Utility of Liquid Biopsy Analysis in Detection of Hepatocellular Carcinoma, Determination of Prognosis, and Disease Monitoring: A Systematic Review.

BACKGROUND & AIMS: Liquid biopsies, or blood samples, can be analyzed to detect circulating tumor cells (CTCs), cell-free DNA (cfDNA), and extracellular vesicles, which might identify patients with hepatocellular carcinoma (HCC) or help determine their prognoses. We performed a systematic review of studies of analyses of liquid biopsies from patients with HCC and their comparisons with other biomarkers. METHODS: We performed a systematic review of original studies published before December 1, 2019. We included studies that compared liquid biopsies alone and in combination with other biomarkers for the detection of HCC, performed multivariate analyses of the accuracy of liquid biopsy analysis in determining patient prognoses, or evaluated the utility of liquid biopsy analysis in monitoring treatment response. RESULTS: Our final analysis included 112 studies: 67 on detection, 46 on determining prognosis, and 25 on treatment monitoring or selection. Ten studies evaluated assays that characterized cfDNA for detection of HCC in combination with measurement of α-fetoprotein (AFP)-these studies found that the combined measurement of cfDNA and AFP more accurately identified patients with HCC than measurement of AFP alone. Six studies evaluated assays for extracellular vesicles and 2 studies evaluated assays for CTC in detection of HCC, with and without other biomarkers-most of these studies found that detection of CTCs or extracellular vesicles with AFP more accurately identified patients with HCC than measurement of AFP alone. Detection of CTCs before surgery was associated with HCC recurrence after resection in 13 of 14 studies; cfDNA and extracellular vesicles have been studied less frequently as prognostic factors. Changes in CTC numbers before vs after treatment more accurately identify patients with HCC recurrence than pretreatment counts alone, and measurements of cfDNA can identify patients with disease recurrence or progression before changes can be detected by imaging. We found little evidence that analyses of liquid biopsies can aid in the selection of treatment for HCC. Quality assessment showed risk of bias in studies of HCC detection and determination of prognosis. CONCLUSIONS: In a systematic review of 112 studies of the accuracy of liquid biopsy analysis, we found that assays for CTCs and cfDNA might aid in determining patient prognoses and monitoring HCC, and assays for cfDNA might aid in HCC detection, but there is a risk of bias in these studies. Studies must be standardized before we can assess the clinical utility of liquid biopsy analysis in the detection and management of patients with HCC.

Efficacy of Fecal Microbiota Transplantation in Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis.

OBJECTIVES: Irritable bowel syndrome (IBS) is a common gastrointestinal condition with a heterogeneous pathophysiology. An altered gut microbiome has been identified in some IBS patients, and fecal microbiota transplantation (FMT) has been suggested to treat IBS. We performed meta-analyses and systematic review of available randomized controlled trials (RCTs) to evaluate the efficacy of FMT in IBS. METHODS: We performed a systematic literature search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science. Selection criteria included RCTs of FMT vs placebo using FMT excipients or autologous FMT in IBS. Meta-analyses were conducted to evaluate the summary relative risk (RR) and 95% confidence intervals (CIs) of combined studies for primary outcome of improvement in global IBS symptoms as measured by accepted integrative symptom questionnaires or dichotomous responses to questions of overall symptom improvement. RESULTS: Among 742 citations identified, 7 were deemed to be potentially relevant, of which 4 studies involving 254 participants met eligibility. No significant difference in global improvement of IBS symptoms was observed at 12 weeks in FMT vs placebo (RR = 0.93; 95% CI 0.48-1.79). Heterogeneity among studies was significant (I = 79%). Subgroup analyses revealed benefits of single-dose FMT using colonoscopy and nasojejunal tubes in comparison with autologous FMT for placebo treatment (number needed to treat = 5, RR = 1.59; 95% CI 1.06-2.39; I = 0%) and a reduction in likelihood of improvement of multiple-dose capsule FMT RCTs (number needed to harm = 3, RR = 0.54; 95% CI 0.34-0.85; I = 13%). Placebo response was 33.7% in nonoral FMT RCTs and 67.8% in capsule FMT RCTs. The Grading of Recommendations Assessment, Development and Evaluation quality of the body of evidence was very low. DISCUSSION: Current evidence from RCTs does not suggest a benefit of FMT for global IBS symptoms. There remain questions regarding the efficacy of FMT in IBS as well as the lack of a clean explanation on the discrepant results among RCTs in subgroup analyses.

