Individualized small bowel preparation for computed tomography enterography: A prospective randomized controlled trial.

BACKGROUND AND AIM: The study aims to evaluate the feasibility of body mass index (BMI)-based individualized small bowel preparation for computed tomography enterography (CTE). METHODS: In this prospective randomized controlled study, patients undergoing CTE were randomly assigned to the individualized group or standardized group. Those in individualized group were given different volumes of mannitol solution based on BMI (1000 mL for patients with BMI < 18.5 kg/m2, 1500 mL for patients with 18.5 kg/m2 ≤ BMI < 25 kg/m2 and 2000 mL for patients with BMI ≥ 25 kg/m2) while patients in the standardized group were all asked to consume 1500-mL mannitol solution. CTE images were reviewed by two experienced radiologists blindly. Each segment of the small bowel was assessed for small bowel image quality and disease detection rates. Patients were invited to record a diary regarding adverse events and acceptance. RESULTS: A total of 203 patients were enrolled and randomly divided into two groups. For patients with BMI < 18.5 kg/m2, 1000-mL mannitol solution permitted a significantly lower rate of flatulence (P = 0.045) and defecating frequency (P = 0.011) as well as higher acceptance score (P = 0.015), but did not affect bowel image quality and diseases detection compared with conventional dosage. For patients with BMI ≥ 25 kg/m2, 2000-mL mannitol solution provided better overall image quality (P = 0.033) but comparable rates of adverse events and patients' acceptance compared with conventional dosage. CONCLUSIONS: Individualized bowel preparation could achieve both satisfactory image quality and patients' acceptance thus might be an acceptable alternative in CTE.

Autophagic blockage by metformin-loaded PLGA nanoparticles causes cell cycle arrest of HepG2 cells.

Aim: To fabricate and characterize metformin-loaded PLGA nanoparticles and investigate their inhibitory effect on HepG2 cells. Materials & methods: The nanoparticles were prepared using a double emulsification method, then characterized and subjected to a series of in vitro assays on HepG2 cells. Results: The nanoparticles were ~277.9 nm in size, and the entrapment efficiency and drug loading of metformin were 31.3 and 14.4%, respectively. In vitro studies suggested that the nanoparticles showed a higher inhibitory effect on HepG2 cells compared with metformin alone, mainly attributed to its blockage of autophagy, and ultimately result in cell cycle inhibition. Conclusion: The metformin-loaded PLGA nanoparticles could inhibit mTOR activity, increase p53 levels and decrease HIF1A levels, which ultimately caused HepG2 cell cycle arrest.

Metformin, a well-known drug for the treatment of diabetes, has potential anticancer effects. Our experiment is fabricating metformin into nanoformulations (tiny particles) to enhance its anticancer effect. Cancer cells respond to nutrient-deficient environments by autophagy, this involves breaking down internal structures to scavenge for nutrients, which is one of the reasons why cancer cells are so resilient. If we can interfere with this autophagy of cancer cells, we can reduce the viability of cancer cells. Speaking of autophagy, we have to mention lysosomes, which are acidic organelles within the cell that are the end point of autophagy. Lysosomes need to maintain an acidic environment to ensure the activity of various enzymes within them. These enzymes break down a variety of biological components into 'building blocks' which can be used to make other structures. Our study found that the nanoformulation disrupts the lysosomal acidic environment and thus causes autophagy blockage. As a result, cancer cells are unable to cope with nutrient deficiencies through autophagy and suffer the negative effects of autophagy blockage, such as the inability to degrade damaged organelles and proteins within the cancer cell. This causes the growth and proliferation of cancer cells to slow down and results in the death of the cancer cells.

Bioaccumulation and translocation of Hg and Cr by tobacco in Sichuan Province, China: understanding the influence of soil pH.

