Τετάρτη, 19 Ιουλίου 2017

Transcanalicular Diode Laser-Assisted Revision Surgery for Failed Dacryocystorhinostomy With or Without Distal or Common Canalicular Obstruction.

Purpose: To report the outcomes of transcanalicular diode laser-assisted revision surgery for failed dacryocystorhinostomy with/without distal or common canalicular obstruction. Methods: The medical records and recorded videos of consecutive transcanalicular diode laser-assisted revision surgeries performed for failed dacryocystorhinostomy between May 2011 and May 2015 were reviewed. Cases of unavailability of video and cases lost to follow up after surgery were excluded from the study. With respect to the level of obstruction, lacrimal drainage systems were divided into Group 1 (obstruction at the level of the ostium) and Group 2 (obstruction at the level of the distal or common canaliculus). Data associated with anatomical and functional success were analyzed. Results: Revision dacryocystorhinostomy surgeries were performed on 68 patients during the study period. Transcanalicular diode laser-assisted revision surgeries were performed on 48 eyes of 39 patients. Mean follow-up period after revision surgery was 13.3 +/- 12.6 months. Overall, anatomical success rate was 83.3% (40/48) and functional success rate was 68.8% (33/48). Anatomical success rates and functional success rates in the 2 groups showed no significant difference (80.0% [24/30] vs. 86.7% [13/15], p = 0.699; 70.0% [21/30] vs. 66.7% [10/15], p = 1.000, respectively). Conclusions: Transcanalicular diode laser-assisted revision surgery may be an alternative technique for failed dacryocystorhinostomy. Distal or common canalicular obstruction did not affect the outcomes of revision surgeries. (C) 2017 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

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Former US Presidential candidate and war hero John McCain diagnosed with brain cancer - Express.co.uk

Express.co.uk
Former US Presidential candidate and war hero John McCain diagnosed with brain cancer
Express.co.uk
Barack Obama tweeted: “John McCain is an American hero & one of the bravest fighters I've ever known. Cancer doesn't know what it's up against. Give it hell, John.” Hillary Clinton tweeted: “John McCain is as tough as they come. Thinking of John, Cindy ...

and more »


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Eating at 'wrong time' affects body weight, circadian rhythms - Science Daily

Science Daily
Eating at 'wrong time' affects body weight, circadian rhythms
Science Daily
Victoria A. Acosta-Rodríguez, Marleen H.M. de Groot, Filipa Rijo-Ferreira, Carla B. Green, Joseph S. Takahashi. Mice under Caloric Restriction Self-Impose a Temporal Restriction of Food Intake as Revealed by an Automated Feeder System. Cell Metabolism ...

and more »


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Abrogation of heat shock factor 1 (Hsf1) phosphorylation deregulates its activity and lowers activation threshold, leading to obesity in mice [Gene Regulation]

Heat shock factor 1 (Hsf1) is transcriptionally activated following exposure of mammalian cells to environmental insults and pathological conditions. The function of Hsf1 as a protector of cells and organisms towards a range of stress stimuli has been well-documented. However, how different Hsf1 post-transcriptional modifications affect its function in vivo is not understood. Hsf1 transcriptional activity is in part regulated by phosphorylation. Hsf1 phosphorylation of amino acid residues at S303 and S307 has been shown to repress Hsf1 transcriptional activity under normal physiological growth conditions. In this study, we used a knock-in mouse model where serine residues S303 and S307 were mutated to alanine (S303A/S307A) in order to reveal the relevance of these phosphorylation sites on Hsf1 activity in vitro and in vivo. Our results indicate that Hsf1303A/307A protein becomes more stable, but remains mostly cytoplasmic under normal physiological growth conditions. However, in contrast to wild type, the Hsf1303A/307A protein exhibits reduced threshold of activation following exposure of cells to a very mild heat stress, or when mice are placed under the conditions of nutrient stimulation. The in vivo consequence of the Hsf1303A/307A mutant protein expression results in an age-dependent obesity, fatty liver disease and insulin resistance. Taken together, these data point to the importance of maintaining dynamic regulation of Hsf1 responses including resolution of Hsf1 activation to restore repression of Hsf1 through phosphorylation of S303 and/or S307. Specifically, we show that the inability to phosphorylate Hsf1 at these amino acid residues can play a role in the development of age-dependent metabolic diseases, such as obesity and insulin resistance.

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Altered Met Receptor Phosphorylation and LRP1 Mediated Uptake in Cells Lacking Carbohydrate-Dependent Lysosomal Targeting [Molecular Bases of Disease]

Acid hydrolases utilize a carbohydrate-dependent mechanism for lysosomal targeting. These hydrolases acquire a mannose 6-phosphate tag by the action of the GlcNAc-1-phosphotransferase enzyme, allowing them to bind receptors and traffic to endosomes. Loss of GlcNAc-1-phosphotransferase results in hydrolase hypersecretion and profound lysosomal storage. Little, however, is known about how these cellular phenotypes affect the trafficking, activity and localization of surface glycoproteins. To address this question, we profiled the abundance of surface glycoproteins in WT and CRISPR-mediated GNPTAB-/- HeLa cells and identified changes in numerous glycoproteins including the uptake receptor LRP1 and multiple receptor tyrosine kinases. Decreased cell surface LRP1 in GNPTAB-/- cells corresponded with a reduction in its steady-state level and less Aβ40 peptide uptake. GNPTAB-/- cells displayed elevated activation of several kinases including Met receptor. We found increased Met phosphorylation within both the kinase and docking domains, and observed that lower concentrations of pervanadate were needed to cause an increase in phospho-Met in GNPTAB-/- cells. Together, these data suggested a decrease in the activity of the receptor and non-receptor protein-tyrosine phosphatases that downregulate Met phosphorylation. GNPTAB-/- cells exhibited elevated levels of reactive oxygen species, known to inactivate cell surface and cytosolic phosphatases by oxidation of active site cysteine residues. Consistent with this mode of action, peroxide treatment of parental HeLa cells elevated phospho-Met levels while antioxidant treatment of GNPTAB-/- cells reduced phospho-Met levels. Collectively, these findings identify new mechanisms whereby impaired lysosomal targeting can impact the activity and recycling of receptors.

