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Τρίτη, 25 Απριλίου 2017

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Waist measurement, not BMI, is stronger predictor of death risk, study finds

People with a normal body mass index (BMI) but a large waist circumference have worse long term survival than people who are overweight or obese but who do not carry their weight around the middle, a...
recent?d=yIl2AUoC8zA recent?d=dnMXMwOfBR0 recent?i=e47LQe1tHdM:BVmcWgzEjrQ:V_sGLiP recent?d=qj6IDK7rITs recent?i=e47LQe1tHdM:BVmcWgzEjrQ:gIN9vFw recent?d=l6gmwiTKsz0 recent?d=7Q72WNTAKBA recent?i=e47LQe1tHdM:BVmcWgzEjrQ:F7zBnMy recent?i=e47LQe1tHdM:BVmcWgzEjrQ:-BTjWOF


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Women having surgery for abdominal aortic aneurysm are nearly twice as likely to die as men

Women undergoing surgery for abdominal aortic aneurysm have nearly twice the 30 day mortality of men, a systematic review has found.1Results also showed that fewer women were considered for...
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Anti-allergic and anti-inflammatory activity of Phellinus linteus grown on Panax ginseng

Abstract

Panax ginseng (PG) or Phellinus linteus (PL) have been widely used as traditional medicine owing to their many biological activities, including anti-inflammatory and anti-allergic activities. Previously, our group produced PL that was grown on PG media (PGP) to enhance anti-cancer activities of PGP. Here we studied the anti-allergic activity of PGP and its mechanism of action. The ethyl acetate fraction of PGP exhibited the anti-allergic activity by suppressing β-hexosaminidase release, a marker of degranulation, from antigen/immunoglobulin E (IgE)-stimulated RBL-2H3 cells. Exposure to PGP inhibited the level of antigen/IgE-induced TNF-alpha in RBL-2H3 cells. It markedly suppressed the phosphorylation of spleen associated tyrosine kinase, GRB2-associated-binding protein 2 (Gab2) and extracellular signal-regulated kinases proteins, which are required for the degranulation and production of pro-inflammatory cytokines. Its anti-inflammatory activity was observed in lipopolysaccharide-stimulated RAW 264.7 cells. In addition, PGP contained higher contents of Rg1 than PG. Our findings suggest that PGP might be developed as a therapeutic agent for IgE-mediated allergic diseases.



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Comparison of trans-fatty acids on proliferation and migration of vascular smooth muscle cells

Abstract

Consumption of trans-fatty acids has been linked to an increased risk of cardiovascular diseases, such as atherosclerosis. Milk and dairy products contain trans-fatty acids, such as transvaccenic acid (TVA) and conjugated linoleic acid (CLA). Although artificially hydrogenated trans-fatty acids (e.g., elaidic acid (EA)) are known to induce atherosclerosis, it is unclear whether ruminant trans-fats, such as TVA, are associated with such diseases. Therefore, we investigated the effects of TVA on vascular smooth muscle cells (VSMCs). VSMCs were treated with TVA, CLA, and EA at 0-100 μM for 24 h. Cell proliferation and migration increased upon treatment with EA, not with TVA and CLA. EA increased protein expression of proliferation-associated proteins (cyclin-dependent kinase 4 (CDK4) and cyclin D1), while TVA and CLA decreased CDK4 expression. These results suggest that TVA is not as risky as other trans-fatty acids such as EA in the vascular system.



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Caulerpa lentillifera inhibits protein-tyrosine phosphatase 1B and protects pancreatic beta cell via its insulin mimetic effect

Abstract

The aim of this study was to determine whether Caulerpa lentillifea extract (CLE) can protect pancreatic beta cells and enhance insulin signaling in adipocytes. We measured the protein tyrosine phosphatase (PTP)-1B inhibitory effect of CLE using an in-vitro enzyme assay. Proteins involved in the pancreatic beta-cell death and insulin signaling were measured by western blotting. Oil-red O staining was used to measure the insulin mimetic effect of CLE. CLE strongly inhibited the PTP1B enzyme. In rat insulinoma (RIN)-m5F cells, CLE decreased the activation of extracellular regulated kinase (ERK)-1/2, P38 mitogen activated protein kinase (P38), c-Jun NH2-terminal kinase (JNK), and nuclear factor kappa-light-chain-enhancer of the activated B cells (NF-κB). Furthermore, CLE showed insulin-mimetic effect and enhanced the activation of insulin-signaling molecules including IRS, AKT, PI3K, and GSK-3β in 3T3-L1 adipocytes. Our results suggested that CLE-inhibited PTP1B, protected the pancreatic beta cells, and enhanced insulin sensitization in the adipocytes.



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Fucosterol inhibits adipogenesis through the activation of AMPK and Wnt/β-catenin signaling pathways

Abstract

Fucosterol is a sterol constituent primarily derived from brown algae. Recently, the antiadipogenic effect of fucosterol has been reported; however, its molecular mechanism remains to be studied. Fucosterol effectively upregulated the phosphorylations of both adenosine monophosphate (AMP)-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), and downregulated the expression levels of lipogenesis-related factors. Moreover, fucosterol activated the major components of the Wnt/β-catenin signaling pathway, including β-catenin, disheveled 2 (DVL2), and cyclin D1 (CCND1), whereas it inactivated glycogen synthase kinase 3β (p-GSK3β) by stimulating its phosphorylation. In the presence or absence of fucosterol, the adipogenic transcriptional factors [peroxisome proliferator activated-receptor γ (PPARγ), CCAAT/enhancer binding protein α (C/EBPα), and sterol regulatory element binding protein-1c (SREBP-1c)] were upregulated by the inhibition of AMPK by compound C or the knockdown of β-catenin by siRNA. Overall, these data demonstrate that fucosterol prevents adipogenesis by mediating both AMPK- and Wnt/β-catenin-signaling pathways.



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Characterization of red ginseng residue protein films incorporated with hibiscus extract

Abstract

An edible film was prepared from red ginseng residue protein (RGRP) and incorporated with hibiscus extract (HE). RGRP was extracted from red ginseng residue, which is an inexpensive by-product of the red ginseng processing industry. Different concentrations of HE were added to an RGRP film-forming solution as a natural antioxidant. The prepared RGRP films without HE had a tensile strength of 16.9 MPa and an elongation at break of 25.1%. The antioxidant activity of the RGRP film increased with increasing concentration of HE. In addition, the RGRP film with 1% HE exhibited the lowest value of water vapor permeability (1.88×10−9 g·m/m2·s·Pa), which indicates that the film has high water barrier property. The results present the production of edible films from discarded red ginseng residue, and the antioxidant activity of RGRP films as a packaging material can prevent lipid oxidation and quality loss of food products.



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Multivariate analysis to discriminate the origin of sesame seeds by multi-element analysis inductively coupled plasma-mass spectrometry

Abstract

In this study, inductively coupled plasma-mass spectrometry (ICP-MS) was used to determine the concentration of 15 elements (Mg, Al, K, Ca, Cr, Mn, Co, Ni, Cu, Zn, Rb, Sr, Cd, Ba, and Pb) of sesame seeds. Multivariate analysis was then performed to discriminate the origin of sesame seeds. Korean (48), Chinese (44), and Indian (21) samples were used to develop the calibration model. Another 10 samples were used to validate this model. All elements were significantly different (p<0.05) among the samples from three countries, and all elements were subjected to both principal component analysis (PCA) and discriminant analysis. The concentrations of multi-element showed a trend of clustering according to the origin of samples based on PCA. They showed a discrimination rate of 92.0% in the discriminant analysis. The results demonstrated that a combination of ICP-MS multi-element determination and multivariate analysis could be used to discriminate the sesame seed origin.



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Prevalence and toxin type of Clostridium perfringens in beef from four different types of meat markets in Seoul, Korea

Abstract

Beef is the primary source of foodborne poisoning caused by Clostridium perfringens. We investigated the prevalence of C. perfringens in retail beef from four different types of meat markets in Seoul using a standard culture method and real-time PCR assay. From June to September 2015, 82 beef samples were collected from 6 department stores (n=12), 14 butcher shops (n=28), 16 traditional markets (n=32), and 5 supermarkets (n=10). The culture method and real-time PCR assay revealed that 4 (4.88%) and 10 (12.20%) samples were positive for C. perfringens, respectively. The beef purchased from the department store showed the highest prevalence (16.67%), followed by the traditional market (3.12%), butcher shop (3.57%), and supermarket (0%) (p>0.05). All isolates were type A and negative for the enterotoxin gene. In conclusion, the real-time PCR assay used in this study could be useful for rapid detection and screening of C. perfringens in beef.



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Monoolein, isolated from Ishige sinicola , inhibits lipopolysaccharide-induced inflammatory response by attenuating mitogen-activated protein kinase and NF-κB pathways

Abstract

Ishige sinicola (I. sinicola) is an edible brown alga native to South Korea. In the present study, we screened the anti-inflammatory activity of monoolein isolated from I. sinicola. Monoolein pretreatment in lipopolysaccharide (LPS)-stimulated primary murine bone marrow-derived dendritic cells (BMDCs) showed strong dose-dependent inhibition of interleukin (IL)-12 p40, IL-6, and TNF-α cytokine production with IC50 values of 1.69±0.02, 6.87±0.37, and 5.19±0.56 μM, respectively. Pretreatment of monoolein attenuated the activation of MAPK and NF-κB pathways in the LPS-stimulated BMDCs by inhibiting the phosphorylation of p38, ERK1/2, JNK1/2, and IκBα. Furthermore, monoolein inhibited the production of NO and iNOS in RAW264.7 cells. Overall, our findings indicate that monoolein has a significant anti-inflammatory activity, and further studies regarding the potential of monoolein for medicinal use is warranted.



