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COVID-19 is a globally infectious viral epidemic of great public health concern caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2) plays its role as the receptor for SARS-CoV-2 through binding with S protein and the binding results in ACE2 expression decrease. The change of ACE2 is supposed to elicit a series of cellular and molecular events. Other than as the receptor, ACE2's roles on infection by regulating other molecules need to be further studied during SARS-CoV-2 infection. In the present study, we established the ACE2 knockdown model using Vero E6 cells to study how ACE2 influenced the downstream signaling molecules. Analysis of transcriptome sequencing discovered that ACE2 alteration

Background Intestinal fibrosis and subsequent stricture formation represent frequent complications of Crohn’s disease (CD). In many organs, fibrosis develops as a result of epithelial to mesenchymal transition (EMT). Recent studies suggested that EMT could be involved in intestinal fibrosis as a result of chronic inflammation. Here, we investigated whether EMT might be involved in stricture formation in CD patients. Methods Human colonic tissue specimens from fibrotic areas of 18 CD and 10 non-IBD control patients were studied. Immunohistochemical staining of CD68 (marker for monocytes/macrophages), transforming growth factor-β1 (TGFβ1), β-catenin, SLUG, E-.cadherin, α-smooth muscle actin and fibroblast activation protein (FAP) were performed using standard techniques. Results In fibrotic areas in the intestine of CD patients, a large number of CD68-positive mononuclear cells was detectable suggesting an inflammatory character of the fibrosis. We found stronger expression of TGFβ1, the most powerful driving force for EMT, in and around the fibrotic lesions of CD patients than in non-IBD control patients. In CD patients membrane staining of β-catenin was generally weaker than in control patients and more cells featured nuclear staining indicating transcriptionally active β-catenin, in fibrotic areas. In these regions we also detected nuclear localisation of the transcription factor, SLUG, which has also been implicated in EMT pathogenesis. Adjacent to the fibrotic tissue regions, we observed high levels of FAP, a marker of reactive fibroblasts. Conclusions We demonstrate the presence of EMT-associated molecules in fibrotic lesions of CD patients. These findings support the hypothesis that EMT might play a role for the development of CD-associated intestinal fibrosis. Electronic supplementary material The online version of this article (doi:10.1186/s40169-015-0046-5) contains supplementary material, which is available to authorized users.

miR-21 is involved in the mechanisms of inflammatory bowel disease (IBD). It negatively regulates PTEN, which is an upstream regulatory gene of the PI3K/Akt/mTOR signaling pathway. But the relationship between miR-21 and immune tolerance and intestinal epithelial injury, and the mechanism by which miR-21 participates in Crohn's disease (CD) have not been studied. We aimed to address these two questions. The results of the present study showed that the levels of miR-21 and PTEN respectively decreased and increased significantly in the intestinal mucosa from active CD compared with control ones. Transfection with miR-21-5p mimics significantly downregulated the expression of PTEN and upregulated PI3K-Akt-mTOR signaling and the downstream pathway in PBMCs, while transfection with a miR-21-5p inhibitor antagomiR-21had the opposite effect. Moreover, the ratio of Treg/Th1 cells differentiated from peripheral blood mononuclear cells (PBMCs) decreased after being transfected with mimics, and increased with the inhibitor. AntagomiR-21 significantly relieved the lesions in colons of mice with TNBS-induced colitis, accompanied by the upregulation of PTEN and downregulation of mTOR. Inhibition of miR-21 also effectively suppressed the process of epithelial-mesenchymal transition (EMT) in vivo. In conclusion, the level of miR-21 decreased in CD, resulting in an upregulated PI3K-Akt-mTOR signaling pathway, compromised immune tolerance, and elevated inflammation.

Background Peptic ulcer bleeding remains a typical medical emergency with significant morbidity and mortality. Peptic ulcer rebleeding often occurs within three days after emergent endoscopic hemostasis. Our study aims to develop a nomogram to predict rebleeding within three days after emergent endoscopic hemostasis for high-risk peptic ulcer bleeding. Methods We retrospectively reviewed the data of 386 patients with bleeding ulcers and high-risk stigmata who underwent emergent endoscopic hemostasis between March 2014 and October 2018. The least absolute shrinkage and selection operator method was used to identify predictors. The model was displayed as a nomogram. Internal validation was carried out using bootstrapping. The model was evaluated using the calibration plot, decision-curve analyses, and clinical impact curve. Results Overall, 386 patients meeting the inclusion criteria were enrolled, with 48 patients developed rebleeding within three days after initial endoscopic hemostasis. Predictors contained in the nomogram included albumin, prothrombin time, shock, haematemesis/melena and Forrest classification. The model showed good discrimination and good calibration with a C-index of 0.854 (C-index: 0.830 via bootstrapping validation). Decision-curve analyses and clinical impact curve also demonstrated that it was clinically valuable. Conclusion This study presents a nomogram that incorporates clinical, laboratory, and endoscopic features, effectively predicting rebleeding within three days after emergent endoscopic hemostasis and identifying high-risk rebleeding patients with peptic ulcer bleeding. Trial registration This clinical trial has been registered in the ClinicalTrials.gov (ID: NCT04895904) approved by the International Committee of Medical Journal Editors (ICMJE).

