Παρασκευή, 24 Μαρτίου 2017

Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer

ABSTRACT

While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP-CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20-1.79, P=1.68x10−4). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92-1.18, P=0.49), 0.94 (95% CI: 0.84-1.05, P= 0.27), and 0.98 (95% CI: 0.85-1.12, P=0.75) respectively. A genetic risk score for 3-hydoxy-3-methylglutaryl-coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR=0.69, 95% CI: 0.49-0.99, P=0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia. This article is protected by copyright. All rights reserved.



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Neuromedin U alters bioenergetics and expands the cancer stem cell phenotype in HER2-positive breast cancer

Abstract

Neuromedin U (NmU) is a neuropeptide belonging to the neuromedin family. Recently, we reported a significant association between NmU and breast cancer, particularly correlating with increased aggressiveness, resistance to HER2-targeted therapies and overall significantly poorer outcome for patients, although the mechanism through which it exerts this effect remained unexplained. Investigating this, here we found that ectopic over-expression of NmU in HER2-positive breast cancer cells induced aberrant metabolism, with increased glycolysis, likely due to enhanced pyruvate dehydrogenase kinase activity. Similar results were observed in HER2-targeted drug-resistant cell variants, which we had previously shown to display increased levels of NmU. Overexpression of NmU also resulted in upregulation of epithelial-mesenchymal transition markers and increased IL-6 secretion which, together with aberrant metabolism, have all been associated with the cancer stem cell (CSC) phenotype. Flow cytometry experiments confirmed that NmU-overexpressing and HER2-targeted drug-resistant cells showed an increased proportion of cells with CSC phenotype (CD44+/CD24-). Taken together, our results report a new mechanism of action for NmU in HER2-overexpressing breast cancer that enhances resistance to HER2-targeted drugs through conferring CSC characteristics and expansion of the CSC phenotype. This article is protected by copyright. All rights reserved.



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Osteosarcoma of the larynx: treatment outcomes and patterns of failure analysis

The incidence of laryngeal sarcoma is exceedingly low with osteosarcomas of the larynx being rarer still, comprising less than 1% of all associated malignancies. To date, only 32 cases have been reported since this pathologic entity was first described in 1942. In this article, we discuss the most recent case of laryngeal osteosarcoma in a patient presenting with respiratory distress found to be due to a tumor mass arising from her cricoid cartilage. We further summarize current knowledge regarding the epidemiology, presentation, and diagnosis of this uncommon disease. Lastly, we synthesize all available information regarding treatment and outcomes of the 32 previously described cases of osteosarcoma of the larynx as well as the presently described case in an attempt to offer some insight regarding optimal treatment in future cases.

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Adamantinoma arising in the distal end of the fibula

Adamantinoma is a rare, low-grade, malignant bone tumor. It frequently occurs in the tibia but rarely arise in the distal end of the fibula. This study reported a case of adamantinoma arising in the distal end of the fibula, resulting in good prognosis. A 38-year old female felt left ankle pain, and was suspected as having a bone tumor at the distal end of the fibula by X-ray. She was diagnosed as the classical adamantinoma of the fibula by open biopsy. En bloc wide resection of the tumor, primary arthrodesis of the ankle was performed. During the follow- up period of 7 years after the surgery, she has lived without any metastasis and local recurrence. A wide resection and arthrodesis of the ankle joint can provide a good outcome for adamantinoma arising in the end of the fibula.

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Renal cancer in recipients of kidney transplant

The aim of our study is to determine characteristics and outcomes of kidney cancer in renal transplant recipients. MEDLINE ® database was searched in June 2015 to identify cases of kidney cancer in renal transplant recipients. We include also a new case. Descriptive statistics were used for analysis. Forty-eight (48) recipients reported in 25 papers met the eligibility criteria. The median age was 47 years (range 9-66); 27% were females. Chronic glomerulonephritis, cystic kidney disease and hypertension were common indications for renal transplant. Among donors 24% were females and the median age was 52.5 years (17- 73); 62% of kidney cancers were donor-derived. The median interval between transplant and cancer diagnosis was shorter for cancer of recipient versus donor origin (150 vs. 210 days). Clear cell carcinoma was diagnosed in 17%. 25% had metastasis at diagnosis. Kidney explantation or excision was done in 90% and 84% of cases with and without metastasis respectively. The median survival was 72 months. Actuarial 1-year and 5-year survival rates were 73.4% and 55.1% respectively. Among the recipients from 7 donors who subsequently developed malignancy, 57% were dead within a year. Kidney transplant recipients have a small risk of kidney cancer, which affects younger patients and occurs within a year of transplant, likely due to immunosuppression. Whether the use of older donors may increase the likelihood needs further investigation. The presence of metastasis, explantation or excision of affected kidney and development of cancer in donors predict outcomes. The results may guide patient education and informed decision-making.