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Phytochemical, antioxidant, and antibacterial activities of fermented Citrus unshiu byproduct

Abstract

Citrus unshiu is an economically important fruit on Jeju Island, Korea, but byproducts are a major source of agricultural waste. The aim of this study is to examine changes in phytochemical, antioxidant, and antibacterial activities of four C. unshiu byproducts: citrus flesh byproduct (CFB), fermented citrus flesh byproduct (FCFB), citrus peel byproduct (CPB), and fermented citrus peel byproduct (FCPB). Fermented citrus byproducts (FCFB and FCPB) exhibited greater inhibition effect on radical scavenging abilities of 2,2-diphenyl-1-picrylhtdrazyl, 2,2’-azinobis(3-ethylbenzothiazolin-6-sulfonic acid)-diammonium salt, and superoxide anion compared with those of CFB and CPB. Total polyphenol contents of FCFB and FCPB were significantly increased compared to those of CFB and CPB. Significant bioconversion of the flavonoid glucosides into corresponding bioactive aglycones during citrus byproduct fermentation was observed. Fermented citrus byproducts exhibited antibacterial activity against Listeria monocytogenes and Escherichia coli suggesting that FCFB and FCPB are potent antioxidant and antibacterial sources due to the remarkable contents of bioactive compounds in them.



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An analysis method for determining residual hexane in health functional food products using static headspace gas chromatography

Abstract

A method for analyzing the contents of residual hexane in health functional food products was developed. The dissolving solvents in the health functional food products and the internal standard selected were N,N-dimethylacetamide and heptane, respectively. The analysis conditions for headspace-gas chromatography/flame ionization detection (HS-GC/FID) and headspace-gas chromatography/mass spectrometry (HS-GC/MS) were determined as 18 mL of headspace volume, 100°C of headspace oven temperature, and 30 min of equilibration time; a Durabond (DB)-624 column was selected for this analysis. To validate this method, which applies N,N-dimethylacetamide as a dissolving solvent, the limit of detection and limit of quantification (LOQ) values based on the HS-GC/FID and HS-GC/MS analyses results were found to be 0.10, 0.29 and 0.16, 0.47 mg/L, respectively. The recoveries and coefficient of variation (CV) obtained by HS-GC/MS were 96.39–119.86% and 0.04–1.25%, respectively, better than those obtained by HS-GC/FID. By applying the HS-GC/MS method, it was possible to analyze the content of the residual hexane in 60 different types of health functional food products.



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Effects of ozone treatment on physicochemical properties of Korean wheat flour

Abstract

The objective of this study was to investigate the effects of ozone treatment on the physicochemical properties of Korean wheat flour. Wheat flour samples were treated with ozone gas at 120 ppm for 15, 30, 45, and 60 min. Color b value, pH, and mold of flour decreased as exposure time to ozone increased. The water absorption index, peak viscosity, and final viscosity of flour increased by ozone treatment. Photomicrographs of flour suspensions under polarized light showed granules tended to lose birefringence owing to ozone during swelling. The result of SDS-PAGE showed that the intensity of protein bands at low molecular weights slightly increased in ozone-treated flours compared to the intensity in the control flour. The results of this study showed ozone gas affected the starch and protein of wheat flour, suggesting a need for further investigation on structural changes in starch and protein by ozone.



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Changes in antioxidant activities and volatile compounds of mixed berry juice through fermentation by lactic acid bacteria

Abstract

The objectives of this study were to analyze antioxidant activities and identify volatile compounds in mixed berry juice after fermentation by lactic acid bacteria (LAB). Antioxidant activity of the mixed berry juice increased significantly from 209.57±2.93 to 268.30±1.75 μmol TE/g after 24 h of fermentation. After LAB fermentation, 34 volatile compounds were identified. Among them, three compounds—benzoic acid, benzaldehyde, and vitispirane—showed significant changes in their concentrations. Peak areas of benzoic acid and benzaldehyde, which are known to possess antioxidant activities, increased by 64 and 188%, respectively, after fermentation. However, the peak area of vitispirane, which is the most abundant terpene compound in berry juices, decreased by 92% after fermentation.



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Development of a quantitative method for organic acid in wine and beer using high performance liquid chromatography

Abstract

This study was conducted to compare the organic acid content in liquors (red wine, white wine, and beer) using three different high-performance liquid chromatography analysis methods. Post-column reaction methods (method 2 and 3) were found to be more promising than UV-detection method (method 1). Using method 2 (two columns), the analyzed red wine was found to contain 2,652.4 mg/L tartaric acid and 1,392.9 mg/L lactic acid but relatively lower amounts of malic acid (271.0 mg/L). Furthermore, tartaric acid (1,160.8–2,749.1 mg/L) and malic acid (470.2–3,107.9 mg/L) were the major components in white wine. Beers were analyzed using method 3 (one column). In the analyzed foreign beers, lactic acid (95.9–226.4 mg/L), malic acid (62.2–110.5 mg/L), acetic acid (93.5–183.8 mg/L), and succinic acid (37.0–56.2 mg/L) were detected. Similar to the foreign beers, the contents of succinic acid in the domestic beers were the lowest. The proposed methods could be useful for quantitative analysis of organic acids in wine and beer.



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Effect of blanching time on the quality characteristics of elderly-friendly kkakdugi

Abstract

For the development of elderly-friendly food, the physicochemical properties and preferences of cooked kkakdugi prepared with various blanching times were examined. As fermentation progressed, significant differences in samples were observed with overall decreasing trends of pH, reducing sugar, lightness (L), yellowness (b), and hardness. Titratable acidity, redness (a), and lactic acid increased during the storage time. The preference test showed that the sample blanched for 3 min (SK3) scored the highest in aroma, taste, texture, and overall acceptance. Overall, SK3 was the most preferred as cooked kkakdugi, which helps elderly people suffering from mastication and deglutition.



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Inhibitory effect of Zizania latifolia chloroform fraction on allergy-related mediator production in RBL-2H3 cells

Abstract

Zizania latifolia exhibits anti-inflammatory and anti-allergic effects; however, the mechanisms behind these effects are unknown. Here the ethanol extract of Z. latifolia was partitioned using hexane, chloroform, ethyl acetate, butanol, and water. Subsequently, the anti-allergic effects of these fractions were evaluated in vitro. The results showed that the chloroform fraction of Z. latifolia inhibited the release of β-hexosaminidase and tumor necrosis factor (TNF-α) from RBL-2H3 cells stimulated with dinitrophenyl-bovine serum albumin (DNP-BSA). In addition, this fraction suppressed the expression of cyclooxygenase-2 (COX-2) and inhibited the activation of mitogen-activated protein kinases (MAPKs). The results obtained suggest that the chloroform fraction of Z. latifolia inhibited mast cell-mediated allergic inflammatory responses.



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Analysis of ethanol in soy sauce using electronic nose for halal food certification

Abstract

The purpose of this study was to analyze ethanol content in soy sauce using mass spectrometry (MS) with electronic nose (e-nose) to determine if MS e-nose can replace gas chromatographic analysis for halal certification. Gas chromatography–flame ionization detector (GC-FID), the standard method of ethanol content, was used to analyze 24 different kinds of soy sauce. Ethanol was detected from 13 soy sauce samples in the concentration range of 0.0004–1.7wt%. The MS e-nose data were analyzed by discriminant function analysis (DFA). Based on an addition method, the results were more than 96.6% accurate when the ethanol concentrations were greater than 0.5%. A high correlation between the first score of the DFA plot and the ethanol concentration was observed. Thus, mass spectrometry based on e-nose is an efficient method for determining ethanol as a primary screening tool for halal certification.



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Effect of plant polyphenols on the formation of advanced glycation end products from β-lactoglobulin

Abstract

Dietary exposure to advanced glycation end products (AGEs) formed from proteins and reducing sugars is of increasing concern to human health. AGEs may form in protein-based powders containing sugars for instant beverages during drying and storage of the product. Chlorogenic acid, a plant phenol characteristic of coffee, was found to protect against the formation of AGEs at a concentration of 50mM during heating of β-lactoglobulin in the presence of glucose as a reducing sugar in 30% aqueous ethanol at 70°C. Epicatechin, a plant phenol characteristic of green tea, had no similar effect for the equivalent concentration of phenol on the formation of AGEs. Immunochemical detection (ELISA) using polyclonal antibodies raised against AGEs showed a dose-dependent effect of protection by chlorogenic acid on AGE formation and is recommended for routine quality control of sugar containing milk-based powders for instant beverages.



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Identifying the geographical origin of protected sea cucumbers ( Apostichopus japonicus ) in China using random amplified polymorphic DNA polymerase chain reaction (RAPD-PCR)

Abstract

Dalian sea cucumber, Yantai sea cucumber, and Weihai sea cucumber, which belong to Apostichopus japonicus, are protected as geographical indications in China based on their high nutritional values and medical propertys. The 26 samples, including Dalian sea cucumbers (9 samples) in Liaoning province, Yantai sea cucumbers (9 samples), and Weihai sea cucumbers (8 samples) in Shandong province, were individually collected from the designated geographical sea areas and the genetic relationships and DNA polymorphisms were evaluated by random amplified polymorphic DNA technology and gene segments sequencing. The RAPD dendrogram showed that the genetic diversity of the three types of sea cucumbers was rich. The neighbor-joining tree shows that the genetic relationship of the samples from the adjacent sea areas is closer. It demonstrates that the gene characteristics of sea cucumbers from different sea areas were obvious and the genetic diversity analysis by RAPD-PCR can be used as a rapid method for geographical discrimination.