Background: Peptic ulcer bleeding remains a typical medical emergency with significant morbidity and mortality. Peptic ulcer rebleeding often occurs within three days after emergency endoscopic hemostasis. Our study aims to develop a nomogram to predict rebleeding within three days after emergency endoscopic hemostasis for peptic ulcer bleedingMethods: We retrospectively reviewed the data of 386 patients with bleeding ulcers who underwent emergency endoscopic hemostasis between March 2014 and October 2018. The least absolute shrinkage and selection operator method were used to identified predictors. The model was displayed as a nomogram. Internal validation was carried out using bootstrapping. The model was evaluated using the calibration plot, decision-curve analyses and clinical impact curve. Results: Overall, 386 patients meeting the inclusion criteria were enrolled, with 48 patients developed rebleeding within three days after initial endoscopic hemostasis. Predictors contained in the nomogram included albumin, prothrombin time, shock, haematemesis/melena and Forrest classification. The model showed good discrimination and good calibration with a C-index of 0.854 (C-index: 0.830 via bootstrapping validation). Decision-curve analyses and clinical impact curve also demonstrated that it was clinically valuable.Conclusion: This study presents a nomogram that incorporates clinical, laboratory, and endoscopic features, effectively predicting rebleeding within three days after emergency endoscopic hemostasis and identifying high-risk rebleeding patients with peptic ulcer bleeding.Trial registration: This clinical trial has been registered in the ClinicalTrials.gov (ID: NCT04895904) approved by the International Committee of Medical Journal Editors (ICMJE).

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus display remarkable efficacy against authentic B.1.351 virus. Surprisingly, structural analysis has revealed that 58G6 and 13G9 both recognize the steric region S470–495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly binds to another region S450–458 in the RBD. Significantly, 58G6 and 510A5 both demonstrate prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. Together, we have evidenced 2 potent neutralizing Abs with unique mechanism targeting authentic SARS-CoV-2 mutants, which can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic., Neutralizing antibodies are currently one versatile strategy to treat SARS-CoV-2 infection. Here, Li et al. characterize three monoclonal antibodies neutralizing authentic virus infection in vitro and in vivo by targeting the receptor binding domain as evidenced by Cryo-EM.

BackgroundFever is one of the postoperative adverse events of endoscopic submucosal dissection and its derived technique, but the probability and risk factors of postoperative fever are still unclear. The aim of the current study was to investigate the incidence and risk factors of postoperative fever after esophageal lesion removal.MethodsWe conducted a retrospective study of 446 patients who underwent esophageal endoscopic submucosal dissection and its derived technique between January 2014 and January 2020. Cases included in this study were divided into fever and non-fever groups.ResultsPostoperative fever developed in 135 patients (30.3%). The median (range) highest fever temperature was 38 (37.8–38.4)°C, the median (range) duration of fever was 1 (1–2) day, and 127 (94.1%) patients developed fever within 24 h after operation. Through logistic regression analysis, factors associated with postoperative fever were age (OR: 1.740, 95% CI: 1.005–3.013, p = 0.048), lesion size (OR: 2.007, 95% CI: 1.198–3.362, p = 0.008), operation time (OR: 3.007, 95% CI: 1.756–5.147, p < 0.001) and nasogastric tube placement (OR: 1.881, 95% CI: 1.165–3.037, p = 0.010), while prophylactic antibiotics (OR: 0.181, 95% CI: 0.082–0.401, p < 0.001) were negatively associated with fever.ConclusionsAge ≥52 years old, lesion size ≥19 mm, operation time ≥37 min, and nasogastric tube placement are risk factors for postoperative fever after esophageal endoscopic submucosal dissection and its derived technique, prophylactic antibiotic use after operation may help reduce fever rate. Attention should be paid to such patients to minimize the risk of postoperative fever.

