Ιατρικά Άρθρα

Παρασκευή 10 Φεβρουαρίου 2017

Hydrozirconated styrene copolymer as a macroinitiator to in situ synthesize polyethylene/polystyrene-g-polyethylene alloy via coordination polymerization

Publication date: 10 March 2017
Source:Polymer, Volume 112
Author(s): Yanhui Wang, Yichao Lin, Jun Zheng, Lin Ye, Zi'an Chen, Tao Tang
A new method to in situ synthesize polyethylene/polystyrene-g-polyethylene (PE/PS-g-PE) alloy based on hydrozirconation reaction with Cp2ZrHCl and coordination polymerization was reported. Hydrozirconation of vinyl-containing polystyrene (copolymer of styrene and 4-(vinylphenyl)-1-butene (PSVS)) was found to be an efficient way for immobilization of zirconocene pre-initiator onto polymer backbone by carbon-zirconium (C-Zr) sigma (σ) bond. By activation with MAO, the resultant hydrozirconated PSVS could act as a macroinitiator with multiple-initiating sites (Zr^δ+-C^δ-) for ethylene insertion and propagation in "graft from" fashion. The hydrozirconation and the following ethylene polymerization were monitored by NMR and GPC, revealing the successful synthesis of PS-g-PE and the following formation of free PE chains due to chain transfer characteristic of metallocene catalyst. Thus we could prepare PE/PS-g-PE alloy through in situ ethylene polymerization by this method. The presence of PS-g-PE in the resultant alloy endowed some special functionalization, for example, acting as compatibilizer in PE/PS blends.

Graphical abstract

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Characterization of hard-segment crystalline phase of thermoplastic polyurethane in the presence of butane and glycerol monosterate and its impact on mechanical property and microcellular morphology

Publication date: 10 March 2017
Source:Polymer, Volume 112
Author(s): N. Hossieny, V. Shaayegan, A. Ameli, M. Saniei, C.B. Park
The effects of glycerol monosterate (GMS) and high-pressure butane on the phase-separation and crystallization of the hard segment (HS) of thermoplastic polyurethane (TPU) were investigated. Small and wide angle x-ray diffraction, polarized optical microscopy and atomic force microscopy were used to characterize the crystalline morphology of TPU under various conditions. Overall, 60% higher HS crystallinity was observed in TPU-GMS samples annealed with butane compared to the neat-TPU samples. The toughness and Young Modulus in the TPU-GMS samples were increased due to the higher HS crystallinity compared to the neat-TPU samples. The HS crystallites were effectively utilized as heterogeneous bubble nucleation sites to induce microcellular morphologies in the TPU microstructure. Compared to neat-TPU, the TPU-GMS microcellular morphology showed higher cell density over the wide saturation temperature of 150–170 °C due to the increased HS phase separation and crystallization mechanism in the presence of GMS and dissolved butane.

Graphical abstract

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Smart polyolefins feeling the force: Color changeable poly(ethylene-vinyl acetate) and poly(ethylene-octene) in response to mechanical force

Publication date: 10 March 2017
Source:Polymer, Volume 112
Author(s): Meng Li, Weifeng Liu, Shiping Zhu
Spiropyran (SP) mechanophore cross-linker was covalently incorporated into two widely used polyolefins, poly(ethylene-vinyl acetate) (EVA) and poly(ethylene-octene) (EOC), through facile cross-linking by peroxide under hot press. It was found that (1'-(2-(methacryloyloxy)ethyl)-3′,3′ dimethylspiro[chromene-2,2'-indolin]-6-yl)methyl methacrylate (SP3) could not be thermally driven to merocyanine (MC) in polyolefins during high temperature cross-linking, which is superior to other types of SP mechanophores used for polymer processing. The force-induced ring-opening reaction of SP-to-MC was demonstrated on SP3-cross-linked EVA. It was found that increasing the SP content resulted in earlier activation and that more MC was driven from SP at a slower strain rate. When held at constant strain, MC gradually reverted to SP. The mechanoactivation of SP was also investigated for SP3-cross-linked EOC. This work represents the first example of color-changeable polyolefins in response to mechanical force and demonstrates the feasibility of applying mechanophores to widely-used commercial polyolefins for stress sensing.

Graphical abstract

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Predatory Invitations from Journals: More Than Just a Nuisance?

Physicians and academic researchers are frequently targeted with spam invitations to submit manuscripts to predatory journals. This study was conducted to understand the nature and characteristics of these invitations. All spam e-mails received by an academic medical oncologist over a 3-month period were collected and categorized. Presumed predatory journal invitations were analyzed and cross-checked against Beall's list of "potential, probable, or possible predatory" journals and publishers. Invitations to submit to predatory journals were the most common single type of spam received. The Oncologist 2017;22:00–00

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Validation of Progression-Free Survival as a Surrogate Endpoint for Overall Survival in Malignant Mesothelioma: Analysis of Cancer and Leukemia Group B and North Central Cancer Treatment Group (Alliance) Trials

Purpose.

The aim of this study was to investigate whether progression-free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in malignant mesothelioma.

Materials and Methods

Individual data were collected from 15 Cancer and Leukemia Group B (615 patients) and 2 North Central Cancer Treatment Group (101 patients) phase II trials. The effects of 5 risk factors for OS and PFS, including age, histology, performance status (PS), white blood cell count, and European Organisation for Research and Treatment of Cancer (EORTC) risk score, were used in the analysis. Individual-level surrogacy was assessed by Kendall's tau through a Clayton bivariate Copula survival (CBCS) model. Summary-level surrogacy was evaluated via the association between logarithms of the hazard ratio (log HR)—log HR_OS and log HR_PFS—measured in R² from a weighted least-square (WLS) regression model and the CBCS model.

Results.

The median PFS for all patients was 3.0 months (95% confidence interval [CI], 2.8–3.5 months) and the median OS was 7.2 months (95% CI, 6.5–8.0 months). Moderate correlations between PFS and OS were observed across all risk factors at the individual level, with Kendall's tau ranging from 0.46 to 0.47. The summary-level surrogacy varied among risk factors. The Copula R² ranged from 0.51 for PS to 0.78 for histology. The WLS R² ranged from 0.26 for EORTC and PS to 0.67 for age.

Conclusions.

The analyses demonstrated low to moderate individual-level surrogacy between PFS and OS. At the summary level, the surrogacy between PFS and OS varied significantly across different risk factors. With a short postprogression survival and a moderate correlation between PFS and OS, there is no evidence that PFS is a valid surrogate endpoint for OS in malignant mesothelioma. The Oncologist 2017;22:000–000

Implications for Practice

For better disease management and for more efficient clinical trial designs, it is important to know if progression-free survival (PFS) is a good surrogate endpoint for overall survival in malignant mesothelioma. With a relatively large database of 17 phase II trials and 716 patients from Cancer and Leukemia Group B and North Central Cancer Treatment Group, we conducted statistical analyses and found that there is no evidence to suggest that PFS is a valid surrogate endpoint for OS for malignant mesothelioma. Future research work is needed to find alternative surrogate endpoints for OS.

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Too Many Journals

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Immune checkpoint receptors in cancer: redundant by design?

Publication date: April 2017
Source:Current Opinion in Immunology, Volume 45
Author(s): Jing Li, Ling Ni, Chen Dong
Co-inhibitory receptors expressed on activated immune cells function to regulate T cell tolerance to self-antigens, also serving by tumor cells to escape from eradication by the host immune system. Therefore, blockade of immune checkpoint receptors (ICR) has become a promising immunotherapeutic strategy for treatment of a wide variety of cancers. However, blockade of one of the immune checkpoint receptors alone is often not sufficiently effective; co-blockade shows synergic effects in reversing immunosuppression. In this article, we summarize the expression patterns, mechanisms of action of different ICRs as well as the stages and sites they function in, and discuss how they execute non-redundant suppressive effects in anti-tumor immunity.

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Dendritic cells in cancer: the role revisited

Publication date: April 2017
Source:Current Opinion in Immunology, Volume 45
Author(s): Filippo Veglia, Dmitry I Gabrilovich
Dendritic cells (DCs) with their potent antigen presenting ability are long considered as critical factor in antitumor immunity. Despite high potential in promoting antitumor responses, tumor-associated DCs are largely defective in their functional activity and can contribute to immune suppression in cancer. In recent years existence of immune suppressive regulatory DCs in tumor microenvironment was described. Monocytic myeloid derived suppressor cells (M-MDSCs) can contribute to the pool of tumor associated DCs by differentiating to inflammatory DCs (inf-DCs), which appear to have specific phenotype and is critical component of antitumor response. Here we examine the role of inf-DCs along with other DC subsets in the regulation of immune responses in cancer. These novel data expand our view on the role of DCs in cancer and may provide new targets for immunotherapy.

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Potential role for growth hormone-releasing hormone in triple-negative breast cancer

Publication date: Available online 10 February 2017
Source:Peptides
Author(s): Alice Lee

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ANGIOTENSIN-(1-7)-DEPENDENT VASORELAXATION OF THE RENAL ARTERY EXHIBITS UNIQUE ANGIOTENSIN AND BRADYKININ RECEPTOR SELECTIVITY

Publication date: Available online 10 February 2017
Source:Peptides
Author(s): Mariam H.M. Yousif, Ibrahim F. Benter, Debra I. Diz, Mark C. Chappell
Angiotensin-(1-7) [Ang-(1-7)] exhibits blood pressure lowering actions, inhibits cell growth, and reduces tissue inflammation and fibrosis which may functionally antagonize an activated Ang II-AT1 receptor axis. Since the vascular actions of Ang-(1-7) and the associated receptor/signaling pathways varies in different vascular beds, the current study established the vasorelaxant properties of the heptapeptide in the renal artery of male Wistar male rats. Ang-(1-7) produced an endothelium-dependent vasodilator relaxation of isolated renal artery segments pre-contracted by a sub-maximal concentration of phenylephrine (PE) (10⁻⁷M). Ang-(1-7) induced vasodilation of the rat renal artery with an ED50 of 3±1nM and a maximal response of 42±6% (N=10). The two antagonists (10⁻⁵M each) for the AT7/Mas receptor (MasR) [D-Pro⁷]-Ang-(1-7) and [D-Ala⁷]-Ang-(1-7) significantly reduced the maximal response to 12±1% and 18±3%, respectively. Surprisingly, the AT2R receptor antagonist PD123319, the AT1R antagonist losartan and B2R antagonist HOE140 (10⁻⁶M each) also significantly reduced Ang-(1-7)-induced relaxation to 12±2%, 22±3% and 14±7%, respectively. Removal of the endothelium or addition of the soluble guanylate cyclase (sGC) inhibitor ODQ (10⁻⁵M) essentially abolished the vasorelaxant response to Ang-(1-7) (10±4% and 10±2%, P <0.05). Finally, the NOS inhibitor LNAME (10⁻⁴M) reduced the response to 13±2% (p<0.05), but the cyclooxygenase inhibitor indomethacin failed to block the Ang-(1-7) response. We conclude that Ang-(1-7) exhibits potent vasorelaxant actions in the isolated renal artery that are dependent on an intact endothelium and the apparent stimulation of a NO-sGC pathway. Moreover, Ang-(1-7)-dependent vasorelaxation was sensitive to antagonists against the AT7/Mas, AT1, AT2 and B2 receptor subtypes.

