Role of the enterocyte in fructose-induced hypertriglyceridaemia

Abstract: Dietary fructose has been linked to an increased post-prandial triglyceride (TG) level, which is an established independent risk factor for cardiovascular disease. Although much research has focused on the effects of fructose consumption on liver-derived very-low density lipoprotein (VLDL), emerging evidence also suggests that fructose may raise post-prandial TG levels by affecting the metabolism of enterocytes of the small intestine. Enterocytes have become well recognised for their ability to transiently store lipids following a meal and to thus control post-prandial TG levels according to the rate of chylomicron (CM) lipoprotein synthesis and secretion. The influence of fructose consumption on several aspects of enterocyte lipid metabolism are discussed, including de novo lipogenesis, apolipoprotein B48 and CM-TG production, based on the findings of animal and human isotopic tracer studies. Methodological issues affecting the interpretation of fructose studies conducted to date are highlighted, including the accurate separation of CM and VLDL. Although the available evidence to date is limited, disruption of enterocyte lipid metabolism may make a meaningful contribution to the hypertriglyceridaemia often associated with fructose consumption

Modelling of Brain Deformation After Decompressive Craniectomy.

Hyperelastic finite element models, with either an idealized cylindrical geometry or with realistic craniectomy geometries, were used to explore clinical issues relating to decompressive craniectomy. The potential damage in the brain tissue was estimated by calculating the volume of material exceeding a critical shear strain. Results from the idealized model showed how the potentially damaged volume of brain tissue increased with an increasing volume of brain tissue herniating from the skull cavity and with a reduction in craniectomy area. For a given herniated volume, there was a critical craniectomy diameter where the volume exceeding a critical shear strain fell to zero. The effects of details at the craniectomy edge, specifically a fillet radius and a chamfer on the bone margin, were found to be relatively slight, assuming that the dura is retained to provide effective protection. The location in the brain associated with volume expansion and details of the material modeling were found to have a relatively modest effect on the predicted damage volume. The volume of highly sheared material in the realistic models of the craniectomy varied roughly in line with differences in the craniectomy area.TLF acknowledges funding from the Engineering and Physical Sciences Research Council (EPSRC). BW is supported by the Studienstiftung des deutschen Volkes, the Max Weber-Programm and the Stiftung Maximilianeum. AGK is supported by a Royal College of Surgeons of England Research Fellowship (funded by the Freemasons and the Rosetrees Trust), a National Institute of Health Research (NIHR) Academic Clinical Fellowship and a Raymond and Beverly Sackler Studentship. PJH is supported by a NIHR Research Professorship and the NIHR Cambridge Biomedical Research Centre.This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s10439-016-1666-

Activity of the DNA minor groove cross-linking agent SG2000 (SJG-136) against canine tumours

BACKGROUND: Cancer is the leading cause of death in older dogs and its prevalence is increasing. There is clearly a need to develop more effective anti-cancer drugs in dogs. SG2000 (SJG-136) is a sequence selective DNA minor groove cross-linking agent. Based on its in vitro potency, the spectrum of in vivo and clinical activity against human tumours, and its tolerability in human patients, SG2000 has potential as a novel therapeutic against spontaneously occurring canine malignancies. RESULTS: In vitro cytotoxicity was assessed using SRB and MTT assays, and in vivo activity was assessed using canine tumour xenografts. DNA interstrand cross-linking (ICL) was determined using a modification of the single cell gel electrophoresis (comet) assay. Effects on cell cycle distribution were assessed by flow cytometry and measurement of γ-H2AX by immunofluorescence and immunohistochemistry. SG2000 had a multi-log differential cytotoxic profile against a panel of 12 canine tumour cell lines representing a range of common tumour types in dogs. In the CMeC-1 melanoma cell line, DNA ICLs increased linearly with dose following a 1 h treatment. Peak ICL was achieved within 1 h and no removal was observed over 48 h. A relationship between DNA ICL formation and cytotoxicity was observed across cell lines. The formation of γ-H2AX foci was slow, becoming evident after 4 h and reaching a peak at 24 h. SG2000 exhibited significant anti-tumour activity against two canine melanoma tumour models in vivo. Anti-tumour activity was observed at 0.15 and 0.3 mg/kg given i.v. either once, or weekly x 3. Dose-dependent DNA ICL was observed in tumours (and to a lower level in peripheral blood mononuclear cells) at 2 h and persisted at 24 h. ICL increased following the second and third doses in a repeated dose schedule. At 24 h, dose dependent γ-H2AX foci were more numerous than at 2 h, and greater in tumours than in peripheral blood mononuclear cells. SG2000-induced H2AX phosphorylation measured by immunohistochemistry showed good correspondence, but less sensitivity, than measurement of foci. CONCLUSIONS: SG2000 displayed potent activity in vitro against canine cancer cell lines as a result of the formation and persistence of DNA ICLs. SG2000 also had significant in vivo antitumour activity against canine melanoma xenografts, and the comet and γ-H2AX foci methods were relevant pharmacodynamic assays. The clinical testing of SG2000 against spontaneous canine cancer is warranted. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12917-015-0534-2) contains supplementary material, which is available to authorized users

