Diet-induced obesity in zebrafish shares common pathophysiological pathways with mammalian obesity

<p>Abstract</p> <p>Background</p> <p>Obesity is a multifactorial disorder influenced by genetic and environmental factors. Animal models of obesity are required to help us understand the signaling pathways underlying this condition. Zebrafish possess many structural and functional similarities with humans and have been used to model various human diseases, including a genetic model of obesity. The purpose of this study was to establish a zebrafish model of diet-induced obesity (DIO).</p> <p>Results</p> <p>Zebrafish were assigned into two dietary groups. One group of zebrafish was overfed with <it>Artemia </it>(60 mg dry weight/day/fish), a living prey consisting of a relatively high amount of fat. The other group of zebrafish was fed with <it>Artemia </it>sufficient to meet their energy requirements (5 mg dry weight/day/fish). Zebrafish were fed under these dietary protocols for 8 weeks. The zebrafish overfed with <it>Artemia </it>exhibited increased body mass index, which was calculated by dividing the body weight by the square of the body length, hypertriglyceridemia and hepatosteatosis, unlike the control zebrafish. Calorie restriction for 2 weeks was applied to zebrafish after the 8-week overfeeding period. The increased body weight and plasma triglyceride level were improved by calorie restriction. We also performed comparative transcriptome analysis of visceral adipose tissue from DIO zebrafish, DIO rats, DIO mice and obese humans. This analysis revealed that obese zebrafish and mammals share common pathophysiological pathways related to the coagulation cascade and lipid metabolism. Furthermore, several regulators were identified in zebrafish and mammals, including APOH, IL-6 and IL-1β in the coagulation cascade, and SREBF1, PPARα/γ, NR1H3 and LEP in lipid metabolism.</p> <p>Conclusion</p> <p>We established a zebrafish model of DIO that shared common pathophysiological pathways with mammalian obesity. The DIO zebrafish can be used to identify putative pharmacological targets and to test novel drugs for the treatment of human obesity.</p

Behavior of vascular resistance undergoing various pressure insufflation and perfusion on decellularized lungs

Bioengineering of functional lung tissue by using whole lung scaffolds has been proposed as a potential alternative for patients awaiting lung transplant. Previous studies have demonstrated that vascular resistance (Rv) could be altered to optimize the process of obtaining suitable lung scaffolds. Therefore, this work was aimed at determining how lung inflation (tracheal pressure) and perfusion (pulmonary arterial pressure) affect vascular resistance. This study was carried out using the lungs excised from 5 healthy male Sprague-Dawley rats. The trachea was cannulated and connected to a continuous positive airway pressure (CPAP) device to provide a tracheal pressure ranging from 0 to 15 cmH(2)O. The pulmonary artery was cannulated and connected to a controlled perfusion system with continuous pressure (gravimetric level) ranging from 5 to 30 cmH(2)O. Effective Rv was calculated by ratio of pulmonary artery pressure (P-PA) by pulmonary artery flow (V'(PA)). Rv in the decellularized lungs scaffolds decreased at increasing V'(PA), stabilizing at a pulmonary arterial pressure greater than 20 cmH(2)O. On the other hand, CPAP had no influence on vascular resistance in the lung scaffolds after being subjected to pulmonary artery pressure of 5 cmH(2)O. In conclusion, compared to positive airway pressure, arterial lung pressure markedly influences the mechanics of vascular resistance in decellularized lungs. (C) 2016 Elsevier Ltd. All rights reserved

School grade and sex differences in domain-specific sedentary behaviors among Japanese elementary school children: a cross-sectional study