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Molecular networks related to the immune system and mitochondria are targets for the pesticide dieldrin in the zebrafish (Danio rerio) central nervous system

Publication date: Available online 10 February 2017
Source:Journal of Proteomics
Author(s): Andrew M. Cowie, Kathleena I. Sarty, Angella Mercer, Jin Koh, Karen A. Kidd, Christopher J. Martyniuk
The objectives of this study were to determine the behavioral and molecular responses in the adult zebrafish (Danio rerio) central nervous system (CNS) following a dietary exposure to the pesticide dieldrin. Zebrafish were fed pellets spiked with 0.03, 0.15, or 1.8μg/g dieldrin for 21days. Behavioral analysis revealed no difference in exploratory behaviors or those related to anxiety. Transcriptional networks for T-cell aggregation and selection were decreased in expression suggesting an immunosuppressive effect of dieldrin, consistent with other studies investigating organochlorine pesticides. Processes related to oxidative phosphorylation were also differentially affected by dieldrin. Quantitative proteomics (iTRAQ) using a hybrid quadrupole-Orbitrap identified 226 proteins that were different in abundance in one or more doses. These included ATP synthase subunits (mitochondrial) and hypoxia up-regulated protein 1 which were decreased and NADH dehydrogenases (mitochondrial) and signal recognition particle 9 which were up-regulated. Thus, proteins affected were functionally associated with the mitochondria and a network implicated PD and Huntington's disease as those associated with proteins. Molecular networks related to mitochondrial dysfunction and T-cell regulation are hypothesized to underlie the association between dieldrin and PD. These data contribute to a comprehensive transcriptomic and proteomic biomarker framework for pesticide exposures and neurodegenerative diseases.Biological significanceDieldrin is a persistent organochlorine pesticide that has been associated with human neurodegenerative disease such as Parkinson's disease. Dieldrin is ranked 18th on the 2015 U.S. Agency for Toxic Substances and Disease Registry and continues to be a pesticide of concern for human health. Transcriptomics and quantitative proteomics (ITRAQ) were employed to characterize the molecular networks in the central nervous system that are altered with dietary exposure to dieldrin. We found that transcriptional and protein networks related to the immune system, mitochondria, and Parkinson's disease were preferentially affected by dieldrin. The study provides new insight into the mechanisms of dieldrin neurotoxicity that may explain, in part, the association between this pesticide and increased risks to neurodegeneration. These data contribute in a significant way to developing a molecular framework for pesticide induced neurotoxicity.

Graphical abstract

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Super-SILAC mix coupled with SIM/AIMS assays for targeted verification of phosphopeptides discovered in a large-scale phosphoproteome analysis of hepatocellular carcinoma

Publication date: Available online 10 February 2017
Source:Journal of Proteomics
Author(s): Yu-Tsun Lin, Kun-Yi Chien, Chia-Chun Wu, Wen-Yu Chang, Lichieh Julie Chu, Min-Chi Chen, Chau-Ting Yeh, Jau-Song Yu
Plentiful studies have established a close association between aberrant phosphorylation and hepatocellular carcinoma (HCC). Here, we applied a quantitative phosphoproteomics platform combining dimethylation labeling and online 3D strong cation exchange chromatography (SCX)-titanium oxide (TiO2)/RP-LTQ-Orbitrap to compare phosphoproteomes between three pairs of HCC tissues and non-tumor counterparts. This analysis yielded 7868 quantifiable phosphopeptides and numerous up- or down-regulated candidates. Increased phosphorylation of LMNA and NIPA was confirmed using specific antibodies. To expand our verification capability, we evaluated the use of LTQ-Orbitrap run in SIM/Accurate inclusion mass screening (AIMS) mode with a super-SILAC mixture as an internal standard to quantify a subset of phosphopeptide candidates in HCC tissue samples. In sample I used for discovery experiment, we successfully quantified 32 (in SIM mode) and 30 (in AIMS mode) phosphopeptides with median coefficients of variation (CVs) of 7.5% and 8.3%, respectively. When the assay was applied to other three pairs of HCC specimens for verification experiment, 40 target phosphopeptides were quantified reliably (~7.5% CV), and more than half of them were differentially expressed between tumor and adjacent non-tumor tissues. Collectively, these results indicate the feasibility of using super-SILAC mix-SIM/AIMS assays for targeted verification of phosphopeptides discovered by large-scale phosphoproteome analyses of HCC specimens.SignificanceIn this study, we developed a strategy for conducting both discovery and targeted verification of deregulated phosphoproteins in HCC tissue specimens on LTQ-Orbitrap. This strategy allowed us to generate a quantitative HCC tissue phosphoproteome dataset containing significantly deregulated phosphoproteins that represents a valuable resource for the identification of potential HCC biomarkers and/or therapeutic targets. Furthermore, our proof-of-concept experiments demonstrated the feasibility of applying LTQ-Orbitrap, operated in SIM/AIMS mode, to multiplex and targeted verification of phosphopeptides in individual tissue specimens using a super-SILAC mix as an internal phosphopeptide standard. This method could be readily applied to verify dozens of phosphopeptide candidates in a larger HCC sample set.

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Calculating the incalculable. Optimal radioiodine dose in Graves’ hyperthyroidism

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Short-term UVB irradiation significantly increases vitamin D serum concentration in obese patients: a clinical pilot study

Abstract

Purpose

Deficiency of vitamin D is very common in obese people and treatment by oral supplementation is not effective in all patients. This exploratory pilot study investigated the influence of different doses of short-term ultraviolet B irradiation on serum 25-hydroxyvitamin-D₃ (25D) and 1,25-dihydroxyvitamin-D₃ (1,25D) levels in obese compared to normal weight subjects and obese controls.

Methods

Participants with skin types II and III (Fitzpatrick skin classification) were assigned to six groups including four intervention groups receiving irradiation (three groups of obese and one group of normal weight subjects) and two control groups without treatment (obese and normal weight). Intervention groups received three sessions of whole body UVB irradiation of three different doses (cumulative doses over three sessions: 0.28, 0.70, 1.75 minimal erythema dose) within 1 week of intervention. Serum 25D and 1,25D were measured at baseline and after irradiation. Outcome differences between groups were analyzed using a linear model.

Results

Serum 25D levels increased significantly in obese (+23.6 and +26.7%, respectively, p = 0.01) and normal weight (+15.6%, p = 0.02) intervention groups who received medium and high doses of ultraviolet B irradiation compared to control groups (+3.5 and −4.0%, respectively, p = 1.0). The increase in obese patients was 51.4% greater compared to normal weight controls irradiated with equal ultraviolet B doses. Low-level ultraviolet irradiation did not result in a significant change in serum 25D (+7.0%, p = 0.61). We did not detect any significant differences of 1,25D between groups (p = 0.25).

Conclusions

The current study indicates that short-term ultraviolet B irradiation increases 25D levels in obese patients.

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Bidirectional relationship between time preference and adolescent smoking and alcohol use: Evidence from longitudinal data

Publication date: July 2017
Source:Addictive Behaviors, Volume 70
Author(s): Young Kyung Do, Eunhae Shin
IntroductionScholarly interest in time preference as a potential predictor of risky health behaviors in adolescents has increased in recent years. However, most of the existing literature is limited due to the exclusive reliance on cross-sectional data, precluding the possibility of establishing the direction of causality. Using longitudinal data from the Korea Youth Panel Survey (2003–7), which followed up a nationally representative sample of 3449 adolescents aged 14years for five years, this study examines a bidirectional relationship between time preference and smoking and drinking behaviors among adolescents.MethodsWe used discrete time hazard models of smoking and drinking initiation as a function of time preference measured at the baseline and fixed-effects ordered logit model of time preference, respectively. Our measure of time preference was derived from the survey question on a hypothetical choice between immediate enjoyment today and likely higher scores on an exam tomorrow.ResultsThe overall results provide evidence on the bidirectional relationship; that is, higher time discounting (i.e., greater relative preference for present utility over future utility) results in an increased risk of engaging in smoking and drinking, and conversely, adopting such behaviors leads to a higher discount rate.ConclusionsThe bidirectional relationship may function as a mechanism for adolescents to engage in increased smoking and drinking or additional negative health behaviors via gateway effects, strengthening the case for preventing the initiation of risky health behaviors among adolescents.

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Assessing the role of impulsivity in smoking & non-smoking disordered gamblers

Publication date: July 2017
Source:Addictive Behaviors, Volume 70
Author(s): Célina A. Boothby, Hyoun S. Kim, Nicole K. Romanow, David C. Hodgins, Daniel S. McGrath
BackgroundCo-morbidity with other addictive behaviors is common in disordered gambling (DG). In particular, tobacco dependence has been found to be among the most prevalent disorders co-morbid with DG. While the extant literature has firmly established the co-occurrence of DG and smoking, there is a paucity of research examining factors that differentiate DGs who smoke from those who do not.ObjectivesTo address this empirical gap, the current study tested whether dimensions of trait impulsivity as measured by the UPPS-P Impulsive Behavior Scale (positive urgency, negative urgency, lack of premeditation, lack of perseverance, and sensation seeking), discriminated between non-DGs and DGs based on their present smoking status: non-smoker, occasional smoker, and daily smoker.MethodsTo this end, 564 community gamblers were recruited through a crowdsourcing platform (Amazon's Mechanical Turk) and completed an online survey, assessing problem gambling severity, tobacco use, and trait impulsivity.ResultsMANOVA analyses revealed significant main effects for both gambling severity and smoking status groups. Importantly, a significant gambling by smoking interaction was also found. Pairwise comparisons revealed that DGs who were daily smokers scored higher on negative urgency than those who smoked occasionally or not all. Furthermore, among non-DGs, smoking status failed to discriminate between mean scores on negative urgency. No other significant interaction effects were found for the remaining UPPS-P impulsivity facets.ConclusionsResults suggest that individual components of trait impulsivity, and more specifically negative urgency, successfully differentiate DGs who do not smoke, or just smoke occasionally, from DGs who smoke daily. These findings suggest that the degree of trait impulsivity may potentially distinguish between DGs and DGs who are dually addicted to other substances such as tobacco.

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A double-mediator based whole cell electrochemical biosensor for acute biotoxicity assessment of wastewater

Publication date: 15 May 2017
Source:Talanta, Volume 167
Author(s): Guanyue Gao, Deyu Fang, Yuan Yu, Liangzhuan Wu, Yu Wang, Jinfang Zhi
This work investigates the feasibility and sensitivity of a double-mediator based whole cell electrochemical biosensor to detect the acute biotoxicity of wastewater. The lipophilic mediator menadione was used to mediate the intracellular metabolic activities whereas hydrophilic potassium ferricyanide was employed as extracellular electron acceptor to transport the electron from the menadiol to anode. A chitosan hydrogel polymer film with boron-doped nanocrystalline diamond (BND) particles was electrodeposited onto a glassy carbon (GC) electrode to immobilize Saccharomyces cerevisiae cells and the mediators. The feasibility of the as-prepared biosensor was verified by determine the acute biotoxicity of four heavy metal ions(Cu²⁺, Cd²⁺, Ni²⁺, Pb²⁺), three phenol pollutants (3,5-dichlorophenol, 4-chlorophenol, phenol) and three real wastewater samples. The IC50 values for Cu²⁺, Cd²⁺, Ni²⁺, Pb²⁺ are 10.12mg/L,13.88mg/L, 17.06mg/L and 34.56mg/L. And the IC50 value is 16.48mg/L, 34.40mg/L and 44.55mg/L for 3,5-dichlorophenol, 4-chlorophenol and phenol, respectively. The results of this work indicate that the double-mediator based whole cell electrochemical biosensor could be applied into the acute toxicity assessment of real wastewater samples with excellent performance and highlight their merit as portable and sensitive, which may providing a reasonable and reliable way for wastewater toxicity online detection.