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Effect of the precutting process on sanitizing treatments for reducing pathogens in vegetables

Abstract

The effectiveness of sanitizing treatments was investigated on reducing pathogens inoculated in whole or cut fresh vegetables, including Brussels sprouts, carrots, cherry tomatoes, paprika, and lettuce. These products were inoculated with Escherichia coli O157:H7, Salmonella enterica serovar Typhimurium, and Listeria monocytogenes and then treated with chlorine and alcohol sanitizers, followed by the subsequent washing procedure in sterile distilled water at 25°C for 5min. Alcohol sanitizer was the most effective in inhibiting E. coli O157:H7, S. Typhimurium, and L. monocytogenes on cut Brussels sprouts, showing bacterial reductions of 4.16, 3.60, and 3.26 log CFU/g, respectively. Interestingly, the effects of sanitizing treatments were significantly lower for fresh cut produce than those for whole products (p<0.05), indicating that the effectiveness of sanitizers would be different, depending on fresh produce and the pre-cut process. Therefore, further information should be obtained to develop an effective sanitizing treatment for fresh produce.



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Quality comparison of dried slices processed from whole persimmons treated with different deastringency methods

Abstract

The effects of different deastringency treatments (untreated, carbon dioxide, warm water, or ethanol), before drying on the quality characteristics of dried fruit slices prepared from whole “Cheongdobansi” persimmons were evaluated. L* (lightness) and a* (redness) values of dried slices from warm water- and ethanol-treated groups were higher, respectively, compared to that of dried slices from other groups. Hardness was lower in dried slices from ethanol-treated fruits. Moisture, water activity, soluble solids, titratable acidity, and sensory properties (color, aroma, texture, sweetness, and overall acceptability) of the dried slices from astringency-removed fruits were higher when compared to those of the dried slices from non-treated persimmons. In particular, the dried slices from ethanol-treated fruits showed the highest values for these parameters. Moreover, soluble tannin and DPPH radical scavenging activity decreased by deastringency treatment. Results suggest that ethanol deastringency treatment before drying could be a useful method to improve most quality characteristics, except antioxidative activity, of dried persimmon slices.



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Dyspepsia

Dyspepsia: Indigestion. A condition characterized by upper abdominal symptoms that may include pain or discomfort, bloating, feeling of fullness with very little intake of food , feeling of unusual fullness following meals, nausea, loss of appetite, heartburn, regurgitation of food or acid, and belching. The term dyspepsia is often used for these symptoms when they are not typical of a well-described disease (for example, gastrointestinal reflux) and the cause is not clear. After a cause for the symptoms has been determined, the term dyspepsia is usually dropped in favor of a more specific diagnosis.



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Immunotherapy of hepatocellular carcinoma using chimeric antigen receptors and bispecific antibodies

Publication date: 28 July 2017
Source:Cancer Letters, Volume 399
Author(s): Sayed Shahabuddin Hoseini, Nai-Kong V. Cheung
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide with an overall survival rate of less than 15% in developed countries. Despite attempts at new therapeutic strategies, the majority of patients succumb to this cancer. Buttressed by the highly successful clinical impact in melanoma, immunotherapy is gaining momentum as the next treatment modality for many human cancers. Chimeric antigen receptors (CAR) contain the antigen binding moieties of a monoclonal antibody and the co-stimulatory and signaling domains associated with effector receptor signaling. Bispecific antibodies (BsAb) combine the binding specificities of two different monoclonal antibodies, one activating a receptor on a killer effector cell, while the other engaging a tumor-associated antigen to initiate tumor cytotoxicity. In this review, we survey the HCC targets for which CARs and bispecific antibodies have been generated. The pros and cons of these targets for T-cell and Natural Killer cell based immunotherapy will be discussed.



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Natural killer cells suppress enzalutamide resistance and cell invasion in the castration resistant prostate cancer via targeting the androgen receptor splicing variant 7 (ARv7)

Publication date: 10 July 2017
Source:Cancer Letters, Volume 398
Author(s): Shin-Jen Lin, Fu-Ju Chou, Lei Li, Chang-Yi Lin, Shuyuan Yeh, Chawnshang Chang
Despite the success of androgen-deprivation therapy (ADT) with the newly developed anti-androgen enzalutamide (Enz, also known as MDV3100) to suppress castration resistant prostate cancer (CRPC) in extending patient survival by an extra 4.8 months, eventually patients die with the development of Enz resistance that may involve the induction of the androgen receptor (AR) splicing variant ARv7. Here we identify an unrecognized role of Natural Killer (NK) cells in the prostate tumor microenvironment that can be better recruited to the CRPC cells to suppress ARv7 expression resulting in suppressing the Enz resistant CRPC cell growth and invasion. Mechanism dissection revealed that CRPC cells, compared to normal prostate epithelial cells, could recruit more NK cells that might then lead to alterations of the microRNA-34 and microRNA-449 to suppress both ARv7 expression and ARv7-induced EZH2 expression to suppress CRPC cell invasion. Together, these results identify a new potential therapy using recruited NK cells to better suppress the Enz resistance and cell invasion in CRPC at the later enzalutamide resistant stage.



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IRE1α links Nck1 deficiency to attenuated PTP1B expression in HepG2 cells

Publication date: Available online 25 April 2017
Source:Cellular Signalling
Author(s): Hui Li, Bing Li, Louise Larose
PTP1B, a prototype of the non-receptor subfamily of the protein tyrosine phosphatase superfamily, plays a key role in regulating intracellular signaling from various receptor and non-receptor protein tyrosine kinases. Previously, we reported that silencing Nck1 in human hepatocellular carcinoma HepG2 cells enhances basal and growth factor-induced activation of the PI3K-Akt pathway through attenuating PTP1B expression. However, the underlying mechanism by which Nck1 depletion represses PTP1B expression remains unclear. In this study, we found that silencing Nck1 attenuates PTP1B expression in HepG2 cells through down-regulation of IRE1α. Indeed, we show that silencing Nck1 in HepG2 cells leads to decreased IRE1α expression and signaling. Accordingly, IRE1α depletion using siRNA in HepG2 cells enhances PI3K-dependent basal and growth factor-induced Akt activation, reproducing the effects of silencing Nck1 on activation of this pathway. In addition, depletion of IRE1α also leads to reduced PTP1B expression, which was rescued by ectopic expression of IRE1α in Nck1-depleted cells. Mechanistically, we found that silencing either Nck1 or IRE1α in HepG2 cells decreases PTP1B mRNA levels and stability. However, despite miR-122 levels, a miRNA targeting PTP1B 3′ UTR and inducing PTP1B mRNA degradation in HepG2 cells, are increased in both Nck1- and IRE1α-depleted HepG2 cells, a miR-122 antagomir did not rescue PTP1B expression in these cells. Overall, this study highlights an important role for Nck1 in fine-tuning IRE1α expression and signaling that regulate PTP1B expression and subsequent activation of the PI3K-Akt pathway in HepG2 cells.



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Identification of NCK1 as a novel downstream effector of STAT3 in colorectal cancer metastasis and angiogenesis

Publication date: Available online 25 April 2017
Source:Cellular Signalling
Author(s): Fan Zhang, Yan-xia Lu, Qing Chen, Hui-mei Zou, Jian-ming Zhang, Yu-han Hu, Xiao-min Li, Wen-juan Zhang, Wei Zhang, Chun Lin, Xue-nong Li
Signal transducer and activator of transcription 3 (STAT3) is known to activate targets associated with invasion, proliferation, and angiogenesis in a wide variety of cancers. The adaptor protein NCK1 is involved in cytoskeletal movement and was identified as a STAT3-associated target in human tumors. However, the underlying molecular mechanism associated with colorectal cancer (CRC) metastasis is not yet completely understood. In this study, we report a novel STAT3 to NCK1 signaling pathway in colorectal cancer (CRC). We investigated the expression of NCK1 and its potential clinical and biological significance in CRC. NCK1 was noticeably up-regulated in human CRC tissues. NCK1 was also significantly associated with serosal invasion, lymph metastasis, and tumor-node-metastasis classification but was inversely correlated with differentiation. Gain-of-function and loss-of-function studies have shown that ectopic expression of NCK1 enhanced metastasis and angiogenesis in CRC cells. By gene expression analyses, we revealed a high co-overexpression of STAT3 and NCK1 in CRC tissues. Ectopic overexpression of STAT3 in CRC cells induced the expression of NCK1, whereas STAT3 knockdown decreased the expression of NCK1. Promoter activation and binding analyses demonstrated that STAT3 promoted the expression of NCK1 via direct action on the NCK1 promoter. The knock down of NCK1 partially reduced the CRC cell metastasis and angiogenesis promoted by STAT3. Additionally, by co-immunoprecipitation assays, we verified that NCK1 interacted with PAK1, which resulted in the activation of the PAK1/ERK pathway. STAT3 induced the transcription of NCK1 and triggered a PAK1/ERK cascade in CRC. These findings suggest a novel STAT3 to NCK1 to PAK1/ERK signaling mechanism that is potentially critical for CRC metastasis and angiogenesis.



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Large differences in proportions of harmful and benign amino acid substitutions between proteins and diseases

Abstract

Genes and proteins are known to have differences in their sensitivity to alterations. Despite numerous sequencing studies, proportions of harmful and harmless substitutions are not known for proteins and groups of proteins. To address this question, we predicted the outcome for all possible single amino acid substitutions in nine representative protein groups by using the PON-P2 method. The effects on 996 proteins were studied and vast differences were noticed. Proteins in the cancer group harbour the largest proportion of harmful variants (42.1%) while the non-disease group of proteins not known to have a disease association and not involved in the housekeeping functions had the lowest number of harmful variants (4.2%). Differences in the proportions of the harmful and benign variants are wide within each group but they still show clear differences between the groups. Frequently appearing protein domains show a wide spectrum of variant frequencies, whereas no major protein structural class-specific differences were noticed. Amino acid substitution types in the original and variant residues showed distinctive patterns, which are shared by all the protein groups. The observations are relevant for understanding genetic bases of diseases, variation interpretation and for the development of methods for that purpose.

This article is protected by copyright. All rights reserved



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Commentary: Reduction Malarplasty that uses Malar Setback Without Resection of Malar Body Strip



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Peanut-free schools: What does it really mean, and are they necessary?