Skin Lesion Analyser: An Efficient Seven-Way Multi-Class Skin Cancer Classification Using MobileNet

Skin cancer, a major form of cancer, is a critical public health problem with 123,000 newly diagnosed melanoma cases and between 2 and 3 million non-melanoma cases worldwide each year. The leading cause of skin cancer is high exposure of skin cells to UV radiation, which can damage the DNA inside skin cells leading to uncontrolled growth of skin cells. Skin cancer is primarily diagnosed visually employing clinical screening, a biopsy, dermoscopic analysis, and histopathological examination. It has been demonstrated that the dermoscopic analysis in the hands of inexperienced dermatologists may cause a reduction in diagnostic accuracy. Early detection and screening of skin cancer have the potential to reduce mortality and morbidity. Previous studies have shown Deep Learning ability to perform better than human experts in several visual recognition tasks. In this paper, we propose an efficient seven-way automated multi-class skin cancer classification system having performance comparable with expert dermatologists. We used a pretrained MobileNet model to train over HAM10000 dataset using transfer learning. The model classifies skin lesion image with a categorical accuracy of 83.1 percent, top2 accuracy of 91.36 percent and top3 accuracy of 95.34 percent. The weighted average of precision, recall, and f1-score were found to be 0.89, 0.83, and 0.83 respectively. The model has been deployed as a web application for public use at (https://saketchaturvedi.github.io). This fast, expansible method holds the potential for substantial clinical impact, including broadening the scope of primary care practice and augmenting clinical decision-making for dermatology specialists.Comment: This is a pre-copyedited version of a contribution published in Advances in Intelligent Systems and Computing, Hassanien A., Bhatnagar R., Darwish A. (eds) published by Chaturvedi S.S., Gupta K., Prasad P.S. The definitive authentication version is available online via https://doi.org/10.1007/978-981-15-3383-9_1

The depression in visual impairment trial (DEPVIT): trial design and protocol

<b>Background</b> The prevalence of depression in people with a visual disability is high but screening for depression and referral for treatment is not yet an integral part of visual rehabilitation service provision. One reason for this may be that there is no good evidence about the effectiveness of treatments in this patient group. This study is the first to evaluate the effect of depression treatments on people with a visual impairment and co morbid depression.<p></p> <b>Methods/design</b> The study is an exploratory, multicentre, individually randomised waiting list controlled trial. Participants will be randomised to receive Problem Solving Therapy (PST), a ‘referral to the GP’ requesting treatment according to the NICE’s ‘stepped care’ recommendations or the waiting list arm of the trial. The primary outcome measure is change (from randomisation) in depressive symptoms as measured by the Beck’s Depression Inventory (BDI-II) at 6 months. Secondary outcomes include change in depressive symptoms at 3 months, change in visual function as measured with the near vision subscale of the VFQ-48 and 7 item NEI-VFQ at 3 and 6 months, change in generic health related quality of life (EQ5D), the costs associated with PST, estimates of incremental cost effectiveness, and recruitment rate estimation.<p></p> <b>Discussion</b> Depression is prevalent in people with disabling visual impairment. This exploratory study will establish depression screening and referral for treatment in visual rehabilitation clinics in the UK. It will be the first to explore the efficacy of PST and the effectiveness of NICE’s ‘stepped care’ approach to the treatment of depression in people with a visual impairment.<p></p&gt