Graphical abstract

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Selective colorimetric analysis of spermine based on the cross-linking aggregation of gold nanoparticles chain assembly

Publication date: 15 May 2017
Source:Talanta, Volume 167
Author(s): Jian Wang, Zhu Lian Wu, Hong Zhi Zhang, Yuan Fang Li, Cheng Zhi Huang
A selective colorimetric assay for spermine was proposed in this work. In a weak alkaline medium, the conformational structure of double-stranded calf thymus DNA (ctDNA) was loosened to install gold nanoparticles (AuNPs) into chains. While, the chain assembly of AuNPs could form cross-linking aggregates when spermine was present, which was attributed to the electrostatic interaction between the positive change of spermine and negative change both of AuNPs and ctDNA, as well as the groove binding between ctDNA and spermine. Under the optimum conditions, the aggregation degree of AuNPs was proportional to the concentration of spermine in the range of 0.1–2.0μM with a limit of detection of 11.6nM. More interestingly, AuNPs changed from red to purple and even to blue depending on the concentration of spermine, which could be developed as the colorimetric analysis of spermine. ctDNA-AuNPs assembly was demonstrated as a novel visual probe for the specific sensing of spermine with high specificity and sensitivity.

Graphical abstract

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Non-enzymatic sensors based on in situ laser-induced synthesis of copper-gold and gold nano-sized microstructures

Publication date: 15 May 2017
Source:Talanta, Volume 167
Author(s): Maxim S. Panov, Olga A. Vereshchagina, Sergey S. Ermakov, Ilya I. Tumkin, Evgeniia M. Khairullina, Mikhail Yu. Skripkin, Andrey S. Mereshchenko, Mikhail N. Ryazantsev, Vladimir A. Kochemirovsky
The synthesis of conductive gold and copper-gold microstructures with high developed surface based on the method of laser-induced metal deposition from solution was developed. The topology and crystallization phase of these structures were observed by means of scanning electron microscopy and X-ray diffraction, respectively. The electrochemical properties of the synthesized materials were investigated using cyclic voltamperometry and amperometry. According to the obtained results, it was found out that copper-gold microstructures demonstrate a linear dependence of Faraday current vs. concentration from 0.025 to 5µM for D-glucose and from 0.025 to 10µM for hydrogen peroxide. In turn, gold deposit exhibits a linear dependence of Faraday current vs. concentration from 0.025 to 50µM for D-glucose and from 0.025 to 1µM for hydrogen peroxide. Moreover, the synthesized materials reveal low detection limits (0.025µM) with respect to the aforementioned analytes, which is quite promising for their potential application in design and fabrication of new non-enzymatic biosensors.

Graphical abstract

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Trastuzumab in combination with weekly paclitaxel and carboplatin as neo-adjuvant treatment for HER2-positive breast cancer: The TRAIN-study

Publication date: March 2017
Source:European Journal of Cancer, Volume 74
Author(s): Mette S. van Ramshorst, Erik van Werkhoven, Ingrid A.M. Mandjes, Margaret Schot, Jelle Wesseling, Marie-Jeanne T.F.D. Vrancken Peeters, Jetske M. Meerum Terwogt, Monique E.M. Bos, Hendrika M. Oosterkamp, Sjoerd Rodenhuis, Sabine C. Linn, Gabe S. Sonke
AimTo determine the efficacy and safety of an anthracycline-free neo-adjuvant regimen consisting of weekly paclitaxel, carboplatin and trastuzumab in HER2-positive breast cancer.Patients and methodsPatients with stage II or III HER2-positive breast cancer received weekly paclitaxel ([P], 70 mg/m²), trastuzumab ([T], 2 mg/kg, loading dose 4 mg/kg) and carboplatin ([C], AUC = 3 mg ml⁻¹ min) for 24 weeks. In weeks 7, 8, 15, 16, 23 and 24, trastuzumab was administered without chemotherapy. The primary end-point was pathologic complete response in the surgical resection specimen, defined as the absence of invasive tumour cells in breast and axilla.ResultsOne hundred and eleven patients were included in the study, and 108 were evaluable for the primary end-point. The pathologic complete response rate was 43% (95% confidence interval [CI]: 33–52). Median follow-up was 52 months, and the 3-year event-free survival was 88% (95% CI: 82–94), and the 3-year overall survival was 92% (95% CI: 88–98). The most common grade 3–4 adverse events were neutropenia (67%) and thrombocytopenia (43%). Less than five percent of patients experienced febrile neutropenia. No symptomatic left ventricular systolic dysfunction was observed during neo-adjuvant treatment.ConclusionAn anthracycline-free neo-adjuvant regimen of weekly paclitaxel, trastuzumab and carboplatin is highly effective in HER2-positive breast cancer with manageable toxicity.

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Human papillomavirus as prognostic marker with rising prevalence in neck squamous cell carcinoma of unknown primary: A retrospective multicentre study

Publication date: March 2017
Source:European Journal of Cancer, Volume 74
Author(s): Lea Schroeder, Paolo Boscolo-Rizzo, Elisa Dal Cin, Salvatore Romeo, Lorena Baboci, Gerhard Dyckhoff, Jochen Hess, Carlota Lucena-Porcel, Anne Byl, Nikolaus Becker, Laia Alemany, Xavier Castellsagué, Miquel Quer, Xavier León, Manuel Wiesenfarth, Michael Pawlita, Dana Holzinger
Patients with neck squamous cell carcinomas of unknown primary tumour (NSCCUP) present with lymph node metastasis without evidence for a primary tumour. Most patients undergo an aggressive multimodal treatment, which induces severe, potentially unnecessary toxicity. Primary tumours of NSCCUP can be hidden in the oropharynx. Human papillomavirus (HPV) is causally involved in a subgroup of oropharyngeal squamous cell carcinomas (OPSCC) associated with early lymph node metastasis and good prognosis. Detection of markers for HPV transformation in NSCCUP could allow focussing on the oropharynx in primary tumour search and could be of value for choice and extent of treatment.In a retrospective multicentre study (Germany, Italy and Spain), we analysed metastatic lymph nodes from 180 NSCCUP patients for the presence of HPV DNA, HPV E6*I mRNA and cellular p16^INK4a overexpression, a surrogate marker for HPV-induced transformation. HPV status, defined as positivity for viral mRNA with at least one additional marker, was correlated with clinical parameters and survival outcome.A substantial proportion (16%) of NSCCUP were HPV-driven, mainly by HPV16 (89%). HPV prevalence increased with year of diagnosis from 9% during 1998–2004 to 23% during 2005–2014 (p = 0.007). HPV-driven NSCCUP had significantly better overall and progression-free survival rates (p ≤ 0.008).Based on this survival benefit, it is contended that HPV RNA status should be included in NSCCUP diagnosis and in therapeutic decision-making. Deintensification of radiation in patients with HPV-driven NSCCUP, while concurrently concentrating on the oropharynx appears to be a promising therapeutic strategy, the efficacy of which should be assessed in prospective trials. To our knowledge, this is the largest study on HPV in NSCCUP.

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Second- and third-generation drugs for immuno-oncology treatment—The more the better?

Publication date: March 2017
Source:European Journal of Cancer, Volume 74
Author(s): Wolfram C.M. Dempke, Klaus Fenchel, Peter Uciechowski, Stephen P. Dale
Recent success in cancer immunotherapy (anti-CTLA-4, anti-PD1/PD-L1) has confirmed the hypothesis that the immune system can control many cancers across various histologies, in some cases producing durable responses in a way not seen with many small-molecule drugs. However, only less than 25% of all patients do respond to immuno-oncology drugs and several resistance mechanisms have been identified (e.g. T-cell exhaustion, overexpression of caspase-8 and β-catenin, PD-1/PD-L1 gene amplification, MHC-I/II mutations). To improve response rates and to overcome resistance, novel second- and third-generation immuno-oncology drugs are currently evaluated in ongoing phase I/II trials (either alone or in combination) including novel inhibitory compounds (e.g. TIM-3, VISTA, LAG-3, IDO, KIR) and newly developed co-stimulatory antibodies (e.g. CD40, GITR, OX40, CD137, ICOS). It is important to note that co-stimulatory agents strikingly differ in their proposed mechanism of action compared with monoclonal antibodies that accomplish immune activation by blocking negative checkpoint molecules such as CTLA-4 or PD-1/PD-1 or others. Indeed, the prospect of combining agonistic with antagonistic agents is enticing and represents a real immunologic opportunity to 'step on the gas' while 'cutting the brakes', although this strategy as a novel cancer therapy has not been universally endorsed so far. Concerns include the prospect of triggering cytokine-release syndromes, autoimmune reactions and hyper immune stimulation leading to activation-induced cell death or tolerance, however, toxicity has not been a major issue in the clinical trials reported so far. Although initial phase I/II clinical trials of agonistic and novel antagonistic drugs have shown highly promising results in the absence of disabling toxicity, both in single-agent studies and in combination with chemotherapy or other immune system targeting drugs; however, numerous questions remain about dose, schedule, route of administration and formulation as well as identifying the appropriate patient populations. In our view, with such a wealth of potential mechanisms of action and with the ability to fine-tune monoclonal antibody structure and function to suit particular requirements, the second and third wave of immuno-oncology drugs are likely to provide rapid advances with new combinations of novel immunotherapy (especially co-stimulatory antibodies). Here, we will review the mechanisms of action and the clinical data of these new antibodies and discuss the major issues facing this rapidly evolving field.

http://ift.tt/2kYICy8

Melanoma and pregnancy

Abstract

Melanoma is the most common cancer in women during their reproductive years and kills more young Australians than any other single cancer. Care of women whose pregnancy is complicated by a diagnosis of malignancy is complex. The risk of delaying treatment to the mother, the short-term and long-term risks of premature delivery to the child, and the immediate risks to the foetus and long-term risks to the child of maternal treatment with surgery, radiotherapy or medical therapies must be considered.

http://ift.tt/2lAf0Vh

Disinfection by-product formation during chlor(am)ination of algal organic matters (AOM) extracted from Microcystis aeruginosa : effect of growth phases, AOM and bromide concentration

Abstract

Algae organic matter (AOM), including extracellular organic matter (EOM) and intracellular organic matter (IOM), has caused a series of problems to the water quality, among which formation of disinfection by-products (DBPs) during subsequent chlor(am)ination process was especially serious and concerned. This study characterized physicochemical properties of the EOM and IOM solution extracted from different growth phases of Microcystis aeruginosa and investigated the corresponding formation potential of DBPs during chlor(am)ination process. Besides, the effects of initial concentration of xEOM, IOM, and Br⁻ on the yields of disinfection by-product formation potential were studied. The results indicated that the specific UV absorbance (SUVA₂₅₄) values of IOM and EOM (1.09 and 2.66 L/mg m) were considerably lower than that of natural organic matter (NOM) (4.79 L/mg m). Fluorescence dates showed the soluble microbial by-product was dominant in both EOM and IOM, and the tryptophan was the main component of AOM. From the excitation–emission matrix figure of EOM and IOM, we found that the content of the high molecular weight protein substance in IOM was higher than EOM. During chlorination of EOM and IOM, the yields of four kinds of DBPs followed the order trichloroethene (TCM) > 1,1-DCP > dichloride acetonitrile (DCAN) > trichloronitromethane (TCNM), while the order was TCM > DCAN > TCNM > 1,1-DCP during chloramination process. The bromine substitution factor (BSF) value increased with the increasing of the concentration of Br⁻. When the concentration of Br⁻ was 500 μg/L, the BSF values of chlorination EOM and IOM were 51.1 and 68.4%, respectively. As the concentration of Br⁻ increased, the formation of Cl–DBPs was inhibited and the formation of Br–DBPs was promoted.