Background: It is vital to reduce the proportion of sedentary behavior in children. Understanding the duration and behavioral context is needed. The present study examined school-grade and sex differences in domain-specificsedentary times and concurrence with screen-time guidelines among Japanese elementary school children.Methods: A total of 625 children (330 boys) were surveyed in 2010 and 2014. Using a questionnaire, data regarding participants’ grade (first through third grades: lower grades; fourth through six grades: higher grades), sex, weight, and height were collected in addition to the time spent per day engaging in each specific sedentary behavior separately:(1) reading or listening to music, (2) TV or video viewing, (3) TV game use, (4) internet use excluding class, (5) homework, and (6) car travel. Two-way analysis of covariance and logistic regression analyses, adjusted for BMI and moderate to vigorous physical activity, were used to examine school-grade and sex differences in sedentary behaviors and the independent risk of exceeding recommended total daily screen time (< 2 h).Results:On 625 children, mean minutes (SD) of sedentary behavior per week in (1) – (6) were 90.3 (123.4), 535.0 (356.6),167.3 (222.1), 23.9 (70.9), 264.9 (185.3), and 33.4 (61.2) in weekdays and 42.1 (70.0), 323.9 (232.0), 123.0 (96.4),15.8 (49.9), 74.4 (96.4), and 71.3 (84.9) in weekends, respectively. There were differences in the minutes of sedentary behavior between participants of 2010 and 2014; e.g., TV game use and homework in weekdays and weekdays and car travel in weekends. Boys spent more time in TV game use, and girls spent more time reading, listening to music, doing homework, and car travel. Higher-grade students spent more time reading or listening to music, using a computer, and doing homework. Higher-grade students were 2.09 times (95% CI: 1.32 − 3.30) in whole week, 2.08 times (95% CI: 1.45 − 3.00) in weekday, and 1.88 times (95% CI: 1.29 − 2.74) in weekend more likely to spend ≥2 h per day in domains (2) − (4) (screen-time) than lower-grade students.Conclusions: Time spent engaging in each domain-specific sedentary behavior differed according to sex and school grade. Higher-grade students were less likely to meet screen-time guidelines. These findings highlight the need fordomain-focused strategies to decrease sedentary behavior in Japanese school-age children

Immunochemotherapy of gastric cancer with levamisole.

In 156 cases of gastric cancer, levamisole (LMS) was administered at a daily dose of 150 mg for three consecutive days every other week. The administration was started 3 days before operation. This medication was repeated for more than one month. The survival rate up to two years after surgery was studied. The survival rate was not affected in patients with Stage I and II gastric cancer, but in patients with Stage III, the difference in the survival rate between the LMS group and the control group was significantly higher than that in the control group (p less than 0.05). In patients with Stage IV, the survival rate in the LMS group was higher than that in the control group although the difference was not significant. In patients of Stage III and IV, the effect of LMS on the survival rate was highest in cases with curative resection (p less than 0.01). In cases with noncurative resection, the difference between the LMS group and the control group was greatest (24.4%) 12 months after surgery but not significant (p less than 0.5), and also in cases without resection the difference between the two groups was greatest (20.3%) 12 months after surgery but not significant (p less than 0.2).</p

In vivo imaging of zebrafish retinal cells using fluorescent coumarin derivatives

<p>Abstract</p> <p>Background</p> <p>The zebrafish visual system is a good research model because the zebrafish retina is very similar to that of humans in terms of the morphologies and functions. Studies of the retina have been facilitated by improvements in imaging techniques. <it>In vitro </it>techniques such as immunohistochemistry and <it>in vivo </it>imaging using transgenic zebrafish have been proven useful for visualizing specific subtypes of retinal cells. In contrast, <it>in vivo </it>imaging using organic fluorescent molecules such as fluorescent sphingolipids allows non-invasive staining and visualization of retinal cells <it>en masse</it>. However, these fluorescent molecules also localize to the interstitial fluid and stain whole larvae.</p> <p>Results</p> <p>We screened fluorescent coumarin derivatives that might preferentially stain neuronal cells including retinal cells. We identified four coumarin derivatives that could be used for <it>in vivo </it>imaging of zebrafish retinal cells. The retinas of living zebrafish could be stained by simply immersing larvae in water containing 1 μg/ml of a coumarin derivative for 30 min. By using confocal laser scanning microscopy, the lamination of the zebrafish retina was clearly visualized. Using these coumarin derivatives, we were able to assess the development of the zebrafish retina and the morphological abnormalities induced by genetic or chemical interventions. The coumarin derivatives were also suitable for counter-staining of transgenic zebrafish expressing fluorescent proteins in specific subtypes of retinal cells.</p> <p>Conclusions</p> <p>The coumarin derivatives identified in this study can stain zebrafish retinal cells in a relatively short time and at low concentrations, making them suitable for <it>in vivo </it>imaging of the zebrafish retina. Therefore, they will be useful tools in genetic and chemical screenings using zebrafish to identify genes and chemicals that may have crucial functions in the retina.</p

Serum Antibody Against NY-ESO-1 and XAGE1 Antigens Potentially Predicts Clinical Responses to Anti–Programmed Cell Death-1 Therapy in NSCLC

