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Dysregulated microRNA (miRNA) expression was profiled through a miRNA array comparison between human colorectal cancer tumors and their adjacent normal tissues. Specifically, using laser capture micro-dissection, miR-133a was shown to be significantly downregulated in primary colorectal cancer specimens compared with matched adjacent normal tissue. Ectopic expression of miR-133a significantly suppressed colorectal cancer cell growth in vitro and in vivo. Cell-cycle analysis revealed that miR-133a induced a G0/G1-phase arrest, concomitant with the upregulation of the key G1-phase regulator p21Cip1. We further revealed that miR-133a markedly increased p53 protein and induced p21Cip1 transcription. Studies in silico revealed that the 3′UTR of the ring finger and FYVE-like domain containing E3-ubiquitin protein ligase (RFFL), which regulates p53 protein, contains an evolutionarily conserved miR-133a binding site. miR-133a repressed RFFL-3′UTR reporter activity and reduced RFFL protein levels, indicating that miR-133a directly bound to RFFL mRNA and inhibited RFFL translation. Moreover, miR-133a sensitized colon cancer cells to doxorubicin and oxaliplatin by enhancing apoptosis and inhibiting cell proliferation. These data add weight to the significance of miR-133a in the development of CRC.Implications: miR-133a serves as a potential tumor suppressor upstream of p53 in colorectal cancer and may sensitize cells to therapeutics. Mol Cancer Res; 11(9); 1051–60. ©2013 AACR.

PDF file - 48K, Characteristics of the CRC patients for miRNA array.

PDF file - 54K, miR-133a expression levels in xenograft models.

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PDF file - 45K, Characteristics of the CRC patients for miRNA validation.

PDF file - 207K, miR-133a exerted inhibitory effects on p53 mutant cell lines DLD1 and HT29.

PDF file - 81K, Clinicopathological correlation of miR-133a expression in CRC.

PDF file - 49K, DNA sequences of primers used in the study.

PDF file - 71K, Ectopic miR-133a expression induced nuclear p21 localization.

Figure S1-S8

Gene amplification is a hallmark of cancer and is frequently observed in colorectal cancer. Previous whole-genome sequencing of colorectal cancer clinical specimens identified amplification of Ring finger protein 6 (RNF6), a RING-domain E3 ubiquitin ligase. In this study, we showed that RNF6 is upregulated in 73.5% (147/200) of patients with colorectal cancer and was positively associated with RNF6 gene amplification. Furthermore, RNF6 expression and its gene amplification were independent prognostic factors for poor outcome of patients with colorectal cancer. RNF6 promoted cell growth, cell-cycle progression, and epithelial-to-mesenchymal transition in colorectal cancer cells; RNF6 also promoted colorectal tumor growth and lung metastasis in mouse models. Mechanistic investigations revealed that RNF6 bound and ubiquitylated transducin-like enhancer of split 3 (TLE3), a transcriptional repressor of the β-catenin/TCF4 complex. RNF6-mediated degradation of TLE3 significantly suppressed the association of TLE3 with TCF4/LEF, which in turn led to recruitment of β-catenin to TCF4/LEF, triggering Wnt/β-catenin activation. Restoration of TLE3 expression abolished the oncogenic effects of RNF6. Taken together, these results demonstrate that RNF6 plays a pivotal oncogenic role in colorectal tumorigenesis.Significance: RNF6-mediated ubiquitination and degradation of TLE3 activates the Wnt/β-catenin pathway in colorectal carcinogenesis. Cancer Res; 78(8); 1958–71. ©2018 AACR.

RNF6 up-regulates in CRC and indicates a poor outcome of CRC patients.

Copy number alterations are crucial for the development of colorectal cancer. Our whole-genome analysis identified tocopherol alpha transfer protein-like (TTPAL) as preferentially amplified in colorectal cancer. Here we demonstrate that frequent copy number gain of TTPAL leads to gene overexpression in colorectal cancer from a Chinese cohort (n = 102), which was further validated by a The Cancer Genome Atlas (TCGA) cohort (n = 376). High expression of TTPAL was significantly associated with shortened survival in patients with colorectal cancer. TTPAL promoted cell viability and clonogenicity, accelerated cell-cycle progression, inhibited cell apoptosis, increased cell migration/invasion ability in vitro, and promoted tumorigenicity and cancer metastasis in vivo. TTPAL significantly activated Wnt signaling and increased β-catenin activation and protein expression of cyclin D1 and c-Myc. Coimmunoprecipitation followed by mass spectrometry identified thyroid receptor–interacting protein 6 (TRIP6) as a direct downstream effector of TTPAL. Depletion of TRIP6 significantly abolished the effects of TTPAL on cell proliferation and Wnt activation. Direct binding of TTPAL with TRIP6 in the cytoplasm inhibited ubiquitin-mediated degradation of TRIP6 and, subsequently, increased levels of TRIP6 displaced β-catenin from the tumor suppressor MAGI1 via competitive binding. This sequence of events allows β-catenin to enter the nucleus and promotes oncogenic Wnt/β-catenin signaling. In conclusion, TTPAL is commonly overexpressed in colorectal cancer due to copy number gain, which promotes colorectal tumorigenesis by activating Wnt/β-catenin signaling via stabilization of TRIP6. TTPAL overexpression may serve as an independent new biomarker for the prognosis of patients with colorectal cancer.Significance:TTPAL, a gene preferentially amplified in colorectal cancer, promotes colon tumorigenesis via activation of the Wnt/β-catenin pathway.