Graphical abstract

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http://ift.tt/2kYNB1J

A chemical and microbiological characterization and toxicity assessment of the Pančevo industrial complex wastewater canal sediments, Serbia

Abstract

The wastewater canal Vojlovica of the Pančevo industrial area, Serbia, is the main collector of the effluents from the local industrial complex. The canal is directly connected to the Europe's second largest river, the Danube. Here, we present a chemical and microbiological analysis of the sediment in order to determine the fate of pollutants over the years, as well as its current condition. Dry matter, clay and organic matter content, a Kjeldahl ammonia, phosphorus, metals, and polychlorinated biphenyls as well as polycyclic aromatic hydrocarbons concentrations were measured. Microbiological analysis included heterotrophic and oil-degrading bacterial counts, isolation of the phenanthrene-degrading bacteria, and identification of cyanobacteria. Generally, in comparison to the results from previous studies, concentrations of the measured pollutants have been in a decline. Specifically, the metal and polycyclic aromatic hydrocarbon concentrations were reduced whereas microbial counts and toxicity tests did not indicate significant pollution. The obtained results are probably a consequence of an improved wastewater treatment and microbial degradation of pollutants.

http://ift.tt/2kYGFBT

Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds

Publication date: Available online 10 February 2017
Source:Free Radical Biology and Medicine
Author(s): Bebiana C. Sousa, Andrew R. Pitt, Corinne M. Spickett
The process of lipid oxidation generates a diverse array of small aldehydes and carbonyl-containing compounds, which may occur in free form or esterified within phospholipids and cholesterol esters. These aldehydes mostly result from fragmentation of fatty acyl chains following radical oxidation, and the products can be subdivided into alkanals, alkenals (usually α,β-unsaturated), γ-substituted alkenals and bis-aldehydes. Isolevuglandins are non-fragmented di-carbonyl compounds derived from H2-isoprostanes, and oxidation of the ω−3-fatty acid docosahexenoic acid yield analogous 22 carbon neuroketals. Non-radical oxidation by hypochlorous acid can generate α-chlorofatty aldehydes from plasmenyl phospholipids. Most of these compounds are reactive and have generally been considered as toxic products of a deleterious process. The reactivity is especially high for the α,β-unsaturated alkenals, such as acrolein and crotonaldehyde, and for γ-substituted alkenals, of which 4-hydroxy-2-nonenal and 4-oxo-2-nonenal are best known. Nevertheless, in recent years several previously neglected aldehydes have been investigated and also found to have significant reactivity and biological effects; notable examples are 4-hydroxy-2-hexenal and 4-hydroxy-dodecadienal. This has led to substantial interest in the biological effects of all of these lipid oxidation products and their roles in disease, including proposals that HNE is a second messenger or signalling molecule. However, it is becoming clear that many of the effects elicited by these compounds relate to their propensity for forming adducts with nucleophilic groups on proteins, DNA and specific phospholipids. This emphasizes the need for good analytical methods, not just for free lipid oxidation products but also for the resulting adducts with biomolecules. The most informative methods are those utilizing HPLC separations and mass spectrometry, although analysis of the wide variety of possible adducts is very challenging. Nevertheless, evidence for the occurrence of lipid-derived aldehyde adducts in biological and clinical samples is building, and offers an exciting area of future research.

Graphical abstract

http://ift.tt/2lyDVI1

REAL-TIME QUANTIFICATION OF SUBCELLULAR H202 AND GLUTATHIONE REDOX POTENTIAL IN LIVING CARDIOVASCULAR TISSUES

Publication date: Available online 10 February 2017
Source:Free Radical Biology and Medicine
Author(s): Emiliano Panieri, Carlo Millia, Massimo M. Santoro
Detecting and measuring the dynamic redox events that occur in vivo is a prerequisite for understanding the impact of oxidants and redox events in normal and pathological conditions. These aspects are particularly relevant in cardiovascular tissues wherein alterations of the redox balance are associated with stroke, aging, and pharmacological intervention. An ambiguous aspect of redox biology is how redox events occur in subcellular organelles including mitochondria, and nuclei. Genetically-encoded Rogfp2 fluorescent probes have become powerful tools for real-time detection of redox events. These probes detect hydrogen peroxide (H2O2) levels and glutathione redox potential (EGSH), both with high spatiotemporal resolution. By generating novel transgenic (Tg) zebrafish lines that express compartment-specific Rogfp2-Orp1 and Grx1-Rogfp2 sensors we analyzed cytosolic, mitochondrial, and the nuclear redox state of endothelial cells and cardiomyocytes of living zebrafish embryos. We provide evidence for the usefulness of these Tg lines for pharmacological compounds screening by addressing the blocking of pentose phosphate pathways (PPP) and glutathione synthesis, thus altering subcellular redox state in vivo. Rogfp2-based transgenic zebrafish lines represent valuable tools to characterize the impact of redox changes in living tissues and offer new opportunities for studying metabolic driven antioxidant response in biomedical research.

Graphical abstract

http://ift.tt/2lytDrx

Hypotensive and vasorelaxant effect of Diapocynin in normotensive rats

Publication date: Available online 10 February 2017
Source:Free Radical Biology and Medicine
Author(s): Simone R. Potje, Jéssica A. Troiano, Murilo E. Graton, Valdecir F. Ximenes, Ana Claúdia M.S. Nakamune, Cristina Antoniali
Nicotinamide adenine dinucleotide phosphate oxidase (NAD(P)H-oxidase) is a multicomponent enzyme system that generates superoxide anion by one-electron reduction of molecular oxygen and represents the major source of reactive oxygen species (ROS) in the vascular cells. Apocynin has been extensively used as an inhibitor of NADPH oxidase (NOX) in phagocytic cells and as an antioxidant in non-phagocytic cells. In phagocytes cells, due to the presence of myeloperoxidase, apocynin can be the converted to diapocynin, which is supposed to be the active form of this phytochemical. Moreover, apocynin was shown to induce hypotension and vasodilatation in many experimental animal models. However, there are no studies showing the effects of diapocynin on blood pressure or in vascular cells. In this present study, we used chemically synthesized diapocynin and analyzed its antioxidant capacity, effect on blood pressure and vascular reactivity. Moreover, it was evaluated the levels of nitric oxide (NO), ROS and calcium in aortic endothelial cells stimulated by diapocynin. All results were compared to apocynin. We found that diapocynin showed higher antioxidant capacity than apocynin. Apocynin and diapocynin, promoted hypotensive effects without changing the heart rate, however the effects of diapocynin were reversed faster than the effects of apocynin, which was long lasting. Diapocynin and apocynin induced endothelium dependent and independent vasodilatation, but diapocynin was less potent than apocynin regarding the capacity of induction of vasodilatation in mesenteric resistance arteries and aorta from Wistar rats. The relaxation induced by apocynin or diapocynin involves sGC and potassium channels in vascular smooth muscle cells and NOS participates of relaxation induced by apocynin or diapocynin in intact mesenteric rings. Apocynin and diapocynin increased NO and decreased ROS levels in endothelial cells, however diapocynin did not alter calcium levels in these cells. In conclusion, these results demonstrated that, similarly to apocynin, diapocynin also induces hypotensive and vasodilator effects in rats and vascular endothelium improves the diapocynin vasodilator effects by increases NO bioavailability.

Graphical abstract

http://ift.tt/2lyprYv

Risk of autoimmune diseases and human papilloma virus (HPV) vaccines: Six years of case-referent surveillance

Publication date: Available online 9 February 2017
Source:Journal of Autoimmunity
Author(s): Lamiae Grimaldi-Bensouda, Michel Rossignol, Isabelle Koné-Paut, Alain Krivitzky, Christine Lebrun-Frenay, Johanna Clet, David Brassat, Caroline Papeix, Marc Nicolino, Pierre-Yves Benhamou, Olivier Fain, Nathalie Costedoat-Chalumeau, Marie-France Courcoux, Jean-François Viallard, Bertrand Godeau, Thomas Papo, Patrick Vermersch, Isabelle Bourgault-Villada, Gerard Breart, Lucien Abenhaim
BackgroundSafety of HPV vaccines is still in question due to reports of autoimmune diseases (ADs) following HPV immunization.ObjectivesTo assess the risk of ADs associated with HPV vaccination of female adolescents/young adults in France.MethodsSystematic prospective case-referent study conducted to assess the risks associated with real-life use of HPV vaccines. Cases were female 11–25 years old with incident ADs [central demyelination/multiple sclerosis (CD/MS), connective tissue disease (CTD), Guillain-Barré syndrome (GBS), type-1 diabetes (T1D), autoimmune thyroiditis (AT), and idiopathic thrombocytopenic purpura (ITP)]. Cases were consecutively and prospectively identified at specialized centers across France (2008–2014) and individually matched by age and place of residence to referents recruited in general practice. Risk was computed using multivariate conditional logistic regression models adjusted for family history of ADs, living in France (north/south), co-medications and co-vaccinations.ResultsWith a total of 478 definite cases matched to 1869 referents, all ADs combined were negatively associated to HPV vaccination with an adjusted odds ratio of 0.58 (95% confidence interval: 0.41–0.83). Similar results were obtained for CD/MS, AT, CT, and T1D, the last two not reaching statistical significance. No association was found for ITP and GBS. Sensitivity analyses combining definite and possible cases with secondary time window showed similar results.ConclusionExposure to HPV vaccines was not associated with an increased risk of ADs within the time period studied. Results were robust to case definitions and time windows of exposure. Continued active surveillance is needed to confirm this finding for individual ADs.

http://ift.tt/2kcUu07

Cross-sectional analysis of universal vitamin D supplementation in former East Germany during the first year of life

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print

http://ift.tt/2kY92jI

Association between CSF biomarkers, hippocampal volume and cognitive function in patients with amnestic mild cognitive impairment (MCI)

Publication date: May 2017
Source:Neurobiology of Aging, Volume 53
Author(s): Pradeep J. Nathan, Yen Ying Lim, Rosemary Abbott, Samantha Galluzzi, Moira Marizzoni, Claudio Babiloni, Diego Albani, David Bartres-Faz, Mira Didic, Lucia Farotti, Lucilla Parnetti, Nicola Salvadori, Bernhard W. Müller, Gianluigi Forloni, Nicola Girtler, Tilman Hensch, Jorge Jovicich, Annebet Leeuwis, Camillo Marra, José Luis Molinuevo, Flavio Nobili, Jeremie Pariente, Pierre Payoux, Jean-Philippe Ranjeva, Elena Rolandi, Paolo Maria Rossini, Peter Schönknecht, Andrea Soricelli, Magda Tsolaki, Pieter Jelle Visser, Jens Wiltfang, Jill C. Richardson, Régis Bordet, Olivier Blin, Giovanni B. Frisoni
Few studies have examined the relationship between CSF and structural biomarkers, and cognitive function in MCI. We examined the relationship between cognitive function, hippocampal volume and cerebrospinal fluid (CSF) Aβ42 and tau in 145 patients with MCI. Patients were assessed on cognitive tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB), the Geriatric Depression Scale and the Functional Activities Questionnaire. Hippocampal volume was measured using magnetic resonance imaging (MRI), and CSF markers of Aβ42, tau and p-tau181 were also measured. Worse performance on a wide range of memory and sustained attention tasks were associated with reduced hippocampal volume, higher CSF tau and p-tau181 and increased tau/Aβ42 ratio. Memory tasks were also associated with lower ability to conduct functional activities of daily living, providing a link between AD biomarkers, memory performance and functional outcome. These results suggest that biomarkers of Aβ and tau are strongly related to cognitive performance as assessed by the CANTAB, and have implications for the early detection and characterization of incipient AD.