Rifaximin alters intestinal bacteria and prevents stress-induced gut inflammation and visceral hyperalgesia in rats.

BACKGROUND & AIMS: Rifaximin is used to treat patients with functional gastrointestinal disorders, but little is known about its therapeutic mechanism. We propose that rifaximin modulates the ileal bacterial community, reduces subclinical inflammation of the intestinal mucosa, and improves gut barrier function to reduce visceral hypersensitivity. METHODS: We induced visceral hyperalgesia in rats, via chronic water avoidance or repeat restraint stressors, and investigated whether rifaximin altered the gut microbiota, prevented intestinal inflammation, and improved gut barrier function. Quantitative polymerase chain reaction (PCR) and 454 pyrosequencing were used to analyze bacterial 16S ribosomal RNA in ileal contents from the rats. Reverse transcription, immunoblot, and histologic analyses were used to evaluate levels of cytokines, the tight junction protein occludin, and mucosal inflammation, respectively. Intestinal permeability and rectal sensitivity were measured. RESULTS: Water avoidance and repeat restraint stress each led to visceral hyperalgesia, accompanied by mucosal inflammation and impaired mucosal barrier function. Oral rifaximin altered the composition of bacterial communities in the ileum (Lactobacillus species became the most abundant) and prevented mucosal inflammation, impairment to intestinal barrier function, and visceral hyperalgesia in response to chronic stress. Neomycin also changed the composition of the ileal bacterial community (Proteobacteria became the most abundant species). Neomycin did not prevent intestinal inflammation or induction of visceral hyperalgesia induced by water avoidance stress. CONCLUSIONS: Rifaximin alters the bacterial population in the ileum of rats, leading to a relative abundance of Lactobacillus. These changes prevent intestinal abnormalities and visceral hyperalgesia in response to chronic psychological stress.

Butyrate-induced colonic hypersensitivity is mediated by mitogen-activated protein kinase activation in rat dorsal root ganglia.

OBJECTIVE: Increased faecal butyrate levels have been reported in irritable bowel syndrome. Rectal instillation of sodium butyrate (NaB) increases visceral sensitivity in rats by an unknown mechanism. We seek to examine the signal transduction pathways responsible for the enhanced neuronal excitability in the dorsal root ganglion (DRG) following NaB enemas and demonstrate that this is responsible for the colonic hypersensitivity reported in this animal model. DESIGN: Colorectal distention (CRD) studies were performed in rats treated with NaB rectal instillation with/without intrathecal or intravenous administration of mitogen-activated protein (MAP) kinase kinase inhibitor U0126. Western blot analysis and immunocytochemistry studies elucidated intracellular signalling pathways that modulate IA. Patch-clamp recordings were performed on isolated DRG neurons treated with NaB, with/without U0126. RESULTS: Visceromotor responses (VMR) were markedly enhanced in NaB-treated rats. Western blot analysis of DRG neurons from NaB-treated rats showed a 2.2-fold increase in phosphorylated ERK1/2 (pEKR1/2) and 1.9-fold increase in phosphorylated voltage-gated potassium channel subunit 4.2 (pKv4.2). Intrathecal or intravenous administration of U0126 reduced VMR to CRD in NaB-treated rats and prevented increases in pERK1/2 and pKv4.2. Patch-clamp recordings of isolated DRG neurons showed that NaB caused a reduction in IA to 48.9%±1.4% of control and an increase in neuronal excitability, accompanied by a twofold increase in pERK1/2 and pKv4.2. Concurrent U0126 administration prevented these changes. CONCLUSIONS: Visceral hypersensitivity induced by colonic NaB treatment is mediated by activation of the MAP kinase-ERK1/2 pathway, which phosphorylates Kv4.2. This results in a reduction in IA and an enhancement of DRG neuronal excitability.