Supplementary methods

Supplementary Table 1. Antibodies used in this study. Supplementary Table 2. Clinicopathologic features of TTPAL mRNA expression with CRC from Chinese cohort 1and protein expression with CRC from Chinese cohort 2. Supplementary Table 3. The list of potential target genes of TTPAL identified by LC-MS.

Supplementary Figure 1. Screening of TTPAL by whole genome sequencing and TTPAL amplification validation in CRC. Supplementary Figure 2. TTPAL effects on signaling pathway. Supplementary Figure 3. TRIP6 was highly expressed in CRC. Supplementary Figure 4. TRIP6 showed oncogenic function in CRC. Supplementary Figure 5. MAGI1 showed tumor suppressor function in CRC.

There remains a paucity of functional biomarkers in gastric cancer. Here, we report the identification of the sodium channel subunit SCNN1B as a candidate biomarker in gastric cancer. SCNN1B mRNA expression was silenced commonly by promoter hypermethylation in gastric cancer cell lines and primary tumor tissues. Tissue microarray analysis revealed that high expression of SCNN1B was an independent prognostic factor for longer survival in gastric cancer patients, especially those with late-stage disease. Functional studies demonstrated that SCNN1B overexpression was sufficient to suppress multiple features of cancer cell pathophysiology in vitro and in vivo. Mechanistic investigations revealed that SCNN1B interacted with the endoplasmic reticulum chaperone, GRP78, and induced its degradation via polyubiquitination, triggering the unfolded protein response (UPR) via activation of PERK, ATF4, XBP1s, and C/EBP homologous protein and leading in turn to caspase-dependent apoptosis. Accordingly, SCNN1B sensitized gastric cancer cells to the UPR-inducing drug tunicamycin. GRP78 overexpression abolished the inhibitory effect of SCNN1B on cell growth and migration, whereas GRP78 silencing aggravated growth inhibition by SCNN1B. In summary, our results identify SCNN1B as a tumor-suppressive function that triggers UPR in gastric cancer cells, with implications for its potential clinical applications as a survival biomarker in gastric cancer patients. Cancer Res; 77(8); 1968–82. ©2017 AACR.

DNA methylation has been identified as a hallmark of gastric cancer (GC). Identifying genes that are repressed by DNA promoter methylation is essential in providing insights into the molecular pathogenesis of gastric cancer. Using genome-wide methylation studies, we identified that transcription factor forkhead box F2 (FOXF2) was preferentially methylated in gastric cancer. We then investigated the functional significance and clinical implication of FOXF2 in gastric cancer. FOXF2 was silenced in gastric cancer cell lines and cancer tissues by promoter methylation, which was negatively associated with mRNA expression. Ectopic expression of FOXF2 inhibited proliferation, colony formation, G1–S cell-cycle transition, induced apoptosis of gastric cancer cell lines, and suppressed growth of xenograft tumors in nude mice; knockdown of FOXF2 elicited opposing effects. FOXF2 inhibited Wnt signaling by inducing β-catenin protein ubiquitination and degradation independently of GSK-3β. FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2-binding protein-like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with β-catenin, increasing its ubiquitination and degradation. Multivariate Cox regression analysis identified FOXF2 hypermethylation as an independent prognostic factor of poor survival in early-stage gastric cancer patients. In conclusion, FOXF2 is a critical tumor suppressor in gastric carcinogenesis whose methylation status serves as an independent prognostic factor for gastric cancer patients.Significance: FOXF2-mediated upregulation of the E3 ligase IRF2BPL drives ubiquitylation and degradation of β-catenin in gastric cancer, blunting Wnt signaling and suppressing carcinogenesis. Cancer Res; 78(7); 1643–56. ©2018 AACR.

