Face-to-Face Instruction and Personalized Regimens Improve the Quality of Inpatient Bowel Preparation for Colonoscopy.

BACKGROUND: Poor bowel preparation is commonly observed in inpatients undergoing colonoscopy, particularly those with higher risks for inadequate bowel preparation. AIMS: The objective of this study was to determine whether personalized bowel preparation regimens combined with face-to-face instruction (FFI) could improve the quality of bowel preparation for inpatient. METHODS: In this endoscopist-blinded, randomized controlled trial, 320 inpatients were enrolled and randomly allocated (1:1) to the control and intervention groups. The intervention group received FFI and personalized bowel preparation regimens, while the control group received the routine bowel preparation regimen and education. The primary outcome was adequate bowel preparation rate. Secondary outcomes included rates of procedure-related adverse events, incorrect diet restriction and laxative intake, etc. RESULTS: The adequate bowel preparation rate in the intervention group was significantly higher compared to control group [intention-to-treat (ITT) analysis: 70.0% vs 51.3%, P < 0.001; per-protocol (PP) analysis: 79.4% vs 58.6%, P < 0.001]. Bowel cleanliness was significantly improved in high-risk inpatients (ITT analysis: 65% vs 44.6%, P = 0.004; PP analysis: 73.0% vs 51.7%, P = 0.004) and in low-risk inpatients (ITT analysis: 80% vs 62.7%, P = 0.037; PP analysis: 92.3% vs 69.8%, P = 0.003). There were no significant differences between two groups regarding procedure-related adverse events. CONCLUSIONS: Personalized bowel preparation regimens combined with FFI improve the rate of adequate bowel preparation, especially for patients with high-risk factors. As such, inpatients could benefit from this novel approach for better bowel preparation to ultimately improve the quality of colonoscopies.

Underwater versus conventional endoscopic mucosal resection for small size non-pedunculated colorectal polyps: a randomized controlled trial : (UEMR vs. CEMR for small size non-pedunculated colorectal polyps).

BACKGROUND: Underwater endoscopic mucosal resection (UEMR) is a recently developed technique and can be performed during water-aided or ordinary colonoscopy for the treatment of colorectal polyps. The objective of this clinical trial was to evaluate the efficacy and safety of UEMR in comparison with conventional endoscopic mucosal resection (CEMR) of small non-pedunculated colorectal polyps. METHODS: Patients with small size, non-pedunculated colorectal polyps (4-9 mm in size) who underwent colonoscopic polypectomy were enrolled in this multicenter randomized controlled clinical trial. The patients were randomly allocated to two groups, an UEMR group and a CEMR group. Efficacy and safety were compared between groups. RESULTS: In the intention-to-treat (ITT) analysis, the complete resection rate was 83.1% (59/71) in the UEMR group and 87.3% (62/71) in the CEMR group. The en-bloc resection rate was 94.4% (67/71) in the UEMR group and 91.5% (65/71) in the CEMR group (difference 2.9%; 90% CI - 4.2 to 9.9%), showed noninferiority (noninferiority margin - 5.7% < - 4.2%). No significant difference in procedure time (81 s vs. 72 s, P = 0.183) was observed. Early bleeding was observed in 1.4% of patients in the CEMR group (1/71) and 1.4% of patients in the UEMR group (1/71). None of the patients in the UEMR group complained of postprocedural bloody stool, whereas two patients in the CEMR group (2/64) reported this adverse event. CONCLUSION: Our results indicate that UEMR is safer and just as effective as CEMR in En-bloc resection for the treatment of small colorectal polyps as such, UEMR is recommended as an alternative approach to excising small and non-pedunculated colorectal adenomatous polyps. TRIAL REGISTRATION: Clinical Trials.gov, NCT03833492 . Retrospectively registered on February 7, 2019.

Dual-channel surface plasmon resonance monitoring of intracellular levels of the p53-MDM2 complex and caspase-3 induced by MDM2 antagonist Nutlin-3.