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Analysis of basophil activation in patients with aspirin-exacerbated respiratory disease

Basophils are a major source of cysteinyl leukotrienes, but little is known about their association with the pathogenesis of aspirin-exacerbated respiratory disease (AERD). We assessed CD203c expression on peripheral basophils of patients with AERD.

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Access to cancer specialist care and treatment in patients with advanced stage lung cancer

MarketScan and SEER-Medicare databases were analyzed separately to evaluate the access to cancer specialists and treatment of patients with advanced stage lung cancer. Between 4% and 12% of the patients were never seen by a cancer specialist, and between 6% and 10% did not receive cancer-directed therapy. Patients seen by a cancer specialist were more likely to receive cancer-directed therapy.

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Systematic Review of Brain Metastases in Patients with Non-Small Cell Lung Cancer in the United States, European Union, and Japan

Brain metastases (BRM) occur frequently in non-small cell lung cancer (NSCLC) and present a substantial unmet medical need. Prior literature on global BRM prevalence, treatment patterns, costs, and outcomes typically has described a subset of these factors. The primary objective of this systematic literature review was to summarize BRM-related epidemiology, treatment patterns, costs, and survival of patients with NSCLC in the United States, European Union, and Japan.

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Growth of Carbon Nanofibers in Phenolic Resin for Carbon-Contained Refractory Using Different Catalysts

Various phenolic resins modified with carbon nanofibers were prepared using Fe(NO3)3, Co(NO3)2, and Ni(NO3)3 as catalyst, respectively. The influences of different catalysts on the phase, microstructure evolution, and oxidation resistance of the modified phenolic resin were investigated by X-ray diffraction analysis, field-emission scanning electron microscopy, and thermal gravimetric analysis. The results showed that, compared with a single catalyst, the mixed catalysts (Co(NO3)2 : Fe(NO3)3 = 1 : 1) promoted the growth of the carbon nanofibers, which have the higher crystallinity, homogeneous dispersion, and nonagglomeration. These carbon nanofibers can effectively reduce carbon losses, increase char yield, and fill the holes in the thermal cracking process of phenolic resins.

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Diabetic Muscle Infarction Masquerading as Necrotizing Fasciitis

A 43-year-old male patient with past medical history of diabetes mellitus (DM), end stage renal disease (ESRD) on hemodialysis (HD), congestive heart failure (CHF), obstructive sleep apnea (OSA), and chronic anemia presented with complaints of left thigh pain. A computerized tomogram (CT) of the thigh revealed evidence of edema with no evidence of a focal collection or gas formation noted. The patient’s clinical symptoms persisted and he underwent magnetic resonance imaging (MRI) of his thigh which was reported to show small areas of muscle necrosis with fluid collection. These findings in the acute setting concerned necrotizing fasciitis. After careful discussion following a multidisciplinary approach, a decision was made to perform a fasciotomy with tissue debridement. The patient was treated with IV antibiotics and discharged with a vacuum assisted wound drain. The surgical pathology revealed evidence of muscle edema with necrosis. Seven weeks later the patient presented with similar complaints on the other thigh (right thigh). MRI of the thighs revealed worsening edema with features suggestive of myositis and possible muscle infarction. A CT guided biopsy of the right quadriceps muscle revealed fibrotic interstitial connective tissue and no evidence of necrosis. This favored a diagnosis of diabetic muscle infarction. The disease was managed with pain control, strict diabetes management, and aggressive dialysis.

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Biochemical Content of Cambium of Abies nephrolepis Eaten by Bears on the Far East of Russia

The peculiarity of bears behavior of stripping of bark is typical for all species. We have described the damage to trees, by Asiatic black bear (Ursus thibetanus) and brown bear (U. arctos) in Primorsky Krai and by brown bears on the Sakhalin Island during 1998–2015. In this study, we studied the damaged bark of the tree only in cases where it was clear that part of the cambium was eaten by bears. Cambium of species Abies nephrolepis is the most preferred for bear consumption in Primorsky Krai. We distinguished very large seasonal fluctuations in the amount of its consumption. The greatest interest of bears in this kind of food is in the summer time. We have analyzed the composition of the cambium of A. nephrolepis. These results suggest that the important purpose of the use of this kind of food is to restore and maintain the normal functioning of the intestines.

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Dynamic Response of a Circular Tunnel in an Elastic Half Space

The vibration of a circular tunnel in an elastic half space subjected to uniformly distributed dynamic pressure at the inner boundary is studied in this paper. For comparison purposes, two different ground materials (soft and hard soil) are considered for the half space. Under the assumption of plane strain, the equations of motion for the tunnel and the surrounding medium are reduced to two wave equations in polar coordinates using Helmholtz potentials. The method of wave expansion is used to construct the displacement fields in terms of displacement potentials. The boundary conditions associated with the problem are satisfied exactly at the inner surface of the tunnel and at the interface between the tunnel and surrounding medium, and they are satisfied approximately at the free surface of the half space. A least-squares technique is used for satisfying the stress-free boundary conditions at the half space. It is shown by comparison that the stresses and displacements are significantly influenced by the properties of the surrounding soil, wave number (i.e., the frequency), depth of embedment, and thickness of the tunnel wall.

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Development of Paper Biosensor for the Detection of Phenol from Industrial Effluents Using Bioconjugate of Tyr-AuNps Mediated by Novel Isolate Streptomyces tuirus DBZ39

Paper biosensor was developed using Tyr-AuNps bioconjugate produced by Streptomyces for the detection of phenol from the effluent of wine, paper, and plastic industries. Among three filter papers assessed, Whatman number 2 filter paper was proved to be the best paper base for the development of biosensor. Tyrosinase and gold nanoparticles being produced by a single novel isolate Streptomyces tuirus DBZ39 proved to be efficient bioconjugate for the detection of phenol constituents, due to its biocompatibility. The substrate specific catalytic activity of the tyrosinase and unique Surface Plasmon Resonance attribute of gold nanoparticles are the cause for efficient detection of phenol constituents from the effluent of wine, paper, and plastic industries in 3 min. The different types and quantity of phenolic constituents in various industrial effluents, such as phenol in wine, dopamine in paper, and catechol in plastic effluents, were accurately detected by the bioconjugate. The efficacy of tyrosinase in the detection of phenol constituents was expected to be enhanced by the gold nanoparticles because of their electron, optical, and magnetic properties. This novel paper strip biosensor could be cost-effective and efficient means of future devices for the detection of phenolic pollutants from any environmental samples.

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Aberrant Pancreatic Tissue in a Mediastinal Enteric Duplication Cyst: A Rarity with Review of Literature

Mediastinal enteric duplication cysts are a rare congenital malformation encountered mainly in neonates and infants. It is a distinct entity within the family of foregut duplication cysts. It can present with respiratory distress due to mass effect and hence surgical excision is the preferred treatment. Histologically, it is characterised by a double layered smooth muscle wall with intestinal lining epithelium. We report a case of mediastinal enteric duplication cyst with aberrant pancreatic tissue in a neonate due to its rarity and early presentation. A neonate presented with respiratory distress and a cystic mass in the right posterior mediastinum. The lesion was excised and on histopathological analysis the diagnosis of mediastinal enteric duplication cyst was made. Also, aberrant pancreatic tissue which has been reported rarely was noted in this case. We discuss this case and review similar cases reported in literature.

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Tumor-Selective Cytotoxicity of Nitidine Results from Its Rapid Accumulation into Mitochondria

We identified a nitidine- (NTD-) accumulating organelle and evaluated the net cytotoxicity of accumulated NTD. To evaluate tumor cell selectivity of the drug, we evaluated its selective cytotoxicity against 39 human cancer cell lines (JFCR39 panel), and the profile was compared with those of known anticancer drugs. Organelle specificity of NTD was visualized using organelle-targeted fluorescent proteins. Real-time analysis of cell growth, proliferation, and cytotoxicity was performed using the xCELLigence system. Selectivity of NTD in the JFCR39 panel was evaluated. Mitochondria-specific accumulation of NTD was observed. Real-time cytotoxicity analysis suggested that the mechanism of NTD-induced cell death is independent of the cell cycle. Short-term treatment indicated that this cytotoxicity only resulted from the accumulation of NTD into the mitochondria. The results from the JFCR39 panel indicated that NTD-mediated cytotoxicity resulted from unique mechanisms compared with those of other known anticancer drugs. These results suggested that the cytotoxicity of NTD is only induced by its accumulation in mitochondria. The drug triggered mitochondrial dysfunction in less than 2 h. Similarity analysis of the selectivity of NTD in 39 tumor cell lines strongly supported the unique tumor cell specificity of NTD. Thus, these features indicate that NTD may be a promising antitumor drug for new combination chemotherapies.

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Abnormal Glucose Metabolism in Rheumatoid Arthritis

The incidence of abnormal glucose metabolism in patients with rheumatoid arthritis was considerably higher than the general population. The persistent systemic inflammatory state in rheumatoid arthritis might be associated with the glucose metabolism dysfunction. In this context, insulin resistance, islet β cell apoptosis, inflammatory cytokines, and other aspects which were linked with abnormal glucose metabolism in rheumatoid arthritis were reviewed. This review will be helpful in understanding the abnormal glucose metabolism mechanism in patients with rheumatoid arthritis and might be conducive to finding an effective treatment.

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Best Proximity Point Results for Some Contractive Mappings in Uniform Spaces

We introduce the concept of -distance (an analogue of -metric), -proximal contraction, and -proximal cyclic contraction for non-self-mappings in Hausdorff uniform spaces. We investigate the existence and uniqueness of best proximity points for these modified contractive mappings. The results obtained extended and generalised some fixed and best proximity points results in literature. Examples are given to validate the main results.