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Effects of short-term hyperoxia on erythropoietin levels and microcirculation in critically Ill patients: a prospective observational pilot study

The normobaric oxygen paradox states that a short exposure to normobaric hyperoxia followed by rapid return to normoxia creates a condition of ‘relative hypoxia’ which stimulates erythropoietin (EPO) productio...

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Response to letter entitled: Distinct metastatic patterns in colorectal cancer patients

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Publication date: May 2017
Source:European Journal of Cancer, Volume 77
Author(s): Julian Walter Holch, Volker Heinemann




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Development and validation of a condition-specific diary to measure severity, bothersomeness and impact on daily activities for patients with acute urinary tract infection in primary care

Urinary tract infection (UTI) is a common condition in primary care. Patient-reported outcome measures (PROMs) are crucial in the evaluation of interventions to improve diagnosis, treatment and prognosis of UT...

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New title will be launched on J-STAGE.Etudes des lettres francaises



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The new issue is now available.Journal of Japanese Society of Biorheology

Vol.29 No.3

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The new issue is now available.Japanese Journal of Cognitive Neuroscience

Vol.18 No.3+4

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The new issue is now available.BUNRUI

Vol.8 No.2

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The new issue is now available.JOURNAL of the JAPAN RESEARCH ASSOCIATION for TEXTILE END-USES

Vol.58 No.3

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The new issue is now available.Trends in Glycoscience and Glycotechnology

Vol.29 No.166

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The new issue is now available.Transactions of the JSME (in Japanese)

Vol.83 No.847

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The new issue is now available.BUNRUI

Vol.9 No.1

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The new issue is now available.BUNRUI

Vol.9 No.2

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The new issue is now available.Journal of Animal Clinical Medicine

Vol.25 No.1

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The new issue is now available.MATERIALS TRANSACTIONS

Vol.58 No.4

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The new issue is now available.BUNRUI

Vol.15 No.2

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The new issue is now available.BUNRUI

Vol.5 No.1

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The new issue is now available.Bulletin of the Japan Society for Industrial and Applied Mathematics

Vol.26 No.4

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The new issue is now available.BUNRUI

Vol.3 No.1

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The new issue is now available.BUNRUI

Vol.1 No.1-2

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The new issue is now available.BUNRUI

Vol.7 No.1

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The new issue is now available.BUNRUI

Vol.10 No.1

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The new issue is now available.BUNRUI

Vol.2 No.1

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The new issue is now available.BUNRUI

Vol.10 No.2

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Importance of stress-response genes to the survival of airborne Escherichia coli under different levels of relative humidity

Other than the needs for infection control to investigate the survival and inactivation of airborne bacterial pathogens, there has been a growing interest in exploring bacterial communities in the air and the ...

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Expressing anti-HIV VRC01 antibody using the murine IgG1 secretion signal in Pichia pastoris

The use of the recombinant expression platform Pichia pastoris to produce pharmaceutically important proteins has been investigated over the past 30 years. Compared to mammalian cultures, expression in P. pastori...

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Atomistic Insights into Nucleation and Formation of Hexagonal Boron Nitride on Nickel from First-Principles-Based Reactive Molecular Dynamics Simulations

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.6b06736
ancac3?d=yIl2AUoC8zA


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Monodispersed Carbon-Coated Cubic NiP2 Nanoparticles Anchored on Carbon Nanotubes as Ultra-Long-Life Anodes for Reversible Lithium Storage

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.6b08223
ancac3?d=yIl2AUoC8zA


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Stray supermassive black hole flung away by gravitational waves

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The Hubble Space Telescope has spotted a one-billion solar mass black hole fleeing its galaxy, showing supermassive black holes can probably merge

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Nanomolar nitric oxide concentrations quickly and reversibly modulate astrocytic energy metabolism [Bioenergetics]

Nitric oxide (NO) is an intercellular messenger involved in multiple bodily functions. Prolonged NO exposure irreversibly inhibits respiration by covalent modification of mitochondrial cytochrome oxidase, a phenomenon of pathological relevance. However, the speed and potency of NO′s metabolic effects at physiological concentrations are incompletely characterized. To this end, we set out to investigate the metabolic effects of NO in cultured astrocytes from mice by taking advantage of the high spatiotemporal resolution afforded by genetically-encoded Foerster resonance energy transfer (FRET) nanosensors. NO exposure resulted in immediate and reversible intracellular glucose depletion and lactate accumulation. Consistent with cytochrome oxidase involvement, the glycolytic effect was enhanced at a low oxygen level and became irreversible at a high NO concentration or after prolonged exposure. Measurements of both glycolytic rate and mitochondrial pyruvate consumption revealed significant effects even at nanomolar NO concentrations. We conclude that NO can modulate astrocytic energy metabolism in the short term, reversibly, and at concentrations known to be released by endothelial cells under physiological conditions. These findings suggest that NO modulates the size of the astrocytic lactate reservoir involved in neuronal fueling and signaling.