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Adaptor Protein p62 Promotes Skin Tumor Growth and Metastasis and is Induced by UVA Radiation [Signal Transduction]

Skin cancer is the most common cancer and exposure to ultraviolet (UV) radiation, namely UVA and UVB is the major risk factor for skin cancer development. UVA is significantly less effective in causing direct DNA damage than UVB, but UVA has been shown to increase skin cancer risk. The mechanism by which UVA contributes to skin cancer remains unclear. Here, using RNA-Seq, we show that UVA induces autophagy and lysosomal gene expression, including the autophagy receptor and substrate p62. We found that UVA activates the transcription factor EB (TFEB), a known regulator of autophagy and lysosomal gene expression, which, in turn, induces p62 transcription. Next, we identified a novel relationship between p62 and cyclooxygenase-2 (COX-2), a prostaglandin synthase critical for skin cancer development. COX-2 expression was up-regulated by UVA-induced p62, suggesting that p62 plays a role in UVA-induced skin cancer. Moreover, we found that p62 stabilizes COX-2 protein through the p62 ubiquitin-associated domain and that p62 regulates prostaglandin E2 (PGE2) production in vitro. In a syngeneic squamous cell carcinoma mouse model, p62 knockdown inhibited tumor growth and metastasis. Furthermore, p62-deficient tumors exhibited reduced immune cell infiltration and increased cell differentiation. As PGE2 is known to promote pro-tumorigenic immune cell infiltration, increase proliferation, and inhibit keratinocyte differentiation in vivo, this work suggests that UVA-induced p62 acts through COX-2 to promote skin tumor growth and progression. These findings expand our understanding of UVA-induced skin tumorigenesis and tumor progression and suggest that targeting p62 can help prevent or treat UVA-associated skin cancer.

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The Axl Kinase Domain in Complex with a Macrocyclic Inhibitor Offers First Structural Insights into an Active TAM Receptor Kinase [Protein Structure and Folding]

The receptor tyrosine kinase (RTK) family consisting of Tyro3, Axl and Mer (TAM) is one of the most recently identified RTK families. TAM receptors are upregulated postnatally and maintained at high levels in adults. They all play an important role in immunity, but Axl has also been implicated in cancer and therefore is a target in the discovery and development of novel therapeutics. However, of the three members of the TAM family, the Axl kinase domain is the only one that has so far eluded structure determination. To this end, using differential scanning fluorimetry and hydrogen-deuterium exchange mass spectrometry (HDX-MS), we show here that a lower stability and greater dynamic nature of the Axl kinase domain may account for its poor crystallizability. We present the first structural characterization of the Axl kinase domain in complex with a small molecule macrocyclic inhibitor. The Axl crystal structure revealed two distinct conformational states of the enzyme, providing a first glimpse of what an active TAM receptor kinase may look like, and suggesting a potential role for the juxtamembrane region in enzyme activity. We noted that the ATP/inhibitor binding sites of the TAM members closely resemble each other, posing a challenge for the design of a selective inhibitor. We propose that the differences in the conformational dynamics among the TAM family members could potentially be exploited to achieve inhibitor selectivity for targeted receptors.

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Hydrogen peroxide produced by superoxide dismutase SOD-2 is required for sperm activation in Caenorhabditis elegans [Signal Transduction]

Superoxide dismutase (SOD) is a ubiquitous antioxidant enzyme that catalytically converts the superoxide radical to hydrogen peroxide (H2O2). In mammals, high SOD activity can be detected in sperm and seminal plasma, and a correlation between loss of SOD activity and male infertility has been observed; however, the underlying mechanisms remain to be clarified. Here, we report that the deletion of two major SOD genes in Caenorhabditis elegans, sod-1 and sod-2, cause sperm activation defects, thereby leading to a significant reduction in brood size. By analyzing the reactivity to the activation signals including Pronase and triethanolamine, we found that sod-1;sod-2 double mutant sperm have defects in pseudopod extension. Neither the content nor oxidative modification of major sperm protein, an essential cytoskeletal component for crawling movement, were significantly affected in sod-1;sod-2 mutant sperm. Surprisingly, H2O2, the dismutation product of SOD, could activate sod-1;sod-2 mutant sperm treated with Pronase. In contrast, the H2O2-scavenger ebselen completely inhibited pseudopod extension in wild-type sperm treated with Pronase. In addition, H2O2 could directly induce pseudopod extension in wild-type sperm. Pronase-triggered sperm activation analysis in sod-1 and sod-2 single mutants revealed that sod-2 is required for pseudopod extension. These results suggest that SOD-2 plays an important role in the sperm activation of C. elegans by producing H2O2 as an activator of pseudopod extension.

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Heterodimers of the transcriptional factors NFATc3 and FosB mediate tissue factor expression for 15(S)-hydroxyeicosatetraenoic acid-induced monocyte trafficking [Molecular Bases of Disease]

Tissue factor (TF) is expressed in vascular and nonvascular tissues and functions in several pathways, including embryonic development, inflammation, and cell migration. Many risk factors for atherosclerosis, including hypertension, diabetes, obesity, and smoking, increase TF expression. To better understand the TF-related mechanisms in atherosclerosis, here we investigated the role of 12/15-lipoxygenase (12/15-LOX) in TF expression. 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), the major product of human 15-LOXs 1 and 2, induced TF expression and activity in a time-dependent manner in the human monocytic cell line THP1. Moreover, TF suppression with neutralizing antibodies blocked 15(S)-HETE-induced monocyte migration. We also found that NADPH- and xanthine oxidase-dependent reactive oxygen species (ROS) production, calcium/calmodulin-dependent protein kinase IV (CaMKIV) activation, and interactions between nuclear factor of activated T cells 3 (NFATc3) and FosB proto-oncogene, AP-1 transcription factor subunit (FosB) are involved in 15(S)-HETE-induced TF expression. Interestingly, NFATc3 first induced the expression of its interaction partner FosB before forming the heterodimeric NFATc3/FosB transcription factor complex, which bound the proximal AP-1 site in the TF gene promoter and activated TF expression. We also observed that macrophages from 12/15-LOX-/- mice exhibit diminished migratory response to monocyte chemotactic protein 1 (MCP-1) and lipopolysaccharide compared with WT-mouse macrophages. Similarly, compared with WT macrophages, monocytes from 12/15-LOX-/- mice displayed diminished trafficking, which was rescued by prior treatment with 12(S)-HETE, in a peritonitis model. These observations indicate that 15(S)-HETE-induced monocyte/macrophage migration and trafficking require ROS-mediated CaMKIV activation leading to formation of NFATc3 and FosB heterodimer, which binds and activates the TF promoter.

