lung squamous cell carcinoma, and its amplification co-occurs with the upregulation of PD-L1 levels. Moreover, IHC analysis showed stronger staining of PD-L1 and USP21 in lung cancer samples than adjacent tissues. Conclusion: We identified USP21 as a novel deubiquitinase of PD-L1. Hopefully, targeting PD-L1 by inhibiting USP21 might be a potentially novel strategy for the treatment of lung cancer.

Ambient fine particulate matter (particle diameter 2.5 μm, or PM

Epidemiological studies have suggested a link between vitamin D deficiency and increased risk for nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanisms have remained unclear. Here, using both clinical samples and experimental rodent models along with several biochemical approaches, we explored the specific effects and mechanisms of vitamin D deficiency in NAFLD pathology. Serum vitamin D levels were significantly lower in individuals with NAFLD and in high-fat diet (HFD)-fed mice than in healthy controls and chow-fed mice, respectively. Vitamin D supplementation ameliorated HFD-induced hepatic steatosis and insulin resistance in mice. Hepatic expression of vitamin D receptor (VDR) was up-regulated in three models of NAFLD, including HFD-fed mice, methionine/choline-deficient diet (MCD)-fed mice, and genetically obese (ob/ob) mice. Liver-specific VDR deletion significantly exacerbated HFD- or MCD-induced hepatic steatosis and insulin resistance and also diminished the protective effect of vitamin D supplementation on NAFLD. Mechanistic experiments revealed that VDR interacted with hepatocyte nuclear factor 4 α (HNF4α) and that overexpression of HNF4α improved HFD-induced NAFLD and metabolic abnormalities in liver-specific VDR-knockout mice. These results suggest that vitamin D ameliorates NAFLD and metabolic abnormalities by activating hepatic VDR, leading to its interaction with HNF4α. Our findings highlight a potential value of using vitamin D for preventing and managing NAFLD by targeting VDR.

Background Air pollution has already become a serious public health concern worldwide, while evidence for the association between air pollution and digestive disease is not consistent. Objective To examine the association between air pollution and peptic ulcer bleeding (PUB). Methods We performed a time-stratified case-crossover study among 1,246,270 gastroscopy records in Zhejiang, China from January 1st, 2013 to June 30th, 2019. Individual exposure to air pollution for each subject was estimated by using data from 55 fixed-sites with an inverse distance weighted method. Conditional logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) for PUB associated with an interquartile range (IQR) increase in air pollution on the entire population. Subgroup analyses were performed for season, age and sex. Results Totally 3543 patients diagnosed with PUB were included in the analyses. Significant associations were observed between NO2, CO and PM2.5 and the risk of PUB. The effect was observed strongest measured as lag06 and an IQR increase of 7-day moving average concentrations of NO2 resulted in a 24.0% increase of getting PUB (95% CI: 2.6%–50.0%). Significance Our findings strengthen the hypothesis that short-term air pollution exposure has adverse health effects on digestive system.

Ambient fine particulate matter (particle diameter 57 million people), which included a total of 647,092 subjects who underwent gastroscopy examination (86,852 subjects were diagnosed with PUDs) recorded in 13 large hospitals from 2014 to 2018. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the relationship between PM2.5 and PUDs, including duodenal ulcers (DUs) and gastric ulcers (GUs). The overall estimated OR (95% CI) associated with every 10-μg/m3 increase in the 1-month average PM2.5 before the detection of PUDs was 1.050 (95% CI: 1.038, 1.063). The association between PM2.5 concentration and the prevalence of PUDs tended to be attenuated but remained significant when considering different exposure periods (OR = 1.030, 95% CI = 1.018–1.043 for the 3-month moving average; OR = 1.020, 95% CI = 1.005–1.037 for the 6-month moving average). Stronger associations were observed for DUs than GUs. The observed positive association of PM2.5 exposure with PUDs remained significant in the two-pollutant models after adjusting for other air pollutants. Our findings could provide scientific evidence for a more general adverse role of air pollution on PUDs.

