Cellulose nanosphere: Preparation and applications of the novel nanocellulose.

Over the past few years, cellulose nanosphere (CNS) has gained growing attention and rapid development. As a new type of nanocellulose materials, CNS can be prepared from native cellulose by using methods which have been adopted extensively to prepare the well-known nanocelluloses, i.e., cellulose nanofiber and cellulose nanocrystal. The particular interest is that the regenerated cellulose and mercerized cellulose can also be used as important feedstocks to produce CNS. In this review, the preparation methods of CNS are described and discussed, via both top-down processes, including chemical, mechanical, and enzymolysis ones, and bottom-up processes by using various cellulose I and II starting materials. This review also highlights the researches relative to cellulose composite nanospheres, and summarizes the applications of spherical cellulose-based nanoparticles. Finally, the future challenges and opportunities of CNS are prospected in this work.

1,3-Benzodioxole-Modified Noscapine Analogues: Synthesis, Antiproliferative Activity, and Tubulin-Bound Structure.

Since the revelation of noscapine's weak anti-mitotic activity, extensive research has been conducted over the past two decades, with the goal of discovering noscapine derivatives with improved potency. To date, noscapine has been explored at the 1, 7, 6', and 9'-positions, though the 1,3-benzodioxole motif in the noscapine scaffold that remains unexplored. The present investigation describes the design, synthesis and pharmacological evaluation of noscapine analogues consisting of modifications to the 1,3-benzodioxole moiety. This includes expansion of the dioxolane ring and inclusion of metabolically robust deuterium and fluorine atoms. Favourable structural modifications were subsequently incorporated into multi-functionalised noscapine derivatives that also possessed modifications previously shown to promote anti-proliferative activity in the 1-, 6'- and 9'-positions. Our research efforts afforded the deuterated noscapine derivative 14 e and the dioxino-containing analogue 20 as potent cytotoxic agents with EC50 values of 1.50 and 0.73 µM, respectively, against breast cancer (MCF-7) cells. Compound 20 also exhibited EC50 values of <2 µM against melanoma, non-small cell lung carcinoma, and cancers of the brain, kidney and breast in an NCI screen. Furthermore, compounds 14 e and 20 inhibit tubulin polymerisation and are not vulnerable to the overexpression of resistance conferring P-gp efflux pumps in drug-resistant breast cancer cells (NCIADR/RES ). We also conducted X-ray crystallography studies that yielded the high-resolution structure of 14 e bound to tubulin. Our structural analysis revealed the key interactions between this noscapinoid and tubulin and will assist with the future design of noscapine derivatives with improved properties.

Exploiting the metabolic energy demands of drug efflux pumps provides a strategy to overcome multidrug resistance in cancer.

BACKGROUND: P-glycoprotein (P-gp) is a prevalent resistance mediator and it requires considerable cellular energy to ensure ATP dependent efflux of anticancer drugs. The glycolytic pathway generates the majority of catabolic energy in cancer cells; however, the high rates of P-gp activity places added strain on its inherently limited capacity to generate ATP. This is particularly relevant for compounds such as verapamil that are believed to trap P-gp in a futile transport process that requires continuing ATP consumption. Ultimately, this leads to cell death and the hypersensitivity of resistant cells to verapamil is termed collateral sensitivity. RESULTS: We show that the addition of verapamil to resistant cells produces a prominent reduction in ATP levels that supports the idea of disrupted energy homeostasis. Even in the absence of verapamil, P-gp expressing cells display near maximal rates of glycolysis and oxidative phosphorylation, which prevents an adequate response to the demand for ATP to sustain transport activity. Moreover, the near perpetually maximal rate of oxidative phosphorylation in the presence of verapamil resulted in elevated levels of reactive oxygen species that affect cell survival and underscore collateral sensitivity. CONCLUSIONS: Our results demonstrate that the strained metabolic profiles of P-gp expressing resistant cancer cells can be overwhelmed by additional ATP demands. GENERAL SIGNIFICANCE: Consequently, collateral sensitising drugs may overcome the resistant phenotype by exploiting, rather than inhibiting, the energy demanding activity of pumps such as P-gp.