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus displayed remarkable efficacy against authentic B.1.351 virus. Each of these 3 mAbs in combination with one neutralizing Ab recognizing non-competing epitope exhibited synergistic effect against authentic SARS-CoV-2 virus. Surprisingly, structural analysis revealed that 58G6 and 13G9, encoded by the IGHV1-58 and the IGKV3-20 germline genes, both recognized the steric region S470-495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly bound to another region S450-458 in the RBD. Significantly, 58G6 and 510A5 both demonstrated prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. These 2 ultrapotent neutralizing Abs can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.

After the pandemic of COVID-19, neutralizing antibodies (NAbs) against SARS-CoV-2 have been developed for the prophylactic and therapeutic purposes. However, few methodologies are described in detail on how to rapidly and efficiently generate effective NAbs to SARS-CoV-2. Here, we integrated and optimized a strategically screening method for NAbs, which has enabled us to obtain SARS-CoV-2 receptor-binding domain (RBD) specific NAbs within 6 days, followed by additional 9 days for antibody production and function analysis. Using this method, we obtained 198 specific Abs against SARS-CoV-2 RBD from the blood samples of COVID-19 convalescent patients, and 96 of them showed neutralizing activity. At least 20% of these NAbs exhibited advanced neutralizing potency and high affinity, with the top two NAbs showing half-maximal inhibitory concentration (IC50) to block authentic SARS-CoV-2 at 9.88 and 11.13 ng/ml, respectively. Altogether, our study provides an effective methodology with high applicable value for discovering potential preventative and therapeutic NAbs for the emerging infectious diseases.

Background Endoscopic submucosal dissection (ESD) and endoscopic submucosal excavation (ESE) have been widely used and have gradually become the main endoscopic treatment for gastrointestinal mucosal and submucosal lesions. Whether antibiotics are necessary for fever after gastric ESD and ESE remain unclear. The aim of this study was to analyse the value of using antibiotics in patients without perforation after ESD or ESE with fever. Methods In this retrospective study, patients with fever without perforation after ESD or ESE from January 2014 to January 2019 were included and divided into 2 groups: the antibiotic group and the non-antibiotic group. Fever and hospitalization time were compared between the 2 groups after propensity score matching. Results Overall, 253 patients meeting the inclusion criteria were enrolled in the present study, with 186 patients in the non-antibiotic group and 67 patients in the antibiotic group before matching, 55 patients in the non-antibiotic group and 55 patients in the antibiotic group after matching with all baseline characteristics balanced (p > 0.05). The duration of fever was not significantly different between the 2 groups (p = 0.12). However, the median hospitalization stay in the antibiotic group was longer than that in the non-antibiotic group (8 vs 7, p = 0.007). Conclusions Antibiotics may be unnecessary for fever in patients without perforation and without serious co-morbidities after gastric ESD or ESE.

Background: Endoscopic submucosal dissection (ESD) has been widely used and has gradually become the main endoscopic treatment for gastrointestinal mucosal and submucosal lesions. Whether antibiotics are necessary for fever after gastric ESD remains unclear. The aim of this study was to analyse the value of the use of antibiotics for fever after ESD. Methods: In this retrospective study, patients with fever after ESD from January 2014 to January 2019 were included and divided into 2 groups: the antibiotic group and the non-antibiotic group. Fever and hospitalization time were compared between the 2 groups after propensity score (PS) matching. Results: A total of 451 patients with fever after ESD were included in the present study. with 240 patients in the non-antibiotics group and 211 patients in antibiotics group before matching and 96 patients in the non-antibiotics group and 96 patients in antibiotics group after matching with all baseline characteristics balanced (p > 0.05). Fever duration was not significantly different between the 2 groups (p=0.074). However, the median hospital stay in the antibiotic group was longer than that in the non-antibiotic group (8 vs 7, p=0.006). Conclusions: Antibiotics for fever after gastric ESD may be unnecessary.