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Modifiers of prion protein biogenesis and recycling identified by a highly-parallel endocytosis kinetics assay [Neurobiology]

The cellular prion protein, PrPC, is attached by a glycosylphosphatidylinositol anchor to the outer leaflet of the plasma membrane. Its misfolded isoform PrPSc is the causative agent of prion diseases. Conversion of PrPC into PrPSc is thought to take place at the cell surface or in endo-lysosomal organelles. Understanding the intracellular trafficking of PrPC may therefore help elucidating the conversion process. Here we describe a time-resolved fluorescence resonance energy transfer (FRET) assay reporting membrane expression and real-time internalization rates of PrPC. The assay is suitable for high-throughput genetic and pharmaceutical screens for modulators of PrPC trafficking. Simultaneous administration of FRET donor and acceptor anti-PrPC antibodies to living cells yielded a measure of PrPC surface density, whereas sequential addition of each antibody visualized the internalization rate of PrPC (Z'-factor > 0.5). RNA interference assays showed that suppression of AP2M1, RAB5A, VPS35 and M6PR blocked PrPC internalization, whereas downregulation of GIT2 and VPS28 increased it. PrPC cell surface expression was reduced by downregulation of RAB5A, VPS28 and VPS35, and enhanced by silencing EHD1. These data identify a network of proteins implicated in PrPC trafficking, and demonstrates the power of this assay for identifying modulators of PrPC trafficking.

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Phospholipase C-related, but catalytically inactive protein (PRIP) upregulates osteoclast differentiation via calcium-calcineurin-NFATc1 signaling [Signal Transduction]

Phospholipase C-related, but catalytically inactive protein (PRIP) was previously identified as a novel inositol 1,4,5-trisphosphate-binding protein with a domain organization similar to that of phospholipase C-δ, but lacking phospholipase activity. We recently showed that PRIP gene knockout (KO) in mice increases bone formation and concomitantly decreases bone resorption, resulting in increased bone mineral density and trabecular bone volume. However, the role of PRIP in osteoclastogenesis has not yet been fully elucidated. Here, we investigated the effects of PRIP on bone remodeling by investigating dynamic tooth movement in mice fitted with orthodontic devices. Morphological analysis indicated that the extent of tooth movement was smaller in the PRIP-KO mice than in wild-type mice. Histological analysis revealed fewer osteoclasts on the bone-resorption side in maxillary bones of PRIP-KO mice, and osteoclast formation assays and flow cytometry indicated lower osteoclast differentiation in bone marrow cells isolated from these mice. The expression of genes implicated in bone resorption was lower in differentiated PRIP-KO cells, and genes involved in osteoclast differentiation, such as the transcription factor NFATc1, exhibited lower expression in immature PRIP-KO cells initiated by M-CSF. Moreover, calcineurin expression and activity were also lower in the PRIP-KO cells. The PRIP-KO cells also displayed fewer M-CSF-induced changes in intracellular Ca2+ and exhibited reduced nuclear localization of NFATc1. Up-regulation of intracellular Ca2+ restored osteoclastogenesis of the PRIP-KO cells. These results indicate that PRIP deficiency impairs osteoclast differentiation, particularly at the early stages and that PRIP stimulates osteoclast differentiation through calcium-calcineurin-NFATc1 signaling via regulating intracellular Ca2+.

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Stray supermassive black hole flung away by gravitational waves

The Hubble Space Telescope has spotted a one-billion solar mass black hole fleeing its galaxy, showing supermassive black holes can probably merge

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Virtual lemonade sends colour and taste to a glass of water

A tumbler that makes water look and taste like lemonade using LED lights and electrodes could allow people to share drinks on social media

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Monitoring cell surface N-glycoproteome dynamics by quantitative proteomics reveals mechanistic insights into macrophage differentiation [Research]