New Evidence for P-gp-Mediated Export of Amyloid-ß PEPTIDES in Molecular, Blood-Brain Barrier and Neuronal Models.

Defective clearance mechanisms lead to the accumulation of amyloid-beta (Aß) peptides in the Alzheimer's brain. Though predominantly generated in neurons, little is known about how these hydrophobic, aggregation-prone, and tightly membrane-associated peptides exit into the extracellular space where they deposit and propagate neurotoxicity. The ability for P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter, to export Aß across the blood-brain barrier (BBB) has previously been reported. However, controversies surrounding the P-gp-Aß interaction persist. Here, molecular data affirm that both Aß40 and Aß42 peptide isoforms directly interact with and are substrates of P-gp. This was reinforced ex vivo by the inhibition of Aß42 transport in brain capillaries from P-gp-knockout mice. Moreover, we explored whether P-gp could exert the same role in neurons. Comparison between non-neuronal CHO-APP and human neuroblastoma SK-N-SH cells revealed that P-gp is expressed and active in both cell types. Inhibiting P-gp activity using verapamil and nicardipine impaired Aß40 and Aß42 secretion from both cell types, as determined by ELISA. Collectively, these findings implicate P-gp in Aß export from neurons, as well as across the BBB endothelium, and suggest that restoring or enhancing P-gp function could be a viable therapeutic approach for removing excess Aß out of the brain in Alzheimer's disease.

Pressure drop mapping using 4D flow MRI in patients with bicuspid aortic valve disease: A novel marker of valvular obstruction.

BACKGROUND: The influence of complex bicuspid aortic valve (BAV) flow patterns on net intraluminal aortic pressure, both among patients with and without significant aortic stenosis, is unknown. Pressure drop (PD), as estimated by 4D Flow MRI, can quantify pre- vs post-valvular pressure at multiple levels simultaneously. METHODS: In this prospective clinical study, 32 patients with BAV with varying degrees of aortic stenosis and regurgitation and 11 healthy subjects were enrolled. 4D flow MRI was processed and analyzed at 9 pre-defined thoracic aortic levels. PD was calculated at each plane relative to a reference located within the left ventricular outflow tract. Conventional 2D phase-contrast imaging was used as reference of hemodynamic obstruction. PD was compared between healthy subjects versus BAV patients using Kruskal-Wallis H test and Mann-Whitney U. Correlation studies were conducted using Spearman's rank-order correlation. RESULTS: Both BAV patients and healthy subjects showed progressive elevation in PD from the aortic root to the distal descending thoracic aorta. However, BAV patients showed higher PD than healthy subjects (p ≤ 0.01) at all analysis planes. Patients with moderate-severe aortic stenosis (n = 5) by 2D phase-contrast (peak PG > 40 mm Hg) showed higher PD than those without in the descending aortic segments (p ≤ 0.005). A correlation (r = 0.88, p < 0.05) was observed between PD at the distal descending thoracic aorta and peak trans-valvular velocity measured by 2D phase-contrast MRI. CONCLUSION: We demonstrated that PD with 4D flow MRI is clinically feasible in BAV patients and provides an additional physiologic description of valve-related hemodynamic obstruction.

A Novel Class of N-Sulfonyl and N-Sulfamoyl Noscapine Derivatives that Promote Mitotic Arrest in Cancer Cells.

Noscapine displays weak anticancer efficacy and numerous research efforts have attempted to generate more potent noscapine analogues. These modifications included the replacement of the N-methyl group in the 6'-position with a range of substituents, where N-ethylcarbamoyl substitution was observed to possess enhanced anticancer activity. Herein, we describe advances in this area, namely the synthesis and pharmacological evaluation of a series of N-sulfonyl and N-sulfamoyl noscapine derivatives. A number of these sulfonyl-containing noscapinoids demonstrated improved activities compared to noscapine. ((R)-5-((S)-4,5-Dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-((1-methyl-1H-imidazol-4-yl)sulfonyl)-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinoline) (14 q) displayed sub-micromolar activities of 560, 980, 271 and 443 nM against MCF-7, PANC-1, MDA-MB-435 and SK-MEL-5 cells, respectively. This antiproliferative effect was also maintained against drug-resistant NCI/AdrRES cells despite high expression of the multidrug efflux pump, P-glycoprotein.