MDM2 can mediate the degradation of tumor suppressor p53 through an autoregulatory feedback loop, in which MDM2 abolishes wild-type p53 function and accelerates malignant transformation. However, the incorporation of MDM2 antagonist Nutlin-3 could reactivate the transcriptional activity of p53, up-regulate caspase-3, and induce apoptosis. In this work, the simultaneous and label-free monitoring of p53-MDM2 complex and caspase-3 levels in cancer cells before and after Nutlin-3 treatment was conducted using dual-channel surface plasmon resonance (SPR). The p53-MDM2 complex was captured in one fluidic channel covered with consensus double-stranded (ds)-DNA, while the other channel was pre-immobilized with caspase-3-specific biotinylated DEVD-containing peptides. To amplify the SPR signals, the attachment of streptavidin (SA)-conjugated anti-MDM2 antibody in both channels was achieved. The signal diversity before and after Nutlin-3 treatment is indicative of the difference in the levels of the intracellular p53-MDM2 complex and caspase-3. The limit of detection for p53-MDM2 and caspase-3 down to 4.54 pM and 0.03 ng mL-1, respectively, was attained. Upon treatment with Nutlin-3, MCF-7 cancer cells with wild-type p53 showed decreased expression of the p53-MDM2 complex and an increased caspase-3 level, while MDA-MB-231 cancer cells with mutant p53 exhibited an elevated caspase-3 level and unchanged p53-MDM2 complex expression. The apoptosis of MCF-7 and MDA-MB-231 cancer cells upon Nutlin-3 treatment follows a p53-dependent and a p53-independent pathway, respectively. The proposed method is sensitive, selective and label-free, holding great promise for assaying intracellular p53-MDM2 complex and caspase-3 levels and differentiating Nutlin-3-mediated p53-dependent or p53-independent apoptotic pathways.

Peptide-Functionalized Phase-Transformation Nanoparticles for Low Intensity Focused Ultrasound-Assisted Tumor Imaging and Therapy.

In this study, we successfully developed novel tumor homing-penetrating peptide-functionalized drug-loaded phase-transformation nanoparticles (tLyP-1-10-HCPT-PFP NPs) for low intensity focused ultrasound (LIFU)-assisted tumor ultrasound molecular imaging and precise therapy. With the nanoscale particle size, tLyP-1-10-HCPT-PFP NPs could pass through the tumor vascular endothelial cell gap. Induced by tLyP-1 peptide with targeting and penetrating efficiency, tLyP-1-10-HCPT-PFP NPs could increase tumor accumulation and penetrate deeply into the extravascular tumor tissue, penetrating through extracellular matrix and the cellular membrane to the cytoplasm. With LIFU assistance, tLyP-1-10-HCPT-PFP NPs could phase-transform into microbubbles and enhance tumor ultrasound molecular imaging for tumor diagnosis. Furthermore, after further irradiation by LIFU, an intracellular "explosion effect" caused by acoustic droplet vaporization, ultrasound targeted microbubble destruction, and release of 10-HCPT could realize physicochemical synergistic antitumor therapy.

Sensitive and simultaneous surface plasmon resonance detection of free and p53-bound MDM2 proteins from human sarcomas.

Murine double minute 2 (MDM2) is an oncoprotein mediating the degradation of the tumor suppressor p53 protein. The physiological levels of MDM2 protein are closely related to malignant transformation and tumor growth. In this work, the simultaneous and label-free determination of free and p53-bound MDM2 proteins from sarcoma tissue extracts was conducted using a dual-channel surface plasmon resonance (SPR) instrument. Free MDM2 protein was measured in one fluidic channel covered with the consensus double-stranded (ds)-DNA/p53 conjugate, while MDM2 bound to p53 was captured by the consensus ds-DNA immobilized onto the other channel. To achieve higher sensitivity and to confirm specificity, an MDM2-specific monoclonal antibody (2A10) was used to recognize both the free and p53-bound MDM2 proteins. The resultant method afforded a detection limit of 0.55 pM of MDM2. The amenability of the method to the analysis of free and p53-bound MDM2 proteins was demonstrated for normal and sarcoma tissue extracts from three patients. Our data reveal that both free and total MDM2 (free and bound forms combined) proteins from sarcoma tissue extracts are of much higher concentrations than those from normal tissue extracts and the p53-bound MDM2 protein only constitutes a small fraction of the total MDM2 concentration. In comparison with enzyme-linked immunosorbent assay (ELISA), the proposed method possesses higher sensitivity, is more cost-effective, and is capable of determining free and p53-bound MDM2 proteins in clinical samples.

