Validation of the novel GLAS algorithm as an aid in the detection of liver fibrosis and cirrhosis based on GP73, LG2m, age, and sex.

BACKGROUND: Diagnosis of liver disease at earlier stages can improve outcomes and reduce the risk of progression to malignancy. Liver biopsy is the gold standard for diagnosis of liver disease, but is invasive and sample acquisition errors are common. Serum biomarkers for liver function and fibrosis, combined with patient factors, may allow for noninvasive detection of liver disease. In this pilot study, we tested and validated the performance of an algorithm that combines GP73 and LG2m serum biomarkers with age and sex (GLAS) to differentiate between patients with liver disease and healthy individuals in two independent cohorts. METHODS: To develop the algorithm, prototype immunoassays were used to measure GP73 and LG2m in residual serum samples collected between 2003 and 2016 from patients with staged fibrosis and cirrhosis of viral or non-viral etiology (n = 260) and healthy subjects (n = 133). The performance of five predictive models using combinations of age, sex, GP73, and/or LG2m from the development cohort were tested. Residual samples from a separate cohort with liver disease (fibrosis, cirrhosis, or chronic liver disease; n = 395) and healthy subjects (n = 106) were used to validate the best performing model. RESULTS: GP73 and LG2m concentrations were higher in patients with liver disease than healthy controls and higher in those with cirrhosis than fibrosis in both the development and validation cohorts. The best performing model included both GP73 and LG2m plus age and sex (GLAS algorithm), which had an AUC of 0.92 (95% CI: 0.90-0.95), a sensitivity of 88.8%, and a specificity of 75.9%. In the validation cohort, the GLAS algorithm had an estimated an AUC of 0.93 (95% CI: 0.90-0.95), a sensitivity of 91.1%, and a specificity of 80.2%. In both cohorts, the GLAS algorithm had high predictive probability for distinguishing between patients with liver disease versus healthy controls. CONCLUSIONS: GP73 and LG2m serum biomarkers, when combined with age and sex (GLAS algorithm), showed high sensitivity and specificity for detection of liver disease in two independent cohorts. The GLAS algorithm will need to be validated and refined in larger cohorts and tested in longitudinal studies for differentiating between stable versus advancing liver disease over time.

[Spatial Distribution Characteristics and Source Analysis of Heavy Metals in Urban River Surface Sediments from the Lanzhou Reach of the Yellow River].

In order to investigate the contamination characteristics and potential sources of heavy metals from the urban river surface sediments in the Yellow River Basin, we selected the Lanzhou reach of the Yellow River as the object of investigation. A total of 46 surface sediment samples were collected along the Lanzhou reach of the Yellow River, and the contents of eight heavy metals, Cr, Ni, Cu, Zn, As, Cd, Hg, and Pb, were determined by using inductively coupled plasma mass spectrometry and an atomic fluorescence spectrometer. Contamination indexes including single factor pollution index (Pi) and geo-accumulation index (Igeo), together with the sediment pollution index (SPI), were used to assess heavy metal pollution characteristics and ecological risk levels in the urban river surface sediments of the Lanzhou reach of the Yellow River. Pearson's correlation analysis (CA), positive matrix factorization (PMF), and principal component analysis/absolute principal component score (PCA/APCS) were jointly employed to quantitatively analyze pollution sources of heavy metals. The results showed that the mean concentrations of the majority of heavy metals exceeded their corresponding background values of Gansu Province and Lanzhou City with the exception of As, and the spatial distribution of high concentrations of heavy metals was mainly concentrated in the corner of the river. Based on the single factor pollution and geo-accumulation indexes of the eight heavy metals, in the Lanzhou reach of the Yellow River, Cr was the dominant pollution element in the urban river surface sediments, followed by Cd and Ni. Additionally, the SPI values for the eight heavy metals in the surface sediments ranged from 0.48 to 8.56, presenting natural to low ecological risk level. Furthermore, source apportionment revealed that a mixture source of industrial and agricultural activities (77.6%) was the largest contributor of Cr, Ni, Zn, As, Cd, and Pb in the urban river surface sediments, followed by natural sources (11.4%) and a mixed source of industrial and traffic activities (11%).

Ripened Pu-erh Tea Extract Promotes Gut Microbiota Resilience against Dextran Sulfate Sodium Induced Colitis.

Ripened Pu-erh tea (RPT) has been shown to be an effective natural ingredient to defend against experimentally induced colitis. We hypothesized that RPT would alleviate dextran sulfate sodium (DSS) induced colitis via modulating intestinal microbiota. The effect of RPT on mice gut microbiota was evaluated using 16S rRNA gene amplicon sequencing, broad-spectrum antibiotic (ABX) treatment, and fecal microbiota transplantation (FMT). Pretreatment with RPT enhanced intestinal barrier function, reduced colonic and serum proinflammatory cytokine and macrophage infiltration, and preserved the resilience of gut microbiota in mice during a DSS challenge. Administration of either RPT-regulated or healthy control-derived gut microbiota showed similar protection against colitis, and such protection could not be recapitulated with fecal microbiota from ABX-treated mice, suggesting a key role of protective consortium in the disease protection. Mechanistically, cecal contents of short-chain fatty acids (SCFAs) and colonic peroxisome proliferator activated receptor-γ (PPAR-γ) expression in colitis mice increased significantly by RPT intervention. Collectively, RPT treatment improved DSS-induced colitis by partially reversing the dysbiosis state of gut microbiota, which might be associated with an increase in SCFA level and PPAR-γ expression.

Hot-water extract of ripened Pu-erh tea attenuates DSS-induced colitis through modulation of the NF-κB and HIF-1α signaling pathways in mice.