http://ift.tt/2kBkkcq

Intrafamilial variable phenotype including Corticobasal Syndrome in a family with p.P301L mutation in the MAPT gene: first report in South America

Publication date: Available online 10 February 2017
Source:Neurobiology of Aging
Author(s): Emilia M. Gatto, Ricardo F. Allegri, Gustavo Da Prat, Patricio Chrem Mendez, David S. Hanna, Michael O. Dorschner, Ezequiel I. Surace, Cyrus P. Zabetian, Ignacio F. Mata
Frontotemporal lobar degeneration (FTLD) is a neuropathological disorder that causes a variety of clinical syndromes including fronto-temporal dementia (FTD), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). FTD associated with parkinsonism occurs frequently as a result of mutations in the C9orf72 gene and also in the genes coding for the protein associated with microtubule tau (MAPT) and progranulin (GRN) on chromosome 17 (FTDP-17).Herein we report an Argentinean family, of Basque ancestry, with an extensive family history of behavioral variant of FTD (bvFTD). Twenty one members over 6 generations composed the pedigree. An extensive neurological and neurocognitive examination was performed on 2 symptomatic individuals and 3 non-symptomatic individuals. Two different phenotypes were identified among affected members, CBS in the proband and FTD in his brother.DNA was extracted from blood for these five individuals and whole-exome sequencing (WES) was performed on 3 of them followed by Sanger sequencing of candidate genes on the other 2. In both affected individuals a missense mutation (p.P301L; rs63751273) in exon 10 of the MAPT gene (chr17q21.3) was identified. Among MAPT mutations, p.P301L is the most frequently associated to different phenotypes: a) aggressive, symmetrical and early-onset Parkinsonism; b) late parkinsonism associated with FTD and c) PSP but only exceptionally it is reported associated to CBS. This is the first report of the occurrence of the p.P301L-MAPT mutation in South America and supports the marked phenotypic heterogeneity among members of the same family as previously reported.

http://ift.tt/2lxNJBY

Non-amyloidogenic processing of amyloid beta precursor protein is associated with retinal function improvement in aging male APPswe/PS1ΔE9 mice

Publication date: Available online 10 February 2017
Source:Neurobiology of Aging
Author(s): Sandrine Joly, Simon Lamoureux, Vincent Pernet
Vision declines during normal aging and in Alzheimer's disease (AD). Although the toxic role of amyloid beta (Aβ) has been established in AD pathogenesis, its influence on the aging retina is unclear. Using APPswe/PS1ΔE9 transgenic (TG) mice, a classical AD model, the retinal cell function and survival was assessed by electroretinogram (ERG) recordings and immunofluorescent stainings. Strikingly, photopic ERG measurements revealed that the retinal response mediated by cones was preserved in aging TG mice relative to WT controls. In contrast to the cortex, the expression of mutated APPswe and PS1ΔE9 did not allow to detect Aβ or amyloid plaques in 13-month old male TG retinae. In addition, the CTFβ/CTFα ratio was significantly lower in retinal samples than in cortical extracts, suggesting that the non-amyloidogenic pathway may endogenously limit Aβ formation in the retina of male mice. Collectively, our data suggest that retinal-specific processing of amyloid may confer protection against AD and selectively preserve cone-dependent vision during aging.

http://ift.tt/2kBFveD

COx-free hydrogen generation via decomposition of ammonia over copper and zinc-based catalysts

Publication date: 15 May 2017
Source:Fuel, Volume 196
Author(s): Venkata D.B.C. Dasireddy, Blaž Likozar
Production of hydrogen without any carbon dioxide or monoxide is of utmost importance for the chemical energy storage and conversion in a future low-carbon economy. Alumina-supported copper and Cu/Zn/Al2O3 catalysts were prepared by incipient wetness- and ultrasonic impregnation, while Zn/Al2O3 catalysts were also prepared to compare the effect of Zn. The characterisation of catalysts was carried out by N2 physisorption, XRD, H2-TPR, N2O chemisorption, NH3-TPD, CO2-TPD, H2-TPD, XPS and TEM. Catalysts prepared via ultrasonic impregnation showed a high metal dispersion and a small crystallite size, whereas Lewis acidic and basic sites were predominant on all catalysts, while the acid–base strength was strongly influenced by the presence of zinc in the case of Cu/Zn/Al2O3 catalysts. A high catalytic activity, reflected through the almost total conversion of ammonia at 600°C with the H2 production rate of 36.2mmolg⁻¹min⁻¹, was achieved over Cu/Zn/Al2O3 catalyst, prepared by ultrasonic impregnation. The dispersion of metal and its acidic or basic nature played an important role, even more so than the presence of the two or three potentially synergistic metals on the surface of a catalyst. Under the applied reaction conditions, the catalysts showed an excellent stability for more than 100h.

Graphical abstract

http://ift.tt/2kY8VVr

Bedload as an indicator of heavy metal contamination in a Brazilian anthropized watershed

Publication date: June 2017
Source:CATENA, Volume 153
Author(s): Yuri Jacques Agra Bezerra da Silva, José Ramon Barros Cantalice, Clístenes Williams Araújo do Nascimento, Vijay P. Singh, Ygor Jacques Agra Bezerra da Silva, Cinthia Maria Cordeiro Atanázio Cruz Silva, Michelangelo de Oliveira Silva, Sérgio M.S. Guerra
Heavy metal contamination has long been a water quality concern worldwide. Most studies have focused on heavy metal concentration in water through suspended sediment and bottom sediment; however, the concentration transported by river-bottom sediment, known as bedload, has not been taken into account. In order to fill this gap, this study aimed to determine the concentration of Hg, Pb, Cd, Ni, Cu, Cr, Zn, As, Fe and Mn in bedload of Ipojuca River which is an environmentally impacted river in Brazil. The use of bedload in heavy metal contamination studies raises the following question: Is the bedload an adequate indicator of heavy metal contamination? To answer this question, sediment contamination assessment was performed using sediment contamination indices, principal component analysis, and comparison with background values and sediment quality guidelines (SQGs). Comparing with sediment quality guidelines, the Probable Effect Level (PEL) and Threshold Effect Level (TEL) seem to underestimate the harmful effect on sediment-dwelling organisms, being essential either to calibrate the SQGs for site specific conditions or develop site specific guidelines. The pollution load index (PLI) indicated that the upstream and downstream sites were not polluted and polluted, respectively. Principal component analysis explained roughly 91% and 81% of the total variance in heavy metal contamination upstream and downstream, respectively, and distinguished natural and anthropogenic contributions in Ipojuca River. Multiple lines of evidence suggested that heavy metal concentrations in bedload were an adequate and feasible indicator of anthropogenic impacts.

http://ift.tt/2kY00TG

Complement’s hidden arsenal: New insights and novel functions inside the cell

Publication date: Available online 10 February 2017
Source:Molecular Immunology
Author(s): M. Kathryn Liszewski, Michelle Elvington, Hrishikesh S. Kulkarni, John P. Atkinson
A key component of both innate and adaptive immunity, new understandings of the complement system are expanding its roles beyond that traditionally appreciated. Evidence is accumulating that complement has an intracellular arsenal of components that provide not only immune defense, but also assist in key interactions for host cell functions. Although early work has primarily centered on T cells, the intracellular complement system likely functions in many if not most cells of the body. Some of these functions may trace their origins to the primitive complement system that began as a primeval form of C3 likely tasked for protection from intracellular pathogen invasion. This later expanded to include extracellular defense as C3 became a secreted protein to patrol the vasculature. Other components were added to the growing system including regulators to protect host cells from the indiscriminate effects of this potent system. Contemporary cells may retain some of these vestigial remnants. We now know that a) C3 serves as a damage-associated molecular pattern (in particular by coating pathogens that translocate into cells), b) most cells store C3 and recycle C3(H2O) for immediate use, and c) C3 assists in cellular survival and metabolic reprogramming. Other components also are part of this hidden arsenal including C5, properdin, factors H and B, and complement receptors. Importantly, better definition of the intracellular complement system may translate into new target discovery to assist in creating the next generation of complement therapeutics.

http://ift.tt/2lzsUaa

Enhanced biodegradation of low and high-density polyethylene by novel bacterial consortia formulated from plastic-contaminated cow dung under thermophilic conditions

Abstract

The current study aimed to devise eco-friendly, safe, and cost-effective strategies for enhanced degradation of low- and high-density polyethylene (LDPE and HDPE) using newly formulated thermophilic microbial consortia from cow dung and to assess the biodegradation end products. The plastic-degrading bacteria from cow dung samples gathered from highly plastic-acclimated environments were enriched by standard protocols. The degradation ability was comprehended by zone of clearance method, and the percentage of degradation was monitored by weight reduction process. The best isolates were characterized by standard microbiological and molecular biology protocols. The best isolates were employed to form several combinations of microbial consortia, and the degradation end products were analyzed. The stability of 16S ribosomal DNA (rDNA) was predicted by bioinformatics approach. This study identified 75 ± 2, 55 ± 2, 60 ± 3, and 43 ± 3% degradation for LDPE strips, pellets, HDPE strips, and pellets, respectively, for a period of 120 days (p < 0.05) at 55 °C by the formulated consortia of IS1-IS4, and the degradation efficiency was found to be better in comparison with other formulations. The end product analysis by Fourier transform infrared, scanning electron microscopy, energy-dispersive spectroscopy, and nuclear magnetic resonance showed major structural changes and formation of bacterial biofilm on plastic surfaces. These novel isolates were designated as Bacillus vallismortis bt-dsce01, Psuedomonas protegens bt-dsce02, Stenotrophomonas sp. bt-dsce03, and Paenibacillus sp.bt-dsce04 by 16S rDNA sequencing and suggested good gene stability with minimum Gibb's free energy. Therefore, this study imparts substantial information regarding the utilization of these thermophilic microbial consortia from cow dung for rapid polyethylene removal.

http://ift.tt/2kcgZSG

Quantification of the fate of mesotrione applied alone or in a herbicide mixture in two Brazilian arable soils