Nanotoxicology: characterizing the scientific literature, 2000–2007

Understanding the toxicity of nanomaterials and nano-enabled products is important for human and environmental health and safety as well as public acceptance. Assessing the state of knowledge about nanotoxicology is an important step in promoting comprehensive understanding of the health and environmental implications of these new materials. To this end, we employed bibliometric techniques to characterize the prevalence and distribution of the current scientific literature. We found that the nano-toxicological literature is dispersed across a range of disciplines and sub-fields; focused on in vitro testing; often does not specify an exposure pathway; and tends to emphasize acute toxicity and mortality rather than chronic exposure and morbidity. Finally, there is very little research on consumer products, particularly on their environmental fate, and most research is on the toxicity of basic nanomaterials. The implications for toxicologists, regulators and social scientists studying nanotechnology and society are discussed

Correlation functions quantify super-resolution images and estimate apparent clustering due to over-counting

We present an analytical method to quantify clustering in super-resolution localization images of static surfaces in two dimensions. The method also describes how over-counting of labeled molecules contributes to apparent self-clustering and how the effective lateral resolution of an image can be determined. This treatment applies to clustering of proteins and lipids in membranes, where there is significant interest in using super-resolution localization techniques to probe membrane heterogeneity. When images are quantified using pair correlation functions, the magnitude of apparent clustering due to over-counting will vary inversely with the surface density of labeled molecules and does not depend on the number of times an average molecule is counted. Over-counting does not yield apparent co-clustering in double label experiments when pair cross-correlation functions are measured. We apply our analytical method to quantify the distribution of the IgE receptor (Fc{\epsilon}RI) on the plasma membranes of chemically fixed RBL-2H3 mast cells from images acquired using stochastic optical reconstruction microscopy (STORM) and scanning electron microscopy (SEM). We find that apparent clustering of labeled IgE bound to Fc{\epsilon}RI detected with both methods arises from over-counting of individual complexes. Thus our results indicate that these receptors are randomly distributed within the resolution and sensitivity limits of these experiments.Comment: 22 pages, 5 figure

High-level production of animal-free recombinant transferrin from saccharomyces cerevisiae

<p>Abstract</p> <p>Background</p> <p>Animal-free recombinant proteins provide a safe and effective alternative to tissue or serum-derived products for both therapeutic and biomanufacturing applications. While recombinant insulin and albumin already exist to replace their human counterparts in cell culture media, until recently there has been no equivalent for serum transferrin.</p> <p>Results</p> <p>The first microbial system for the high-level secretion of a recombinant transferrin (rTf) has been developed from <it>Saccharomyces cerevisiae </it>strains originally engineered for the commercial production of recombinant human albumin (Novozymes' Recombumin^®USP-NF) and albumin fusion proteins (Novozymes' albufuse^®). A full-length non-N-linked glycosylated rTf was secreted at levels around ten-fold higher than from commonly used laboratory strains. Modification of the yeast 2 μm-based expression vector to allow overexpression of the ER chaperone, protein disulphide isomerase, further increased the secretion of rTf approximately twelve-fold in high cell density fermentation. The rTf produced was functionally equivalent to plasma-derived transferrin.</p> <p>Conclusions</p> <p>A <it>Saccharomyces cerevisiae </it>expression system has enabled the cGMP manufacture of an animal-free rTf for industrial cell culture application without the risk of prion and viral contamination, and provides a high-quality platform for the development of transferrin-based therapeutics.</p