Multi-Armed Bandit-Based User Network Node Selection.

In the scenario of an integrated space-air-ground emergency communication network, users encounter the challenge of rapidly identifying the optimal network node amidst the uncertainty and stochastic fluctuations of network states. This study introduces a Multi-Armed Bandit (MAB) model and proposes an optimization algorithm leveraging dynamic variance sampling (DVS). The algorithm posits that the prior distribution of each node's network state conforms to a normal distribution, and by constructing the distribution's expected value and variance, it maximizes the utilization of sample data, thereby maintaining an equilibrium between data exploitation and the exploration of the unknown. Theoretical substantiation is provided to illustrate that the Bayesian regret associated with the algorithm exhibits sublinear growth. Empirical simulations corroborate that the algorithm in question outperforms traditional ε-greedy, Upper Confidence Bound (UCB), and Thompson sampling algorithms in terms of higher cumulative rewards, diminished total regret, accelerated convergence rates, and enhanced system throughput.

tiRNAs: A novel class of small noncoding RNAs that helps cells respond to stressors and plays roles in cancer progression.

tRNA-derived stress-induced RNAs (tiRNAs), important components of tRNA-derived fragments, are gaining popularity for their functions as small noncoding RNAs involved in cancer progression. Under cellular stress, tiRNAs are generated when mature tRNA is specifically cleaved by angiogenin and suggested to act as transducers or effectors involved in cellular stress responses. tiRNAs facilitate cells to respond to stresses mainly via reprogramming translation, inhibiting apoptosis, degrading mRNA, and generating stress granules. This review introduces the cellular biogenesis, molecular mechanisms, and biological roles of tiRNAs in stress response and disease regulation. A better understanding of their roles in regulating cancer may provide novel biomarkers or therapeutic targets for diagnosis and treatment.

Correction to: Case report of cryptogenic multifocal ulcerous stenosing enteritis (CMUSE): a rare isease may contribute to endoscopy-capsule retention in the small intestine.

Following publication of the original article [1], the author reported the wrong version of Table 1 has been published. The word of 'Capsule' was mistakenly written as 'Capusle'.

Case report of cryptogenic multifocal ulcerous stenosing enteritis (CMUSE): a rare disease may contribute to endoscopy-capsule retention in the small intestine.

BACKGROUND: CMUSE is a rare disease whose diagnosis remains difficult because the lesion is confined to the small bowel. CASE PRESENTATION: Here, we present a case of 43-year-old female patient suffered chronic abdominal pain for 20 years, and finally diagnosed with CMUSE. Capsule endoscopy was performed when general endoscopic investigation failed to find the lesion, but the capsule was stranded in the small intestine. Moreover, capsule retention results in acute intestinal obstruction. Thus, surgery was performed and CMUSE was confirmed. The patient was recovered after partial small intestine resection. CONCLUSIONS: Capsule retention occurred in nearly 60% of patients with CMUSE. Capsule endoscopy should be avoided when the patient is suspected of CMUSE, especially with severe anemia and radiologic finding in the ileum.

Effect of immunosuppressive therapy on interferon γ release assay for latent tuberculosis screening in patients with autoimmune diseases: a systematic review and meta-analysis.

OBJECTIVE: Interferon γ release assay (IGRA) is commonly used to diagnose latent TB infection (LTBI). Immunosuppressive therapy may affect its performance but data are conflicting. We aimed to determine the effect of immunosuppressive therapy on the performance of IGRA in patients with autoimmune diseases. METHODS: We searched PubMed, MEDLINE, EMBASE and the Cochrane Library up to December 2014. We included studies that reported the IGRA results in patients with autoimmune disease with or without immunosuppressive therapy. The pooled effect of immunosuppressive therapy on IGRA was estimated using a Peto fixed-effects model. RESULTS: We included 17 studies with 3197 participants in the meta-analysis. Among the subjects, 71.5% were taking immunosuppressive therapy and 56.7% had received Bacillus Calmette-Guérin vaccination. Compared with patients not on immunosuppressants, patients receiving immunosuppressive therapy were less likely to have a positive IGRA result (OR 0.66, 95% CI 0.53 to 0.83, I(2)=23%), especially patients receiving anti-tumour necrosis factor (anti-TNF) treatment (OR 0.50, 95% CI 0.29 to 0.88). The use of immunosuppressive therapy was also associated with a lower rate of positive tuberculin skin test result (OR 0.51, 95% CI 0.42 to 0.61). CONCLUSIONS: Our meta-analysis showed that IGRA results are negatively affected by immunosuppressive therapy. IGRA alone may not be sufficiently sensitive to diagnose LTBI in patients on immunosuppressive therapy. Patients should preferably be screened for LTBI before initiation of immunosuppressive therapy, especially before anti-TNF therapy.