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Phase I dose escalation study of NMS-1286937, an orally available Polo-Like Kinase 1 inhibitor, in patients with advanced or metastatic solid tumors

Summary

Background Pharmacological inhibition of polo-like kinase 1 (PLK1) represents a new approach for the treatment of solid tumors. This study was aimed at determining the first cycle dose-limiting toxicities (DLTs) and related maximum tolerated dose (MTD) of NMS-1286937, a selective ATP-competitive PLK1-specific inhibitor. Secondary objectives included evaluation of its safety and pharmacokinetic (PK) profile in plasma, its antitumor activity, and its ability to modulate intracellular targets in biopsied tissue. Methods This was a Phase I, open-label, dose-escalation trial in patients with advanced/metastatic solid tumors. A treatment cycle comprised 5 days of oral administration followed by 16 days of rest, for a total of 21 days (3-week cycle). Results Nineteen of 21 enrolled patients with confirmed metastatic disease received study medication. No DLTs occurred at the first 3 dose levels (6, 12, and 24 mg/m2/day). At the subsequent dose level (48 mg/m2/day), 2 of 3 patients developed DLTs. An intermediate level of 36 mg/m2/day was therefore investigated. Four patients were treated and two DLTs were observed. After further cohort expansion, the MTD and recommended phase II dose (RP2D) were determined to be 24 mg/m2/day. Disease stabilization, observed in several patients, was the best treatment response observed. Hematological toxicity (mostly thrombocytopenia and neutropenia) was the major DLT. Systemic exposure to NMS-1286937 increased with dose and was comparable between two cycles of treatment following oral administration of the drug. Conclusions This study successfully identified the MTD and DLTs for NMS-1286937 and characterized its safety profile.



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Clonal composition of human ovarian cancer based on copy number analysis reveals a reciprocal relation with oncogenic mutation status

Intratumoral heterogeneity of cancer cells remains largely unexplored. Here we investigated the composition of ovarian cancer and its biological relevance. A whole-genome single nucleotide polymorphism array was applied to detect the clonal composition of 24 formalin-fixed, paraffin-embedded samples of human ovarian cancer. Genome-wide segmentation data consisting of the log2 ratio (log2R) and B allele frequency (BAF) were used to calculate an estimate of the clonal composition number (CC number) for each tumor.

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Impact of Geriatric Syndromes on Diabetes Management

Abstract

Purpose of Review

In this review, we describe the components and importance of geriatric syndrome, a term describing age-related disorders coexisting in older adults with diabetes. With the aging of the population, and a higher prevalence of diabetes in older adults, we are seeing a higher prevalence of age-related conditions in older diabetes patients, resulting in high human and economic costs. Successful education and management of diabetes in older adults warrants a better understanding of these unique challenges faced by individual older adults.

Recent Findings

Expert opinions have established the importance of recognizing geriatric syndrome and its management in older adults with diabetes. However, recent studies have shown that this approach is not yet common in patient care. Patients with significant burden of comorbidities are being treated similarly to those without this burden. Newer studies have identified individualized glycemic goals and strategies to de-intensify treatment regimens in older adults.

Summary

It is important that before forming management plans, the physical, social, and emotional/cognitive status of an older individual with diabetes are considered. In doing so, individualized goals for management of diabetes as well as other coexisting diseases can be established, leading to optimized treatment efficacy, adherence, and improved health outcomes that are relevant to the older population. The objective of this review is to raise clinician awareness of the presence of geriatric syndrome in this increasingly large patient population.



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Clonal composition of human ovarian cancer based on copy number analysis reveals a reciprocal relation with oncogenic mutation status

Intratumoral heterogeneity of cancer cells remains largely unexplored. Here we investigated the composition of ovarian cancer and its biological relevance. A whole-genome single nucleotide polymorphism array was applied to detect the clonal composition of 24 formalin-fixed, paraffin-embedded samples of human ovarian cancer. Genome-wide segmentation data consisting of the log2 ratio (log2R) and B allele frequency (BAF) were used to calculate an estimate of the clonal composition number (CC number) for each tumor.

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Former US Presidential candidate and war hero John McCain diagnosed with brain cancer - Express.co.uk

Express.co.uk
Former US Presidential candidate and war hero John McCain diagnosed with brain cancer
Express.co.uk
Barack Obama tweeted: “John McCain is an American hero & one of the bravest fighters I've ever known. Cancer doesn't know what it's up against. Give it hell, John.” Hillary Clinton tweeted: “John McCain is as tough as they come. Thinking of John, Cindy ...
Explained: John McCain's skull surgery - and why his blood clot could have caused him to act so bizarrely in the ...Daily Mail

all 614 news articles »


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Pediatric primary Sjögren syndrome presenting with bilateral ranulas: A case report and systematic review of the literature

Primary Sjögren syndrome is uncommon in children, and the standard clinical criteria used in diagnosis of adult Sjögren syndrome will miss many children with the disease. Floor of mouth ranulas have not been described in Sjögren syndrome.

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The risk ratio for development of hereditary sensorineural hearing loss in consanguineous marriage offspring

This study aims to define the relative risk of development of hearing loss in offspring of consanguineous marriages.