The present study investigated the bioaccumulation and translocation of mercury (Hg) and chromium (Cr) in Yunyan 87 flue-cured tobacco (Nicotiana tabacum) and assessed the influence of soil pH on the metal uptake by plant organs at the field scale. The study was conducted in 4 different regions selected from Sichuan Province, China: Guangyuan, Luzhou, Panzhihua, and Yibin. The results revealed that Hg highly contaminated Yibin soils at 0.29 mg kg-1 and by Cr at 147 mg kg-1, which is above the permissible limit. The levels of Hg in tobacco plant organs were predominantly in the order of leaves > root > stem. The overall trend for Cr contents in tobacco organs was in the order of root > leaves > stem. The results of an index of bioaccumulation (IBA) and translocation factor (TF) showed that the values observed in Panzhihua and Guangyuan tobacco leaves were generally higher, despite the low levels of soil contamination. The linear mixed model (LMM) demonstrated that the log of Hg IBA in tobacco organs was likely to decrease with soil pH increase, whereas the log of Cr IBA only decreased in the root but gradually increased in the aerial parts with soil pH increase. The total random variation in the log of metals' IBA due to regions indicated that for Hg, 33.42% of the variation was explained by regional differences, while for Cr, only 13% was accounted. The results suggested that Yibin and Luzhou need to correct the soil acidity if they are set to reduce Hg contamination in tobacco-growing soils. Guangyuan and Panzhihua need efforts to keep the soil pH on track to avoid high contamination levels, and effective measures of soil nutrients supply are required to produce high tobacco leaf quality free from heavy metal content. The findings of this study may be used to ascertain regional differences in heavy metals, particularly Hg and Cr uptake by tobacco plant organs, and to prevent the cultivation areas contamination through soil pH monitoring.

Role of interleukins in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a hematological malignancy with strong heterogeneity. Immune disorders are a feature of various malignancies, including AML. Interleukins (ILs) and other cytokines participate in a series of biological processes of immune disorders in the microenvironment, and serve as a bridge for communication between various cellular components in the immune system. The role of ILs in AML is complex and pleiotropic. It can not only play an anti-AML role by enhancing anti-leukemia immunity and directly inducing AML cell apoptosis, but also promote the growth, proliferation and drug resistance of AML. These properties of ILs can be used to explore their potential efficacy in disease monitoring, prognosis assessment, and development of new treatment strategies for AML. This review aims to clarify some of the complex roles of ILs in AML and their clinical applications.

Fisetin treatment alleviates kidney injury in mice with diabetes-exacerbated atherosclerosis through inhibiting CD36/fibrosis pathway.

Diabetes-related vascular complications include diabetic cardiovascular diseases (CVD), diabetic nephropathy (DN) and diabetic retinopathy, etc. DN can promote the process of end-stage renal disease. On the other hand, atherosclerosis accelerates kidney damage. It is really an urge to explore the mechanisms of diabetes-exacerbated atherosclerosis as well as new agents for treatment of diabetes-exacerbated atherosclerosis and the complications. In this study we investigated the therapeutic effects of fisetin, a natural flavonoid from fruits and vegetables, on kidney injury caused by streptozotocin (STZ)-induced diabetic atherosclerosis in low density lipoprotein receptor deficient (LDLR-/-) mice. Diabetes was induced in LDLR-/- mice by injecting STZ, and the mice were fed high-fat diet (HFD) containing fisetin for 12 weeks. We found that fisetin treatment effectively attenuated diabetes-exacerbated atherosclerosis. Furthermore, we showed that fisetin treatment significantly ameliorated atherosclerosis-enhanced diabetic kidney injury, evidenced by regulating uric acid, urea and creatinine levels in urine and serum, and ameliorating morphological damages and fibrosis in the kidney. In addition, we found that the improvement of glomerular function by fisetin was mediated by reducing the production of reactive oxygen species (ROS), advanced glycosylation end products (AGEs) and inflammatory cytokines. Furthermore, fisetin treatment reduced accumulation of extracellular matrix (ECM) in the kidney by inhibiting the expression of vascular endothelial growth factor A (VEGFA), fibronectin and collagens, while enhancing matrix metalloproteinases 2 (MMP2) and MMP9, which was mainly mediated by inactivating transforming growth factor ß (TGFß)/SMAD family member 2/3 (Smad2/3) pathways. In both in vivo and in vitro experiments, we demonstrated that the therapeutic effects of fisetin on kidney fibrosis resulted from inhibiting CD36 expression. In conclusion, our results suggest that fisetin is a promising natural agent for the treatment of renal injury caused by diabetes and atherosclerosis. We reveal that fisetin is an inhibitor of CD36 for reducing the progression of kidney fibrosis, and fisetin-regulated CD36 may be a therapeutic target for the treatment of renal fibrosis.