Serrated polyps and the risk of synchronous colorectal advanced neoplasia: a systematic review and meta-analysis.

OBJECTIVES: Serrated polyps of the colon comprise a heterogeneous group of lesions with distinct histological and malignant features. The presence of serrated polyps has been associated with synchronous advanced neoplasia, although the magnitude of this relationship is unclear. METHODS: Using studies identified from systematic literature search up to February 2014, we performed a systematic review and meta-analysis to estimate the pooled prevalence of serrated polyps and their association with synchronous advanced neoplasia. Random-effects models were used to combine estimates from heterogeneous studies, and odds ratios (ORs) with 95% confidence intervals (CIs) were presented. RESULTS: Nine studies with 34,084 participants were included. The mean age of subjects was 59.9±6.6 years and 52.5% of the subjects were male. Pooled prevalence of serrated polyps was 15.6% (95% CI, 10.3-22.9%). The pooled OR of advanced neoplasia in individuals with serrated polyps was 2.05 (95% CI, 1.38-3.04). Pooled analysis showed that the presence of proximal serrated polyps (OR=2.77, 95% CI, 1.71-4.46) and large serrated polyps (OR=4.10, 95% CI, 2.69-6.26) was associated with an increased risk of synchronous advanced neoplasia. The pooled OR for advanced neoplasia in individuals with proximal and large serrated polyps was 3.35 (95% CI, 2.51-4.46). Considerable heterogeneity was observed in most analyses. CONCLUSIONS: Our meta-analysis showed that serrated polyps are associated with a more than twofold increased risk of detection of synchronous advanced neoplasia. Individuals with proximal and large serrated polyps have the highest risk. These individuals deserve surveillance colonoscopy.

Evaluation and clinical significance of the stomach age model for evaluating aging of the stomach-a multicenter study in China.

BACKGROUND: A higher prevalence of chronic atrophic gastritis (CAG) occurs in younger adults in Asia. We used Stomach Age to examine the different mechanisms of CAG between younger adults and elderly individuals, and established a simple model of cancer risk that can be applied to CAG surveillance. METHODS: Stomach Age was determined by FISH examination of telomere length in stomach biopsies. Δψm was also determined by flow cytometry. Sixty volunteers were used to confirm the linear relationship between telomere length and age while 120 subjects were used to build a mathematical model by a multivariate analysis. Overall, 146 subjects were used to evaluate the validity of the model, and 1,007 subjects were used to evaluate the relationship between prognosis and Δage (calculated from the mathematical model). ROC curves were used to evaluate the relationship between prognosis and Δage and to determine the cut-off point for Δage. RESULTS: We established that a tight linear relationship between the telomere length and the age. The telomere length was obvious different between patients with and without CAG even in the same age. Δψm decreased in individuals whose Stomach Age was greater than real age, especially in younger adults. A mathematical model of Stomach Age (real age + Δage) was successfully constructed which was easy to apply in clinical work. A higher Δage was correlated with a worse outcome. The criterion of Δage >3.11 should be considered as the cut-off to select the subgroup of patients who require endoscopic surveillance. CONCLUSION: Variation in Stomach Age between individuals of the same biological age was confirmed. Attention should be paid to those with a greater Stomach Age, especially in younger adults. The Δage in the Simple Model can be used as a criterion to select CAG patients for gastric cancer surveillance.

Meta-analysis of the efficacy and safety of Lactobacillus-containing and Bifidobacterium-containing probiotic compound preparation in Helicobacter pylori eradication therapy.