Ligation of thoracic duct during thoracoscopic esophagectomy can lead to decrease of T lymphocyte.

BACKGROUND: Video-assisted thoracoscopic esophagectomy has been one of the most preferable surgical treatments for early esophageal cancer. Some scholars suggested that the thoracic duct should be routinely ligated to reduce the incidence of postoperative chylothorax, while another group raised an objection. As a classic indicator of immune function, T lymphocyte subsets can be applied to assess the effects of prophylactic thoracic duct ligation during thoracoscopic esophagectomy. METHODS: A total of 60 patients were recruited and randomized into thoracic duct ligation group and nonligation group. Venous blood was collected before and after video-assisted esophagectomy. The lymphocyte count and percentage, T lymphocyte subsets percentage were measured with fully automatic hemacytometer analyzer and flow cytometry. The difference between two groups was compared with t-test and the classified data were compared with Chi-square test. RESULTS: No significant difference was observed in peripheral blood CD3+, CD3+CD4+, and CD3+CD8+ lymphocyte percentage between the two groups before operation (P > 0.05). The mean value of peripheral blood CD3+, CD3+CD4+ lymphocyte percentage in ligation group was obviously less than that of in nonligation group after operation (P < 0.05). The mean of CD3+CD8+ lymphocyte percentage in ligation group was obviously higher than that of in nonligation group after operation (P < 0.05). CONCLUSION: Ligation of thoracic duct during esophagectomy could lead to decreased percentage of T lymphocyte and CD4+ Tlymphocyte, especially after arch of azygos vein had been transected. The thoracic duct should be selectively ligated during esophagectomy.

Community delivery of semiautomated fractal analysis tool in cardiac mr for trabecular phenotyping.

PURPOSE: To report the development of easy-to-use magnetic resonance imaging (MRI) fractal tools deployed on platforms accessible to all. The trabeculae of the left ventricle vary in health and disease but their measurement is difficult. Fractal analysis of cardiac MR images can measure trabecular complexity as a fractal dimension (FD). MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act (HIPAA)-compliant study was approved by the local Institutional Review Board. Participants provided written informed consent. The original MatLab implementation (region-based level set segmentation and box-counting algorithm) was recoded for two platforms (OsiriX and a clinical MR reporting platform [cvi42 , Circle Cardiovascular Imaging, Calgary, Canada]). For validation, 100 subjects were scanned at 1.5T and 20 imaged twice for interstudy reproducibility. Cines were analyzed by the three tools and FD variability determined. Manual trabecular delineation by an expert reader (R1) provided ground truth contours for validation of segmentation accuracy by point-to-curve (P2C) distance estimates. Manual delineation was repeated by R1 and a second reader (R2) on 15 cases for intra/interobserver variability. RESULTS: FD by OsiriX and the clinical MR reporting platform showed high correlation with MatLab values (correlation coefficients: 0.96 [95% CI: 0.95-0.97] and 0.96 [0.95-0.96]) and high interstudy and intraplatform reproducibility. Semiautomated contours in OsiriX and the clinical MR reporting platform were highly correlated with ground truth contours evidenced by low P2C errors: 0.882 ± 0.76 mm and 0.709 ± 0.617 mm. Validity of ground truth contours was inferred from low P2C errors between readers (R1-R1: 0.798 ± 0.718 mm; R1-R2: 0.804 ± 0.649 mm). CONCLUSION: This set of accessible fractal tools that measure trabeculation in the heart have been validated and released to the cardiac MR community (http://j.mp/29xOw3B) to encourage novel clinical applications of fractals in the cardiac imaging domain. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1082-1088.