Transcription factor 21 accelerates vascular calcification in mice by activating the IL-6/STAT3 signaling pathway and the interplay between VSMCs and ECs.

Vascular calcification is caused by the deposition of calcium salts in the intimal or tunica media layer of the aorta, which increases the risk of cardiovascular events and all-cause mortality. However, the mechanisms underlying vascular calcification are not fully clarified. Recently it has been shown that transcription factor 21 (TCF21) is highly expressed in human and mouse atherosclerotic plaques. In this study we investigated the role of TCF21 in vascular calcification and the underlying mechanisms. In carotid artery atherosclerotic plaques collected from 6 patients, we found that TCF21 expression was upregulated in calcific areas. We further demonstrated TCF21 expression was increased in an in vitro vascular smooth muscle cell (VSMC) osteogenesis model. TCF21 overexpression promoted osteogenic differentiation of VSMC, whereas TCF21 knockdown in VSMC attenuated the calcification. Similar results were observed in ex vivo mouse thoracic aorta rings. Previous reports showed that TCF21 bound to myocardin (MYOCD) to inhibit the transcriptional activity of serum response factor (SRF)-MYOCD complex. We found that SRF overexpression significantly attenuated TCF21-induced VSMC and aortic ring calcification. Overexpression of SRF, but not MYOCD, reversed TCF21-inhibited expression of contractile genes SMA and SM22. More importantly, under high inorganic phosphate (3 mM) condition, SRF overexpression reduced TCF21-induced expression of calcification-related genes (BMP2 and RUNX2) as well as vascular calcification. Moreover, TCF21 overexpression enhanced IL-6 expression and downstream STAT3 activation to facilitate vascular calcification. Both LPS and STAT3 could induce TCF21 expression, suggesting that the inflammation and TCF21 might form a positive feedback loop to amplify the activation of IL-6/STAT3 signaling pathway. On the other hand, TCF21 induced production of inflammatory cytokines IL-1ß and IL-6 in endothelial cells (ECs) to promote VSMC osteogenesis. In EC-specific TCF21 knockout (TCF21ECKO) mice, VD3 and nicotine-induced vascular calcification was significantly reduced. Our results suggest that TCF21 aggravates vascular calcification by activating IL-6/STAT3 signaling and interplay between VSMC and EC, which provides new insights into the pathogenesis of vascular calcification. TCF21 enhances vascular calcification by activating the IL-6-STAT3 signaling pathway. TCF21 inhibition may be a new potential therapeutic strategy for the prevention and treatment of vascular calcification.

Liver X receptor agonists exert antitumor effects against hepatocellular carcinoma via inducing REPS2 expression.

Recent studies show that liver X receptor (LXR) agonists exert significant antitumor effects in a variety of tumor cell lines including hepatocellular carcinoma (HCC). But the molecular mechanisms underlying LXR antitumor activity are not fully understood. In this study we investigated the effect of LXR agonist T0901317 (T317) on HCC development and its relationship with RalA binding protein 1 (RALBP1)-associated EPS domain containing 2 (REPS2)/epidermal growth factor receptor (EGFR) signaling axis. We showed that T317 (0.1-0.5 µM) dose-dependently increased REPS2 expression in normal hepatocytes (BNLCL.2 and LO2) and HCC cells (HepG2 and Huh-7). Using promoter activity assay and chromatin immunoprecipitation (CHIP) assay we demonstrated that T317 enhanced REPS2 expression at the transcriptional level via promoting the binding of LXR protein to the LXR-response element (LXRE) in the REPS2 promoter region. We showed that the inhibitory effect of T317 on the proliferation and migration of HCC cells was closely related to REPS2. Moreover, we revealed that T317 (400 nM) increased expression of REPS2 in HepG2 cells, thus inhibiting epidermal growth factor (EGF)-mediated endocytosis of EGFR as well as the downstream activation of AKT/NF-κB, p38MAPK, and ERK1/2 signaling pathways. Clinical data analysis revealed that REPS2 expression levels were inversely correlated with the development of HCC and reduced REPS2 expression associated with poor prognosis, suggesting that REPS2 might be involved in the development of HCC. In conclusion, this study provides new insights into the potential mechanisms of LXR agonist-inhibited HCC.