Background: To estimate the short term effect of particulate matter (particle diameter < 2.5 μm, or PM2.5) on the risk of peptic ulcer diseases (PUDs). Methods: A retrospective hospital-based cohort study was conducted in seven major cities in Zhejiang province, China (combined population > 57 million) which included a total of 647,092 subjects underwent gastroscopy examination (86,852 subjects among them were diagnosed as PUDs) recorded in 13 large hospitals from 2014 to 2018 to analyze relationship between PM2.5 and PUDs including duodenal ulcer (DU) and gastric ulcer (GU). Findings: Pooled estimated OR (95%CI) associated with a 10μg/m3 increase of 1-month average PM2.5 before the detection of PUDs was 1.050 (95%CI:1.038, 1.063). When the 3-month moving average and 6-month moving average concentrations were used as the exposure window, the association between PM2.5 concentrations and the incident of PUDs tends to be attenuated but remained significant (OR=1.030, 95%CI= 1.018-1.043 for 3-month moving average and OR=1.020, 95%CI=1.005-1.037 for 6-month moving average, respectively). The observed association tended to be stronger in DU and the association of PM2.5 and PUDs remained significant in the two-pollutant models. Interpretation: We observed a significant association between short-term exposure to PM2.5 and in a multi-site and large sample size study in China. Our findings could contribute to the evidence that a more general adverse role of air pollution on PUDs. Funding Statement: This study was supported by National Key Research and Development Program of China (No.2017YFC0908900 to Yu CH). Declaration of Interests: None of the authors have any competing interest to declare. Ethics Approval Statement: This study was approved by the Institutional Review Board of each executing hospital. Participants were verbally informed about the study.

A method of liquid chromatographic retention time-dependent intelligent selected reaction monitoring mass spectrometry (iSRM MS) was established for the identification of targeted proteome, and was compared in detail with the method without liquid chromatographic retention time-dependent iSRM MS in the analysis results of different samples, such as the peptide mixtures from bovine serum albumin, six standard proteins or Thermoanaerobacter tengcongensis extract digested by trypsin. The results showed that the throughput of the identified peptides and the proteins was evidently increased with the method of liquid chromatographic retention time-dependent iSRM MS, especially in the complex sample such as Thermoanaerobacter tengcongensis extract. The coverage of the identified peptides and proteins from Thermoanaerobacter tengcongensis extract was reached 89.62% and 92.41% of the number of targeted peptides and proteins respectively. Higher sensitivity and reproducibility were also obtained. In addition, peptides with the same m/z but different retention times could be identified accurately when the method was used. With the higher throughput, better sensitivity and excellent reproducibility, the method of liquid chromatographic retention time-dependent iSRM MS can play an important role in the identification of targeted proteomes of complex biological samples in the future.

RATIONALE Chimera spectra make it challenging to identify proteins in complex mixtures by LC/MS/MS. Approximately half of the spectra collected are chimera spectra even when high-resolution tandem mass spectrometry is used. Chimera spectra are generated from the co-fragmentation of different co-elute peptides, and it is often difficult to distinguish monoisotopic precursors of these peptides from each other. METHODS In this paper, we propose a peak intensity ratio-based monoisotopic peak determination algorithm (PIRMD) to distinguish different monoisotopic precursors of chimera spectra. Monoisotopic peaks in non-overlapping clusters are detected by the edge features of the isotopic peak intensity ratios. For multiple overlapping clusters grouped as one cluster, monoisotopic peaks can be detected by an advanced estimation of the similarity between the estimated and the experimental isotopic distribution based on the isotopic peak intensity ratios. RESULTS High-resolution mass spectrometric datasets acquired from mixtures of 30 synthetic peptides and mixtures of 18 proteins were used to evaluate the efficiency and accuracy of PIRMD. The results indicate that PIRMD can recognize monoisotopic precursors from the chimera spectra containing non-overlapping and overlapping isotopic clusters. Compared to several published algorithms, PIRMD identifies approximately 2 ~ 14% more spectra and has fewer false positives. CONCLUSIONS The results on standard datasets and actual samples demonstrated that PIRMD could notably improve the successful identification rates of the spectra by identifying more chimera spectra, and of the identified spectra, approximately 25% are chimera spectra. This novel algorithm will help to interpret spectra produced by shotgun strategy in proteomics. Copyright © 2012 John Wiley & Sons, Ltd.