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Prenatal antidepressant use and risk of autism

Although the causes of autism spectrum disorder are largely unknown, among the first clues were observations of greater than expected aggregation of psychiatric disorders in families of children with...
recent?d=yIl2AUoC8zA recent?d=dnMXMwOfBR0 recent?i=jcrmSTzJYFY:o022kkiEjWU:V_sGLiP recent?d=qj6IDK7rITs recent?i=jcrmSTzJYFY:o022kkiEjWU:gIN9vFw recent?d=l6gmwiTKsz0 recent?d=7Q72WNTAKBA recent?i=jcrmSTzJYFY:o022kkiEjWU:F7zBnMy recent?i=jcrmSTzJYFY:o022kkiEjWU:-BTjWOF


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Effect of diet and physical activity based interventions in pregnancy on gestational weight gain and pregnancy outcomes: meta-analysis of individual participant data from randomised trials

Objective To synthesise the evidence on the overall and differential effects of interventions based on diet and physical activity during pregnancy, primarily on gestational weight gain and maternal...
recent?d=yIl2AUoC8zA recent?d=dnMXMwOfBR0 recent?i=1JNWkGfpaq8:xsFHmoI_7x4:V_sGLiP recent?d=qj6IDK7rITs recent?i=1JNWkGfpaq8:xsFHmoI_7x4:gIN9vFw recent?d=l6gmwiTKsz0 recent?d=7Q72WNTAKBA recent?i=1JNWkGfpaq8:xsFHmoI_7x4:F7zBnMy recent?i=1JNWkGfpaq8:xsFHmoI_7x4:-BTjWOF


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The new article is now available. Nippon Ronen Igakkai Zasshi. Japanese Journal of Geriatrics

[ Advance Publication ] [ Title ] [ Author ] [ Advance Pub. date ] 2017-07-20 [ DOI ] http://ift.tt/2tsivEN

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The new article is now available. Nippon Ronen Igakkai Zasshi. Japanese Journal of Geriatrics

[ Advance Publication ] [ Title ] [ Author ] , [ Advance Pub. date ] 2017-07-20 [ DOI ] http://ift.tt/2ts4p6y

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Identification of new tumor suppressor genes in triple-negative breast cancer

Although genomic sequencing has provided a better understating of the genetic landmarks in triple-negative breast cancer (TNBC), functional validation of candidate cancer genes (CCG) remains unsolved. In this study, we used a transposon mutagenesis strategy based on a two-step Sleeping Beauty (SB) forward genetic screen to identify and validate new tumor suppressors (TS) in this disease. We generated 120 siRNAs targeting 40 SB-identified candidate breast cancer TS genes and used them to downregulate expression of these genes in four human TNBC cell lines. Among CCG whose SB-mediated genetic mutation resulted in increased cellular proliferation in all cell lines tested, the genes ADNP, AP2B1, TOMM70A and ZNF326 showed tumor suppressor (TS) activity in tumor xenograft studies. Subsequent studies showed that ZNF326 regulated expression of multiple EMT and cancer stem cell (CSC) pathway genes. It also modulated expression of TS genes involved in the regulation of migration and cellular invasion and was a direct transcriptional activator of genes that regulate CSC self-renewal. ZNF326 expression associated with TNBC patient survival, with ZNF326 protein levels showing a marked reduction in TNBC. Our validation of several new tumor suppressor genes in TNBC demonstrate the utility of two-step forward genetic screens in mice, and offer an invaluable tool to identify novel candidate therapeutic pathways and targets.

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quality of care; +1347 new citations

1347 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

quality of care

These pubmed results were generated on 2017/07/19

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.



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Regenerative Potential of Spermatogonial Stem Cells, Endothelial Progenitor Cells, and Epithelial Progenitor Cells of C57Bl/6 Male Mice with Metabolic Disorders

The properties of spermatogonial stem cells, endothelial progenitor cells, and the epithelial progenitors of C57Bl/6 mice under conditions of metabolic disorders were studied using the model of busulfan-induced suppression of spermatogenesis and in vitro culture technique. Spermatogonial stem cells CD117—CD90+ and epithelial progenitors CD45—CD31—Sca-1+CD49f+ derived from the testes of mice with metabolic disturbances demonstrated 17- and 28-fold increase in the respective cell mass and generated cell colonies in vitro. In contrast, spermatogonial stem cells with immune phenotype CD51—CD24+CD52+ had reduced selfrenewal capacity. Spermatogonial stem cells CD117—CD90+ and CD117+CD90+ as well as endothelial progenitors CD45—CD31+ derived from the testes of donor mice with metabolic disorders demonstrated high transplantation capacity in C57Bl/6 mouse testes damaged by cytostatic busulfan.



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Virtual Experimental Validation of Dynamic Osteosynthesis in the Treatment of Fractures of the Proximal Femur

Volume model of transtrochanteric fracture of the femoral bone fixed by Targon PF dynamic fixator was studied by the finite element analysis. The following parameters were measured: magnitude and direction of displacement of system elements, pressure between fragments, and von Mises stress distribution in the fixator depending on support screw plunging into the sleeve. The results indicate that stability of the bone-nail system increases during fracture union and 10-mm shortening of the femoral neck axis, which is seen from a decrease in system deformation under load by 16.8%, stress in the implant by 20.2%, and pressure in the zone of fragments contact by 19.8%.



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Dipeptidyl Peptidase 4 Inhibitors Diprotin A and Sitagliptin Administered on Weeks 2-3 of Postnatal Development Modulate Monoamine Metabolism in the Striatum of Adult Rats

The levels of monoamines and their metabolites in brain structures of adult (3-month-old) rats with emotional and motivational disorders induced by inhibitors of dipeptidyl peptidase 4 (DPP-4; EC 3.4.14.5) diprotin A and sitagliptin on weeks 2-3 of postnatal development (postnatal days 5-18) were studied by HPLC with electrochemical detection. A significant decrease in the level of serotonin metabolite, 5-hydroxyindoleacetic acid, and a pronounced tendency towards reduced serotonin level were detected in the striatum of rats in both study groups. In adult rats treated with diprotin A during the neonatal period, a tendency towards activation of dopamine metabolism was observed (judging from DOPAC/DA ratio). The levels of monoamines and their metabolites in the frontal cortex, hypothalamus, and amygdala remained unchanged. The findings suggest that administration of DPP-4 inhibitors during the neonatal period induces long-term dysfunction of the serotonergic and dopaminergic systems of the brain.