A novel flexible auxiliary single-arm transluminal endoscopic robot facilitates endoscopic submucosal dissection of gastric lesions (with video).

BACKGROUND: Using conventional endoscope to perform endoscopic submucosal dissection (ESD) is difficult because of the one-handed operation and blind dissection caused by gravity. Poor visualization of the submucosal plane causes ESD to be associated with a high risk of bleeding and perforation. This study aimed to develop a novel ESD-assistive robot system and to evaluate its efficacy. METHODS: A novel flexible auxiliary single-arm transluminal endoscopic robot (FASTER) was developed. A total of 36 artificial lesions in ex vivo porcine stomachs were removed using the FASTER-assisted ESD method (n = 18) and the conventional ESD method (n = 18). Lesions were 2 cm or 4 cm in diameter, located on the anterior and posterior walls of the antrum. Primary outcome measurements were dissection time and dissection speed. RESULTS: The dissection time in FASTER-assisted ESD was significantly shorter than that in conventional ESD (7 min vs 13 min, p = 0.012), mainly because of the faster dissection speed (148.6 vs 97.0 mm2/min, p = 0.002). The total procedure time in FASTER-assisted ESD was shorter than that in conventional ESD, but the difference was not significant (16 min vs 24 min, p = 0.252). Complete en bloc resection was achieved in all lesions. No perforations were detected. The FASTER exhibited the ability of regrasp, multidirectional traction, and proper tension control during ESD. CONCLUSION: FASTER significantly increased the dissection speed by providing proper traction and achieving good submucosal vision. This new device is expected to facilitate ESD in clinical practice.

Effects of enhanced education for patients with the Helicobacter pylori infection: A systematic review and meta-analysis.

BACKGROUND: Helicobacter pylori (H. pylori) infections are of serious concern due to the associated risk of gastric cancer. However, many patients have poor medication and therapy compliance, which makes it difficult to eradicate their infections. This points to the need for stronger educational interventions aimed at enhancing compliance, thus increasing the potential for treatment success. As such, this study conducted a meta-analysis to clarify the effects of enhanced patient education (EPE) programs for H. pylori. MATERIALS AND METHODS: We searched electronic databases (PubMed, EMBASE, Web of Science, and Cochrane Library) for randomized controlled trials (RCTs) on health education for patients infected with H. pylori from inception to June 2021. The primary outcome was the eradication rate of H. pylori, while the secondary outcomes included the incidence of individual adverse symptoms, treatment compliance, clinical symptom remission after treatment, and patient satisfaction. We used the fixed or random-effects model to pool the risk ratio (RR), with 95% confidence interval. We also conducted sensitivity and subgroup analyses. RESULTS: Our search returned seven relevant studies across a total of 1,433 patients. Compared with controls, EPE was significantly associated with improved H. pylori eradication rates (RR = 1.16, 95%CI: 1.04-1.29, p = 0.006) and patient compliance (RR = 1.48, 95%CI: 1.14-1.93, p = 0.003). A subgroup analysis also showed that EPE benefits were consistent across patients with different eradication programs, WeChat intervention plans, and intervention frequencies (p < 0.05). However, there were no significant differences in the total adverse effects, common side effects (diarrhea, nausea, abdominal pain, taste disorder, and skin rash), or discontinuation rate (p > 0.05). CONCLUSIONS: Patient education is inexpensive, safe, and convenient. In this context, our findings suggest that enhanced educational interventions have positive effects on both the H. pylori eradication rate and adherence among infected patients, and thus constitute promising complements to clinical treatment regimens.

Simplified robot-assisted endoscopic submucosal dissection for esophageal and gastric lesions: a randomized controlled porcine study (with videos).