The spread of SARS-CoV-2 confers a serious threat to the public health without effective intervention strategies1–3. Its variant carrying mutated Spike (S) protein D614G (SD614G) has become the most prevalent form in the current global pandemic4,5. We have identified a large panel of potential neutralizing antibodies (NAbs) targeting the receptor-binding domain (RBD) of SARS-CoV-2 S6. Here, we focused on the top 20 potential NAbs for the mechanism study. Of them, the top 4 NAbs could individually neutralize both authentic SARS-CoV-2 and SD614G pseudovirus efficiently. Our epitope mapping revealed that 16/20 potent NAbs overlapped the same steric epitope. Excitingly, we found that one of these potent NAbs (58G6) exclusively bound to a linear epitope on S-RBD (termed as 58G6e), and the interaction of 58G6e and the recombinant ACE2 could be blocked by 58G6. We confirmed that 58G6e represented a key site of vulnerability on S-RBD and it could positively react with COVID-19 convalescent patients’ plasma. We are the first, as far as we know, to provide direct evidences of a linear epitope that can be recognized by a potent NAb against SARS-CoV-2 S-RBD. This study paves the way for the applications of these NAbs and the potential safe and effective vaccine design.

Neutralizing antibodies (Abs) have been considered as promising therapeutics for the prevention and treatment of pathogens. After the outbreak of COVID-19, potent neutralizing Abs to SARS-CoV-2 were promptly developed, and a few of those neutralizing Abs are being tested in clinical studies. However, there were few methodologies detailly reported on how to rapidly and efficiently generate neutralizing Abs of interest. Here, we present a strategically optimized method for precisive screening of neutralizing monoclonal antibodies (mAbs), which enabled us to identify SARS-CoV-2 receptor-binding domain (RBD) specific Abs within 4 days, followed by another 2 days for neutralization activity evaluation. By applying the screening system, we obtained 198 Abs against the RBD of SARS-CoV-2. Excitingly, we found that approximately 50% (96/198) of them were candidate neutralizing Abs in a preliminary screening of SARS-CoV-2 pseudovirus and 20 of these 96 neutralizing Abs were confirmed with high potency. Furthermore, 2 mAbs with the highest neutralizing potency were identified to block authentic SARS-CoV-2 with the half-maximal inhibitory concentration (IC50) at concentrations of 9.88 ng/ml and 11.13 ng/ml. In this report, we demonstrated that the optimized neutralizing Abs screening system is useful for the rapid and efficient discovery of potent neutralizing Abs against SARS-CoV-2. Our study provides a methodology for the generation of preventive and therapeutic antibody drugs for emerging infectious diseases.

Previous studies have indicated that thalidomide may be effective in achieving clinical remission and response; however, there is a lack of studies on its effect in endoscopic remission. The aim of this study was to assess the efficacy and safety of thalidomide in inducing and maintaining endoscopic remission.A retrospective study was conducted in adult Crohn's disease (CD) patients treated with thalidomide. Patients were assessed based on their medical records. Endoscopy was performed after 4-6 months of thalidomide administration, and the simple endoscopic score for CD (SES-CD) was obtained.Twenty of the 21 (95.2%) eligible patients were recruited. Endoscopic remission was achieved in 7 of the 14 (50%) endoscopy active patients who received thalidomide treatment, whereas 10 (71.4%) patients showed an endoscopy response. The other 6 patients in endoscopic remission still maintained remission after thalidomide treatment. The SES-CD in endoscopy active patients was significantly reduced after thalidomide treatment (P0.05). A total of 32 adverse events occurred in 17 of the 21 (81.0%) patients. Adverse events resolved spontaneously in 11 (64.7%) patients and resulted in treatment discontinuation and dose reduction in 4 (19.1%) and 2 (9.5%) patients, respectively.Thalidomide therapy is effective in inducing and maintaining endoscopic remission in adult CD patients. However, side effects may limit its clinical use in CD treatment.

Rationale: Intestinal Behçet disease (intestinal BD) and inflammatory bowel disease (IBD) share a lot of characteristics, including genetic background, clinical manifestations, and therapeutic strategies, especially the extraintestinal manifestations, such as oral ulcers, arthralgia, eye lesions, skin lesions, etc, but the coexistence of these 2 diseases are uncommon. Behçet disease with gastrointestinal involvement in ulcerative colitis (UC) patient has been reported in just 1 previous case report, but, which can not be diagnosed as definite intestinal BD based on Korean novel diagnositic criteria due to lacking the typical ileocecal ulcer. Patient concerns: We present a 23-year-old woman with ulcerative disease who developed typical intestinal BD, which is the first case report of patient with coexisting UC and typical intestinal BD. Diagnoses: This patient was diagnosed as coexistence of intestinal BD and UC base on the clinical manifestations, extra intestinal manifestations and typical colonoscopic findings. Interventions: Steroid and methotrexate were administered. Outcomes: This patient achieved clinical remission and mucosal healing. Lessons: Coexistence of intestinal BD and UC is uncommon, and the combination with steroid, methotrexate, and 5-aminosalicylic acids is an effective therapy.