Tea consumption has been found to be associated with low incidence of inflammatory bowel disease in Asian countries. However, there is very limited knowledge of such potential protection and its underlying mechanism. Ripened Pu-erh tea (RPT) belongs to the variety of microbial fermented tea, but its function regarding anti-inflammation remains unclear. In the present study, we investigated the effects of RPT on dextran sulfate sodium (DSS)-induced colitis in mice. The results demonstrated that RPT significantly relieved the loss of body weight, disease severity and shortening of colon length, and remarkably inhibited the secretion of pro-inflammatory cytokines by lessening the infiltration of inflammatory cells. Furthermore, we found that RPT suppressed the activation of the NF-κB pathway and down-regulated the expression of HIF-1α. Thus, it was concluded that RPT attenuated the progress of colitis via suppressing the HIF-1α/NF-κB signaling pathways thus reducing inflammation. This suggests that RPT may be a potential anti-inflammatory nutraceutical for the prevention and treatment of colonic colitis.

GE11-PDA-Pt@USPIOs nano-formulation for relief of tumor hypoxia and MRI/PAI-guided tumor radio-chemotherapy.

Radio-chemo combination therapy has synergetic therapeutic effects on tumors. However, the tumor microenvironment, e.g. hypoxia and elevated H2S levels, limits its treatment efficacy. In this study, we developed a cisplatin-loaded, poly dopamine-coated and GE11 peptide-conjugated multi-functional theranostic system (GE11-PDA-Pt@USPIOs) based on poly acrylic acid-coated ultra-small superparamagnetic iron oxide nanoparticles (PAA@USPIOs) for modulation of the tumor hypoxic microenvironment and magnetic resonance imaging/photoacoustic imaging (MRI/PAI) guided radio-chemotherapy of tumors. The thick PAA coating on the USPIOs allowed highly efficient cisplatin loading by complexing the carboxylic groups on PAA with activated cisplatin. A subsequent thin layer of polydopamine (PDA) encapsulation following drug loading provided a means of further surface functionalization; it endowed the particles with photo-thermal properties but did not impede release of the drug or iron ions. GE11-PDA-Pt@USPIOs had high specificity for EGFR-positive tumor cells, could catalyze decomposition of H2O2 to oxygen and exhibited radio-chemo synergetic therapeutic effects under hypothermia conditions in vitro. Once administered intravenously, MRI and PA imaging revealed that the probes were able to accumulate in tumors with high efficiency; this relieved the tumor hypoxic conditions, sensitizing the tumors to radiation therapy. As a result, radio-chemo combination therapy significantly inhibited tumor growth. Our study illustrates for the first time that USPIOs can relieve tumor hypoxia and that GE11-PDA-Pt@USPIOs are highly effective for radio-chemotherapy of EGFR-positive tumors.

Wnt4 is significantly upregulated during the early phases of cisplatin-induced acute kidney injury.

Wnt4 is a secreted growth factor associated with renal tubulogenesis. Our previous studies identified that renal and urinary Wnt4 are upregulated following ischemia-reperfusion injury in mice, but the roles of Wnt4 in other forms of acute kidney injury (AKI) remain unclear. Here, we investigated the changes in Wnt4 expression using a cisplatin-induced AKI model. We found that renal and urinary Wnt4 expression increased as early as 12 hours, peaked at day 4 following cisplatin-induced AKI and was closely correlated with histopathological alterations. By contrast, the serum creatinine level was significantly elevated until day 3, indicating that Wnt4 is more sensitive to early tubular injury than serum creatinine. In addition, renal Wnt4 was co-stained with aquaporin-1 and thiazide-sensitive NaCl cotransporter, suggesting that Wnt4 can detect both proximal and distal tubular injuries. These data were further confirmed in a clinical study. Increased urinary Wnt4 expression was detected earlier than serum creatinine and eGFR in patients with contrast-induced AKI after vascular intervention. This study is the first to demonstrate that increased expression of renal and urinary Wnt4 can be detected earlier than serum creatinine after drug-induced AKI. In particular, urinary Wnt4 can potentially serve as a noninvasive biomarker for monitoring patients with tubular injury.

[Simultaneous determination of 7 active ingredients in Scutellaria barbata D. Don by capillary micellar electrokinetic chromatography].

A method of capillary micellar electrokinetic chromatography with a diode array detector was developed for the simultaneous determination of 7 active ingredients (baicalein, naringenin, wogonin, scutellarin, apigenin, luteolin, and protocatechuic acid) in Scutellaria barbata D. Don and its ointment. The 7 ingredients in samples were extracted with methanol in an ultrasonic bath. The important factors, such as pH, running buffer concentration, additive, detection wavelength, separation voltage and injection time, were optimized. Under the optimum conditions, the 7 analytes were separated within 12 min at a separation voltage of 25 kV in a 50 mmol/L borate-0.20 mol/L boric acid buffer (pH 8.4) containing 8.5 mmol/L sodium dodecyl sulfate (SDS). The detection was carried out at 260 nm and 335 nm. Notably, the linearity ranged from 8 x 10(-6) to 3.2 x 10(-4) mol/L with the correlation coefficients (r2) at the range of 0.996 5 - 0.999 9. The detection limits (S/N = 3) ranged from 7.0 x 10(-8) mol/L to 2.0 x 10(-6) mol/L for all the 7 analytes. The recoveries of the 7 active ingredients were all over 85%. This method is of good sensitivity, simple preparation, good reproducibility and reliability. It was successfully applied to the analysis of the 7 active ingredients in Scutellaria barbata D. Don and its ointment.