Abstract

The effects of mesotrione, S-metolachlor, and terbuthylazine, applied in mixture, on soil biodegradation remain insufficiently researched. However, herbicide mixtures have been a common practice in agricultural systems in the last years. Understanding the fate of soil-applied herbicides may help on planning weed management tactics towards more sustainable and efficient weed control. Therefore, this study evaluated the fate of mesotrione alone and in mixture with S-metolachlor and terbuthylazine when applied to two contrasting arable Brazilian soils. Mineralization and degradation experiments were conducted using ¹⁴C-mesotrione alone or in mixture. From the 49-day laboratory incubation data, increased mineralization half-life of mesotrione was observed for the mixture of herbicides, ranging from a 4-day increase for the sandy loam soil to a 1-day increase in the sandy clay texture soils. Mesotrione degradation rate had a twofold increase in the sandy loam compared to the sandy clay soil. Two metabolites can be identified from mesotrione degradation, 4-methyl-sulfonyl-2-nitrobenzoic acid (MNBA) and 2-amino-4-methylsulfonyl benzoic acid (AMBA). Indices for the score of ubiquity in groundwater indicated mesotrione possesses leaching potential for both soils. Applying mesotrione alone or in mixture did not influence the amount of bound residues from mesotrione. However, mesotrione degradation rate was influenced by soil texture regardless if applied alone or in mixture. Mesotrione biotransformation was relatively quick, indicating that this herbicide has low persistence and, consequently, low residual effect on crops and weeds when present in similar soils to this present study.

http://ift.tt/2kdSyzt

Concentrations of some heavy metals in underground water samples from a Nigerian crude oil producing community

Abstract

Pollution due to oil exploration activities in the Niger Delta region of Nigeria and government under-investments in potable water infrastructure has led to the dependence of the population on personal boreholes. Yet, there are little quality or surveillance reports on such waters. The concentrations of heavy metals in underground water samples from an oil producing area, Umuebulu, in the Niger Delta were therefore investigated. Water samples were collected from three test points, each approximately 300 m from (1) wellhead area (WHA), (2) flare area (FA) and (3) effluent discharge area (EDA), and one control point located 10 km away from any oil-related activity. The concentrations of lead, arsenic and cadmium were determined in the samples using atomic absorption spectrophotometry. All three heavy metals were present in the test, and control water samples at concentrations significantly (P < 0.05) exceeding the maximum contaminant levels recommended by the World Health Organization. The total hazard index of the water samples showed that their consumption constituted significant health risks in the order EDA > FA > WHA > Control. Appropriate water treatment and surveillance is warranted and therefore recommended for underground water resources of the studied community.

http://ift.tt/2kch0G6

Successful TEVAR with a Through and Through Guidewire in an Extremely Tortuous Aorta

Publication date: Available online 10 February 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): B. Fiorucci, N. Tsilimparis

http://ift.tt/2kcbp2y

Calculating the incalculable. Optimal radioiodine dose in Graves’ hyperthyroidism

http://ift.tt/2kuIOln

Short-term UVB irradiation significantly increases vitamin D serum concentration in obese patients: a clinical pilot study

Abstract

Purpose

Methods

Results

Conclusions

The current study indicates that short-term ultraviolet B irradiation increases 25D levels in obese patients.

http://ift.tt/2kXBr9k

CD8+ T Cells Orchestrate pDC-XCR1+ Dendritic Cell Spatial and Functional Cooperativity to Optimize Priming

Publication date: Available online 9 February 2017
Source:Immunity
Author(s): Anna Brewitz, Sarah Eickhoff, Sabrina Dähling, Thomas Quast, Sammy Bedoui, Richard A. Kroczek, Christian Kurts, Natalio Garbi, Winfried Barchet, Matteo Iannacone, Frederick Klauschen, Waldemar Kolanus, Tsuneyasu Kaisho, Marco Colonna, Ronald N. Germain, Wolfgang Kastenmüller
Adaptive cellular immunity is initiated by antigen-specific interactions between T lymphocytes and dendritic cells (DCs). Plasmacytoid DCs (pDCs) support antiviral immunity by linking innate and adaptive immune responses. Here we examined pDC spatiotemporal dynamics during viral infection to uncover when, where, and how they exert their functions. We found that pDCs accumulated at sites of CD8⁺ T cell antigen-driven activation in a CCR5-dependent fashion. Furthermore, activated CD8⁺ T cells orchestrated the local recruitment of lymph node-resident XCR1 chemokine receptor-expressing DCs via secretion of the XCL1 chemokine. Functionally, this CD8⁺ T cell-mediated reorganization of the local DC network allowed for the interaction and cooperation of pDCs and XCR1⁺ DCs, thereby optimizing XCR1⁺ DC maturation and cross-presentation. These data support a model in which CD8⁺ T cells upon activation create their own optimal priming microenvironment by recruiting additional DC subsets to the site of initial antigen recognition.

Graphical abstract

Teaser

pDCs and XCR1⁺ dendritic cells are critical for the generation of antiviral CD8⁺ T cell responses. Brewitz and colleagues demonstrate that primed CD8⁺ T cells reorganize the intranodal dendritic cell network to optimize pDC and XCR1⁺ DC cooperativity and thereby enhance CD8⁺ T cell immunity.

http://ift.tt/2l2dAVU

Feasibility of Patient Reporting of Symptomatic Adverse Events via the PRO-CTCAE in a Chemoradiotherapy Cooperative Group Multicenter Clinical Trial

Publication date: Available online 10 February 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Ethan Basch, Stephanie L. Pugh, Amylou C. Dueck, Sandra A. Mitchell, Lawrence Berk, Shannon Fogh, Lauren J. Rogak, Marcha Gatewood, Bryce B. Reeve, Tito R. Mendoza, Ann O'Mara, Andrea Denicoff, Lori Minasian, Antonia V. Bennett, Ann Setser, Deborah Schrag, Kevin Roof, Joan K. Moore, Thomas Gergel, Kevin Stephans, Andreas Rimner, Albert DeNittis, Deborah Watkins Bruner
PurposeTo assess the feasibility of measuring symptomatic adverse events (AEs) in a multicenter clinical trial using the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).Methods and MaterialsPatients enrolled in Trial XXXX (XXXX) were asked to self-report 53 PRO-CTCAE items representing 30 symptomatic AEs at 6 time points (baseline; weekly x4 during treatment; 12-weeks post-treatment). Reporting was conducted via wireless tablet computers in clinic waiting areas. Compliance was defined as the proportion of visits when an expected PRO-CTCAE assessment was completed.ResultsAmong 226 study sites participating in Trial XXXX, 100% completed 35-minute PRO-CTCAE training for clinical research associates (CRAs); 80 sites enrolled patients of which 34 (43%) required tablet computers to be provided. All 152 patients in Trial XXXX agreed to self-report using the PRO-CTCAE (median age 66; 47% female; 84% white). Median time for CRAs to learn the system was 60 minutes (range 30-240), and median time for CRAs to teach a patient to self-report was 10 minutes (range 2-60). Compliance was high, particularly during active treatment when patients self-reported at 86% of expected time points, although compliance was lower post-treatment (72%). Common reasons for non-compliance were institutional errors such as forgetting to provide computers to participants; patients missing clinic visits; internet connectivity; and patients feeling "too sick".ConclusionsMost patients enrolled in a multicenter chemoradiotherapy trial were willing and able to self-report symptomatic adverse events at visits using tablet computers. Minimal effort was required by local site staff to support this system. The observed causes of missing data may be obviated by allowing patients to self-report electronically between-visits, and by employing central compliance monitoring. These approaches are being incorporated into ongoing studies.

Teaser

The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) was developed by the National Cancer Institute to enable patient-reporting of toxicities in clinical research. To assess feasibility of implementation, PRO-CTCAE was integrated into an NRG Oncology trial. During treatment, patients reported via tablet computers at 86% of visits. Reasons for missing reports included staff errors, missed appointments, and internet connectivity. Strategies to address these reasons are being assessed in ongoing studies.

http://ift.tt/2kB64QZ

Direct access: how is it working?

British Dental Journal 222, 191 (2017). doi:10.1038/sj.bdj.2017.123

Authors: S. Turner & M. Ross

http://ift.tt/2lssrtD

Introducing a new alcohol-free hand disinfectant foam

British Dental Journal 222, 222 (2017). doi:10.1038/sj.bdj.2017.139

http://ift.tt/2lsH5Bl

Patient safety: Needle breakage

British Dental Journal 222, 140 (2017). doi:10.1038/sj.bdj.2017.94

Authors: M. Makwana & S. Walsh

http://ift.tt/2lsxPwZ

What red means in waste management

British Dental Journal 222, 220 (2017). doi:10.1038/sj.bdj.2017.131

http://ift.tt/2lsyuON

Anticoagulants: Updates on idarucizumab

British Dental Journal 222, 140 (2017). doi:10.1038/sj.bdj.2017.95

Authors: S. J. Chandan, T. Thomas & S. H. Baryah

http://ift.tt/2lswOFe

Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study

British Dental Journal 222, 170 (2017). doi:10.1038/sj.bdj.2017.119

http://ift.tt/2lsAAy2

Antimicrobial resistance: The antibiotic cure-all myth

British Dental Journal 222, 141 (2017). doi:10.1038/sj.bdj.2017.96

Author: R. Wilson

http://ift.tt/2lsv4LU

Gastrointestinal diseases and their oro-dental manifestations: Part 4: Peutz-Jeghers syndrome

British Dental Journal 222, 214 (2017). doi:10.1038/sj.bdj.2017.127

Authors: S. E. Korsse, M. E. van Leerdam & E. Dekker

http://ift.tt/2lssqpz

The toolkit blah

British Dental Journal 222, 141 (2017). doi:10.1038/sj.bdj.2017.97

Author: M. Wint

http://ift.tt/2lsyIpf

Love is ... fresh breath and a white smile

British Dental Journal 222, 221 (2017). doi:10.1038/sj.bdj.2017.135

http://ift.tt/2lsmY5Z

Literature reviews: Patient-centred care

British Dental Journal 222, 141 (2017). doi:10.1038/sj.bdj.2017.98

Author: C. A. Yeung

http://ift.tt/2lsyI8J

Corporates – friend or foe?

British Dental Journal 222, 139 (2017). doi:10.1038/sj.bdj.2017.93

Author: Peter Ward

http://ift.tt/2lstxFI

Restorative dentistry: Incredulous restorations

British Dental Journal 222, 142 (2017). doi:10.1038/sj.bdj.2017.100

Author: D. King

http://ift.tt/2lsyrT7

The financial burden for the surgical management of osteoradionecrosis

British Dental Journal 222, 177 (2017). doi:10.1038/sj.bdj.2017.121

Authors: V. Patel, L. Ormondroyd, A. Lyons & M. McGurk

http://ift.tt/2lshBDY

Endodontics: No rubber dam, no root canal

British Dental Journal 222, 142 (2017). doi:10.1038/sj.bdj.2017.101

Author: J. Webber

http://ift.tt/2lsAhUh

Academic performance of undergraduate dental students with learning disabilities

British Dental Journal 222, 205 (2017). doi:10.1038/sj.bdj.2017.125

Authors: K. Ali, D. Zahra, C. Coelho, G. Jones & C. Tredwin

http://ift.tt/2lsqa1y

Prevention: Fluoride varnish flavours

British Dental Journal 222, 142 (2017). doi:10.1038/sj.bdj.2017.99

Authors: M. Sherborne & S. Oliver

http://ift.tt/2lsAAOy

Imagine a universal solution

British Dental Journal 222, 219 (2017). doi:10.1038/sj.bdj.2017.129

http://ift.tt/2lsnWzk

Conference report: National Conference on Socially Inclusive Dentistry 2016

British Dental Journal 222, 144 (2017). doi:10.1038/sj.bdj.2017.102

http://ift.tt/2lsxL0d

Save the date for the Digital Symposium

British Dental Journal 222, 220 (2017). doi:10.1038/sj.bdj.2017.133

http://ift.tt/2lsptp8

Upregulation of inhibitory signaling receptor programmed death marker-1 (PD-1) in disease evolution from cutaneous lymphoid dyscrasias to mycosis fungoides and Sezary's syndrome