Cardiac magnetic resonance tissue tracking in right ventricle: Feasibility and normal values.

PURPOSE: To investigate right ventricular (RV) strain in patients without identified cardiac pathology using cardiac magnetic resonance tissue tracking (CMR TT). METHODS: A total of 50 consecutive patients with no identified cardiac pathology were analyzed. RV longitudinal and circumferential strain was assessed by CMR TT. The age range was 4-81years with a median of 32years (interquartile range, 15 to 56years). RESULTS: Analysis time per patient was <5min. The peak longitudinal strain (Ell) was -22.11±3.51%. The peak circumferential strains (Ecc) for global, basal, mid-cavity and apical segments were as follows: -11.69±2.25%, -11.00±2.45%, -11.17±3.36%, -12.90±3.34%. There were significant gender differences in peak Ecc at the base (P=0.04) and the mid-cavity (P=0.03) with greater deformation in females than in males. On Bland-Altman analysis, peak Ell (mean bias, 0.22±1.67; 95% CI -3.05 to 3.49) and mid-cavity Ecc (mean bias, 0.036±1.75; 95% CI, -3.39 to 3.47) had the best intra-observer agreement and inter-observer agreement, respectively. CONCLUSIONS: RV longitudinal and circumferential strains can be quickly assessed with good intra-observer and inter-observer variability using TT.

Knockdown of Long Noncoding RNA uc.338 by siRNA Inhibits Cellular Migration and Invasion in Human Lung Cancer Cells.

Lung cancer remains a critical health concern worldwide. Long noncoding RNAs with ultraconserved elements have recently been implicated in human tumorigenesis. The present study investigated the role of ultraconserved element 338 (uc.338) in the regulation of cell proliferation and metastasis in human lung cancer. Our data showed that the expression of uc.338 in lung cancer was remarkably increased in vivo and in vitro. Depletion of uc.338 with specific siRNA interference retarded the cell proliferative rate in lung cancer cell lines NCI-H929 and H1688. Furthermore, knockdown of uc.338 caused cell cycle arrest in the G0/G1 phase in both cell lines. Transwell assays showed that inhibition of uc.338 notably decreased migration and invasion in NCI-H929 and H1688 cells. Moreover, uc.338 depletion decreased the expression of cyclin B1, Cdc25C, Snail, vimentin, and N-cadherin while increasing the protein level of E-cadherin, shown with Western blot analysis. These results suggested the pro-oncogenic potential of uc.338 in lung cancer, which might provide novel clues for the diagnosis and treatment of lung cancer in the clinic.

Convergent evidence from systematic analysis of GWAS revealed genetic basis of esophageal cancer.

Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with risk of esophageal cancer (EC). However, investigation of genetic basis from the perspective of systematic biology and integrative genomics remains scarce.In this study, we explored genetic basis of EC based on GWAS data and implemented a series of bioinformatics methods including functional annotation, expression quantitative trait loci (eQTL) analysis, pathway enrichment analysis and pathway grouped network analysis.Two hundred and thirteen risk SNPs were identified, in which 44 SNPs were found to have significantly differential gene expression in esophageal tissues by eQTL analysis. By pathway enrichment analysis, 170 risk genes mapped by risk SNPs were enriched into 38 significant GO terms and 17 significant KEGG pathways, which were significantly grouped into 9 sub-networks by pathway grouped network analysis. The 9 groups of interconnected pathways were mainly involved with muscle cell proliferation, cellular response to interleukin-6, cell adhesion molecules, and ethanol oxidation, which might participate in the development of EC.Our findings provide genetic evidence and new insight for exploring the molecular mechanisms of EC.

Fractal frontiers in cardiovascular magnetic resonance: towards clinical implementation.