Clinicopathological features of CRC patients

Table S1-S6

Supplementary Figure S1: No effect of miR-490-3p on necrosis and apoptosis.

Supplementary Table S1: Absolute expression levels of miR-490-3p, miR-375 and let-7b in non-cancerous gastric mucosa.

PDF file - 4.4MB, Figure S1 Apoptogenic function and mechanism of LL-37 in LoVo colon cancer cells

Chromatin remodeling has emerged as a hallmark of gastric cancer, but the regulation of chromatin regulators other than genetic change is unknown. Helicobacter pylori causes epigenetic dysregulation to promote gastric carcinogenesis, but the roles and functions of microRNAs (miRNA) in this multistage cascade are not fully explored. In this study, miRNA expression in preneoplastic and neoplastic lesions in murine stomachs induced by H. pylori and N-methyl-N-nitrosourea (MNU) was profiled by miRNA expression array. miR-490-3p exhibited progressive downregulation in gastritis, intestinal metaplasia, and adenocarcinoma during H. pylori and MNU-induced gastric carcinogenesis. Significant downregulation of miR-490-3p was confirmed in human gastric cancer tissues in which its regulatory region was found to be hypermethylated. miR-490-3p exerted growth- and metastasis-suppressive effects on gastric cancer cells through directly targeting SMARCD1, a SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex subunit. Knockdown of SMARCD1 significantly attenuated the protumorigenic effects of miR-490-3p inhibitor, whereas enforced expression of SMARCD1 promoted in vitro and in vivo oncogenic phenotypes of gastric cancer cells. SMARCD1 was markedly upregulated in gastric cancer in which its high expression was associated with shortened patients' survival independent of TNM staging. In conclusion, hypermethylation-mediated silencing of miR-490-3p reactivates SMARCD1 to confer malignant phenotypes, mechanistically linking H. pylori, chromatin remodeling, and gastric carcinogenesis. Cancer Res; 75(4); 754–65. ©2014 AACR.

Supplementary Materials and Methods

Supplementary Figure Legends

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The effectiveness of the hemostatic powder TC-325 as a single endoscopic treatment for acute nonvariceal upper gastrointestinal bleeding is uncertain.To compare TC-325 with standard endoscopic hemostatic treatments in the control of active bleeding from nonvariceal upper gastrointestinal causes.One-sided, noninferiority, randomized, controlled trial. (ClinicalTrials.gov: NCT02534571).University teaching hospitals in the Asia-Pacific region.224 adult patients with acute bleeding from a nonvariceal cause on upper gastrointestinal endoscopy.TC-325 (The primary outcome was control of bleeding within 30 days. Other outcomes included failure to control bleeding during index endoscopy, recurrent bleeding after initial hemostasis, further interventions, blood transfusion, hospitalization, and death.224 patients were enrolled (136 with gastroduodenal ulcers [60.7%], 33 with tumors [14.7%], and 55 with other causes of bleeding [24.6%]). Bleeding was controlled within 30 days in 100 of 111 patients (90.1%) in the TC-325 group and 92 of 113 (81.4%) in the standard treatment group (risk difference, 8.7 percentage points [1-sided 95% CI, 0.95 percentage point]). There were fewer failures of hemostasis during index endoscopy with TC-325 (3 [2.7%] vs. 11 [9.7%]; odds ratio, 0.26 [CI, 0.07 to 0.95]). Recurrent bleeding within 30 days did not differ between groups (9 [8.1%] vs. 10 [8.8%]). The need for further interventions also did not differ between groups (further endoscopic treatment: 8 [7.2%] vs. 10 [8.8%]; angiography: 2 [1.8%] vs. 4 [3.5%]; surgery: 1 [0.9%] vs. 0). There were 14 deaths in each group (12.6% vs. 12.4%).Clinicians were not blinded to treatment.TC-325 is not inferior to standard treatment in the endoscopic control of bleeding from nonvariceal upper gastrointestinal causes.General Research Fund to the University Grants Committee, Hong Kong SAR Government.