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A Study of the Protective Properties of an Antibody-Based Antidote Metabolizing Organophosphorus Pesticide Paraoxon

A catalytic antibody A17 and its mutants highly efficiently interact with organophosphorus pesticide paraoxon. In this work, we studied the protective properties of antibody A17-K47 in paraoxon poisoning using a mouse model. The optimal paraoxon dose simulating the acute toxic effect of organophosphorus compounds was 550 μg/kg. The pharmacokinetic parameters of A17-K47 antibody were t1/2distr =7.2±1.4 min, t1/2el =330±20 min. The antibody did not cause toxic effects when administered at a ten-fold calculated therapeutic dose (610 mg/kg). The drug did not reduce mortality from acute paraoxon poisoning; however, the absence of drug toxicity opens up prospects for its use in symptomatic treatment of chronic paraoxon poisoning.



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Mechanisms of Sensitivity of Soft Tissue Sarcoma Cells to Temozolomide

We studied the mechanisms of sensitivity of soft tissue sarcoma cells to alkylating agent temozolomide. The mechanisms of tumor cell sensitivity to temozolomide are complex and are determined by not only the level of O6-methylguanine-DNA-methyltransferase (MGTM) expression, but also activity of oncosuppressor protein p53. A-673 Ewing’s sarcoma cells were found to be the most sensitive to temozolomide, whereas temozolomide-treated SK-LMS-1 leiomyosarcoma cells exhibited signs of cell aging.



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Immunolocation of Heme Oxygenases in the Walls of Cerebral Arteries of Various Diameters in Rats

The distribution of two enzymes involved in the formation of carbon monoxide, heme oxygenases 1 and 2, in the pial branches of orders I-V of the middle cerebral artery basin and in intracerebral vessels was studied in adult Wistar rats. Immunohistochemical studies detected hemeoxygenase-2 in the endothelium of the small pial and intracerebral arterioles and in myocytes of pial branches I-III. Heme oxygenase 1, an inducible form of the enzyme, is normally not expressed in the cerebral vessels, but the enzyme is expressed in response to sodium metaarsenite. In this case, heme oxygenase markers are detected in myocytes of pial arteries I-II and in the endothelium of small pial and intracerebral vessels. Sodium meta-arsenite is inessential for immunolocation and quantitative distribution of heme oxygenase 2 in the vessels.



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Study of Proliferative Activity of Vaginal Epithelium in Women with Stress Urinary Incontinence Treated by Er:YAG Laser

The expression of Ki-67 proliferation marker was studied in vaginal biopsy specimens from women with stress urinary incontinence treated using a Fotona nonablative erbium laser. Cells expressing Ki-67 were located in all cases in the parabasal and basal levels of stratified squamous epithelium, the index of labeled nuclei before Er:YAG laser exposure was 19.05±2.86%. After 1-2 months of laser therapy, the index of labeled nuclei in the epithelium increased significantly and reached 31.79±2.25%. These changes were interpreted as a result of epithelial-stromal interactions. Presumably, the increase in proliferative activity of the vaginal epithelium after exposure to Er:YAG laser was due to the presence of an appreciable level of synthetically active fibroblasts in the subepithelial stroma.



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Cysteine-Containing Peptides Stimulate Monocyte Migration through NADPH-Oxidase Activation

We analyzed migration of monocytes under the effect of apocinin (NADPH inhibitor) and PD98059 (blocker of extracellular MEK/ERK kinase involved in Nox4 oxidase-mediated migration of monocytes). Migration of monocytes stimulated by cysteine-containing peptides (fragments of chemokines with free thiol group MCP-1 and fractalkine) was completely inhibited by apocinin and MEK/ERK blocker. It is assumed that the stimulating effect of cysteine-containing peptides on monocyte migration is mediated by the NADPH-oxidase system, in particular, Nox4.



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Characteristics of Mel Ibr Melanoma Line Subclone after Treatment with Chicken Embryo Extract

We continue analysis of the phenotype of human melanoma cell Mel Ibr subclone obtained previously by treatment of the parental cell line by chicken embryo extract. The present study is focused on detection of markers of epithelial-mesenchymal transition that determine enhanced metastatic and invasive potential of malignant tumors of various locations. Analysis of the expression of E-cadherin and vimentin genes in the subclone and parental cells detected activation of epithelial-mesenchymal transition in the subclone. Immunological markers CD90, CD271, and CD95 were present in the parental population, but were not detected on the subclone cells. In contrast to the parental line, cells of the analyzed subclone retain viability in serum-free medium and formed vessel-like structures characteristic of vasculogenic mimicry.



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Approaches to Controlled Co-Amplification of Genes for Production of Biopharmaceuticals: Study of the Insertion and Amplification Dynamics of Genetic Cassettes in the Genome of Chinese Hamster Ovary Cells during Co-Expression of Compatible Pair of Plasmids

Plasmid vector family p1.1 based on non-coding regions of Chinese hamster housekeeping gene EEF1A and concatemer of Epstein—Barr virus terminal repeat increases the frequency of genome integration and provides rapid amplification of the target genes in the genome. For a pair of fluorescent proteins eGFP and mCherry it was shown that p1.1 vectors bearing dihydrofolate reductase and glutamine synthetase selection markers upon co-transfection into CHO DG44 cell line allow obtaining a polyclonal cell population in which ~70% of cells express both genes. The subsequent one-step gene amplification of the genome-integrated genetic cassettes under the selective pressure of increased concentrations of methotrexate can increase the expression of both integrated genes up to 8.2% eGFP and 9.9% mCherry of total protein. This approach can be used for the development of cell lines for the production of functional heterodimeric proteins, e.g. polypeptide hormones and therapeutic antibodies.



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Effect of Phenibut and Glufimet, a Novel Glutamic Acid Derivative, on Respiration of Heart and Brain Mitochondria from Animals Exposed to Stress against the Background of Inducible NO-Synthase Blockade

Increased oxygen consumption by heart and brain mitochondria in the absence of ADP and reduced mitochondrial respiration in the presence of ADP were observed in rats exposed to stress simulated by suspension by the dorsal neck skin fold for 24 h, which attests to uncoupling of substrate oxidation and ATP synthesis and can cause electron drain from the respiratory chain, formation of ROS, and oxidative damage to cell structures. Blockade of inducible NO synthase with aminoguanidine (single intraperitoneal dose of 50 mg/kg before stress exposure) increased coupling of respiration and oxidative phosphorylation in heart and brain mitochondria of rats exposed to immobilization-painful stress, which was especially pronounced in cardiomyocytes. The test compounds glufimet (single intraperitoneal dose of 29 mg/kg before stress exposure) and phenibut (single intraperitoneal dose of 50 mg/kg before stress exposure) limited stress-induced mitochondrial damage against the background of inducible NO synthase blockade and without it, which was seen from increased respiratory control ratio in comparison with that in untreated rats exposed to stress (control).