Many of the structures and parameters that are detected, measured and reported in cardiovascular magnetic resonance (CMR) have at least some properties that are fractal, meaning complex and self-similar at different scales. To date however, there has been little use of fractal geometry in CMR; by comparison, many more applications of fractal analysis have been published in MR imaging of the brain.This review explains the fundamental principles of fractal geometry, places the fractal dimension into a meaningful context within the realms of Euclidean and topological space, and defines its role in digital image processing. It summarises the basic mathematics, highlights strengths and potential limitations of its application to biomedical imaging, shows key current examples and suggests a simple route for its successful clinical implementation by the CMR community.By simplifying some of the more abstract concepts of deterministic fractals, this review invites CMR scientists (clinicians, technologists, physicists) to experiment with fractal analysis as a means of developing the next generation of intelligent quantitative cardiac imaging tools.

Colometer: a real-time quality feedback system for screening colonoscopy.

AIM: To investigate the performance of a new software-based colonoscopy quality assessment system. METHODS: The software-based system employs a novel image processing algorithm which detects the levels of image clarity, withdrawal velocity, and level of the bowel preparation in a real-time fashion from live video signal. Threshold levels of image blurriness and the withdrawal velocity below which the visualization could be considered adequate have initially been determined arbitrarily by review of sample colonoscopy videos by two experienced endoscopists. Subsequently, an overall colonoscopy quality rating was computed based on the percentage of the withdrawal time with adequate visualization (scored 1-5; 1, when the percentage was 1%-20%; 2, when the percentage was 21%-40%, etc.). In order to test the proposed velocity and blurriness thresholds, screening colonoscopy withdrawal videos from a specialized ambulatory colon cancer screening center were collected, automatically processed and rated. Quality ratings on the withdrawal were compared to the insertion in the same patients. Then, 3 experienced endoscopists reviewed the collected videos in a blinded fashion and rated the overall quality of each withdrawal (scored 1-5; 1, poor; 3, average; 5, excellent) based on 3 major aspects: image quality, colon preparation, and withdrawal velocity. The automated quality ratings were compared to the averaged endoscopist quality ratings using Spearman correlation coefficient. RESULTS: Fourteen screening colonoscopies were assessed. Adenomatous polyps were detected in 4/14 (29%) of the collected colonoscopy video samples. As a proof of concept, the Colometer software rated colonoscope withdrawal as having better visualization than the insertion in the 10 videos which did not have any polyps (average percent time with adequate visualization: 79% ± 5% for withdrawal and 50% ± 14% for insertion, P < 0.01). Withdrawal times during which no polyps were removed ranged from 4-12 min. The median quality rating from the automated system and the reviewers was 3.45 [interquartile range (IQR), 3.1-3.68] and 3.00 (IQR, 2.33-3.67) respectively for all colonoscopy video samples. The automated rating revealed a strong correlation with the reviewer's rating (ρ coefficient= 0.65, P = 0.01). There was good correlation of the automated overall quality rating and the mean endoscopist withdrawal speed rating (Spearman r coefficient= 0.59, P = 0.03). There was no correlation of automated overall quality rating with mean endoscopists image quality rating (Spearman r coefficient= 0.41, P = 0.15). CONCLUSION: The results from a novel automated real-time colonoscopy quality feedback system strongly agreed with the endoscopists' quality assessments. Further study is required to validate this approach.

Pilot study of longitudinal ultrasonic sensor for dynamic volumetric assessment of gastroesophageal reflux.

In patients with gastroesophageal reflux disease (GERD), esophageal symptoms are traditionally diagnosed by monitoring the contact time between the reflux content and the esophagus using multichannel intraluminal impedance and pH (MII-pH) catheters. However, esophageal catheter for quantifying the volume of reflux content is still lacking. The present work proposes an innovative method to develop a longitudinal ultrasonic catheter and an information extraction system for reflux event detection and reflux volume estimation. Gastroesophageal model that mimics reflux events was developed to test the proposed catheter. Ultrasonic sensing was evaluated by simulating different volumes of reflux. The obtained signals showed good consistency in detecting reflux events and measuring reflux volume. During an in vivo human testing, a MII-pH catheter was used simultaneously to compare the ultrasonic output. Both in vitro and in vivo human testing results demonstrated the feasibility of utilizing the proposed method for gastroesophageal reflux (GER) detection and reflux volume estimation.