Introduction: The COVID-19 outbreak abruptly restricted gastrointestinal (GI) endoscopy services during the first wave of the pandemic. We aimed to assess the impact of COVID-19 on the practice of GI endoscopy in Asian countries. Methods: This was an International Questionnaire-based Internet Survey conducted at multiple facilities by the International Gastrointestinal Consensus Symposium. A total of 166 respondents in Japan, China, Hong Kong, South Korea, Philippines, Thailand, Indonesia, and Singapore participated in this study. Results: The volume of endoscopic screening or follow-up endoscopies and therapeutic endoscopies were markedly reduced during the first wave of the pandemic, which was mainly attributed to the decreased number of outpatients, cancellations by patients, and adherence to the guidelines of academic societies. The most common indications for GI endoscopy during the first wave were GI bleeding, cholangitis or obstructive jaundice, and a highly suspicious case of neoplasia. The most common GI symptoms of COVID-19 patients during the infected period included diarrhea, nausea, and vomiting. The pandemic exacerbated some GI diseases, such as functional dyspepsia and irritable bowel syndrome. There were cases with delayed diagnosis of cancers due to postponed endoscopic procedures, and the prescription of proton pump inhibitors/potassium-competitive acid blockers, steroids, immunosuppressive agents, and biologics was delayed or canceled. The personal protective equipment used during endoscopic procedures for high-risk patients were disposable gloves, disposable gowns, N95 or equivalent masks, and face shields. However, the devices on the patient side during endoscopic procedures included modified surgical masks, mouthpieces with filters, and disposable vinyl boxes or aerosol boxes covering the head. Furthermore, the time for education, basic research, clinical research, and daily clinical practice decreased during the first wave. Conclusion: This study demonstrated that the COVID-19 pandemic profoundly affected the method of performing GI endoscopy and medical treatment for patients with GI diseases in Asian countries.

Background Coronavirus disease 2019 (COVID-19) caused by the enveloped RNA virus SARS-CoV-2 primarily affects the respiratory and gastrointestinal tracts. SARS-CoV-2 was isolated from fecal samples, and active viral replication was reported in human intestinal cells. The human gut also harbors an enormous amount of resident viruses (collectively known as the virome) that play a role in regulating host immunity and disease pathophysiology. Understanding gut virome perturbation that underlies SARS-CoV-2 infection and severity is an unmet need. Methods We enrolled 98 COVID-19 patients with varying disease severity (3 asymptomatic, 53 mild, 34 moderate, 5 severe, 3 critical) and 78 non-COVID-19 controls matched for gender and co-morbidities. All subjects had fecal specimens sampled at inclusion. Blood specimens were collected for COVID-19 patients at admission to test for inflammatory markers and white cell counts. Among COVID-19 cases, 37 (38%) patients had serial fecal samples collected 2 to 3 times per week from time of hospitalization until after discharge. Using shotgun metagenomics sequencing, we sequenced and profiled the fecal RNA and DNA virome. We investigated alterations and longitudinal dynamics of the gut virome in association with disease severity and blood parameters. Results Patients with COVID-19 showed underrepresentation of Pepper mild mottle virus (RNA virus) and multiple bacteriophage lineages (DNA viruses) and enrichment of environment-derived eukaryotic DNA viruses in fecal samples, compared to non-COVID-19 subjects. Such gut virome alterations persisted up to 30 days after disease resolution. Fecal virome in SARS-CoV-2 infection harbored more stress-, inflammation-, and virulence-associated gene encoding capacities including those pertaining to bacteriophage integration, DNA repair, and metabolism and virulence associated with their bacterial host. Baseline fecal abundance of 10 virus species (1 RNA virus, pepper chlorotic spot virus, and 9 DNA virus species) inversely correlated with disease COVID-19 severity. These viruses inversely correlated with blood levels of pro-inflammatory proteins, white cells, and neutrophils. Among the 10 COVID-19 severity-associated DNA virus species, 4 showed inverse correlation with age; 5 showed persistent lower abundance both during disease course and after disease resolution relative to non-COVID-19 subjects. Conclusions Both enteric RNA and DNA virome in COVID-19 patients were different from non-COVID-19 subjects, which persisted after disease resolution of COVID-19. Gut virome may calibrate host immunity and regulate severity to SARS-CoV-2 infection. Our observation that gut viruses inversely correlated with both severity of COVID-19 and host age may partly explain that older subjects are prone to severe and worse COVID-19 outcomes. Altogether, our data highlight the importance of human gut virome in severity and potentially therapeutics of COVID-19.

BackgroundThere were limited data on the risk of post-polypectomy bleeding (PPB) in patients on direct oral anticoagulants (DOAC). We aimed to evaluate the PPB and thromboembolic risks among DOAC and warfarin users in a population-based cohort.MethodsWe performed a territory-wide retrospective cohort study involving patients in Hong Kong from 2012 to 2020. Patients who received an oral anticoagulant and had undergone colonoscopy with polypectomy were identified. Propensity-score models with inverse probability of treatment weighting were developed for the warfarin-DOAC and between-DOAC comparisons. The primary outcome was clinically significant delayed PPB, defined as repeat colonoscopy requiring haemostasis within 30 days. The secondary outcomes were 30-day blood transfusion requirement and new thromboembolic event.ResultsApixaban was associated with lower PPB risk than warfarin (adjusted HR (aHR) 0.39, 95% CI 0.24 to 0.63, pFor thromboembolic events, apixaban was associated with lower risk than warfarin (aHR 0.22, 95% CI 0.11 to 0.45, pConclusionsApixaban was associated with a significantly lower risk of PPB and thromboembolism than warfarin, dabigatran and rivaroxaban, particularly in older patients with right-sided polyps.