Design of Cooperative Output Regulators for Heterogeneous Uncertain Nonlinear Multiagent Systems.

Cooperative output regulation (COR) of multiagent systems having heterogeneous uncertain nonlinear dynamics is often challenging because of the complex system dynamics and the coupling among agents. This article develops an adaptive internal model-based distributed regulator such that the outputs of a network of nonlinear agents are all regulated to a reference despite external disturbances. Specifically, we consider heterogeneous agents having nonlinear strict-feedback forms, with nonidentical unknown control directions, and subject to an unknown linear exosystem. Addressing the nonlinear COR problem shows the capability and flexibility of the proposed output regulator. The simulation results of output synchronization of Lorenz systems and cooperative tracking control of multiple ships are presented to show the capability of the proposed regulator.

Event-Based Practical Output Regulation for a Class of Multiagent Nonlinear Systems.

This paper explores a cooperative practical output regulation problem for a class of heterogeneous multiagent nonlinear systems by event-based output feedback. Specifically, we shall restrict our attention to the situation of sampled-data-based local measurements. As usual, due to agents heterogeneity, we first convert the problem into a stabilization one for the so-called augmented system, composed of the agent systems and suitably designed continuous-time internal models. Then, we show that this stabilization can be solved by measurement feedback. It finally allows us to establish a valid event-based protocol, leading to a global practical stability property and meanwhile guaranteeing Zeno-free condition.

The feasibility of 1-stop examination of coronary CT angiography and abdominal enhanced CT.

This study aims to evaluate the feasibility of performing coronary computed tomography angiography (CCTA) and abdominal enhanced computed tomography (CT) with 1-time injection of the agent.CCTA images (right coronary artery, left anterior descending coronary artery, and left circumflex coronary artery) were collected from 20 patients who completed a 1-stop combined examination of CCTA and abdominal enhanced CT (group A), 20 patients who only underwent abdominal enhanced CT (group B1), and 20 patients who only underwent CCTA (group B2). These images were interpreted using the 5-point Likert scale system by 2 experienced radiologists, and abdominal images were observed for breathing artifact. CT value, signal-to-noise ratio (SNR), and CTDI were recorded and compare among the 3 groups.The difference in image quality of the coronary and total volume of the contrast agent between group A and group B1 was not statistical significant (P > .05). The CT value and SNR in group B1 (CCTA) (CT: 394.65 ±â€Š59.23, SNR: 17.38 ±â€Š4.13) increased, compare with Group A (CT: 360.35 ±â€Š34.16, SNR: 13.76 ±â€Š1.84, P = .03, .01), while CTDI was undifferentiated between group A (17.14 ±â€Š6.20) and group B1 (18.38 ±â€Š9.79) (P = .64). The difference in CT value and SNR at the arterial phase and CT value at the venous phase between group A (abdomen) and group B2 were statistically significant, the CTDI in group A (9.09 ±â€Š1.05) increased, compared with group B2 (8.23 ±â€Š1.33) (P = .03), and SNR at the venous phase in group B2 (12.50 ±â€Š2.43) increased, compared with group A (10.89 ±â€Š2.03) (P = .03).Revolution CT can capture full images and very rapidly switch to the scan mode, enabling a 1-stop axial CCTA and enhanced helical abdominal scan. The 1-stop combined scan resulted in a satisfactory image quality, which reduced the contrast agent dose and simplified the workflow.The 1-stop combined scan allows for the high success rate of the examination, reduces the number of examinations, and decreases the dose and risk of injection of the contrast agent. This would be helpful for patients to obtain diagnostic images in time.

TRIM14 regulates cell proliferation and invasion in osteosarcoma via promotion of the AKT signaling pathway.