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A New Method to Measure Crack Extension in Nuclear Graphite Based on Digital Image Correlation

Graphite components, used as moderators, reflectors, and core-support structures in a High-Temperature Gas-Cooled Reactor, play an important role in the safety of the reactor. Specifically, they provide channels for the fuel elements, control rods, and coolant flow. Fracture is the main failure mode for graphite, and breaching of the above channels by crack extension will seriously threaten the safety of a reactor. In this paper, a new method based on digital image correlation (DIC) is introduced for measuring crack extension in brittle materials. Cross-correlation of the displacements measured by DIC with a step function was employed to identify the advancing crack tip in a graphite beam specimen under three-point bending. The load-crack extension curve, which is required for analyzing the R-curve and tension softening behaviors, was obtained for this material. Furthermore, a sensitivity analysis of the threshold value employed for the cross-correlation parameter in the crack identification process was conducted. Finally, the results were verified using the finite element method.

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Delay-Induced Oscillations in a Competitor-Competitor-Mutualist Lotka-Volterra Model

This paper deals with a competitor-competitor-mutualist Lotka-Volterra model. A series of sufficient criteria guaranteeing the stability and the occurrence of Hopf bifurcation for the model are obtained. Several concrete formulae determine the properties of bifurcating periodic solutions by applying the normal form theory and the center manifold principle. Computer simulations are given to support the theoretical predictions. At last, biological meaning and a conclusion are presented.

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A Class of Optimal Portfolio Liquidation Problems with a Linear Decreasing Impact

A problem of an optimal liquidation is investigated by using the Almgren-Chriss market impact model on the background that the agents liquidate assets completely. The impact of market is divided into three components: unaffected price process, permanent impact, and temporary impact. The key element is that the variable temporary market impact is analyzed. When the temporary market impact is decreasing linearly, the optimal problem is described by a Nash equilibrium in finite time horizon. The stochastic component of the price process is eliminated from the mean-variance. Mathematically, the Nash equilibrium is considered as the second-order linear differential equation with variable coefficients. We prove the existence and uniqueness of solutions for the differential equation with two boundaries and find the closed-form solutions in special situations. The numerical examples and properties of the solution are given. The corresponding finance phenomenon is interpreted.

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Improved Object Proposals with Geometrical Features for Autonomous Driving

This paper aims at generating high-quality object proposals for object detection in autonomous driving. Most existing proposal generation methods are designed for the general object detection, which may not perform well in a particular scene. We propose several geometrical features suited for autonomous driving and integrate them into state-of-the-art general proposal generation methods. In particular, we formulate the integration as a feature fusion problem by fusing the geometrical features with existing proposal generation methods in a Bayesian framework. Experiments on the challenging KITTI benchmark demonstrate that our approach improves the existing methods significantly. Combined with a convolutional neural net detector, our approach achieves state-of-the-art performance on all three KITTI object classes.

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Editorial Board



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Biosynthesis of proresolving lipid mediators by vascular cells and tissues [Research]

Recent evidence suggests that specialized proresolving lipid mediators (SPMs) generated from docosahexaenoic acid (DHA) can modulate the vascular injury response. However, cellular sources for these autacoids within the vessel wall remain unclear. Here, we investigated whether isolated vascular cells and tissues can produce SPMs and assessed expression and subcellular localization of the key SPM biosynthetic enzyme 5-lipoxygenase (LOX) in vascular cells. Intact human arteries incubated with DHA ex vivo produced 17-hydroxy DHA (17-HDHA) and D-series resolvins, as assessed by liquid chromatography-tandem mass spectrometry. Addition of 17-HDHA to human arteries similarly increased resolvin production. Primary cultures of human saphenous vein endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) converted 17-HDHA to SPMs, including resolvin (Rv)D1 and other D-series resolvins and protectins. This was accompanied by a rapid translocation of 5-LOX from nucleus to cytoplasm in both ECs and VSMCs, potentially facilitating SPM biosynthesis. Conditioned medium from cells exposed to 17-HDHA inhibited monocyte adhesion to TNF-α–stimulated EC monolayers. These downstream effects were partially reversed by antibodies against the RvD1 receptors ALX/FPR2 and GPR32. These results suggest that autocrine and/or paracrine signaling via locally generated SPMs in the vasculature may represent a novel homeostatic mechanism of relevance to vascular health and disease.—Chatterjee, A., Komshian, S., Sansbury, B. E., Wu, B., Mottola, G., Chen, M., Spite, M., Conte, M. S. Biosynthesis of proresolving lipid mediators by vascular cells and tissues.



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Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides [Research]

Gangliosides (sialylated glycolipids) play an essential role in the CNS by regulating recognition and signaling in neurons. Metabolic blocks in processing and catabolism of gangliosides result in the development of severe neurologic disorders, including gangliosidoses manifesting with neurodegeneration and neuroinflammation. We demonstrate that 2 mammalian enzymes, neuraminidases 3 and 4, play important roles in catabolic processing of brain gangliosides by cleaving terminal sialic acid residues in their glycan chains. In neuraminidase 3 and 4 double-knockout mice, GM3 ganglioside is stored in microglia, vascular pericytes, and neurons, causing micro- and astrogliosis, neuroinflammation, accumulation of lipofuscin bodies, and memory loss, whereas their cortical and hippocampal neurons have lower rate of neuritogenesis in vitro. Double-knockout mice also have reduced levels of GM1 ganglioside and myelin in neuronal axons. Furthermore, neuraminidase 3 deficiency drastically increased storage of GM2 in the brain tissues of an asymptomatic mouse model of Tay-Sachs disease, a severe human gangliosidosis, indicating that this enzyme is responsible for the metabolic bypass of β-hexosaminidase A deficiency. Together, our results provide the first in vivo evidence that neuraminidases 3 and 4 have important roles in CNS function by catabolizing gangliosides and preventing their storage in lipofuscin bodies.—Pan, X., De Britto Pará De Aragão, C., Velasco-Martin, J. P., Priestman, D. A., Wu, H. Y., Takahashi, K., Yamaguchi, K., Sturiale, L., Garozzo, D., Platt, F. M., Lamarche-Vane, N., Morales, C. R., Miyagi, T., Pshezhetsky, A. V. Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides.



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Keratin 8/18 regulation of insulin receptor signaling and trafficking in hepatocytes through a concerted phosphoinositide-dependent Akt and Rab5 modulation [Research]

Keratins (Ks) are epithelial cell intermediate filament (IF) proteins that are expressed as pairs in a differentiation-regulated manner. Hepatocyte IFs are made only of K8/K18 pairs, which means that a K8 loss in K8-null mice leads to degradation of K18. Functionally, there is accumulating evidence that IFs contribute to signaling platforms. Here, we investigate the role of K8/K18 IFs in the regulation of insulin receptor (IR) signaling and trafficking in hepatocytes. We find that the IR substrate 1 (IRS1)/PI3K/Akt signaling cascade—downstream of IR—display prolonged activation in K8-null compared with wild-type hepatocytes. Assessment of the Akt/mammalian target of rapamycin complex 1–mediated feedback loop to IRS1/PI3K, in the absence or presence of drug inhibitors, further supports a preferential K8/K18 IF intervention at the surface membrane. In K8-null hepatocytes, IR trafficking vesicles that are labeled by Rab5/EEA1/phosphatidylinositol 3-phosphate accumulate at a juxtanuclear region via a microtubule-dependent process. Moreover, interference with phosphatidylinositol 4,5-biphosphate signaling aggravates IR/Rab5 accumulation. Overall, results uncover K8/K18 IF regulation of IR signaling via a concerted modulation of phosphatidylinositol 4,5-biphosphate–dependent IRS1/PI3K/Akt signaling and Rab5/phosphatidylinositol 3-phosphate/microtubule trafficking in hepatocytes.—Roux, A., Loranger, A., Lavoie, J. N., Marceau, N. Keratin 8/18 regulation of insulin receptor signaling and trafficking in hepatocytes through a concerted phosphoinositide-dependent Akt and Rab5 modulation.



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Modeled structural basis for the recognition of {alpha}2-3-sialyllactose by soluble Klotho [Research]

Soluble Klotho (sKlotho) is the shed ectodomain of antiaging membrane Klotho that contains 2 extracellular domains KL1 and KL2, each of which shares sequence homology to glycosyl hydrolases. sKlotho elicits pleiotropic cellular responses with a poorly understood mechanism of actions. Notably, in injury settings, sKlotho confers cardiac and renal protection by down-regulating calcium-permeable transient receptor potential canonical type isoform 6 (TRPC6) channels in cardiomyocytes and glomerular podocytes. Inhibition of PI3K-dependent exocytosis of TRPC6 is thought to be the underlying mechanism, and recent studies showed that sKlotho interacts with α2-3-sialyllactose-containing gangliosides enriched in lipid rafts to inhibit raft-dependent PI3K signaling. However, the structural basis for binding and recognition of α2-3-sialyllactose by sKlotho is unknown. Using homology modeling followed by docking, we identified key protein residues in the KL1 domain that are likely involved in binding sialyllactose. Functional experiments based on the ability of Klotho to down-regulate TRPC6 channel activity confirm the importance of these residues. Furthermore, KL1 domain binds α2-3-sialyllactose, down-regulates TRPC6 channels, and exerts protection against stress-induced cardiac hypertrophy in mice. Our results support the notion that sialogangliosides and lipid rafts are membrane receptors for sKlotho and that the KL1 domain is sufficient for the tested biologic activities. These findings can help guide the design of a simpler Klotho mimetic.—Wright, J. D., An, S.-W., Xie, J., Yoon, J., Nischan, N., Kohler, J. J., Oliver, N., Lim, C., Huang, C.-L. Modeled structural basis for the recognition of α2-3-sialyllactose by soluble Klotho.