GOALS: To meta-analyze whether Lactobacillus-containing and Bifidobacterium-containing probiotic compound preparation could improve Helicobacter pylori (H. pylori) eradication rates and reduce side effects. BACKGROUND: There have been several studies demonstrating that Lactobacillus and Bifidobacterium species have an inhibitory effect on H. pylori. The application of probiotics in clinical practice is more often in the form of Lactobacillus-containing and Bifidobacterium-containing probiotic compound preparation. STUDY: We included all parallel controlled trials comparing Lactobacillus-containing and Bifidobacterium-containing probiotic compound preparation supplementation or not during H. pylori eradication therapy in meta-analysis. Statistical analysis was performed with the Stata version 11.0 software. Subgroup analysis and sensitivity analysis were also performed. RESULTS: Ten clinical trials were included in our meta-analysis. Eradication odds ratio (OR) was available for 1469 patients (708 in the probiotics supplementation group and 761 in the control group). The pooled OR by intention-to-treat analysis and by per-protocol analysis in the probiotics supplementation versus without probiotics was 2.066 [95% confidence interval (CI), 1.398-3.055] and 2.321 (95% CI, 1.715-3.142), respectively. The pooled OR of incidence of total side effects was significantly decreased in the probiotics supplementation group (OR=0.305; 95% CI, 0.117-0.793) by the random model without significant publication bias. CONCLUSIONS: Lactobacillus-containing and Bifidobacterium-containing probiotic compound preparation during initial H. pylori eradication therapy in the adult may have beneficial effects on eradication rate and incidence of total side effects.

tRNA modifications: insights into their role in human cancers.

Transfer RNA (tRNA) plays a central role in translation by functioning as a biological link between messenger RNA (mRNA) and proteins. One prominent feature of the tRNA molecule is its heavily modified status, which greatly affects its biogenesis and function. Modifications within the anticodon loop are crucial for translation efficiency and accuracy, whereas other modifications in the body region affect tRNA structure and stability. Recent research has revealed that these diverse modifications are critical regulators of gene expression. They are involved in many important physiological and pathological processes, including cancers. In this review we focus on six different tRNA modifications to delineate their functions and mechanisms in tumorigenesis and tumor progression, providing insights into their clinical potential as biomarkers and therapeutic targets.

New management of surveillance in patients with baseline serrated polyps: a large single-center retrospective cohort study in China.

BACKGROUND: Serrate d polyps (SP) is associated with an increased risk of colorectal cancer. Patients with SP history tend to have SP recurrence. However, the risk factors for metachronous polyps (MP) in those patients are not well established. METHODS: Data of colonoscopy were retrospectively reviewed from October 2012 to October 2021. The pathology database, electronic medical records and telephone follow-up data were also observed. RESULTS: A total of 906 patients were studied including 278 patients with MPs and 628 patients without. The multiplicity of polyps (OR, 13.63; 95% CI, 8.80-21.75), older age (OR, 5.71; 95% CI, 1.87-20.63), abdominal obesity (OR, 2.46; 95% CI, 0.98-6.42), current smoker (OR, 2.93; 95% CI, 1.15-7.83) and sedentary lifestyle (OR, 1.41; 95% CI, 1.22-1.65) are significantly associated with the risk of MPs. Patients with baseline SP < 10 mm were more likely to develop higher or same risk-grade polyps (HSRGP) ( P = 0.0014). Patients with non-clinically significant SPs whether coexisted with adenoma or not were more likely to develop HSRGPs when compared to others ( P < 0.001). CONCLUSION: Total number of polyps, older age, sedentary behavior, abdominal obesity and smoking status contributed to the risk of MPs at surveillance colonoscopy. Patients with grade 1 SPs might require closer surveillance. SPs coexisting with conventional adenoma did not increase the risk of MPs but may increase the risk of developing HSRGPs.

Berberine might block colorectal carcinogenesis by inhibiting the regulation of B-cell function by Veillonella parvula.

BACKGROUND: Colorectal carcinogenesis and progression are related to the gut microbiota and the tumor immune microenvironment. Our previous clinical trial demonstrated that berberine (BBR) hydrochloride might reduce the recurrence and canceration of colorectal adenoma (CRA). The present study aimed to further explore the mechanism of BBR in preventing colorectal cancer (CRC). METHODS: We performed metagenomics sequencing on fecal specimens obtained from the BBR intervention trial, and the differential bacteria before and after medication were validated using quantitative polymerase chain reaction. We further performed ApcMin/+ animal intervention tests, RNA sequencing, flow cytometry, immunohistochemistry, and enzyme-linked immunosorbent assays. RESULTS: The abundance of fecal Veillonella parvula ( V . parvula ) decreased significantly after BBR administration ( P = 0.0016) and increased through the development from CRA to CRC. Patients with CRC with a higher V. parvula abundance had worse tumor staging and a higher lymph node metastasis rate. The intestinal immune pathway of Immunoglobulin A production was activated, and the expression of TNFSF13B (Tumor necrosis factor superfamily 13b, encoding B lymphocyte stimulator [BLyS]), the representative gene of this pathway, and the genes encoding its receptors (interleukin-10 and transforming growth factor beta) were significantly upregulated. Animal experiments revealed that V. parvula promoted colorectal carcinogenesis and increased BLyS levels, while BBR reversed this effect. CONCLUSION: BBR might inhibit V. parvula and further weaken the immunomodulatory effect of B cells induced by V. parvula , thereby blocking the development of colorectal tumors. TRIAL REGISTRAION: ClinicalTrials.gov, No. NCT02226185.