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Trajectories of health-related quality of life among family caregivers of individuals with dementia: A home-based caregiver-training program matters.

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Trajectories of health-related quality of life among family caregivers of individuals with dementia: A home-based caregiver-training program matters.

Geriatr Nurs. 2017 Mar - Apr;38(2):124-132

Authors: Kuo LM, Huang HL, Liang J, Kwok YT, Hsu WC, Liu CY, Shyu YL

Abstract
To determine distinct courses of change in health-related quality of life (HRQoL) among family caregivers of individuals with dementia and how participating in a home-based caregiver-training program affects the probability of belonging to each course. Sixty three caregivers were in the intervention group, and 66 caregivers were in the control group of a single-blinded randomized clinical trial. Two distinct trajectories of HRQoL were identified: a well-functioning trajectory and a poor-functioning trajectory. Caregivers who received the training program were more likely than those who did not have a well-functioning trajectory of HRQoL over 18 months. This trajectory included bodily pain (b = 1.02, odds ratio [OR] = 2.76), general health perception (b = 1.28, OR = 3.60), social functioning (b = 1.12, OR = 3.05), vitality (b = 1.51, OR = 4.49), general mental health (b = 1.08, OR = 2.94), and mental component summary (b = 1.27, OR = 3.55). Home-based caregiver training can be considered as part of the protocol for managing patients with dementia and their caregivers.
TRIAL REGISTRATION NUMBER: NCT02667951.

PMID: 27720499 [PubMed - indexed for MEDLINE]



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Compassion fatigue among nurses working with older adults.

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Compassion fatigue among nurses working with older adults.

Geriatr Nurs. 2017 Mar - Apr;38(2):106-109

Authors: Kolthoff KL, Hickman SE

Abstract
Nurses who care for older patients are exposed to significant suffering and loss that can lead to the development of compassion fatigue and burnout. An exploratory descriptive study was conducted to assess compassion fatigue, burnout, and compassion satisfaction in a group of 42 nurses who worked on a geriatric medicine unit using the Professional Quality of Life (ProQOL) compassion satisfaction and compassion fatigue 5 scale. Nurses reported average levels of compassion fatigue, burnout, and compassion satisfaction. However, new nurses reported higher levels of compassion fatigue (p < .01) and burnout (p = .02) than experienced nurses. Findings suggest the need to purposely build a supportive environment that focuses on new nurses to reduce compassion fatigue and burnout while enhancing compassion satisfaction.

PMID: 27600754 [PubMed - indexed for MEDLINE]



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A Multifactorial Weight Reduction Programme for Children with Overweight and Asthma: A Randomized Controlled Trial.

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A Multifactorial Weight Reduction Programme for Children with Overweight and Asthma: A Randomized Controlled Trial.

PLoS One. 2016;11(6):e0157158

Authors: Willeboordse M, van de Kant KDG, Tan FE, Mulkens S, Schellings J, Crijns Y, Ploeg Lv, van Schayck CP, Dompeling E

Abstract
BACKGROUND: There is increasing evidence that obesity is related to asthma development and severity. However, it is largely unknown whether weight reduction can influence asthma management, especially in children.
OBJECTIVE: To determine the effects of a multifactorial weight reduction intervention on asthma management in overweight/obese children with (a high risk of developing) asthma.
METHODS: An 18-month weight-reduction randomized controlled trial was conducted in 87 children with overweight/obesity and asthma. Every six months, measurements of anthropometry, lung function, lifestyle parameters and inflammatory markers were assessed. Analyses were performed with linear mixed models for longitudinal analyses.
RESULTS: After 18 months, the body mass index-standard deviation score decreased by -0.14±0.29 points (p<0.01) in the intervention group and -0.12±0.34 points (p<0.01) in the control group. This change over time did not differ between groups (p>0.05). Asthma features (including asthma control and asthma-related quality of life) and lung function indices (static and dynamic) improved significantly over time in both groups. The FVC% predicted improved over time by 10.1 ± 8.7% in the intervention group (p<0.001), which was significantly greater than the 6.1 ± 8.4% in the control group (p<0.05).
CONCLUSIONS & CLINICAL RELEVANCE: Clinically relevant improvements in body weight, lung function and asthma features were found in both the intervention and control group, although some effects were more pronounced in the intervention group (FVC, asthma control, and quality of life). This implies that a weight reduction intervention could be clinically beneficial for children with asthma.
TRIAL REGISTRATION: ClinicalTrials.gov NCT00998413.

PMID: 27294869 [PubMed - indexed for MEDLINE]



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Validating a Patient-Reported Comorbidity Measure with Respect to Quality of Life in End-Stage Renal Disease.

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Validating a Patient-Reported Comorbidity Measure with Respect to Quality of Life in End-Stage Renal Disease.

PLoS One. 2016;11(6):e0157506

Authors: Robinski M, Strich F, Mau W, Girndt M

Abstract
PURPOSE: Medical record-derived comorbidity measures such as the Charlson Comorbidity Index (CCI) do not predict functional limitations or quality of life (QoL) in the chronically ill. Although these shortcomings are known since the 1980s, they have been largely ignored by the international literature. Recently, QoL has received growing interest as an end-point of interventional trials in Nephrology. The aim of this study is to compare a patient-reported comorbidity measure and the CCI with respect to its validity regarding QoL.
METHODS: The German Self-Administered Comorbidity Questionnaire (SCQ-G) was completed by 780 adult end-stage renal disease-patients recruited from 55 dialysis units throughout Germany. Acceptance was evaluated via response rates. Content validity was examined by comparing the typical comorbidity pattern in dialysis patients and the pattern retrieved from our data. Convergent validity was assessed via kappa statistics. Data was compared to the CCI. Linear associations with QoL were examined (criterion validity).
RESULTS: The SCQ-G was very well accepted by dialysis patients of all ages (response rate: 99%). Content validity can be interpreted as high (corresponding comorbidity items: 73.7%). Convergent validity was rather weak (.27≤ρ≤.29) but increased when comparing only concordant items (.39≤ρ≤.43). With respect to criterion validity, the SCQ-G performed better than the CCI regarding the correlation with QoL (e.g., SF-12-physical: SCQ-G total score: ρ = -.49 vs. CCI: ρ = -.36).
CONCLUSIONS: The patient-reported measure proved to be more valid than the external assessment when aiming at insights on QoL. Due to the inclusion of subjective limitations, the SCQ-G is more substantial with respect to patient-centered outcomes and might be used as additional measure in clinical trials.