Recent studies have shown that some members of the tripartite motif-containing protein (TRIM) family serve as important regulators of tumorigenesis. However, the biological role of TRIM14 in osteosarcoma remains to be established. In this study, we showed that TRIM14 is upregulated in human osteosarcoma specimens and cell lines, and correlated with osteosarcoma progression and shorter patient survival times. Functional studies demonstrated that overexpression of TRIM14 enhances osteosarcoma cell proliferation, clone formation, cell cycle procession, migration and invasion in vitro and promotes tumor growth in vivo, and conversely, its silencing has the opposite effects. Furthermore, TRIM14 overexpression induced activation of the AKT pathway. Inhibition of AKT expression reversed the TRIM14-mediated promotory effects on cell growth and mobility, in addition to TRIM14-induced epithelial-to-mesenchymal transition (EMT) and cyclin D1 upregulation. Our findings collectively suggest that TRIM14 functions as an oncogene by upregulating the AKT signaling pathway in osteosarcoma cells, supporting its potential utility as a therapeutic target for this disease.

Visceral sensitivity to gastric stimulation and its correlation with alterations in gastric emptying and accommodation in humans.

BACKGROUND: The aim of this study was to investigate the visceral sensation to gastric stimulation and its correlation with the stimulation-induced alterations in gastric accommodation and gastric emptying. METHODS: The study was performed in 12 healthy human controls. Gastric stimulation was performed using bipolar electrodes attached to the mucosa of the distal stomach under endoscopy. Experiments were conducted on 3 consecutive days to investigate the effects of gastric stimulation with various parameters on visceral sensation, maximum intake of water and gastric emptying of solids. RESULTS: 1) The stimulation energy was 265.6 +/- 134.9 smA 2 for the first sensation and 2,020.0 +/- 865.1 smA2 for the maximum tolerance, and there was a large variation among the subjects; 2) Gastric stimulation with stimulation energy less than 50% of that required to induce the first sensation significantly reduced the maximum intake of water and delayed gastric emptying of solids without inducing symptoms; 3) The stimulation energy of the first sensation was significantly correlated with the stimulation-induced reduction in water intake (r=-0.80, P=0.02) and the stimulation-induced prolongation of gastric emptying (r=-0.78, P=0.003). That is, the inhibitory effects of gastric stimulation were more obvious in those subjects who were viscerally more sensitive to gastric stimulation. CONCLUSIONS: Gastric stimulation via the distal stomach reduces gastric accommodation and delays gastric emptying. These inhibitory effects are correlated with the visceral sensitivity of the individual to gastric stimulation. It is worthy to further investigate whether the outcome of the implantable gastric stimulation (IGS) therapy for obesity may be predicted from the visceral sensitivity of the patient to temporary gastric stimulation using endoscopically placed mucosal electrodes.

Visceral response to acute retrograde gastric electrical stimulation in healthy human.

AIM: To investigate the visceral response to acute retrograde gastric electrical stimulation (RGES) in healthy humans and to derive optimal parameters for treatment of patients with obesity. METHODS: RGES with a series of effective parameters were performed via a bipolar mucosal electrode implanted along the great curvature 5 cm above pylorus of stomach in 12 healthy human subjects. Symptoms associated with dyspepsia and other discomfort were observed and graded during RGES at different settings, including long pulse and pulse train. Gastric myoelectrical activity at baseline and during different settings of stimulation was recorded by a multi-channel electrogastrography. RESULTS: The gastric slow wave was entrained in all the subjects at the pacing parameter of 9 cpm in frequency, 500 ms in pulse width, and 5 mA in amplitude. The frequently appeared symptoms during stimulation were satiety, bloating, discomfort, pain, sting, and nausea. The total symptom score for each subject significantly increased as the amplitude or pulse width was adjusted to a higher scale in both long pulse and pulse train. There was a wide diversity of visceral responses to RGES among individuals. CONCLUSION: Acute RGES can result in a series of symptoms associated with dyspepsia, which is beneficial to the treatment of obesity. Optimal parameter should be determined according to the individual sensitivity to electrical stimulation.