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Peroxisome proliferator-activated receptor-{gamma} agonists attenuate biofilm formation by Pseudomonas aeruginosa [Research]

Pseudomonas aeruginosa is a significant contributor to recalcitrant multidrug- resistant infections, especially in immunocompromised and hospitalized patients. The pathogenic profile of P. aeruginosa is related to its ability to secrete a variety of virulence factors and to promote biofilm formation. Quorum sensing (QS) is a mechanism wherein P. aeruginosa secretes small diffusible molecules, specifically acyl homo serine lactones, such as N-(3-oxo-dodecanoyl)-l-homoserine lactone (3O-C12-HSL), that promote biofilm formation and virulence via interbacterial communication. Strategies that strengthen the host’s ability to inhibit bacterial virulence would enhance host defenses and improve the treatment of resistant infections. We have recently shown that peroxisome proliferator-activated receptor (PPAR) agonists are potent immunostimulators that play a pivotal role in host response to virulent P. aeruginosa. Here, we show that QS genes in P. aeruginosa (PAO1) and 3O-C12-HSL attenuate PPAR expression in bronchial epithelial cells. PAO1 and 3O-C12-HSL induce barrier derangements in bronchial epithelial cells by lowering the expression of junctional proteins, such as zonula occludens-1, occludin, and claudin-4. Expression of these proteins was restored in cells that were treated with pioglitazone, a PPAR agonist, before infection with PAO1 and 3O-C12-HSL. Barrier function and bacterial permeation studies that have been performed in primary human epithelial cells showed that PPAR agonists are able to restore barrier integrity and function that are disrupted by PAO1 and 3O-C12-HSL. Mechanistically, we show that these effects are dependent on the induction of paraoxonase-2, a QS hydrolyzing enzyme, that mitigates the effects of QS molecules. Importantly, our data show that pioglitazone, a PPAR agonist, significantly inhibits biofilm formation on epithelial cells by a mechanism that is mediated via paraoxonase-2. These findings elucidate a novel role for PPAR in host defense against P. aeruginosa. Strategies that activate PPAR can provide a therapeutic complement for treatment of resistant P. aeruginosa infections.—Bedi, B., Maurice, N. M., Ciavatta, V. T., Lynn, K. S., Yuan, Z., Molina, S. A., Joo, M., Tyor, W. R., Goldberg, J. B., Koval, M., Hart, C. M., Sadikot, R. T. Peroxisome proliferator-activated receptor- agonists attenuate biofilm formation by Pseudomonas aeruginosa.



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Structure and energetics of pairwise interactions between proteasome subunits RPN2, RPN13, and ubiquitin clarify a substrate recruitment mechanism. [Protein Structure and Folding]

The 26S proteasome is a large cellular assembly that mediates the selective degradation of proteins in the nucleus and cytosol and is an established target for anti-cancer therapeutics. Protein substrates are typically targeted to the proteasome through modification with a polyubiquitin chain, which can be recognized by several proteasome-associated ubiquitin receptors. One of these receptors, RPN13/ADRM1, is recruited to the proteasome through direct interaction with the large scaffolding protein RPN2 within the 19S regulatory particle. To better understand the interactions between RPN13, RPN2, and ubiquitin, we used human proteins to map the RPN13-binding epitope to the C-terminal 14 residues of RPN2, which, like ubiquitin, binds the N-terminal PRU domain of RPN13. We also report crystal structures of the RPN13 PRU domain in complex with peptides corresponding to the RPN2 C-terminus and ubiquitin. Through mutational analysis, we validated the RPN2 binding interface revealed by our structures and quantified binding interactions with surface plasmon resonance and fluorescence polarization. In contrast to a previous report, we find that RPN13 binds ubiquitin with an affinity similar to that of other proteasome-associated ubiquitin receptors and that RPN2, ubiquitin, and the deubiquitylase UCH37 bind to RPN13 with independent energetics. These findings provide a detailed characterization of interactions that are important for proteasome function, indicate ubiquitin affinities that are consistent with the role of RPN13 as a proteasomal ubiquitin receptor, and have major implications for the development of novel anticancer therapeutics.

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The R753Q polymorphism in Toll-like receptor 2 (TLR2) attenuates innate immune responses to mycobacteria and impairs MyD88 adapter recruitment to TLR2 [Signal Transduction]

Toll-like receptor (TLR) 2 plays a critical role in host defenses against mycobacterial infections. The Arg753Gln (R753Q) TLR2 polymorphism has been associated with increased incidence of tuberculosis and infections with non-tuberculous mycobacteria in human populations, but the mechanisms by which this polymorphism affects TLR2 signaling are unclear. In this study, we determined the impact of the R753Q TLR2 polymorphism on macrophage sensing of Mycobacterium smegmatis. Upon infection with M. smegmatis, macrophages from knock-in (KI) mice harboring R753Q TLR2 expressed lower levels of TNF-α, IL-1β, IL-6 and IL-10 compared to cells from wild-type (WT) mice but both R753Q TLR2 and WT mice exhibited comparable bacterial burdens. The decreased cytokine responses in R753Q TLR2-expressing macrophages were accompanied by impaired phosphorylation of IL-1R associated kinase (IRAK)-1, p38 and ERK1/2 MAPKs and p65 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), suggesting that the R753Q TLR2 polymorphism alters functions of the myeloid differentiation primary response protein (MyD88)-IRAK-dependent signaling axis. Supporting this notion, HEK 293 cells stably transfected with YFP-tagged R753Q TLR2 displayed reduced recruitment of MyD88 to TLR2, decreased NF-κB activation, and impaired IL-8 expression upon exposure to M. smegmatis. Collectively, our results indicate that the R753Q polymorphism alters TLR2 signaling competence, leading to impaired MyD88-TLR2 assembly, reduced phosphorylation of IRAK-1, diminished activation of MAPKs and NF-κB, and deficient induction of cytokines in macrophages infected with M. smegmatis.

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Cell Cycle-dependent Degradation of the Methyltransferase SETD3 Attenuates Cell Proliferation and Liver Tumorigenesis [Signal Transduction]

Histone modifications, including lysine methylation, are epigenetic marks that influence many biological pathways. Accordingly, many methyltransferases have critical roles in various biological processes, and their dysregulation is often associated with cancer. However, the biological functions and regulation of many methyltransferases are unclear. Here, we report that a human homolog of the methyltransferase SET domain containing 3 (SETD3) is cell cycle regulated: SETD3 protein levels peaked in S phase and were lowest in M phase. We found that the β-isoform of the tumor suppressor F-box and WD repeat domain containing 7 (FBXW7β) specifically mediates SETD3 degradation. Aligning the SETD3 sequence with those of well-known FBXW7 substrates, we identified six potential noncanonical Cdc4 phosphodegrons (CPDs), and one of them, CPD1, is primarily phosphorylated by the kinase glycogen synthase kinase 3 (GSK3β) required for FBXW7β-mediated recognition and degradation. Moreover, depletion or inhibition of GSK3β or FBXW7β resulted in elevated SETD3 levels. Mutations of the phosphorylated residues of in CPD1 of SETD3 abolished the interaction between FBXW7β and SETD3 and prevented SETD3 degradation. Our data further indicated that SETD3 levels positively correlated with cell proliferation of liver cancer cells and liver tumorigenesis in a xenograft mouse model, and that overexpression of FBXW7β counteracts the SETD3's tumorigenic role. We also show that SETD3 levels correlate with cancer malignancy, indicated by SETD3 levels that were 2-fold higher in 54 liver tumor samples than in adjacent tissues. These findings indicate that a GSK3β-FBXW7β-dependent mechanism controls SETD3 protein levels during the cell cycle and attenuates SETD3's oncogenic role in liver tumorigenesis.

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The phospholipase iPLA2{gamma} is a maȷor mediator releasing oxidized aliphatic chains from cardiolipin integrating mitochondrial bioenergetics and signaling [Lipids]

Cardiolipin (CL) is a dimeric phospholipid with critical roles in mitochondrial bioenergetics and signaling. Recently, inhibition of the release of oxidized fatty acyl chains from CL by the calcium independent phospholipase A2γ (iPLA2γ) selective inhibitor (R)-BEL suggested that iPLA2γ is responsible for the hydrolysis of oxidized CL and subsequent signaling mediated by the released oxidized fatty acids. However, chemical inhibition by BEL is subject to off-target pharmacologic effects. Accordingly, to unambiguously determine the role of iPLA2γ in the hydrolysis of oxidized CL, we compared alterations in oxidized CLs and the release of oxidized aliphatic chains from CL in experiments with purified recombinant iPLA2γ, germline iPLA2γ-/- mice, cardiac myocyte-specific iPLA2γ transgenic mice, and wild-type mice. Using charge-switch high mass accuracy LC-MS/MS with selected reaction monitoring and product ion accurate masses, we demonstrated that iPLA2γ is the major enzyme responsible for the release of oxidized aliphatic chains from CL. Our results also indicated that iPLA2γ selectively hydrolyzes 9-hydroxy-octadecenoic acid in comparison to 13-hydroxy-octadecenoic acid from oxidized CLs. Moreover, oxidative stress (ADP, NADPH, and Fe3+) resulted in the robust production of oxidized CLs in intact mitochondria from iPLA2γ-/- mice. In sharp contrast, oxidized CLs were readily hydrolyzed in mitochondria from wild-type mice during oxidative stress. Finally, we demonstrated that CL activates the iPLA2γ-mediated hydrolysis of arachidonic acid from phosphatidylcholine, thereby integrating the production of lipid messengers from different lipid classes in mitochondria. Collectively, these results demonstrate the integrated roles of CL and iPLA2γ in lipid second-messenger production and mitochondrial bioenergetics during oxidative stress.