BACKGROUND AND AIMS: Effective countertraction is a main challenging issue in endoscopic submucosal dissection (ESD). Several countertraction methods have been developed to address this issue. The aim of this study was to compare the efficacy of ESD using a novel simplified robot, the flexible auxiliary single-arm transluminal endoscopic robot (FASTER), with a traditional technique. METHODS: This was a prospective, randomized animal study. Forty-eight ESDs in 6 pigs were carried out at 8 different locations (gastric antrum, gastric body, lower esophagus, and middle esophagus) by the conventional method (n = 24) and by the FASTER-assisted method (n = 24). The primary outcomes were total procedure time, dissection time, and rate of direct-vision dissection. Secondary endpoints were completeness of en-bloc resection and adverse event rate. RESULTS: The total procedure time was significantly shorter in FASTER-assisted ESD than in conventional ESD (18.8 vs 32.8 minutes; P < .001). In contrast to the median direct-vision dissection rate of 73% with conventional ESD, the FASTER-assisted group had a significantly higher rate of 96% (P < .001). The number of sites of muscular damage was significantly lower using the FASTER-assisted method than the conventional method (6 vs 21, respectively; P = .018). This improvement was more apparent in esophageal lesions compared with gastric lesions. CONCLUSIONS: This study demonstrated that using a simplified robot during ESD is technically feasible and enables the endoscopist to dynamically use countertraction. This device could significantly reduce procedure time compared with conventional ESD techniques.

Methyltransferase-like 3 contributes to inflammatory pain by targeting TET1 in YTHDF2-dependent manner.

ABSTRACT: The methyltransferase-like 3 (Mettl3) is a key component of the large N6-adenosine-methyltransferase complex in mammalian responsible for RNA N6-methyladenosine (m6A) modification, which plays an important role in gene post-transcription modulation. Although RNA m6A is enriched in mammalian neurons, its regulatory function in nociceptive information processing remains elusive. Here, we reported that Complete Freund's Adjuvant (CFA)-induced inflammatory pain significantly decreased global m6A level and m6A writer Mettl3 in the spinal cord. Mimicking this decease by knocking down or conditionally deleting spinal Mettl3 elevated the levels of m6A in ten-eleven translocation methylcytosine dioxygenases 1 (Tet1) mRNA and TET1 protein in the spinal cord, leading to production of pain hypersensitivity. By contrast, overexpressing Mettl3 reversed a loss of m6A in Tet1 mRNA and blocked the CFA-induced increase of TET1 in the spinal cord, resulting in the attenuation of pain behavior. Furthermore, the decreased level of spinal YT521-B homology domain family protein 2 (YTHDF2), an RNA m6A reader, stabilized upregulation of spinal TET1 because of the reduction of Tet1 mRNA decay by the binding to m6A in Tet1 mRNA in the spinal cord after CFA. This study reveals a novel mechanism for downregulated spinal cord METTL3 coordinating with YTHDF2 contributes to the modulation of inflammatory pain through stabilizing upregulation of TET1 in spinal neurons.

Real-time artificial intelligence for endoscopic diagnosis of early esophageal squamous cell cancer (with video).

BACKGROUND AND AIMS: Endoscopic diagnosis of early esophageal squamous cell cancer (ESCC) is complicated and dependent on operators' experience. This study aimed to develop an artificial intelligence (AI) model for automatic diagnosis of early ESCC. METHODS: Non-magnifying and magnifying endoscopic images of normal/noncancerous lesions, early ESCC, and advanced esophageal cancer (AEC) were retrospectively obtained from Qilu Hospital of Shandong University. A total of 10,988 images from 5075 cases were chosen for training and validation. Another 2309 images from 1055 cases were collected for testing. One hundred and four real-time videos were also collected to evaluate the diagnostic performance of the AI model. The diagnostic performance of the AI model was compared with endoscopists by magnifying images and the assistant efficiency of the AI model for novices was evaluated. RESULTS: The AI diagnosis for non-magnifying images showed a per-patient accuracy, sensitivity, and specificity of 99.5%, 100%, 99.5% for white light imaging, and 97.0%, 97.2%, 96.4% for optical enhancement/iodine straining images. Regarding diagnosis for magnifying images, the per-patient accuracy, sensitivity, and specificity were 88.1%, 90.9%, and 85.0%. The diagnostic accuracy of the AI model was similar to experts (84.5%, P = 0.205) and superior to novices (68.5%, P = 0.005). The diagnostic performance of novices was significantly improved by AI assistance. When it comes to the diagnosis for real-time videos, the AI model showed acceptable performance as well. CONCLUSIONS: The AI model could accurately recognize early ESCC among noncancerous mucosa and AEC. It could be a potential assistant for endoscopists, especially for novices.