PMID: 27294867 [PubMed - indexed for MEDLINE]



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Computational validation of the recently proposed pollen season definition criteria.

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Computational validation of the recently proposed pollen season definition criteria.

Allergy. 2017 Jul 18;:

Authors: Karatzas K, Riga M, Berger U, Werchan M, Pfaar O, Bergmann KC

Abstract
In a recently published paper (Pfaar et al., 2016), a Task Force of the Immunotherapy and Aerobiology and Pollution Interest Groups of the EAACI suggested specific criteria for the definition of pollen exposure times for three types of pollen events: (a) Pollen Season (PS) start and end, (b) high pollen season (or Peak Pollen Period-PPP) start and end, and (c) high pollen days. Species addressed included Birch, Grasses, Cypress, Olive, and Ragweed. Two important questions arise from the aforementioned definitions: (i) do they lead to a narrow (thus well defined) time interval identifying start and end event dates (robustness of the criteria) and (ii) if slightly altered, will they result to a narrow (thus again well defined) fluctuation of start and end event dates (sensitivity of the criteria)? In an effort to provide with responses to aforementioned questions, we analyzed Poaceae pollen count data coming from Germany (up to 40 pollen monitoring stations, years 2012-2016). The analysis addressed all pollen events for the first question, and focused on the PS and PPP start and end events for the second question. This article is protected by copyright. All rights reserved.

PMID: 28718953 [PubMed - as supplied by publisher]



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Secreted Protein Acidic and Rich in Cysteine (SPARC) Enhances Cell Proliferation, Migration, and Epithelial Mesenchymal Transition, and SPARC Expression is Associated with Tumor Grade in Head and Neck Cancer.

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Secreted Protein Acidic and Rich in Cysteine (SPARC) Enhances Cell Proliferation, Migration, and Epithelial Mesenchymal Transition, and SPARC Expression is Associated with Tumor Grade in Head and Neck Cancer.

Int J Mol Sci. 2017 Jul 18;18(7):

Authors: Chang CH, Yen MC, Liao SH, Hsu YL, Lai CS, Chang KP, Hsu YL

Abstract
Secreted protein acidic and rich in cysteine (SPARC) is a secreted protein which is involved in various biological processes. SPARC expression is associated with tumor metastasis and poor prognosis in several types of cancer. However, the SPARC-induced signaling pathway was not fully understood in head and neck cancer. In this study, our results showed that SPARC treatment promoted cell proliferation and migration in head and neck cancer cell lines FaDu and Detroit 562. In addition, SPARC induced expression of epithelial mesenchymal transition (EMT) regulators, including Slug, Snail, and Twist in Detroit 562. The results of phospho-kinase array analysis showed that SPARC treatment increased phosphorylation of some molecules including protein kinase B (PKB/AKT), ribosomal S6 kinase (RSK), and extracellular signal-regulated kinases (ERK). The expression of SPARC-induced EMT regulator Slug was suppressed by AKT inhibitor, but not ERK and RSK inhibitors. The SPARC expression in grade IV tumor samples is higher when compared to that in grade I-III tumor samples. Our results suggest that SPARC treatment enhances the EMT signaling pathway via activation of AKT, and exogenous SPARC and tumor expressing SPARC might be associated with tumor progression in head and neck cancers.

PMID: 28718842 [PubMed - in process]



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Regional Delivery of Chimeric Antigen Receptor (CAR) T-Cells for Cancer Therapy.

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Regional Delivery of Chimeric Antigen Receptor (CAR) T-Cells for Cancer Therapy.

Cancers (Basel). 2017 Jul 18;9(7):

Authors: Sridhar P, Petrocca F

Abstract
Chimeric Antigen Receptor (CAR) T-cells are T-cells with recombinant receptors targeted to tumor antigens. CAR-T cell therapy has emerged as a mode of immunotherapy and is now being extensively explored in hematologic cancer. In contrast, CAR-T cell use in solid tumors has been hampered by multiple obstacles. Several approaches have been taken to circumvent these obstacles, including the regional delivery of CAR-T cells. Regional CAR-T cell delivery can theoretically compensate for poor T-cell trafficking and tumor antigen specificity while avoiding systemic toxicity associated with intravenous delivery. We reviewed completed clinical trials for the treatment of glioblastoma and metastatic colorectal cancer and examined the data in these studies for safety, efficacy, and potential advantages that regional delivery may confer over systemic delivery. Our appraisal of the available literature revealed that regional delivery of CAR-T cells in both glioblastoma and hepatic colorectal metastases was generally well tolerated and efficacious in select instances. We propose that the regional delivery of CAR-T cells is an area of potential growth in the solid tumor immunotherapy, and look towards future clinical trials in head and neck cancer, mesothelioma, and peritoneal carcinomatosis as the use of this technique expands.

PMID: 28718815 [PubMed]



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Therapeutic Efficacy of the Novel Stimuli-Sensitive Nano-Ferritins Containing Doxorubicin in a Head and Neck Cancer Model.

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Therapeutic Efficacy of the Novel Stimuli-Sensitive Nano-Ferritins Containing Doxorubicin in a Head and Neck Cancer Model.