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Beta-2 Adrenergic Receptor Activation Mobilizes Intracellular Calcium via a Non-Canonical cAMP-Independent Signaling Pathway [Signal Transduction]

Beta adrenergic receptors (βARs) are G protein-coupled receptors essential for physiological responses to the hormones/neurotransmitters epinephrine and norepinephrine which are found in the nervous system and throughout the body. They are the targets of numerous widely used drugs, especially in the case of the most extensively studied βAR, β2AR, whose ligands are used for asthma and cardiovascular disease. βARs signal through Gαs G proteins and via activation of adenylyl cyclase and cAMP-dependent protein kinase, but some alternative downstream pathways have also been proposed, which could be important for understanding normal physiological functioning of β2AR signaling and its disruption in disease. Using fluorescence-based Ca2+ flux assays combined with pharmacology and gene knockout methods, we discovered a previously unrecognized endogenous pathway in HEK-293 cells whereby β2AR activation leads to robust Ca2+ mobilization from intracellular stores via activation of phospholipase-C and opening of inositol trisphosphate (InsP3) receptors. This pathway did not involve cAMP, Gαs, or Gαi or the participation of the other members of the canonical β2AR signaling cascade, and therefore constitutes a novel signaling mechanism for this receptor. This newly uncovered mechanism for Ca2+ mobilization by β2AR has broad implications for adrenergic signaling, crosstalk with other signaling pathways, and the effects of βAR-directed drugs.

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Coordination Chemistry Controls the Thiol Oxidase Activity of the B12 Trafficking Protein CblC [Enzymology]

The cobalamin or B12 cofactor supports sulfur and one-carbon metabolism and the catabolism of odd-chain fatty acids, branched-chain amino acids and cholesterol. CblC is a B12 processing enzyme involved in an early cytoplasmic step in the cofactor trafficking pathway. It catalyzes the glutathione (GSH)-dependent dealkylation of alkylcobalamins and the reductive decyanation of cyanocobalamin. CblC from Caenorhabdiitis elegans (ceCblC) also exhibits a robust thiol oxidase activity converting reduced GSH to oxidized GSSG with concomitant scrubbing of ambient dissolved O2. The mechanism of thiol oxidation catalyzed by ceCblC is not known. In this study, we demonstrate that novel coordination chemistry accessible to ceCblC-bound cobalamin, supports its thiol oxidase activity via a glutathionyl-cobalamin intermediate. Deglutathionylation of glutathionyl-cobalamin by a second molecule of GSH yields GSSG. The crystal structure of ceCblC provides insights into how architectural differences at the α- and β-faces of cobalamin promote the thiol oxidase activity of ceCblC but mute it in wild-type human CblC. The R161G and R161Q mutations in human CblC unmask its latent thiol oxidase activity and are correlated with increased cellular oxidative stress disease. In summary, we have uncovered key architectural features in the cobalamin-binding pocket that support unusual cob(II)alamin coordination chemistry and enable the thiol oxidase activity of ceCblC.

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Determination of dendritic spine morphology by the striatin scaffold protein STRN4 through interaction with the phosphatase PP2A [Cell Biology]

Dendritic spines are heterogeneous and exist with various morphologies. Altered spine morphology might underlie the cognitive deficits in neurodevelopmental disorders such as autism, but how different subtypes of dendritic spines are selectively maintained along development is still poorly understood. Spine maturation requires spontaneous activity of N-methyl-D-aspartate (NMDA) receptor and local dendritic protein synthesis. STRN4 (also called Zinedin) belongs to the striatin family of scaffold proteins, and some of the potential striatin-interacting proteins are encoded by autism risk genes. Although previous studies have demonstrated their localization in dendritic spines, the function of various striatin family members in neuron remains unknown. Here we demonstrate that STRN4 mRNA is present in neuronal dendrites and the local expression of STRN4 protein depends on NMDA receptor activation. Notably, STRN4 is preferentially expressed in mushroom spines, and STRN4 specifically maintains mushroom spines but not thin spines and filopodia through interaction with the phosphatase PP2A. Our findings have therefore unraveled the local expression of STRN4 as a novel mechanism for the control of dendritic spine morphology.

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The Mark of the Mosasaur

A 90 million year old bite mark raises questions about what seagoing lizards really ate.

-- Read more on ScientificAmerican.com
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Obituary for Professor Renato Fior

Professor Renato Fior.

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Editorial Board



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Pediatric sinonasal malignancies: A population-based analysis

Pediatric Sinonasal Malignancies (PedsSNM) are rare and usually associated with a poor prognosis. We aim to investigate the epidemiology, tumor characteristics, and survival of PedsSNM using a population-based database to augment the scant literature on this topic.

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04/24/17 PHD comic: 'Meeting comprehension'

Piled Higher & Deeper by Jorge Cham
www.phdcomics.com
Click on the title below to read the comic
title: "Meeting comprehension" - originally published 4/24/2017

For the latest news in PHD Comics, CLICK HERE!



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Antibiotics, Vol. 6, Pages 11: Erythromycin Modification That Improves Its Acidic Stability while Optimizing It for Local Drug Delivery

The antibiotic erythromycin has limited efficacy and bioavailability due to its instability and conversion under acidic conditions via an intramolecular dehydration reaction. To improve the stability of erythromycin, several analogs have been developed—such as azithromycin and clarithromycin—which decrease the rate of intramolecular dehydration. We set out to build upon this prior work by developing a conjugate of erythromycin with improved pH stability, bioavailability, and preferential release from a drug delivery system directly at the low pH of an infection site. To develop this new drug conjugate, adamantane-1-carbohydrazide was covalently attached to erythromycin via a pH-degradable hydrazone bond. Since Staphylococcus aureus infection sites are slightly acidic, the hydrazone bond will undergo hydrolysis liberating erythromycin directly at the infection site. The adamantane group provides interaction with the drug delivery system. This local delivery strategy has the potential of reducing off-target and systemic side-effects. This work demonstrates the synthesis of a pH-cleavable, erythromycin conjugate that retains the inherent antimicrobial activity of erythromycin, has an increased hydrophobicity, and improved stability in acidic conditions; thereby enhancing erythromycin’s bioavailability while simultaneously reducing its toxicity.

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Editorial Board



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The second-generation ALK inhibitor alectinib effectively induces apoptosis in human neuroblastoma cells and inhibits tumor growth in a TH-MYCN transgenic neuroblastoma mouse model

Activating germline mutations of anaplastic lymphoma kinase (ALK) occur in most cases of hereditary neuroblastoma (NB) and the constitutively active kinase activity of ALK promotes cell proliferation and survival in NB. Therefore, ALK kinase is a potential therapeutic target for NB. In this study, we show that the novel ALK inhibitor alectinib effectively suppressed cell proliferation and induces apoptosis in NB cell lines with either wild-type ALK or mutated ALK (F1174L and D1091N) by blocking ALK-mediated PI3K/Akt/mTOR signaling.

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RE: Cancer incidence and mortality in China, 2013 by Chen et al

The article by Chen et al. [1] in this issue of the Journal reports cancer incidence and mortality rates in mainland China in 2013 based on data from 255 local cancer registries. These estimates, equivalent to more than 10,000 new cancers and 6,000 deaths in China every day, represents a huge challenge to the Chinese government, both at the Central and local levels. Having the most accurate and contemporary cancer statistics for China is critical in understanding the effectiveness of cancer control in that country, guiding their future health policy planning, and providing greater insights into the global patterns of cancer.

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GOT1-Mediated Anaplerotic Glutamine Metabolism Regulates Chronic Acidosis Stress In Pancreatic Cancer Cells

The increased rate of glycolysis and reduced oxidative metabolism are the principal biochemical phenotypes observed in pancreatic ductal adenocarcinoma (PDAC) that lead to the development of an acidic tumor microenvironment. The pH of most epithelial cell-derived tumors is reported to be lower than that of plasma. However, little is known regarding the physiology and metabolism of cancer cells enduring chronic acidosis. Here, we cultured PDAC cells in chronic acidosis (pH 6.9∼7.0) and observed that cells cultured in low pH had reduced clonogenic capacity.

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In vitro and in vivo anti-uveal melanoma activity of JSL-1, a novel HDAC inhibitor

Uveal melanoma (UM) is the most common intraocular malignant neoplasm in adults. Despite the availability of enucleation, radiation and chemotherapy, the prognosis of patients with metastasis remains poor. Therefore, novel effective therapies for patients with metastatic UM are urgently needed. In the present study, we demonstrated that JSL-1, a novel HDAC inhibitor, effectively inhibited the proliferation. JSL-1 induced apoptosis with increased expression of proapoptotic BH3-only protein BIM in UM cells.

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RCCD1 depletion attenuates TGF-β-induced EMT and cell migration by stabilizing cytoskeletal microtubules in NSCLC cells

Lung cancer is one of the most lethal cancers due to its highly metastatic spreading. The motility of lung cancer cells is regulated by paracrine factors, such as TGF-β, in the tumor microenvironment through the induction of epithelial-to-mesenchymal transition (EMT). The stability of microtubules is reported to be associated with the EMT process and the migration of cancer cells. Here, we observed that RCC1 domain-containing protein 1 (RCCD1) is highly expressed in non-small cell lung cancer (NSCLC) patients with poor prognosis, and RCCD1 is much higher expressed in tumor tissues compared with adjacent normal tissues.

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Fn14•TRAIL fusion protein is oligomerized by TWEAK into a superefficient TRAIL analog

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) demonstrates specific anti-cancer activity, but insufficient efficacy in patients. A fusion protein Fn14•TRAIL, that combines soluble TRAIL molecule with a specific TWEAK receptor Fn14, is a better apoptosis-inducer for hepatocellular carcinomas than soluble TRAIL. However, Fn14•TRAIL does not effectively induce apoptosis in tumors of the lymphoid origin. As malignant cell apoptosis is strongly enhanced by secondary oligomerization of TRAIL, we tested the hypothesis that soluble Fn14•TRAIL can be oligomerized and become more active by adding TWEAK, a cytokine secreted in the tumor environment.