Green tea and incidence of colorectal cancer: evidence from prospective cohort studies.

A systematic meta-analysis of prospective cohort studies on green tea consumption and colorectal cancer was performed to determine whether green tea has a chemopreventive effect against colorectal cancer. Six eligible cohort studies involving 352,275 participants and 1675 cases of colorectal cancer were identified. Combined relative risk (RR) ratios for the highest vs. lowest and increment of 1 cup/day green tea consumption levels were calculated. The combined RR of 0.90 (95% CI: 0.72-1.08) was found comparing highest vs. lowest green tea consumption levels for colorectal cancer. No significant differences by cancer-site were found, but an inverse association between green tea and incidence of colorectal cancer (RR: 0.70; 95% CI: 0.55-0.85) and colon cancer (RR: 0.69; 95% CI: 0.48-0.98) was demonstrated in Shanghai population. Singapore men had a higher risk of colorectal cancer (RR: 1.36; 95% CI: 1.06-1.74). Furthermore, an increase in green tea consumption of 1 cup/day was not associated with incidence of colorectal cancer (RR: 0.97; 95% CI: 0.91-1.03). Despite the limited evidence from Shanghai studies in support of green tea as potential chemopreventive agents against colorectal cancer, available data from prospective cohort studies are insufficient to conclude that green tea may protect against colorectal cancer.

A novel model might predict the risk of chronic atrophic gastritis: a multicenter prospective study in China.

OBJECTIVE: To find a new way to predict the risk of chronic atrophic gastritis (CAG). MATERIAL AND METHODS: All the participants received endoscopy and histological examination as well as a standard questionnaire. Multivariate analysis was performed by logistic regression to build the CAG risk model. The accuracy was evaluated by 1418 subjects recruited from six medical centers. 63 subjects received another endoscopy after 1-year follow-up and divided into three groups according to the comparison of the histological results (improved, no change and worse). RESULTS: The model showed relatively good discrimination, with an AUROC of 0.888 (95% CI 0.852-0.925). A final probability cut-off score of 0.73 was used to predict the presence (>0.73) or absence of CAG (≤0.73). Sensitivity, specificity, PPV and NPV were 82.8%, 74.7%, 91.8% and 56%, respectively. The predicted results of 1418 subjects compared with the histological results were quite similar. There was a significant difference of the scores between three groups who were followed-up for 1 year (F = 3.248, p = 0.046). In multiple comparisons, a significant difference existed between Group A (the histological results had improved after 1-year follow-up) and Group C (the results were worse) (p = 0.019). CONCLUSIONS: This is the first demonstration of the use of a mathematical model for CAG risk screening. Endoscopy should be recommended to those who are positive according to the model, to detect CAG early and conserve medical resources. In those who have a high-risk score, closer follow-up is needed.

Sirtuin5 protects colorectal cancer from DNA damage by keeping nucleotide availability.

In our previous study, we reported that sirtuin5 (SIRT5), a member of the NAD+-dependent class III histone deacetylase family, is highly expressed in colorectal cancer (CRC). Herein we show that SIRT5 knockdown impairs the production of ribose-5-phosphate, which is essential for nucleotide synthesis, resulting in continuous and irreparable DNA damage and consequently leading to cell cycle arrest and enhanced apoptosis in CRC cells. These SIRT5 silencing-induced effects can be reversed by nucleoside supplementation. Mechanistically, SIRT5 activates transketolase (TKT), a key enzyme in the non-oxidative pentose phosphate pathway, in a demalonylation-dependent manner. Furthermore, TKT is essential for SIRT5-induced malignant phenotypes of CRC both in vivo and in vitro. Altogether, SIRT5 silencing induces DNA damage in CRC via post-translational modifications and inhibits tumor growth, suggesting that SIRT5 can serve as a promising target for CRC treatment.