We review the latest advances in management of peptic ulcer bleeding and the updates from international guidelines. A low Glasgow Blatchford score of ≤ 1 can safely identify low-risk patients to manage in out-patient settings. Except patients with persistent haemodynamic instability, early endoscopy within 24 h appears safe when compared with earlier intervention. Over-the-scope-clips (OTSC) show promising result as first-line and second-line endoscopic haemostaic therapy, while haemostatic spray can be considered as a stop-gap treatment. After endoscopic intervention, high-dose oral proton-pump-inhibitor (PPI) is an alternative to intravenous use in selected cases. Retrospective data shows new-generation P2Y12 inhibitors (prasugrel and ticagrelor) have higher risk of bleeding when compared with clopidogrel. Vonoprazan, a potassium-competitive acid blocker and a potent acid suppressor, shows encouraging initial results in management of gastrointestinal bleeding. Endoscopic therapy remains the mainstay of treatment of peptic ulcer bleeding and future research will clarify the role of new endoscopic treatment modalities such as OTSC. Good peri-endoscopic treatment remains crucial, and more data is needed to guide management in patients on new generation anti-platelet drugs and direct oral anti-coagulants.

Background Previous observational studies have demonstrated inconsistent and inconclusive results of changes in the intestinal microbiota in patients with obesity and metabolic disorders. We performed a systematic review to explore evidence for this association across different geography and populations. Methods We performed a systematic search of MEDLINE (OvidSP) and Embase (OvidSP) of articles published from Sept 1, 2010, to July 10, 2021, for case–control studies comparing intestinal microbiome of individuals with obesity and metabolic disorders with the microbiome of non-obese, metabolically healthy individuals (controls). The primary outcome was bacterial taxonomic changes in patients with obesity and metabolic disorders as compared to controls. Taxa were defined as “lean-associated” if they were depleted in patients with obesity and metabolic disorders or negatively associated with abnormal metabolic parameters. Taxa were defined as “obesity-associated” if they were enriched in patients with obesity and metabolic disorders or positively associated with abnormal metabolic parameters. Results Among 2390 reports screened, we identified 110 full-text articles and 60 studies were included. Proteobacteria was the most consistently reported obesity-associated phylum. Thirteen, nine, and ten studies, respectively, reported Faecalibacterium, Akkermansia, and Alistipes as lean-associated genera. Prevotella and Ruminococcus were obesity-associated genera in studies from the West but lean-associated in the East. Roseburia and Bifidobacterium were lean-associated genera only in the East, whereas Lactobacillus was an obesity-associated genus in the West. Conclusions We identified specific bacteria associated with obesity and metabolic disorders in western and eastern populations. Mechanistic studies are required to determine whether these microbes are a cause or product of obesity and metabolic disorders.

KEY POINTS Hong Kong, a special administrative region of the People’s Republic of China, is located in southern China and shares a border with mainland China. It has a population of more than 7.45 million and is a regional travel hub, with the eighth busiest airport in the world and with more than

ObjectiveFusobacteria are not common nor relatively abundant in non-colorectal cancer (CRC) populations, however, we identified multiple Fusobacterium taxa nearly absent in western and rural populations to be comparatively more prevalent and relatively abundant in southern Chinese populations. We investigated whether these represented known or novel lineages in the Fusobacterium genus, and assessed their genomes for features implicated in development of cancer.MethodsPrevalence and relative abundances of fusobacterial species were calculated from 3157 CRC and non-CRC gut metagenomes representing 16 populations from various biogeographies. Microbial genomes were assembled and compared with existing reference genomes to assess novel fusobacterial diversity. Phylogenetic distribution of virulence genes implicated in CRC was investigated.ResultsIrrespective of CRC disease status, southern Chinese populations harboured increased prevalence (maximum 39% vs 7%) and relative abundances (average 0.4% vs 0.04% of gut community) of multiple recognised and novel fusobacterial taxa phylogenetically distinct from Fusobacterium nucleatum. Genomes assembled from southern Chinese gut metagenomes increased existing fusobacterial diversity by 14.3%. Homologues of the FadA adhesin linked to CRC were consistently detected in several monophyletic lineages sister to and inclusive of F. varium and F. ulcerans, but not F. mortiferum. We also detected increased prevalence and relative abundances of F. varium in CRC compared with non-CRC cohorts, which together with distribution of FadA homologues supports a possible association with gut disease.ConclusionThe proportion of fusobacteria in guts of southern Chinese populations are higher compared with several western and rural populations in line with the notion of environment/biogeography driving human gut microbiome composition. Several non-nucleatum taxa possess FadA homologues and were enriched in CRC cohorts; whether this imposes a risk in developing CRC and other gut diseases deserves further investigation.

BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed medications, but they are associated with a number of serious adverse effects, including hypertension, cardiovascular disease, kidney injury and GI complications.ObjectiveTo develop a set of multidisciplinary recommendations for the safe prescription of NSAIDs.MethodsRandomised control trials and observational studies published before January 2018 were reviewed, with 329 papers included for the synthesis of evidence-based recommendations.ResultsWhenever possible, a NSAID should be avoided in patients with treatment-resistant hypertension, high risk of cardiovascular disease and severe chronic kidney disease (CKD). Before treatment with a NSAID is started, blood pressure should be measured, unrecognised CKD should be screened in high risk cases, and unexplained iron-deficiency anaemia should be investigated. For patients with high cardiovascular risk, and if NSAID treatment cannot be avoided, naproxen or celecoxib are preferred. For patients with a moderate risk of peptic ulcer disease, monotherapy with a non-selective NSAID plus a proton pump inhibitor (PPI), or a selective cyclo-oxygenase-2 (COX-2) inhibitor should be used; for those with a high risk of peptic ulcer disease, a selective COX-2 inhibitor plus PPI are needed. For patients with pre-existing hypertension receiving renin-angiotensin system blockers, empirical addition (or increase in the dose) of an antihypertensive agent of a different class should be considered. Blood pressure and renal function should be monitored in most cases.ConclusionNSAIDs are a valuable armamentarium in clinical medicine, but appropriate recognition of high-risk cases, selection of a specific agent, choice of ulcer prophylaxis and monitoring after therapy are necessary to minimise the risk of adverse events.

ObjectiveThere is a need for early detection of colorectal cancer (CRC) at precancerous-stage adenoma. Here, we identified novel faecal bacterial markers for diagnosing adenoma.DesignThis study included 1012 subjects (274 CRC, 353 adenoma and 385 controls) from two independent Asian groups. Candidate markers were identified by metagenomics and validated by targeted quantitative PCR.ResultsMetagenomic analysis identified ‘m3’ from a Lachnoclostridium sp., Fusobacterium nucleatum (Fn) and Clostridium hathewayi (Ch) to be significantly enriched in adenoma. Faecal m3 and Fn were significantly increased from normal to adenoma to CRC (pm3 may perform better than Fn in distinguishing adenoma from controls (areas under the receiver operating characteristic curve (AUROCs) m3=0.675 vs Fn=0.620, p=0.09), while Fn performed better in diagnosing CRC (AUROCs Fn=0.862 vs m3=0.741, pm3 and Fn showed sensitivities of 48.3% and 33.8% for adenoma, and 62.1% and 77.8% for CRC, respectively. In a subgroup tested with faecal immunochemical test (FIT; n=642), m3 performed better than FIT in detecting adenoma (sensitivities for non-advanced and advanced adenomas of 44.2% and 50.8% by m3 (specificity=79.6%) vs 0% and 16.1% by FIT (specificity=98.5%)). Combining with FIT improved sensitivity of m3 for advanced adenoma to 56.8%. The combination of m3 with Fn, Ch, Bacteroides clarus and FIT performed best for diagnosing CRC (specificity=81.2% and sensitivity=93.8%).ConclusionThis study identifies a novel bacterial marker m3 for the non-invasive diagnosis of colorectal adenoma.