Int J Mol Sci. 2017 Jul 18;18(7):

Authors: Damiani V, Falvo E, Fracasso G, Federici L, Pitea M, De Laurenzi V, Sala G, Ceci P

Abstract
Doxorubicin is employed alone or in combination for the treatment of several hematological and solid malignancies; despite its efficacy, there are associated cardiotoxicity limits both in its application in patients with heart disease risk factors and also in its long-term use. HFt-MP-PAS40 is a genetically engineered human ferritin heavy chain (HFt)-based construct able to efficiently entrap and deliver doxorubicin to cancer cells. HF-MP-PAS contains a short motif sequence (defined as MP) responsive to proteolytic cleavage by tumor matrix metalloproteases (MMPs), located between each HFt subunit and a masking polypeptide sequence rich in proline (P), alanine (A), and serine (S) residues (PAS). This carrier displayed excellent therapeutic efficacy in a xenogenic pancreatic cancer model in vivo, leading to a significant increase in overall animal survival in treated mice. Herein, we describe the HFt-MP-PAS40-Dox efficacy against squamous cell carcinomas of the head and neck (HNSCC) with the goal of validating the application of our nano-drug for the treatment of different solid tumors. In addition, a tolerability study in healthy mice was also performed. The results indicate that HFt-MP-PAS40-Dox produced increased anti-tumor effects both in vitro and in vivo in comparison to the free drug in several HNSCC cell lines. In the acute toxicity studies, the maximum tolerated dose (MTD) of HFt-MP-PAS40-Dox was about 3.5 higher than the free drug: 25 mg/kg versus 7 mg/kg doxorubicin equivalents. Importantly, evaluation of heart tissues provided evidence that doxorubicin is less cardio-toxic when encapsulated inside the ferritin carrier. In conclusion, HFt-MP-PAS40-Dox may be administered safely at higher doses compared with the free drug, resulting in superior efficacy to control HNSCC malignancies.

PMID: 28718812 [PubMed - in process]



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Efficient Approximation of the Labeled Multi-Bernoulli Filter for Online Multitarget Tracking

Online tracking time-varying number of targets is a challenging issue due to measurement noise, target birth or death, and association uncertainty, especially when target number is large. In this paper, we propose an efficient approximation of the Labeled Multi-Bernoulli (LMB) filter to perform online multitarget state estimation and track maintenance efficiently. On the basis of the original LMB filer, we propose a target posterior approximation technique to use a weighted single Gaussian component representing each individual target. Moreover, we present the Gaussian mixture implementation of the proposed efficient approximation of the LMB filter under linear, Gaussian assumptions on the target dynamic model and measurement model. Numerical results verify that our proposed efficient approximation of the LMB filer achieves accurate tracking performance and runs several times faster than the original LMB filer.

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The Role of Intereukin-31 in Pathogenesis of Itch and Its Intensity in a Course of Bullous Pemphigoid and Dermatitis Herpetiformis

Itch which is one of the major, subjective symptoms in a course of bullous pemphigoid and dermatitis herpetiformis makes those two diseases totally different than other autoimmune blistering diseases. Its pathogenesis is still not fully known. The aim of this research was to assess the role of IL-31 in development of itch as well as to measure its intensity. Obtained results, as well as literature data, show that lower concentration of IL-31 in patients’ serum may be correlated with its role in JAK/STAT signaling pathway which is involved in development of autoimmune blistering disease. Intensity of itch is surprisingly huge problem for the patients and the obtained results are comparable with results presented by atopic patients.

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Osteopontin induced vascular endothelial growth factor production in dispersed nasal polyp cells through the phosphatidylinositol 3-kinase‐protein kinase B and the extracellular signal-regulated kinase 1/2 pathways



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Proteolytic effects of gingipains on trefoil factor family peptides

Abstract

Objectives

The present study was aimed to determine whether trefoil factor family (TFF) peptides which were generally considered to be resistant to proteolysis could be digested by gingipains, a major proteinases produced by Porphyromonas gingivalis.

Materials and methods

Recombinant human TFF1, TFF2, and TFF3 peptides were used as substrates. Gingipains including arginine gingipain (RgpB) and lysine gingipain (Kgp) were used as enzymes. Trypsin was used as a control protease. Matrix-assisted laser desorption/ionization with time-of-flight/time-of-flight (MALDI-TOF/TOF) and liquid chromatography mass spectrometry (LC-MS) were used for analyzing peptide mass signals and amino acid sequences of digested TFF peptides.

Results

MALDI-TOF/TOF analyses demonstrated that Kgp, RgpB, and trypsin were able to cleave TFF1 and TFF2 peptides, resulting in different patterns of digested fragments. However, impurity in recombinant TFF3 peptide substrates affected the interpretations of enzymatic reaction by MALDI-TOF/TOF. LC-MS analyses demonstrated that identified fragments of TFF1, TFF2, and TFF3 from digestion by gingipains were similar to those by trypsin.

Conclusions

Using MALDI-TOF/TOF and LC-MS, the present study provides new information that gingipains containing trypsin-like activities are able to digest TFF peptides.

Clinical relevance

The proteolytic effects of gingipains on TFF peptides may be responsible for reduction of salivary TFF peptides in chronic periodontitis patients. Further investigations to determine the pathological effects of gingipains on TFF peptides in saliva and periodontal tissues of patients with chronic periodontitis would be of interest.



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Specialised in Head & Neck cancer: 93-bed cancer hospital to come up in Mazgaon - The Indian Express

cancer.jpg

The Indian Express
Specialised in Head & Neck cancer: 93-bed cancer hospital to come up in Mazgaon
The Indian Express
Tata hospital alone receives over 70,000 cancer patients from across India in a year. Planned with a budget of Rs 140 crore under PPP, the hospital will specialise in head and neck cancer treatment and will cost at par with Tata Memorial Hospital ...



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Paleo Profile: The Elephant Bird Mimic

A fossil foot gives away a new dinosaur species.

-- Read more on ScientificAmerican.com
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Experimental Determination of the Ionization Energies of MoSe2, WS2, and MoS2 on SiO2 Using Photoemission Electron Microscopy

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b03242
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Competing Annulene and Radialene Structures in a Single Anti-Aromatic Molecule Studied by High-Resolution Atomic Force Microscopy

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ACS Nano
DOI: 10.1021/acsnano.7b02973
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Flexible and Robust Superomniphobic Surfaces Created by Localized Photofluidization of Azopolymer Pillars

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b01783
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Paleo Profile: Currie's Alberta Hunter

albertavenator-skull.jpg

Sometimes a single bone can give away the presence of an unknown dinosaur.

-- Read more on ScientificAmerican.com
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