A method of concatamers of Q peptides (QconCATs) protein labeled with 18O-multiple reaction monitoring mass spectrometry for absolute quantification of proteins is established. The purity of the QconCAT recombinant protein was characterized by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), and its purity was above 99%. The relative molecular mass was approximately 63.4 kDa. The peptides digested from the QconCAT recombinant protein and the extract of Thermoanaerobacter tengcongensis (TTE) were analyzed by mass spectrometry. The raw data were processed by pFind and pLabel softwares. The results showed that the efficiencies of protein digestion and the 18O labeling efficiency were able to meet the need of the protein quantification. The performance of the method was evaluated. The absolute contents of the selected proteins in TTE were determined with the relative standard deviations of less than 20% and the accuracy is high. The method not only avoid using the expensive reagent of stable isotope labeling with amino acids in cell culture (SILAC), but also provides an alternative way for the accurately absolute quantification of proteins in biological samples for quantitative proteomic research.

Chimera spectra make it challenging to identify proteins in complex mixtures by LC/MS/MS. Approximately half of the spectra collected are chimera spectra even when high-resolution tandem mass spectrometry is used. Chimera spectra are generated from the co-fragmentation of different co-elute peptides, and it is often difficult to distinguish monoisotopic precursors of these peptides from each other.In this paper, we propose a peak intensity ratio-based monoisotopic peak determination algorithm (PIRMD) to distinguish different monoisotopic precursors of chimera spectra. Monoisotopic peaks in non-overlapping clusters are detected by the edge features of the isotopic peak intensity ratios. For multiple overlapping clusters grouped as one cluster, monoisotopic peaks can be detected by an advanced estimation of the similarity between the estimated and the experimental isotopic distribution based on the isotopic peak intensity ratios.High-resolution mass spectrometric datasets acquired from mixtures of 30 synthetic peptides and mixtures of 18 proteins were used to evaluate the efficiency and accuracy of PIRMD. The results indicate that PIRMD can recognize monoisotopic precursors from the chimera spectra containing non-overlapping and overlapping isotopic clusters. Compared to several published algorithms, PIRMD identifies approximately 2 ~ 14% more spectra and has fewer false positives.The results on standard datasets and actual samples demonstrated that PIRMD could notably improve the successful identification rates of the spectra by identifying more chimera spectra, and of the identified spectra, approximately 25% are chimera spectra. This novel algorithm will help to interpret spectra produced by shotgun strategy in proteomics.

A method of liquid chromatographic retention time-dependent intelligent selected reaction monitoring mass spectrometry (iSRM MS) was established for the identification of targeted proteome, and was compared in detail with the method without liquid chromatographic retention time-dependent iSRM MS in the analysis results of different samples, such as the peptide mixtures from bovine serum albumin, six standard proteins or Thermoanaerobacter tengcongensis extract digested by trypsin. The results showed that the throughput of the identified peptides and the proteins was evidently increased with the method of liquid chromatographic retention time-dependent iSRM MS, especially in the complex sample such as Thermoanaerobacter tengcongensis extract. The coverage of the identified peptides and proteins from Thermoanaerobacter tengcongensis extract was reached 89.62% and 92.41% of the number of targeted peptides and proteins respectively. Higher sensitivity and reproducibility were also obtained. In addition, peptides with the same m/z but different retention times could be identified accurately when the method was used. With the higher throughput, better sensitivity and excellent reproducibility, the method of liquid chromatographic retention time-dependent iSRM MS can play an important role in the identification of targeted proteomes of complex biological samples in the future.