Silencing of poly(ADP-ribose) polymerase-1 suppresses hyperstretch-induced expression of inflammatory cytokines in vitro.

In addition to biochemical stimuli, physical forces also play a critical role in regulating the structure, function, and metabolism of the lung. Hyperstretch can induce the inflammatory responses in asthma, but the mechanism remains unclear. Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that can regulate a variety of inflammatory cytokines expression. In the present study, we aimed to investigate the role and mechanism of PARP-1 in mechanical stretch-induced inflammation in human bronchial epithelial cells (HBEpiCs). HBEpiCs were simulated by mechanical stretch and cells under static were used as the control. PARP-1 expression was interfered by small interfering RNA. Oxidative stress was evaluated by DHE staining. DNA damage was assessed by comet assay. The results showed that interleukin-8 (IL-8) and vascular cell adhesion molecule-1 (VCAM-1) expression were regulated by hyperstretch in a time-dependent manner. Hyperstretch could increase PARP-1 expression and activity by inducing superoxide production and DNA damage. Silencing of PARP-1 attenuated hyperstretch-induced IL-8 and VCAM-1 up-regulation as well as monocytes adhesion, which were related to the inhibition of nuclear factor-kappa B (NF-κB) translocation. Our study showed that hyperstretch could induce inflammatory response and superoxide production as well as DNA damage in HBEpiCs. PARP-1 silencing decreased IL-8 and VCAM-1 expression, partly through inhibition of NF-κB translocation. PARP-1 played a fundamental role in hyperstretch-induced inflammation. PARP-1 silencing could be used as a potential therapeutic approach to reverse bronchial epithelial inflammation in asthma.

Sensitive surface plasmon resonance detection of methyltransferase activity and screening of its inhibitors amplified by p53 protein bound to methylation-specific ds-DNA consensus sites.

Abnormal DNA methylation is closely related to cancer initiation and progression, and strategies to assay methyltransferase activity and screen its inhibitors are essential for cancer diagnosis and therapy. In this work, surface plasmon resonance (SPR)-based assay for real-time and sensitive monitoring of DNA methyltransferase activity and screening of its inhibitors was conducted via methylation of double-stranded (ds)-DNA consensus sites and the follow-up p53 protein recognition. The consensus ds-DNA possesses a specific sequence of 5'-CCGG-3' in which the second C base can be methylated by M.SssI methyltransferase (M.SssI MTase) and the methylation process impedes the recognition and cleavage of the ds-DNA by HpaII endonuclease, thus, the attachment of p53 protein leads to remarkable SPR signals. In contrast, inhibition of M.SssI MTase activity by a potent inhibitor leaves the consensus ds-DNA unmethylated, and the cleavage of the ds-DNA by HpaII prevents p53 protein from adsorbing onto the chip surface, leading to tiny SPR signals. The binding affinity (KD) between p53 protein and the methylated consensus ds-DNA was deduced to be 3.04 nM, evidencing the strong binding capability. Two nucleoside inhibitors of 5-Azacytidine (5-Aza) and 5-aza-2'-deoxycytidine (5-Aza-dC), and a non-nucleoside inhibitor of procaine were examined, and their half-maximal inhibiting concentration (IC50) values were highly comparable with those by other methods. The sensing protocol has been successfully utilized for the assay of M.SssI MTase activity in normal and cancer cell lysates. The proof-of-concept experiments demonstrate that SPR serves as a viable means for sensitive detection of methyltransferase activity and screening of its inhibitors using p53 protein bound to methylation-specific ds-DNA consensus sites.

Next-generation Metabolomics in the Development of New Antidepressants: Using Albiflorin as an Example.