Identification of ankylosing spondylitis-associated genes by expression profiling.

Ankylosing spondylitis (AS) is a chronic inflammation attacking the sacroiliac joints and the spine. Certain genes have been associated with the occurrence of AS. Gene chip data were utilized to recognize genes associated with AS for the association of the clinical diagnosis and the biomedical study. Microarray expression data of AS were acquired from the public microarray database GEO (gene expression omnibus), and AS-related genes were obtained by differential gene expression profiling. The transcriptional and translational levels of these genes were further examined. The transcriptional and translational levels of three genes were shown to be upregulated in a mouse model of AS by real-time PCR and Elisa assay, respectively. Differential expression of AS-related genes was identified by analysis of gene chip data, contributing to the advancement of the understanding of the pathogenesis of AS.

Diabetic visceral hypersensitivity is associated with activation of mitogen-activated kinase in rat dorsal root ganglia.

OBJECTIVE: Diabetic patients often experience visceral hypersensitivity and anorectal dysfunction. We hypothesize that the enhanced excitability of colon projecting dorsal root ganglia (DRG) neurons observed in diabetes is caused by a decrease in the amplitude of the transient A-type K(+) (I(A)) currents resulting from increased phosphorylation of mitogen-activated protein kinases (MAPK) and reduced opening of K(v)4.2 channels. RESEARCH DESIGN AND METHODS: We performed patch-clamp recordings of colon projecting DRG neurons from control and streptozotocin-induced diabetic (STZ-D) rats. Western blot analyses and immunocytochemistry studies were used to elucidate the intracellular signaling pathways that modulate the I(A) current. In vivo studies were performed to demonstrate that abnormal MAPK signaling is responsible for the enhanced visceromotor response to colorectal distention in STZ-D rats. RESULTS: Patch-clamp studies demonstrated that I(A) current was diminished in the colon projecting DRG neurons of STZ-D rats. Western blot analysis of STZ-D DRG neurons revealed increases in phosphorylated MAPK and K(V)4.2. In diabetic DRG neurons, increased intracellular Ca(2+) ([Ca(2+)](i)), protein kinase C (PKC), and MAPK were involved in the regulation of I(A) current through modulation of K(v)4.2. Hypersensitive visceromotor responses to colorectal distention in STZ-D rats were normalized by administration of MAPK inhibitor U0126. CONCLUSIONS: We demonstrated that reduction of the I(A) current in STZ-D DRG neurons is triggered by impaired [Ca(2+)](i) ion homeostasis, and this in turn activates the PKC-MAPK pathways, resulting in decreased opening of the K(v)4.2 channels. Hence, the PKC-MAPK-K(v)4.2 pathways represent a potential therapeutic target for treating visceral hypersensitivity in diabetes.

Retrograde gastric pacing reduces food intake and delays gastric emptying in humans: a potential therapy for obesity?

Obesity is one of the most prevalent health problems in the world with a lack of satisfactory therapies and gastric electrical stimulation has recently been proposed for the treatment of obesity. The aim of this study was to investigate the effects of retrograde gastric pacing (RGP) on food and water intake, and gastric emptying in humans. RGP with a tachygastrial frequency of 9 cycles/min was performed via a pair of submucosal gastric electrodes implanted 5 cm above the pylorus in 12 subjects. The water load test, food intake test and scintigraphic gastric emptying test were performed to assess the efficacy of RGP. RGP resulted in a 13% reduction in the consumption of water, a 16% reduction in food intake and a 15% increase in gastric retention of a solid meal. No significant symptoms were recorded with RGP using the parameters used for the water-load, food intake and scintigraphic gastric emptying tests. Acute RGP at a tachygastrial frequency results in a significant reduction of water and food intake and a delay in gastric emptying without inducing any unacceptable symptoms. It is worthy to explore its therapeutic potential for obesity.