Autophagic blockage by bismuth sulfide nanoparticles inhibits migration and invasion of HepG2 cells.

The biological effects of nanoparticles are of great importance for the in-depth understanding of safety issues in biomedical applications. Induction of autophagy is a cellular response after nanoparticle exposure. Bismuth sulfide nanoparticles (Bi2S3 NPs) are often used as a CT contrast agent because of their excellent photoelectric conversion ability. Yet there has been no previous detailed study other than a cell toxicity assessment. In this study, three types of Bi2S3 NPs with different shapes (Bi2S3 nano rods (BSNR), hollow microsphere Bi2S3 NPs (BSHS) and urchin-like hollow microsphere Bi2S3 NPs (ULBSHS)) were used to evaluatecytotoxicity, autophagy induction, cell migration and invasion in human hepatocellular carcinoma cells (HepG2). Results showed that all three Bi2S3 NPs lead to blockage in autophagic flux, causing p62 protein accumulation. The cell death caused by these Bi2S3 NPs is proved to be autophagy related, rather than related to apoptosis. Moreover, Bi2S3 NPs can reduce the migration and invasion in HepG2 cells in an autophagy-dependent manner. ULBSHS is the most cytotoxic among three Bi2S3 NPs and has the best tumor metastasis suppression. These results demonstrated that, even with relatively low toxicity of Bi2S3 NPs, autophagy blockage may still substantially influence cell fate and thus significantly impact their biomedical applications, and that surface topography is a key factor regulating their biological response.

TRIB3-EGFR interaction promotes lung cancer progression and defines a therapeutic target.

High expression or aberrant activation of epidermal growth factor receptor (EGFR) is related to tumor progression and therapy resistance across cancer types, including non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are first-line therapy for NSCLC. However, patients eventually deteriorate after inevitable acquisition of EGFR TKI-resistant mutations, highlighting the need for therapeutics with alternative mechanisms of action. Here, we report that the elevated tribbles pseudokinase 3 (TRIB3) is positively associated with EGFR stability and NSCLC progression. TRIB3 interacts with EGFR and recruits PKCα to induce a Thr654 phosphorylation and WWP1-induced Lys689 ubiquitination in the EGFR juxtamembrane region, which enhances EGFR recycling, stability, downstream activity, and NSCLC stemness. Disturbing the TRIB3-EGFR interaction with a stapled peptide attenuates NSCLC progression by accelerating EGFR degradation and sensitizes NSCLC cells to chemotherapeutic agents. These findings indicate that targeting EGFR degradation is a previously unappreciated therapeutic option in EGFR-related NSCLC.

Endocuff-assisted colonoscopy versus cap-assisted colonoscopy for adenoma detection rate: A meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Add-on devices have been widely used in clinical practice. The aim of this meta-analysis was to compare the adenoma detection rate between Endocuff-assisted colonoscopy (EAC) and cap-assisted colonoscopy (CAC). METHODS: PubMed, EMBASE, SCOPUS, and Cochrane databases were searched. Outcomes included adenoma detection rate, cecal intubation rate, cecal intubation time, and withdrawal time. Dichotomous data were pooled to obtain the odds ratio or risk ratio. Continuous data were pooled using the mean difference. RESULTS: Of the 240 articles reviewed, six randomized controlled trials were included, with a total of 1994 patients. In the meta-analysis, no statistical difference in adenoma detection rate was detected between EAC and CAC (47.0% vs 45.1%; P = 0.33). EAC significantly improved detection rate of diminutive adenomas/polyps compared with CAC (P = 0.01). Cecal intubation was achieved in 96.5% in EAC group and 97.9% in CAC group (P = 0.04). Besides, no statistical difference was found in cecal intubation time (P = 0.86), withdrawal time (P = 0.88), small adenomas/polyps (P = 0.60), or large adenomas/polyps (P = 0.95). CONCLUSION: EAC and CAC have their respective merits. EAC significantly improve the detection of diminutive adenomas/polyps. CAC was better in cecal intubation rate.