Depression is a highly prevalent disorder that affects more than 300 million adults worldwide in 2015. Depression also frequently coexists with many other conditions such as osteoporosis and one-third of the Intensive Care Unit (ICU) survivors had depressive symptoms. Antidepressants have become the most commonly prescribed drugs in the United States. In addition to the regular process, drug discovery and development (R&D) for depression presents extra challenges because of the heterogeneity of the symptoms and various co-occurring disorders. Botanical medicine with multi-functional nature has been proposed to be more effective, providing rapid control of core and comorbid conditions of depression. With the technical advances in analytical instruments, metabolomics is entering into a "new generation". Next-generation metabolomics (NGM) has the capability to comprehensively characterize drug-induced metabolic changes in the biological systems. NGM has demonstrated great potential in all the stages of pharmaceutical R&D in the last 10 years. Albiflorin isolated from Peony roots is a promising drug candidate with multi-target for depression and is currently under development by Beijing Wonner Biotech. In this work, we summarized the common analytical platforms for NGM and its main applications in drug R&D. We used albiflorin as an example to illustrate how NGM improves our understanding of drug candidate actions and facilitates drug safety evaluation. Future directions on how to expand the use of NGM for new antidepressant development in pharmaceutical industry were also discussed.

Applications and development of permeability imaging in ischemic stroke.

Brain permeability imaging techniques are specific for the assessment of blood-brain barrier integrity. The present review article primarily focuses on the application of permeability imaging in cases of ischemic stroke. The permeability maps may be used to predict future hemorrhagic transformation in patients following acute ischemic stroke, that have been treated with tissue plasminogen activator (tPA) or recanalization therapy. The permeability imaging would help make the clinical decision to administer tPA following acute ischemic stroke or not, which is not only due to the current 3-4.5 h time window. Additionally, permeability imaging may also be used to evaluate the collateral circulation in the perfusion and permeability of the ischemic area of the brain.

Dual-Channel Surface Plasmon Resonance for Quantification of ApoE Gene and Genotype Discrimination in Unamplified Genomic DNA Extracts.

Identification of gene variation is of great importance for attaining information related to disease susceptibility. A highly sensitive and specific surface plasmon resonance (SPR) method for quantification of the apoE gene and genotype discrimination was demonstrated. The complementary sequences with the specific recognition sites of GCGC bases upon hybridization to the preimmobilized biotinylated probes could be cleaved by the restriction enzyme HhaI, while the existence of the single-base mismatch (GTGC) prevented the cleavage reaction. In both cases, the incorporation of streptavidin increased the sensitivity of the SPR assay, and the detection levels of 10 fM and 50 fM for the complementary and single-base mismatched sequences were attained, respectively. The sensing protocol is simple, label-free, and quantitative, thus avoiding the complicated polymerase chain reaction (PCR) amplification procedures. The proposed method serves as a viable means for facile and sensitive analyses of apoE genes in four unamplified genomic DNA extracts.

Triple Stimuli-Responsive Magnetic Hollow Porous Carbon-Based Nanodrug Delivery System for Magnetic Resonance Imaging-Guided Synergistic Photothermal/Chemotherapy of Cancer.

The premature leakage of anticancer drugs during blood circulation may the damage immune system, normal cells, and tissues. Constructing targeted nanocarriers with pH, glutathione, and NIR triple-responsive property can effectively avoid the leakage of anticancer drugs before they arrive at the targeted site. In this paper, magnetic hollow porous carbon nanoparticles (MHPCNs) were successfully fabricated as nanocarrier. Poly(γ-glutamic acid) was used to cap the pores of MHPCNs. The photothermal conversion property of carbon and iron oxide (Fe3O4) nanomaterials was utilized to perform photothermal therapy to overcome multidrug-resistance produced by chemotherapy. The biodistribution of nanoparticles was investigated by magnetic resonance imaging. Experiments in vivo confirm the efficient accumulations of nanoparticles at tumor sites. Meanwhile, tumor growth was effectively inhibited via synergistic photothermal/chemotherapy with minimal side effects.

New LC-MS/MS Method for the Analysis of Allura Red Level in Takeaway Chinese Dishes and Urine of an Adult Chinese Population.