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The Role of the NORE1A Tumor Suppressor in Oncogene-Induced Senescence

The Ras genes are the most frequently mutated oncogenes in human cancer. However, Ras biology is quite complex. While Ras promotes tumorigenesis by regulating numerous growth promoting pathways, activated Ras can paradoxically also lead to cell cycle arrest, death, and Oncogene-Induced Senescence (OIS). OIS is thought to be a critical pathway that serves to protect cells against aberrant Ras signaling. Multiple reports have highlighted the importance of the p53 and Rb tumor suppressors in Ras mediated OIS.

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Hepatitis B Virus PreS1 Facilitates Hepatocellular Carcinoma Development by Promoting Appearance and Self-renewal of Liver Cancer Stem Cells

Hepatitis B virus (HBV) is a major etiologic agent of hepatocellular carcinoma (HCC). However, the molecular mechanism by which HBV infection contributes to HCC development is not fully understood. Here, we initially showed that HBV stimulates the production of cancer stem cells (CSCs)-related markers (CD133, CD117 and CD90) and CSCs-related genes (Klf4, Sox2, Nanog, c-Myc and Oct4) and facilitates the self-renewal of CSCs in human hepatoma cells. Cellular and clinical studies revealed that HBV facilitates hepatoma cell growth and migration, enhances white blood cell (WBC) production in the sera of patients, stimulates CD133 and CD117 expression in HCC tissues, and promotes the CSCs generation of human hepatoma cells and clinical cancer tissues.

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Protection against Legionnaire's Disease: Recombinant Flagellin A of Legionella pneumophila Can Induce Protective Immunity against Bacteremia in a BALB/c Murine Model

To investigate the immunoprotective effects of the recombinant type A flagellin (FLA), the flaA gene of Legionella pneumophila serogroup 1 strain Paris was cloned into pET28a(+). Recombinant FLA (rFLA) was overexpressed in E. coli BL21 (DE3) and purified by Ni2+ exchange chromatography. Female BALB/c aged 6-8 weeks were immunized with 20 μg of rFLA. Nonimmunized mice along with mice inoculated with a sublethal dose of live L. pneumophila intravenously were considered as negative and positive controls, respectively. A significant serum antibody response was observed in female BALB/c mice immunized with rFLA. Production of IFN-#x03B3; and IL-12, and TNF-α in the serum and the splenocyte cultures, and antigen-specific splenocyte proliferation suggested a strong innate and adaptive cell-mediated immunity response in rFLA-immunized mice. Intravenous lethal challenge with L. pneumophila serogroup 1 (strain Paris) showed that 60% of mice immunized with rFLA survived in a 10-day follow-up survey. These results show that rFLA from L. pneumophila can elicit strong innate and adaptive immune responses and suggest the possibility of a long-term immunity against lethal challenge with L. pneumophila.
J Mol Microbiol Biotechnol 2017;27:110-116

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THE EBOLA EPIDEMIC IN LIBERIA AND MANAGING THE DEAD − A FUTURE ROLE FOR HUMANITARIAN FORENSIC ACTION?

With some of their economies, communities and health systems weakened by decades of war and poor governance, it was no accident that an epidemic of Ebola virus disease broke out in west Africa. Being spread in part by contact with body fluids of those who had died from the disease, funerary rites and the way dead bodies were managed were important modes of transmission. The Liberian Red Cross, supported by the International Federation of Red Cross and Red Crescent Societies and the International Committee of the Red Cross, undertook the challenging task of managing the dead bodies in Monrovia during the epidemic.

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Editorial Board



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Skull base osteomyelitis secondary to malignant otitis externa mimicking advanced nasopharyngeal cancer: MR imaging features at initial presentation

Skull base osteomyelitis (SBOM) is an inflammatory process which often arises from malignant otitis externa (MOE); the diffuse skull base and adjacent soft tissue involvement may be mistaken at initial imaging for advanced nasopharyngeal carcinoma (NPC), especially if there is no prior knowledge of MOE, direct spread from the sphenoid sinus or in atypical presentations of MOE. This study aims to evaluate imaging features on MR that may differentiate SBOM from NPC.

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Teaching and practice patterns of lateral osteotomies for rhinoplasty

Lateral osteotomies are important during rhinoplasty and represent a challenging technique that otolaryngology and plastic surgery trainees must learn. The approaches for osteotomies are difficult to teach as they are accomplished through tactile feedback. Trends in teaching and practice patterns of lateral osteotomies are poorly described in the literature, and this study aims to fill this knowledge gap.

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#cancer patients treated with checkpoint inhibitors including #nivolumab may be at greater risk after #flu vaccine :https://t.co/KnEnDu9hrz

#cancer patients treated with checkpoint inhibitors including #nivolumab may be at greater risk after #flu vaccine : https://t.co/KnEnDu9hrz

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Annual flu jab may pose greater risk for lung cancer patients under immunotherapy

Lung cancer patients treated with PD-1/PD-L1 checkpoint inhibitors may be at increased risk of adverse events after receiving the seasonal influenza vaccination, according to the first study measuring this effect. The results, presented today at the...

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Preoperative clinical pathway of breast cancer patients: determinants of compliance with EUSOMA quality indicators

Preoperative clinical pathway of breast cancer patients: determinants of compliance with EUSOMA quality indicators

British Journal of Cancer advance online publication, April 25 2017. doi:10.1038/bjc.2017.114

Authors: Delphine Héquet, Cyrille Huchon, Sandrine Baffert, Séverine Alran, Fabien Reyal, Thuy Nguyen, Alix Combes, Caroline Trichot, Karine Alves, Hélène Berseneff & Roman Rouzier



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Text-message Reminders in Colorectal Cancer Screening (TRICCS): a randomised controlled trial

Text-message Reminders in Colorectal Cancer Screening (TRICCS): a randomised controlled trial

British Journal of Cancer advance online publication, April 25 2017. doi:10.1038/bjc.2017.117

Authors: Yasemin Hirst, Hanna Skrobanski, Robert S Kerrison, Lindsay C Kobayashi, Nicholas Counsell, Natasha Djedovic, Josephine Ruwende, Mark Stewart & Christian von Wagner



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Hopefully devoted to Q: targeting glutamine addiction in cancer

Hopefully devoted to Q: targeting glutamine addiction in cancer

British Journal of Cancer advance online publication, April 25 2017. doi:10.1038/bjc.2017.113

Authors: Emma R Still & Mariia O Yuneva



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Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers

Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers

British Journal of Cancer advance online publication, April 25 2017. doi:10.1038/bjc.2017.116

Authors: Concetta Di Mauro, Roberta Rosa, Valentina D'Amato, Paola Ciciola, Alberto Servetto, Roberta Marciano, Roberta Clara Orsini, Luigi Formisano, Sandro De Falco, Valeria Cicatiello, Maurizio Di Bonito, Monica Cantile, Francesca Collina, Angela Chambery, Bianca Maria Veneziani, Sabino De Placido & Roberto Bianco



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The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma

The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma

British Journal of Cancer advance online publication, April 25 2017. doi:10.1038/bjc.2017.119

Authors: Rachna T Shroff, Mark Yarchoan, Ashley O'Connor, Denise Gallagher, Marianna L Zahurak, Gary Rosner, Chimela Ohaji, Susan Sartorius-Mergenthaler, Vivek Subbiah, Ralph Zinner & Nilofer S Azad



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Comparison of general obesity and measures of body fat distribution in older adults in relation to cancer risk: meta-analysis of individual participant data of seven prospective cohorts in Europe

Comparison of general obesity and measures of body fat distribution in older adults in relation to cancer risk: meta-analysis of individual participant data of seven prospective cohorts in Europe

British Journal of Cancer advance online publication, April 25 2017. doi:10.1038/bjc.2017.106

Authors: Heinz Freisling, Melina Arnold, Isabelle Soerjomataram, Mark George O'Doherty, José Manuel Ordóñez-Mena, Christina Bamia, Ellen Kampman, Michael Leitzmann, Isabelle Romieu, Frank Kee, Konstantinos Tsilidis, Anne Tjønneland, Antonia Trichopoulou, Paolo Boffetta, Vassiliki Benetou, H B(as) Bueno-de-Mesquita, José María Huerta, Hermann Brenner, Tom Wilsgaard & Mazda Jenab



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Neue Ansätze zur Prävention aktinischer Keratosen

Zusammenfassung

Aktinische Keratosen gehören zu den häufigsten Hautkrankheiten. Aufgrund der aktuellen demografischen Entwicklung ist von einem weiteren Häufigkeitsanstieg auszugehen. Ihrer Prävention kommt daher zunehmende Bedeutung zu. Die mit Abstand wichtigste Ursache ist die chronische, kumulative Bestrahlung der menschlichen Haut mit ultravioletter B‑ und A‑Strahlung des natürlichen Sonnenlichts. Es besteht kein Zweifel, dass die Anwendung von Sonnenschutzmitteln das Risiko, aktinische Keratosen zu entwickeln, reduzieren kann. Zudem weisen neuere Studien darauf hin, dass insbesondere für Hochrisikogruppen die regelmäßige Anwendung von Medizinprodukten, die über einen sehr hohen Lichtschutzfaktor verfügen und zudem liposomal verpackte DNS-Reparaturenzyme beinhalten, selbst bei einer bestehenden Feldkanzerisierung das Auftreten neuer aktinischer Keratosen verhindern kann. Darüber hinaus scheinen auch orale photoprotektive Strategien, wie z. B. die Einnahme von Vitamin B3, für die Prävention aktinischer Keratosen geeignet zu sein.



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Post-Science March we Must Stay Engaged

Our real work starts now and we have a great deal to do over the coming years

-- Read more on ScientificAmerican.com
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Authors’ reply to Mȷoen and Holdaas

We thank Mjøen and Holdaas for their comments.12 However, we did not say that there was no increased mortality after kidney donation.We refer to the paper of 62 nephrectomies as a small case-control...
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