The plasma membrane proteome plays a crucial role in inter- and intracellular signaling, cell survival and cell identity. As such it is a prominent target for pharmacological intervention. The relatively low abundance of this subproteome in conjunction with challenging extractability and solubility still hampers their comprehensive analysis. Here, we combined a chemical glycoprotein tagging strategy with mass spectrometry to enable comprehensive analysis of the cell surface glycoprotome. To benchmark this workflow and provide guidance for cell line selection for functional experiments, we generated an inventory of the N-linked cell surface glycoproteome of 15 standard laboratory human cell lines and three primary lymphocytic cell types. On average about 900 plasma membrane and secreted proteins were identified per experiment including more than 300 transporters and ion channels. Primary cells displayed distinct expression of surface markers and transporters underpinning the importance of carefully validating model cell lines selected for the study of cell surface-mediated processes. To monitor dynamic changes of the cell surface proteome in a highly multiplexed experiment, we employed an isobaric mass tag-based chemical labeling strategy. This enabled the time-resolved analysis of plasma membrane protein presentation during differentiation of the monocytic suspension cell line THP1 into macrophage-like adherent cells. Time-dependent changes observed in membrane protein presentation reflect functional remodeling during the phenotypic transition in three distinct phases: rapid surface presentation and secretion of proteins from intracellular pools concurrent with rapid internalization of no longer needed proteins and finally delayed presentation of newly synthesized macrophage markers. Perturbation of this process using marketed receptor tyrosine kinase inhibitors revealed dasatinib to severely compromise macrophage differentiation due to an off-target activity. This finding suggests that dynamic processes can be highly vulnerable to drug treatment and should be monitored more rigorously to identify adverse drug effects.



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Virtual lemonade sends colour and taste to a glass of water

rexfeatures_5846169a.jpg

A tumbler that makes water look and taste like lemonade using LED lights and electrodes could allow people to share drinks on social media

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Correction: The TIR Homologue Lies near Resistance Genes in Staphylococcus aureus, Coupling Modulation of Virulence and Antimicrobial Susceptibility

by Sabine Patot, Paul R. C. Imbert, Jessica Baude, Patricia Martins Simões, Jean-Baptiste Campergue, Arthur Louche, Reindert Nijland, Michèle Bès, Anne Tristan, Frédéric Laurent, Adrien Fischer, Jacques Schrenzel, François Vandenesch, Suzana P. Salcedo, Patrice François, Gérard Lina



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You can earn EACCME points upon successful completion of our @siog #elearning modules: https://t.co/WzhE3KcT2C https://t.co/gpXlw4bwtq

You can earn EACCME points upon successful completion of our @siog #elearning modules: https://t.co/WzhE3KcT2C https://t.co/gpXlw4bwtq

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PET agent wins positive CHMP opinion

Molecular imaging diagnostics firm Blue Earth Diagnostics said it has received...


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Analogic to launch MR-ultrasound prostate biopsy software

Analogic plans to launch new MR fusion prostate biopsy software for ultrasound...


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Authors’ reply to Farrar

Farrar questions the finding of our systematic review—that low intensity pulsed ultrasound (LIPUS) was not effective12—based on two hypotheses. Firstly, that despite being ineffective in fresh...
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Compliance affects success of ultrasound for bone healing

I regularly use pulsed ultrasound to treat non-union of fractures and have observed excellent outcomes, with success rates of 90%-100%.1 I have made considerable cost savings for my trust by avoiding...
recent?d=yIl2AUoC8zA recent?d=dnMXMwOfBR0 recent?i=S8EEoiSHuPI:uBoMEQHE_9M:V_sGLiP recent?d=qj6IDK7rITs recent?i=S8EEoiSHuPI:uBoMEQHE_9M:gIN9vFw recent?d=l6gmwiTKsz0 recent?d=7Q72WNTAKBA recent?i=S8EEoiSHuPI:uBoMEQHE_9M:F7zBnMy recent?i=S8EEoiSHuPI:uBoMEQHE_9M:-BTjWOF


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Indian doctors take to streets to demand better security

Nearly 40 000 doctors in Delhi and Mumbai have gone on strike to demand better security in government hospitals throughout India after a spate of attacks on medical professionals. If the government...
recent?d=yIl2AUoC8zA recent?d=dnMXMwOfBR0 recent?i=IMyjOq95IFw:os8ZAluwxo0:V_sGLiP recent?d=qj6IDK7rITs recent?i=IMyjOq95IFw:os8ZAluwxo0:gIN9vFw recent?d=l6gmwiTKsz0 recent?d=7Q72WNTAKBA recent?i=IMyjOq95IFw:os8ZAluwxo0:F7zBnMy recent?i=IMyjOq95IFw:os8ZAluwxo0:-BTjWOF


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Abortion care in Canada is decided between a woman and her doctor, without recourse to criminal law

As the UK debates decriminalisation of abortion and people wonder about the effects it might have,1 it may be useful to consider the Canadian experience of nearly 30 years without a criminal law to...
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