Allura red is a widely used synthetic food dye. In this study, we developed and validated a LC-MS/MS method for the quantification of allura red in three popular takeaway Chinese dishes (braised pork, soy sauce chicken, sweet and sour pork) and human urine samples. High levels of allura red ranging from 2.85 to 8.38 mg/g wet weight were detected in the surveyed Chinese dishes. Of 113 participants who frequently consume the surveyed Chinese dishes (>once a week in the past 2 years), the median of their urinary allura red level was 22.29 nM/mM creatinine (95% CI = 19.48-25.03) . Risk assessment using Cox proportional hazard models showed that a 10-fold increase in urinary allura red was positively associated with high blood pressure (odds ratio of 1.75 (95% CI = 0.78-3.96)). Our findings provide new insights for the potential risk of hypertension for long-term allura red overconsumption.

[Diagnostic value of citrulline and intestinal fatty acid binding protein on acute gastrointestinal injury in critical patients: a prospective study of 530 patients].

OBJECTIVE: To observe the incidence of acute gastrointestinal injury (AGI) in intensive care unit (ICU) patients, and to approach the value of serum citrulline and intestinal fatty acid binding protein (IFABP) on diagnosis of AGI in critical patients. METHODS: A prospective study was conducted. 576 critical patients admitted to ICU of Yantai Yuhuangding Hospital from February 2016 to February 2017 were enrolled. According to the AGI classification proposed by European Society of Intensive Care Medicine (ESICM) in 2012, the AGI and severity of the patients were observed. The general data, severity and prognosis of patients with different AGI grades were recorded. According to the random number table, 20 patients with normal kidney function from AGI I to IV were selected. The femoral artery blood was collected within 12 hours of ICU admission, and serum citrulline level was detected by high performance liquid chromatography (HPLC). Serum IFABP level was determined by enzyme-linked immunosorbent assay (ELISA). Twenty healthy subjects were selected as controls. The receiver operating characteristic curve (ROC) was drawn, and the predictive values of citrulline and IFABP for AGI diagnosis were evaluated. RESULTS: (1) 576 patients were enrolled in the analysis. Of which 530 patients (92.0%) had AGI, and 289 patients with grade I (54.5%), 154 with grade II (29.1%), 64 with grade III (12.1%), and 23 with grade IV (4.3%). With the increase in AGI classification, acute physiology and chronic health evaluation system II (APACHE II) score, sequential organ failure score (SOFA), the length of ICU stay and 28-day mortality were gradually increased. (2) Compared with health control group, the levels of serum citrulline in patients with different AGI grades were significantly decreased, and IFABP was significantly increased. With the increase in AGI classification, the citrulline level was gradually decreased, and IFABP level was gradually increased [citrulline levels (µmol/L) in AGI I,II,III,IV groups were 14.1±3.6, 12.7±3.1, 8.3±2.7, and 5.6±3.4, F = 3.287, P = 0.027, and IFABP levels (ng/L) were 526.7±204.9, 698.4±273.8, 894.7±455.9, and 1 062.8±532.2, F = 2.903, P = 0.043]. ROC curve analysis showed that citrulline had a higher predictive value for AGI diagnosis. The area under the ROC curve (AUC) was 0.927. When the cut-off value of citrulline was 9.7 µmol/L, the sensitivity and specificity were 87.5% and 87.5%, respectively. The AUC of IFABP was 0.043, which has no predictive value for the diagnosis of AGI. CONCLUSIONS: The AGI is extremely common in ICU. The higher the AGI grade is, the worse the prognosis is. Citrulline has high diagnostic value for AGI in critical patients, but IFABP has no predictive value on the diagnosis of AGI.

TMPyP Inhibits Amyloid-ß Aggregation and Alleviates Amyloid-Induced Cytotoxicity.

The aggregation or misfolding of amyloid-ß (Aß) is a major pathological hallmark of Alzheimer's disease (AD). The regulation of Aß aggregation is thought to be an effective strategy for AD treatment. The capability of a water-soluble porphyrin, 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP), to inhibit Aß aggregation and to lower Aß-induced toxicity was demonstrated. As evidenced by surface plasmon resonance and circular dichroism, TMPyP can not only disrupt Aß aggregation but also disassemble the preformed Aß aggregates. The atomic force microscopy imaging proves that TMPyP inhibits the formation of both oligomers and fibrils. Molecular dynamic simulations provide an insight into the interaction between TMPyP and Aß at the molecular level. The half-maximal inhibitory concentrations of TMPyP acting on the oligomers and fibrils were determined to be 0.6 and 0.43 µM, respectively. As a member of porphyrin family, TMPyP is of rather low cytotoxicity, and the cytotoxicity of the Aß aggregates was also relieved upon coincubation with TMPyP. The excellent performance of TMPyP thus makes it a potential drug candidate for AD therapy.