Fecal Enterotoxigenic Bacteroides fragilis-Peptostreptococcus stomatis-Parvimonas micra Biomarker for Noninvasive Diagnosis and Prognosis of Colorectal Laterally Spreading Tumor.

OBJECTIVE: Up to now, non-invasive diagnosis of laterally spreading tumor (LST) and prediction of adenoma recurrence after endoscopic resection of LSTs is inevitable. This study aimed to identify a microbial signature with clinical significance of diagnosing LSTs and predicting adenoma recurrence after LSTs colectomy. METHODS: We performed 16S rRNA sequencing in 24 mucosal samples, including 5 healthy controls (HC), 8 colorectal adenoma (CRA) patients, and 11 LST patients. The differentiating microbiota in fecal samples was quantified by qPCR in 475 cases with 113 HC, 208 CRA patients, 109 LST patients, and 45 colorectal cancer (CRC) patients. We identified differentially abundant taxa among cases and controls using linear discriminant analysis effect size analysis. ROC curve was used to evaluate diagnostic values of the bacterial candidates. Pairwise comparison of AUCs was performed by using the Delong's test. The Mantel-Haenszel hazard models were performed to determine the effects of microbial compositions on recurrence free survival. RESULTS: The microbial dysbiosis of LST was characterized by relative high abundance of the genus Lactobacillus-Streptococcus and the species enterotoxigenic Bacteroides fragilis (ETBF)-Peptostreptococcus stomatis (P. stomatis)-Parvimonas micra (P. micra). The abundance of ETBF, P. stomatis, and P. micra were steadily increasing in LST and CRC groups. P. stomatis behaved stronger value on diagnosing LST than the other two bacteria (AUC 0.887, 95% CI 0.842-0.931). The combination of P. stomatis, P. micra, and ETBF (AUC 0.922, 95% CI 0.887-0.958) revealed strongest diagnostic power with 88.7% sensitivity and 81.4% specificity. ETBF, P. stomatis, and P. micra were associated with malignant LST (PP.stomatis = 0.0015, PP.micra = 0.0255, PETBF = 0.0169) and the abundance of IL-6. The high abundance of P. stomatis was related to the adenoma recurrence after LST resection (HR = 3.88, P = 0.008). CONCLUSIONS: Fecal microbiome signature (ETBF-P. stomatis-P. micra) can diagnose LSTs with high accuracy. ETBF, P. stomatis, and P. micra were related to malignant LST and P. stomatis exhibited high predictive value on the adenoma recurrence after resection of LSTs. The fecal microbiome signature of LST may provide a noninvasive alternative to early detect LST and predict the adenoma recurrence risk after resections of LSTs.

A specific tRNA half, 5'tiRNA-His-GTG, responds to hypoxia via the HIF1α/ANG axis and promotes colorectal cancer progression by regulating LATS2.

BACKGROUND: Currently, tRNA-derived small RNAs (tsRNAs) are recognized as a novel and potential type of non-coding RNAs (ncRNAs), which participate in various cellular processes and play an essential role in cancer progression. However, tsRNAs involvement in colorectal cancer (CRC) progression remains unclear. METHODS: Sequencing analyses were performed to explore the tsRNAs with differential expression in CRC. Gain- and loss-of functions of 5'tiRNA-His-GTG were performed in CRC cells and xenograft tumor to discover its role in the progression of CRC. Hypoxia culture and hypoxia inducible factor 1 subunit alpha (HIF1α) inhibitors were performed to uncover the biogenesis of 5'tiRNA-His-GTG. The regulation of 5'tiRNA-His-GTG for large tumor suppressor kinase 2 (LATS2) were identified by luciferase reporter assay, western blot, and rescue experiments. RESULTS: Here, our study uncovered the profile of tsRNAs in human CRC tissues and confirmed a specific tRNA half, 5'tiRNA-His-GTG, is upregulated in CRC tissues. Then, in vitro and in vivo experiments revealed the oncogenic role of 5'tiRNA-His-GTG in CRC and found that targeting 5'tiRNA-His-GTG can induce cell apoptosis. Mechanistically, the generation of 5'tiRNA-His-GTG seems to be a responsive process of tumor hypoxic microenvironment, and it is regulated via the HIF1α/angiogenin (ANG) axis. Remarkably, LATS2 was found to be an important and major target of 5'tiRNA-His-GTG, which renders 5'tiRNA-His-GTG to "turn off" hippo signaling pathway and finally promotes the expression of pro-proliferation and anti-apoptosis related genes. CONCLUSIONS: In summary, the findings revealed a specific 5'tiRNA-His-GTG-engaged pathway in CRC progression and provided clues to design a novel therapeutic target in CRC.