Introduction: Programmed cell death-1 (PD-1) inhibitors effectively treat NSCLC and prolong survival. Robust biomarkers for predicting clinical benefits of good response and long survival with anti-PD-1 therapy have yet to be identified; therefore, predictive biomarkers are needed to select patients with benefits. Methods: We conducted a prospective study to explore whether serum antibody against NY-ESO-1 and/or XAGE1 cancer-testis antigens predicted primarily good clinical response and secondarily long survival with anti-PD-1 therapy for NSCLC. The serum antibody was detected by enzyme-linked immunosorbent assay, and tumor immune microenvironment and mutation burden were analyzed by immunohistochemistry and next-generation sequencing. Results: In the discovery cohort (n = 13), six antibody-positive NSCLC cases responded to anti-PD-1 therapy (two complete and four partial responses), whereas seven antibody-negative NSCLC cases did not. Antibody positivity was associated with good response and survival, regardless of tumor programmed death ligand 1 (PD-L1) expression, mutation burden, and CD8+ T-cell infiltration. In the validation cohort (n = 75), 17 antibody-positive NSCLC cases responded well to anti-PD-1 therapy as compared with 58 negative NSCLC cases (objective response rate 65% versus 19%, p = 0.0006) and showed significantly prolonged progression-free survival and overall survival. Antibody titers highly correlated with tumor reduction rates. In the multivariate analysis, response biomarkers were tumor programmed death ligand 1 expression and antibody positivity, and only antibody positivity was a significantly better predictive biomarker of progression-free survival (hazard ratio = 0.4, p = 0.01) and overall survival (hazard ratio = 0.2, p = 0.004). Conclusions: Our results suggest that NY-ESO-1 and/or XAGE1 serum antibodies are useful biomarkers for predicting clinical benefits in anti-PD-1 therapy for NSCLC and probably for other cancers

Usefulness of fecal calprotectin by monoclonal antibody testing in adult Japanese with inflammatory bowel diseases: a prospective multicenter study

Background/Aims Noninvasive objective monitoring is advantageous for optimizing treatment strategies in patients inflammatory bowel disease (IBD). Fecal calprotectin (FCP) is superior to traditional biomarkers in terms of assessing the activity in patients with IBD. However, there are the differences among several FCP assays in the dynamics of FCP. In this prospective multicenter trial, we investigated the usefulness of FCP measurements in adult Japanese patients with IBD by reliable enzyme immunoassay using a monoclonal antibody. Methods We assessed the relationship between FCP levels and disease or endoscopic activity in patients with ulcerative colitis (UC, n=64) or Crohn’s disease (CD, n=46) compared with healthy controls (HCs, n=64). Results FCP levels in UC patients strongly correlated with the Disease Activity Index (rs=0.676, P<0.0001) and Mayo endoscopic subscore (MES; rs=0.677, P<0.0001). FCP levels were significantly higher even in patients with inactive UC or CD compared with HCs (P=0.0068, P<0.0001). The optimal cutoff value between MES 1 and 2 exhibited higher sensitivity (94.1%). FCP levels were significantly higher in active UC patients than in inactive patients (P<0.001), except those with proctitis. The Crohn’s Disease Activity Index tended to correlate with the FCP level (rs=0.283, P=0.0565). Conclusions Our testing method using a monoclonal antibody for FCP was well-validated and differentiated IBD patients from HCs. FCP may be a useful biomarker for objective assessment of disease activity in adult Japanese IBD patients, especially those with UC

Plasma Thrombopoietin Levels are Unlikely to Account for the Platelet-sparing Effect of Paclitaxel in Lung Cancer Patients

Purpose: The present study was designed to determine whether the combination of carboplatin (CBDCA) with paclitaxel (PTX) spared CBDCA-induced thrombocytopenia by increased plasma thrombopoietin (TPO) levels. Methods: Patients with non-small-cell and small-cell lung cancer were consecutively assigned to CBDCA with PTX regimen (CBDCA/PTX) and CBDCA with irinotecan (CPT-11) regimen (CBDCA/CPT-11), respectively. Results: Ten patients were entered into either CBDCA/PTX (n=5) or CBDCA/CPT-11 (n=5). CBDCA/PTX showed a lesser reduction of platelet counts than CBDCA/CPT-11 (p<0.05), although more severe neutropenia was observed in CBDCA/PTX (p<0.01). The plasma TPO levels were inversely correlated with circulating platelet counts in CBDCA/PTX and CBDCA/CPT-11. However, the increased rate of plasma TPO levels in CBDCA/PTX was not significantly different from that in CBDCA/CPT-11. Conclusions: These findings suggest that the increased plasma TPO levels in CBDCA/PTX result secondarily from thrombocytopenia, and that circulating TPO is probably not involved in the platelet-sparing effect of PTX