Amplified voltammetric detection of miRNA from serum samples of glioma patients via combination of conducting magnetic microbeads and ferrocene-capped gold nanoparticle/streptavidin conjugates.

MicroRNA (miRNA) plays a key regulatory role in many biological processes, emerging as an important biomarker for a large variety of cancer diseases. Employing gold nanoparticle (AuNP)-coated magnetic microbeads (AuNP-MMBs) as an immobilization matrix for higher loading density of hairpin-structured DNA probes and then ferrocene (Fc)-capped gold nanoparticle/streptavidin conjugates, amplified electrochemical assay of miRNA has been performed. In the presence of target miRNA, a novel assembly was formed via linking biotinylated hairpin DNA probe-covered AuNP-MMBs with Fc-capped gold nanoparticle/streptavidin conjugates and then collected by magnetic electrodes for voltammetric detection. The enlarged surface area, good conductivity of AuNP-MMBs and the multiple Fc tags on the electrode surface ensure high sensitivity of the method. The oxidation peak current of Fc tags is proportional to the concentrations of miRNA ranging from 5 fM to 100 fM, and a detection limit of 0.14 fM was achieved. The proposed assay is highly selective and reproducible, serving as a viable alternative for the detection of miRNA-182 from serum samples of glioma patients.

Blood hemoperfusion with resin adsorption combined continuous veno-venous hemofiltration for patients with multiple organ dysfunction syndrome.

BACKGROUND: Blood hemoperfusion with resin adsorption can clean larger molecules that exceed the molecular weight cutoff of combined continuous veno-venous hemofiltration (CVVH). Hence blood hemoperfusion with resin adsorption combined CVVH (HP+CVVH) has higher ability of mediator clearance, and can improve clinical outcomes in theory. This study aimed to investigate the effect of blood hemoperfusion with resin adsorption combined continuous veno-venous hemofiltration (HP+CVVH) on plasm cytokines like TNF-α, IL-1ß, IL-6, cellular immunity and prognosis in patients with multiple organ dysfunction syndrome (MODS). METHODS: This was a prospective, randomized clinical trial. A total of 30 patients who had been diagnosed with MODS were enrolled in this study. Patients were randomly allocated to routine treatment+HP+CVVH group (treatment group) and routine treatment+only CVVH group (control group). In the treatment group, patients received blood hemoperfusion with resin adsorption for 2 hours, and then received CVVH for 10 hours every day. In the control group, patients received CVVH for 12 hours only every day. The patients in the two groups received blood purification therapy for three days. The plasma of patients in the treatment group was obtained at 0, 2, 12, 24, 26, 36, 48, 50, 60 hours, 5th day, 7th day and 10th day, respectively. The plasma of patients in the control group was obtained at 0, 12, 24, 36, 48, 60 hours, 5th day, 7th day and 10th day, respectively. APACHE II score, T-lymphocytes subpopulations, blood lactate acid concentration, heart rate, breathing rate, and oxygenation index were observed. RESULTS: Plasma cytokines like TNF-α, IL-1ß, IL-6 decreased markedly after HP (P<0.01); T-lymphocytes subpopulations CD3+, CD4+, CD8+, CD4+/CD8+ increased after HP+CVVH or only CVVH. The plasma concentrations of TNF-α, IL-1ß and IL-6 in the two groups were not markedly different at 12, 36, and 50 hours. But on the 5th day, the plasma concentrations of TNF-α, IL-1ß and IL-6 in the treatment group were lower than those in the control group (P<0.05). On the 28th day, 5 patients died in the treatment group, and 6 patients in the control group. CONCLUSIONS: Both HP+CVVH and CVVH can clean plasma cytokines like TNF-α, IL-1ß, and IL-6, and improve cellular immunity and clinical symptoms and signs of patients. Compared with only CVVH, the plasma concentrations of TNF-α, IL-1ß and IL-6 were lower on the 5th day, and patients have an increased survival rate on the 28 day in the HP+CVVH group.