The Coexistence of Colorectal Polyps in the Right Colon Increases the Malignant Risk of Laterally Spreading Tumors.

BACKGROUND: The coexistence of colorectal polyps with laterally spreading tumors (LSTs) is commonly observed during colonoscopy. However, there are rare studies that assess the malignant risks for LSTs with colorectal polyps, which might largely contribute to further strategies of treatment and follow-up plans in LSTs. METHODS: We conducted a retrospective cohort study that enrolled 206 patients with LSTs in the Endoscopy Center and Endoscopy Research Institute, Renji Hospital, Shanghai Jiao Tong University, China. The subjects with LSTs were divided into two groups: the nonpolyp group with 89 patients and the polyp group with 117 patients. Binary logistic regression was used to identify the independent predictors of outcomes of interest. RESULTS: The risk of the polyps' coexistence phenomenon increased in males compared with females (OR = 2.138, p = 0.047), especially in those between 50 and 75 years old (OR = 7.074, p = 0.036). Tumor size (3-4 cm), LSTs with tubulovillous types, and history of polyps statistically increased the risk of the polyp coexistence phenomenon (OR = 5.768, p = 0.003; OR = 36.345, p = 0.024; OR = 13.245, p < 0.0001, respectively). LST-NG-PD (OR = 20.982, p = 0.017) and LSTs ≥ 5 cm (OR = 37.604, p = 0.038) notably increased the malignant risk of LSTs. When the simultaneous polyps are located in the right colon, the risk of malignant LSTs (OR = 58.540, p = 0.013) positively increased. CONCLUSION: The simultaneous colorectal polyps in the right colon were the most important risk factor to predict the malignant risk of LSTs.

JMJD2B-induced amino acid alterations enhance the survival of colorectal cancer cells under glucose-deprivation via autophagy.

Rationale: Post-translational modifications have emerged as vital players in alterations to tumor metabolism, including amino acid metabolic reprogramming. Jumonji domain-containing protein 2B (JMJD2B) enhances colorectal cancer (CRC) cell survival upon glucose deficiency. In the present study, we hypothesized that JMJD2B affects tumor cell amino acid metabolism in CRC and consequently promotes survival of CRC cells upon glucose deprivation. Methods: Non-target metabolic profiling was used to evaluate the roles of JMJD2B in CRC cell metabolism under glucose starvation. The roles of amino acid alterations induced by JMJD2B on CRC cell survival were determined by cell viability, immunoblotting, and clonogenic assays, and flow cytometry. The underlying mechanisms by which JMJD2B affected CRC cell metabolism were assessed using immunofluorescence staining, chromatin immunoprecipitation assays, electron microscopy in CRC cell lines, and using xenograft models. The correlation between JMJD2B and LC3B expression in human CRC specimens was assessed using immunohistochemistry. Results: Profound metabolic reprogramming was detected in JMJD2B knockdown CRC cells under glucose deficiency, especially those involving amino acid metabolites. Silencing of JMJD2B reduced the levels of certain amino acids that were induced by glucose deficiency. Among these amino acids, asparagine (Asn), phenylalanine (Phe), and histidine (His) promoted CRC cell survival under glucose starvation when JMJD2B was knocked down. Mechanistically, downregulation of JMJD2B inhibited autophagy in CRC cells through epigenetic regulation of microtubule associated protein 1 light chain 3 beta (LC3B), and subsequently decreased intracellular amino acid (Asn, Phe, His) levels under glucose deprivation, thus suppressing the survival of CRC cells. Using a nude mouse xenograft model, we verified that inhibiting JMJD2B could decrease the levels of amino acids (Asn, Phe, His). In addition, the inhibitory effects of JMJD2B-knockdown on tumor growth and amino acids level were rescued by overexpression of LC3B. Furthermore, we observed that the high expression of LC3B was more likely detected in tissuses with high expression of JMJD2B (P < 0.001) in 60 human CRC tissues. Conclusion: These results indicated that JMJD2B sustained the intracellular amino acids derived from autophagy in CRC cells upon glucose deficiency, partly through epigenetic regulation of LC3B, thus driving the malignancy of CRC.