Background Emerging data suggest that alterations in gut fungi may be associated with the pathogenesis of inflammatory bowel disease (IBD). In healthy individuals, gut commensal fungi act synergistically with other members of the microbiota to maintain homeostasis but their role in IBD is less clear. Aim To review the role of gut fungi and their trans-kingdom interactions with bacteria in IBD METHODS: A literature search was conducted on Ovid and Pubmed to select relevant animal and human studies that have reported fungi and IBD. Results There is an increased total fungal load particularly of Candida and Malassezia species in the faeces and mucosa of Crohn's disease patients, and a lower fungal diversity in the faeces of ulcerative colitis patients. Caspase recruitment domain-containing protein (CARD)-9 polymorphism in Crohn's disease patients favours Malassezia colonisation that worsens gut inflammation. Diet high in carbohydrates increased the total abundance of Candida species, whereas protein-rich diet had the opposite effect. Anti-fungal therapies are mostly used to treat Candida albicans or Histoplasma capsulatum infections in IBD, whereas pilot studies of supplementing fungal probiotics Saccharomycopsis fibuligera, Saccharomyces boulardii and Saccharomyces cerevisiae CNCM I-3856 strain showed therapeutic effects in IBD. Conclusions Gut fungi are altered in patients with Crohn's disease and ulcerative colitis. Modulation of the fungal microbiota can be considered as a therapeutic approach for IBD. Future research should focus on understanding how the fungal microbiota interacts with other components of the gut microbiota in association with the pathogenesis and development of IBD.

ObjectiveThe underlying microbial basis, predictors of therapeutic outcome and active constituent(s) of faecal microbiota transplantation (FMT) mediating benefit remain unknown. An international panel of experts presented key elements that will shape forthcoming FMT research and practice.DesignSystematic search was performed, FMT literature was critically appraised and a 1-day round-table discussion was conducted to derive expert consensus on key issues in FMT research.Results16 experts convened and discussed five questions regarding (1) the role of donor and recipient microbial (bacteria, viruses, fungi) parameters in FMT; (2) methods to assess microbiota alterations; (3) concept of keystone species and microbial predictors of FMT, (4) influence of recipient profile and antibiotics pretreatment on FMT engraftment and maintenance and (5) new developments in FMT formulations and delivery. The panel considered that variable outcomes of FMT relate to compositional and functional differences in recipient’s microbiota, and likely donor-associated and recipient-associated physiological and genetic factors. Taxonomic composition of donor intestinal microbiota may influence the efficacy of FMT in recurrentClostridioides difficileinfections and UC. FMT not only alters bacteria composition but also establishes trans-kingdom equilibrium between gut fungi, viruses and bacteria to promote the recovery of microbial homeostasis. FMT is not a one size fits all and studies are required to identify microbial components that have specific effects in patients with different diseases.ConclusionFMT requires optimisation before their therapeutic promise can be evaluated for different diseases. This summary will guide future directions and priorities in advancement of the science and practice of FMT.

Background Evidence regarding the use of proton-pump inhibitors (PPIs) in COVID-19 patients remains elusive. We examined the impact of PPI use on clinical outcomes of COVID-19 patients in a territory-wide cohort. Methods We performed a retrospective cohort study using data from an electronic healthcare database managed by the Hospital Authority, Hong Kong. COVID-19 patients diagnosed virologically between 23 January 2020 and 1 January 2021 in Hong Kong were identified. The primary endpoint was a composite of intensive care unit admission, use of invasive mechanical ventilation, and/or death. PPI user was identified by PPI use within 12 months before the diagnosis of COVID-19. In subgroup analysis, current PPI users were defined as patients who used PPIs within 1 month before the diagnosis of COVID-19;past PPI users were defined as patients who used PPIs 1 to 12 months before COVID-19 diagnosis. We performed sensitivity analysis after excluding patients with short-term new NSAID use within 1 month before COVID-19 diagnosis to minimize reverse causation bias. Results We identified 8,675 COVID-19 patients (mean age 46 years, 49% male, 97.6% of all the reported cases in Hong Kong);579 (6.7%) patients had used PPI. PPI users were older, more likely to have comorbidities, concomitant medications and unfavorable laboratory parameters than non-users. Of 8,675 COVID-19 patients, 500 (5.8%) developed the primary endpoint. After propensity score (PS) balancing for patients' demographics, comorbidities, laboratory parameters, and use of medications, PPI use was not associated with the development of primary endpoint in PS weighting (weighted hazard ratio [HR] 1.11, 95% confidence interval [CI] 0.83-1.47, P=0.482) (IDDF2021-ABS- 0122 Figure 1. Cumulative incidence of primary endpoint (a composite endpoint of intensive care unit [ICU] admission, use of invasive mechanical ventilation [IMV], and death) in COVID-19 patients who were and were not proton- pump inhibitor (PPI) users after propensity score (PS) weighting in a single multiple imputation data set.), and PS matching analysis (weighted HR 0.81, 95%CI 0.57-1.14, P=0.228) (IDDF2021-ABS-0122 Figure 2. Cumulative incidence of primary endpoint (a composite endpoint of intensive care unit [ICU] admission, use of invasive mechanical ventilation [IMV], and death) in COVID-19 patients who were and were not proton-pump inhibitor (PPI) users after propensity score (PS) matching in a single multiple imputation data set). Consistent non-association was observed after multivariable adjustment (adjusted HR 0.84, 95%CI 0.66- 1.07, P=0.151), in subgroups of current and past PPI users, and in sensitivity analysis after excluding short-term new NSAID users. Conclusions PPI use is not associated with adverse clinical outcomes in COVID-19 patients. The result remains robust after PS weighting, PS matching, multivariable adjustment, and subgroup analyses.