Enterotoxigenic Bacteroides fragilis induces the stemness in colorectal cancer via upregulating histone demethylase JMJD2B.

The enrichment of Enterotoxigenic Bacteroides fragilis (ETBF) has been identified in CRC patients and associated with worse prognosis. Cancer stem cells (CSCs) play essential roles in CRC development. However, whether ETBF is involved in CSCs regulation is unknown. To clarify the role of ETBF in CSCs properties, we performed extreme limited dilution assays (ELDA) in nude mice injected with ETBF-treated or untreated CRC cells subcutaneously, tumor organoids culture in azoxymethane (AOM) mouse model after gavaging with or without ETBF, and cell sphere formation assay after incubating CRC cell lines with or without ETBF. The results indicated that ETBF increased the stemness of CRC cells in vivo and in vitro. Furthermore, ETBF enhanced the expression of core stemness transcription factors Nanog homeobox (NANOG) and sex determining region Y-box 2 (SOX2). Histone H3 Lysine 9 trimethylation (H3K9me3) is critical in regulating CSCs properties. As an epigenetic and transcriptional regulator, JmjC-domain containing histone demethylase 2B (JMJD2B) is essential for embryonic stem cell (ESC) transformation and H3K9me3 demethylation. Mechanistically, ETBF infection significantly upregulated JMJD2B levels in CRC cell lines and nude mice xenograft model. JMJD2B epigenetically upregulated NANOG expression via demethylating its promoter H3K9me3, to mediate ETBF-induced stemness of CRC cells. Subsequently, we found that the Toll-like receptor 4 (TLR4) pathway, activated by ETBF, contributed to the enhanced expression of JMJD2B via nuclear transcription factor nuclear factor of activated T cells 5 (NFAT5). Finally, in human CRC samples, the amount of ETBF positively correlated with nuclear NFAT5, JMJD2B, and NANOG expression levels. In summary, ETBF upregulated JMJD2B levels in a TLR4-NFAT5-dependent pathway, and played an important role in stemness regulation, which promoted colorectal carcinogenesis.

Berberine versus placebo for the prevention of recurrence of colorectal adenoma: a multicentre, double-blinded, randomised controlled study.

BACKGROUND: Chemoprevention of colorectal adenoma and colorectal cancer remains an important public health goal. The present study aimed to investigate the clinical potential and safety of berberine for prevention of colorectal adenoma recurrence. METHODS: This double-blind, randomised, placebo-controlled trial was done in seven hospital centres across six provinces in China. Individuals aged 18-75 years who had at least one but no more than six histologically confirmed colorectal adenomas that had undergone complete polypectomy within the 6 months before recruitment were recruited and randomly assigned (1:1) to receive berberine (0·3 g twice daily) or placebo tablets via block randomisation (block size of six). Participants were to undergo a first follow-up colonoscopy 1 year after enrolment, and if no colorectal adenomas were detected, a second follow-up colonoscopy at 2 years was planned. The study continued until the last enrolled participant reached the 2-year follow-up point. All participants, investigators, endoscopists, and pathologists were blinded to treatment assignment. The primary efficacy endpoint was the recurrence of adenomas at any follow-up colonoscopy. Analysis was based on modified intention-to-treat, with the full analysis set including all randomised participants who received at least one dose of study medication and who had available efficacy data. The study is registered with ClinicalTrials.gov, number NCT02226185; the trial has ended and this report represents the final analysis. FINDINGS: Between Nov 14, 2014, and Dec 30, 2016, 553 participants were randomly assigned to the berberine group and 555 to the placebo group. The full analysis set consisted of 429 participants in the berberine group and 462 in the placebo group. 155 (36%) participants in the berberine group and 216 (47%) in the placebo group were found to have recurrent adenoma during follow-up (unadjusted relative risk ratio for recurrence 0·77, 95% CI 0·66-0·91; p=0·001). No colorectal cancers were detected during follow-up. The most common adverse event was constipation (six [1%] of 446 patients in the berberine group vs one [<0·5%] of 478 in the placebo group). No serious adverse events were reported. INTERPRETATION: Berberine 0·3 g twice daily was safe and effective in reducing the risk of recurrence of colorectal adenoma and could be an option for chemoprevention after polypectomy. FUNDING: National Natural Science Foundation of China.