Probiotics, as live microorganisms that improve intestinal microbial balance, have been implicated in the modulation of neurodegenerative diseases via the microbiome-gut-brain axis by improving gut dysbiosis. This review examines the association between probiotics and neurocognitive function in age-related dementia.We searched MEDLINE, Embase, Scopus, Web of Science and Cochrane library for in vivo studies using equivalent combinations of "probiotics" and "dementia" as per PRISMA. From the 52 in vivo studies identified, 5 human and 22 animal studies with comparable quantitative outcomes on neurocognitive/behavioural function were meta-analysed by forest plots, subgroup analysis and meta-regression. The analysis of biomarkers, risk of bias and publication bias were also performed.In elderly humans, probiotics correlates with a non-significant difference of neurocognitive function in Mini-Mental State Examination, but with significant improvement only in those diagnosed with Alzheimer's disease. In animals, probiotics significantly improved neurocognitive function as measured by Morris Water Maze, Y-Maze, and Passive Avoidance. Further analysis by subgrouping and meta-regression found that the probiotics-neurodegeneration association is age dependent in humans but is neither dose dependent nor duration dependent in animals or humans. Analysis of biomarkers suggested that the neurocognitive effect of probiotics is associated with an altered gut microbiome profile, downregulated proteinopathic, inflammatory and autophagic pathways, and upregulated anti-oxidative, neurotrophic, and cholinergic pathways.Overall, we report promising results in animal studies but limited evidence of probiotics leading to neurocognitive improvement in humans. More research into probiotics should be conducted, especially on live biotherapeutic products for targeted treatment of gut dysbiosis and age-related dementia.

Evidence of prophylactic clipping is inconsistent except for proximal and large colonic lesions in the general population. Although warfarin and direct oral anticoagulants (DOACs) are significant risk factors of postpolypectomy bleeding (PPB), dedicated studies to examine the benefit of prophylactic clipping in these high-risk patients remain limited.We performed a propensity score-weighted retrospective cohort study from 2012 to 2020. Patients who received an oral anticoagulant and underwent colonoscopic polypectomy were included. Data were collected on baseline demographics, medications (anticoagulant, antiplatelet, and heparin bridging), and endoscopies (polyp number, location, size, morphology, histopathology, resection method and prophylactic clipping). Propensity-score models with inverse probability of treatment weighting were developed between prophylactic clipping and no clipping groups. Unbalanced variables were included in a doubly robust model with multivariate analysis. The primary outcome was clinically significant delayed PPB, defined as a composite endpoint of hemoglobin drop ≥2 g/dL, blood transfusion, or repeat colonoscopy for hemostasis within 30 days.Five hundred forty-seven patients with 1485 polyps were included. Prophylactic clipping was not associated with a reduced risk of PPB (odds ratio [OR], 1.19; 95% confidence interval [CI], .73-1.95; P = .497). The hot resection method was associated with a significantly higher risk of PPB (OR, 9.76; 95% CI, 3.94-32.60; P .001) compared with cold biopsy or snare polypectomy. In a subgroup analysis, prophylactic clipping was associated with a lower PPB risk in patients on DOACs (OR, .36; 95% CI, .16-.82; P = .015).Prophylactic clipping was not associated with an overall reduced risk of PPB in patients on oral anticoagulants. The use of cold snare polypectomy should be maximized in anticoagulated patients.

The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global threat to human health. Using a multidisciplinary approach, we identified and validated the hepatitis C virus (HCV) protease inhibitor simeprevir as an especially promising repurposable drug for treating COVID-19. Simeprevir potently reduces SARS-CoV-2 viral load by multiple orders of magnitude and synergizes with remdesivir in vitro. Mechanistically, we showed that simeprevir not only inhibits the main protease (Mpro) and unexpectedly the RNA-dependent RNA polymerase (RdRp) but also modulates host immune responses. Our results thus reveal the possible anti-SARS-CoV-2 mechanism of simeprevir and highlight the translational potential of optimizing simeprevir as a therapeutic agent for managing COVID-19 and future outbreaks of CoV., Simeprevir, an HCV drug, suppresses SARS-CoV-2 replication by inhibiting two viral proteins and modulating host immune responses, thus providing novel insights in anti-CoV drug design.