Publication date: Available online 10 February 2017
Source:Annals of Diagnostic Pathology
Author(s): Giang Huong Nguyen, Luke C. Olson, Cynthia M. Magro
BackgroundNegative immunoregulatory checkpoints impede effective immune responses to tumor and reduce the action of anticancer agents. One such example is programmed death marker-1 (PD-1), an inhibitory signaling receptor expressed on activated and regulatory T-cells. PD-1 expression was reported in a few reports, but the expression profile of PD-1 and mycosis fungoides (MF) remains largely to be characterized.DesignIn this study, skin biopsies from 42 prelymphomatous T-cell dyscrasias (CLD), 9 Sezary's syndrome (SS), 103 MF, and 20 CD30+ lymphoproliferative diseases (LPD) were examined for PD-1 using immunohistochemistry.ResultsPD-1 staining was observed amidst many neoplastic T-cells in 6/9(66.7%) and 62/103 (60.2%) cases of SS and MF respectively, while only 6/42 (14.3%) cases of CLD and 0/20 (0%) cases of CD30+ LPD (P<0.001). Three cases are from same patients representing different stages of disease evolution from CLD to MF and SS with a corresponding enrichment of PD-1 positivity. In all cases there was variable staining of PD-1 amidst macrophages. There was no correlation with disease progression among MF cases. Twenty cases of CD30+ LPD did not show any PD-1 positivity.ConclusionPD-1 seems to correlate with disease progression in epitheliotropic T cell dyscrasias ranging from minimal staining in prelymphomatous dyscrasias to significant staining in MF, likely reflecting the effects of PD-1 on inhibiting tumor surveillance regulatory T cell populations. PD-1 was consistently expressed in MF while it was consistently negative in primary CD30+ LPD, suggesting the possibility of using PD-1 as a means of distinguishing CD30+ MF from primary cutaneous ALCL.

http://ift.tt/2kXBylv

Solid pseudopapillary neoplasm of the pancreas: management and long-term outcome

Publication date: Available online 10 February 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Nir Lubezky, Michail Papoulas, Yonatan Lessing, Gilad Gitstein, Eli Brazowski, Ido Nachmany, Guy Lahat, Yaacov Goykhman, Amir Ben-Yehuda, Richard Nakache, Joseph M. Klausner
BackgroundSolid pseudopapillary neoplasm (SPN) of pancreas is a rare pancreatic neoplasm with a low metastatic potential. Our aim was to study the clinical-pathological characteristics, and long-term outcome of this tumor.MaterialsRretrospective single center study of patients operated for SPN of pancreas. Clinical and pathological data were collected.ResultsFrom 1995 to 2016, 1,320 patients underwent pancreatic resection. SPN was confirmed in 32 cases (2.46%), including 29 (90.6%) female and three (9.4%) male, with a mean age of 28.4 ± 12.2 years. SPN was the most common pathology among female patients under age of 40 (72.4%). Abdominal pain was the most frequent presenting symptom (48%), whereas none of the patients presented with jaundice. Mean tumor diameter was 5.9cm (range, 0.9 to 14cm). All patients underwent margin-negative surgical resection. Two patients demonstrated gross malignant features, including liver metastases at presentation (n=1), and adjacent organ and vascular invasion (n=1). Microscopic malignant features were present in thirteen patients (40.6%). Recurrence occurred in the retroperitoneal lymph nodes (n=1, 7 years post resection) and in the liver (n=2, 1 and 5 years post resection). Mean follow-up was 49.2 months (range, 1 to 228 months). Five and 10-year disease-free survival was 96.5% and 89.6% respectively.ConclusionsSPNs are low-grade tumors with a good prognosis. Margin-negative surgical resection is curative in most patients. However, almost 15% of patients demonstrate malignant features including invasion of adjacent organs or metastatic disease. Patients with malignant disease are still expected to have long survival, and aggressive surgical approach is advocated.

http://ift.tt/2kbLdoK

Genome Editing in hPSCs Reveals GATA6 Haploinsufficiency and a Genetic Interaction with GATA4 in Human Pancreatic Development

Publication date: Available online 9 February 2017
Source:Cell Stem Cell
Author(s): Zhong-Dong Shi, Kihyun Lee, Dapeng Yang, Sadaf Amin, Nipun Verma, Qing V. Li, Zengrong Zhu, Chew-Li Soh, Ritu Kumar, Todd Evans, Shuibing Chen, Danwei Huangfu
Human disease phenotypes associated with haploinsufficient gene requirements are often not recapitulated well in animal models. Here, we have investigated the association between human GATA6 haploinsufficiency and a wide range of clinical phenotypes that include neonatal and adult-onset diabetes using CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9-mediated genome editing coupled with human pluripotent stem cell (hPSC) directed differentiation. We found that loss of one GATA6 allele specifically affects the differentiation of human pancreatic progenitors from the early PDX1+ stage to the more mature PDX1+NKX6.1+ stage, leading to impaired formation of glucose-responsive β-like cells. In addition to this GATA6 haploinsufficiency, we also identified dosage-sensitive requirements for GATA6 and GATA4 in the formation of both definitive endoderm and pancreatic progenitor cells. Our work expands the application of hPSCs from studying the impact of individual gene loci to investigation of multigenic human traits, and it establishes an approach for identifying genetic modifiers of human disease.

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Huangfu, Chen, and colleagues model human pancreatic disease by stepwise differentiation of genetically modified hPSCs to characterize the phenotypic effects of GATA6 haploinsufficiency not evident in mouse models and its genetic interaction with GATA4.

http://ift.tt/2kPT9Jw

Cholinergic Signals from the CNS Regulate G-CSF-Mediated HSC Mobilization from Bone Marrow via a Glucocorticoid Signaling Relay

Publication date: Available online 9 February 2017
Source:Cell Stem Cell
Author(s): Halley Pierce, Dachuan Zhang, Claire Magnon, Daniel Lucas, John R. Christin, Matthew Huggins, Gary J. Schwartz, Paul S. Frenette
Hematopoietic stem cells (HSCs) are mobilized from niches in the bone marrow (BM) to the blood circulation by the cytokine granulocyte colony-stimulating factor (G-CSF) through complex mechanisms. Among these, signals from the sympathetic nervous system regulate HSC egress via its niche, but how the brain communicates with the BM remains largely unknown. Here we show that muscarinic receptor type-1 (Chrm1) signaling in the hypothalamus promotes G-CSF-elicited HSC mobilization via hormonal priming of the hypothalamic-pituitary-adrenal (HPA) axis. Blockade of Chrm1 in the CNS, but not the periphery, reduces HSC mobilization. Mobilization is impaired in Chrm1^−∕− mice and rescued by parabiosis with wild-type mice, suggesting a relay by a blood-borne factor. We have identified the glucocorticoid (GC) hormones as critical for optimal mobilization. Physiological levels of corticosterone promote HSC migration via the GC receptor Nr3c1-dependent signaling and upregulation of actin-organizing molecules. These results uncover long-range regulation of HSC migration emerging from the brain.

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Teaser

Pierce et al. show that the muscarinic receptor type-1 (Chrm1) expression in the brain regulates HSC mobilization from bone marrow via the hypothalamic-pituitary-adrenal axis, leading to glucocorticoid-mediated control of actin organization pathways.

http://ift.tt/2kPWpEA

Potential of GPCRs to modulate MAPK and mTOR pathways in Alzheimer’s disease

Publication date: Available online 9 February 2017
Source:Progress in Neurobiology
Author(s): Rafael Franco, Eva Martínez-Pinilla, Gemma Navarro, Marta Zamarbide
Despite efforts to understand the mechanism of neuronal cell death, finding effective therapies for neurodegenerative diseases is still a challenge. Cognitive deficits are often associated with neurodegenerative diseases. Remarkably, in the absence of consensus biomarkers, diagnosis of diseases such as Alzheimer's still relies on cognitive tests. Unfortunately, all efforts to translate findings in animal models to the patients have been unsuccessful. Alzheimer's disease may be addressed from two different points of view, neuroprotection or cognitive enhancement. Based on recent data, the mammalian target of rapamycin (mTOR) pathway arises as a versatile player whose modulation may impact on mechanisms of both neuroprotection and cognition. Whereas direct targeting of mTOR does not seem to constitute a convenient approach in drug discovery, its indirect modulation by other signaling pathways seems promising. In fact, G-protein-coupled receptors (GPCRs) remain the most common 'druggable' targets and as such pharmacological manipulation of GPCRs with selective ligands may modulate phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), mitogen-activated protein (MAP) kinase and mTOR signaling pathways. Thus, GPCRs become important targets for potential drug treatments in different neurodegenerative disorders including, but not limited to, Alzheimer's disease. GPCR-mediated modulation of mTOR may take advantage of different GPRCs coupled to different G-dependent and G-independent signal transduction routes, of functional selectivity and/or of biased agonism. Signals mediated by GPCRs may act as coincidence detectors to achieve different benefits in different stages of the neurodegenerative disease.

http://ift.tt/2kbQAnV

UV extinction in the atmosphere and its spatial variation in North China

Publication date: April 2017
Source:Atmospheric Environment, Volume 154
Author(s): Jianhui Bai
It is important to determine the distribution of solar radiation between the top of the atmosphere and the surface. Based on an empirical model for estimating hourly ultraviolet radiation irradiance (UVI) under all sky conditions in North China, UVI at the surface and at the top of the atmosphere were obtained. An important phenomenon of UV utilization by "water vapor or absorbing factor" in the 290–400 nm range was studied, its mechanism was that UV energy can be absorbed indirectly once they react OH radicals and H2O and/or consumed directly by gases, liquids, particles (GLPs). The UVI loss in the atmosphere contributed by "absorbing" and scattering materials were 19.30 and 35.31 W m⁻², respectively, which depend on the region and season. The energy loss related to the "absorbing substances" would exist in other regions and should be considered in models (e.g., radiative transfer, chemistry and photochemistry, climate) for better understanding the basic processes in the atmosphere.

http://ift.tt/2lwX1OL

A new passive sampler for collecting atmospheric tritiated water vapor

Publication date: April 2017
Source:Atmospheric Environment, Volume 154
Author(s): Bin Feng, Bo Chen, Weihai Zhuo, Weiyuan Zhang
A new passive sampler was developed for collecting environmental tritiated water vapor. The construction of the sampler was improved according to computational fluid dynamics (CFD) simulations in which the influence on vapor collection by the turbulence inside the sampler was considered. Through changes in temperature from 5 °C to 35 °C and relative humidity from 45% to 90%, the new sampler revealed stable performance of the sampling rate. Compared with the previous samplers, the new sampler significantly lowered the effect of wind speed. Using the adsorption kinetic curve of the sampler provided in the co-comparison experiments, the quantitative relationship between the mass of adsorbed water and the cumulative absolute humidity exposure was established. Field applications in the vicinity of a nuclear power plant show that the data obtained by the new samplers is consistent with the active measurement. The sampler was preliminarily proven to be reliable and flexible for field investigation of HTO in the atmosphere.

http://ift.tt/2kbB6R7

Treatment Options for EGFR T790M-Negative EGFR Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer

Abstract

The introduction of first- and second-generation EGFR-tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib and afatinib) for the treatment of advanced EGFR-mutant non-small cell lung cancer (NSCLC) has dramatically improved patients' prognosis and quality of life (QoL). Unfortunately, after an initial and sometimes durable benefit from EGFR-TKI therapy, all patients with EGFR-mutant lung cancer eventually become resistant to the treatment and experience disease progression. In approximately 50% of these patients, genomic alterations in the EGFR kinase domain resulting in the mutant T790M are responsible for the resistance and this has led to the development of novel EGFR inhibitors active against mutant-T790M EGFR. The remaining 50% of patients with acquired resistance (AR) to EGFR-TKIs do not harbour the T790M mutation. In these cases, other mechanisms are involved in the development of AR such as perturbations of downstream pathways (e.g. K-RAS mutations), activation of alternative bypassing pathways (including c-Met, AXL, PIK3CA, BRAF), or histologic transformation. This review summarizes the main treatment strategies for this particular and heterogeneous group of "T790M-negative" patients.

http://ift.tt/2kd5XYF

ALUternative Regulation for Gene Expression

Publication date: Available online 10 February 2017
Source:Trends in Cell Biology
Author(s): Ling-Ling Chen, Li Yang
Alu elements belong to the primate-specific SINE family of retrotransposons and constitute almost 11% of the human genome. Alus are transcribed by RNA polymerase (Pol) III and are inserted back into the genome with the help of autonomous LINE retroelements. Since Alu elements are preferentially located near to or within gene-rich regions, they can affect gene expression by distinct mechanisms of action at both DNA and RNA levels. In this review we focus on recent advances of how Alu elements are pervasively involved in gene regulation. We discuss the impacts of Alu DNA sequences that are in close proximity to genes, Pol-III-transcribed free Alu RNAs, and Pol-II-transcribed Alu RNAs that are embedded within coding or noncoding RNA transcripts. The recent elucidation of Alu functions reveals previously underestimated roles of these selfish or junk DNA sequences in the human genome.

http://ift.tt/2kcV8pq

Retrospective Analysis of Different Treatment Schemes After Gefitinib Resistance in Advanced Non–Small Cell Lung Cancer

Publication date: Available online 9 February 2017
Source:Clinical Therapeutics
Author(s): Huijuan Wang, Mina Zhang, Peng Li, Guowei Zhang, Xiangtao Yan, Zhiyong Ma
PurposeThe goal of this study was to assess the survival of patients with acquired resistance to gefitinib who underwent different subsequent treatments.MethodsFrom September 2007 to July 2014, a total of 103 patients with pathologically confirmed advanced non–small cell lung cancer and acquired resistance to gefitinib were retrospectively analyzed. Fifty-eight (56%) patients received chemotherapy; 36 were treated with chemotherapy and gefitinib continuation (CT + G), and 22 patients received chemotherapy (CT) alone. Twenty-two patients (22%) received continued gefitinib medication and local therapy (LT + G), and 23 (22%) received best supportive care (BSC).FindingsThe median age of the patients was 62 years and 99 (96%) were diagnosed with adeno-carcinoma and 93 (90%) were stage IV cases. In the chemotherapy groups, patients had high objective response rates and disease control rates (CT + G, 16.7% and 42.7%; CT, 9.1% and 40.9%, respectively). The median progression-free survival times from the beginning of gefitinib resistance was 5.3 months in the CT + G group, 3.6 months in the CT group, 3.1 months in the LT + G group, and 1.4 months in the BSC group (P < 0.005). Moreover, the median overall survival time after gefitinib resistance in the CT + G group was 11.6 months, which was significantly longer than for CT (9.6 months), LT + G (8.1 months), and BSC (3.7 months) patients (P < 0.001).ImplicationsSubsequent chemotherapy after acquired gefitinib resistance led to better survival rates, particularly when combined with continued gefitinib treatment. Local treatment combined with continued gefitinib is an alternative therapy when local progression has occurred. However, larger sample size studies in similar or other population groups are necessary to validate these findings.

http://ift.tt/2kcWHDC

Lipid-Lowering Therapy in Patients With High Cardiovascular Risk: Dose or Combination?

Publication date: Available online 9 February 2017
Source:Clinical Therapeutics
Author(s): Leonardo Roever, Giuseppe Biondi-Zoccai, Sunil V. Rao
Cardiovascular disease is the leading cause of death in the world. Dyslipidemia, manifested by elevated low-density lipoprotein cholesterol (LDL-C) levels, is central to the development and progression of atherosclerosis. Dyslipidemia has become a primary target of intervention in strategies for the prevention of cardiovascular events. Therapeutic lifestyle changes, such as increased physical activity, weight loss, smoking cessation, and adoption of a healthier diet, are effectively reducing cardiovascular risk in primary and secondary prevention. The combination therapy lowered LDL-C levels and achieved the LDL-C target in patients with high cardiovascular risk.

http://ift.tt/2kX6yC2

Cost of Bleeding-related Episodes in Adult Patients With Primary Immune Thrombocytopenia: A Population-based Retrospective Cohort Study of Administrative Claims Data for Commercial Payers in the United States

Publication date: Available online 9 February 2017
Source:Clinical Therapeutics
Author(s): Junji Lin, Xinke Zhang, Xiaoyan Li, David Chandler, Ivy Altomare, Jeffrey S. Wasser, Karynsa Cetin
PurposeWe estimated the real-world costs of bleeding-related episodes (BREs) in adults with primary immune thrombocytopenia (ITP).MethodsThis retrospective cohort study used the MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits databases. We identified adult patients diagnosed with primary ITP between 2007 and 2012, defined by at least 2 outpatient claims separated by ≥30 days or 1 inpatient claim (International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code for primary ITP [287.31]). BRE was defined according to a combination of diagnosis codes and/or procedure codes indicating bleeding or use of rescue therapies. Costs were estimated using total reimbursed amount received by providers (including out-of-pocket costs and reimbursement from insurance, adjusted to 2015 US dollars).FindingsIn 6551 patients, 14,115 BREs were identified, mean (SD) age was 55 (18) years, and 62% of patients were women. Mean total reimbursement per BRE was $6022, with significantly higher mean inpatient ($45,114) versus outpatient ($2150) reimbursements (P < 0.0001). Mean BRE reimbursements were higher in splenectomized patients compared with nonsplenectomized patients ($8365 vs $5858); however, the difference was not statistically significant. Mean reimbursement for BREs associated with bleeding alone was $10,396, and with rescue therapy alone it was $2787. Reimbursement for BREs that included both bleeding and rescue therapy was $11,065.ImplicationsThe real-world reimbursement rates of BREs in adult patients with primary ITP can be substantial, with significantly higher values among patients requiring hospitalization and for those with bleeding events. Additionally, there is a trend toward higher reimbursement rates among splenectomized patients.

http://ift.tt/2kcUM22

RE: “CONTROLLING FOR INFORMED PRESENCE BIAS DUE TO THE NUMBER OF HEALTH ENCOUNTERS IN AN ELECTRONIC HEALTH RECORD”

http://ift.tt/2kcK5wt

RE: “EFFICIENT ESTIMATION OF SMOOTH DISTRIBUTIONS FROM COARSELY GROUPED DATA”

http://ift.tt/2kXgwDn

Risk of Breast Cancer With Long-Term Use of Calcium Channel Blockers or Angiotensin-Converting Enzyme Inhibitors Among Older Women

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Controversy exists about breast cancer risk associated with long-term use of calcium channel blockers (CCBs) or angiotensin-converting enzyme inhibitors (ACEis), respectively. Our objective in this study was to separately evaluate associations between duration of CCB or ACEi use and breast cancer in hypertensive women aged ≥55 years at 3 sites in the Kaiser Permanente health-care system (1997–2012). Exposures included CCB or ACEi use of 1–12 years' duration, determined from pharmacy dispensings. Outcomes included invasive lobular or ductal carcinoma. Statistical methods included discrete-time survival analyses. The cohort included 19,674 (17.9%) CCB users and 90,078 (82.1%) ACEi users. Two percent (<span style="font-style:italic;">n</span> = 397) of CCB users and 1.9% (<span style="font-style:italic;">n</span> = 1,733) of ACEi users developed breast cancer. Compared with 1–<2 years of use, in adjusted analysis, there was no association between CCB use for 2–<12 years and breast cancer: All 95% confidence intervals included 1. Increasing duration of ACEi use was associated with reduced breast cancer risk: Compared with 1–<2 years of use, the adjusted hazard ratio was 0.76 (95% confidence interval: 0.63, 0.92) for 5–<6 years of use and 0.63 (95% confidence interval: 0.43, 0.93) for 9–<10 years of use. We conclude that among older women with hypertension, long-term CCB use does not increase breast cancer risk and long-term treatment with ACEis may confer protection against breast cancer.</span>

http://ift.tt/2kcLwuP

Time-Course of Cause-Specific Hospital Admissions During Snowstorms: An Analysis of Electronic Medical Records From Major Hospitals in Boston, Massachusetts

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<span class="paragraphSection"><div class="boxTitle">Abstract</div>With global climate change, more frequent severe snowstorms are expected; however, evidence regarding their health effects is very limited. We gathered detailed medical records on hospital admissions (<span style="font-style:italic;">n</span> = 433,037 admissions) from the 4 largest hospitals in Boston, Massachusetts, during the winters of 2010–2015. We estimated the percentage increase in hospitalizations for cardiovascular and cold-related diseases, falls, and injuries on the day of and for 6 days after a day with low (0.05–5.0 inches), moderate (5.1–10.0 inches), or high (>10.0 inches) snowfall using distributed lag regression models. We found that cardiovascular disease admissions decreased by 32% on high snowfall days (relative risk (RR) = 0.68, 95% confidence interval (CI): 0.54, 0.85) but increased by 23% 2 days after (RR = 1.23, 95% CI: 1.01, 1.49); cold-related admissions increased by 3.7% on high snowfall days (RR = 3.7, 95% CI: 1.6, 8.6) and remained high for 5 days after; and admissions for falls increased by 18% on average in the 6 days after a moderate snowfall day (RR = 1.18, 95% CI: 1.09, 1.27). We did not find a higher risk of hospitalizations for injuries. To our knowledge, this is the first study in which the time course of hospitalizations during and immediately after snowfall days has been examined. These findings can be translated into interventions that prevent hospitalizations and protect public health during harsh winter conditions.</span>

http://ift.tt/2kXbN4L

In-Work Poverty and Self-Rated Health in a Cohort of Working Germans: A Hybrid Approach for Decomposing Within-Person and Between-Persons Estimates of In-Work Poverty Status

<span class="paragraphSection"><div class="boxTitle">Abstract</div>In this study, we investigated whether self-rated health (SRH) can be predicted by in-work poverty and how between-persons and within-person differences in the poverty status of people who are working contribute to this relationship. We used a logistic random-effects model designed to test within-person and between-persons differences with data from a nationally representative German sample with 19 waves of data collection (1995–2013) to estimate effects of between-persons and within-person differences in working poverty status on poor SRH. Interactions by age and sex were tested, and models controlled for sociodemographic, socioeconomic, and work-related characteristics. We found significant differences in SRH between individuals with different working poverty status but no evidence that within-person differences in working poverty status are associated with poor SRH. The association between in-work poverty and SRH was significantly stronger for women but did not differ significantly by age. All findings were robust when including sociodemographic, socioeconomic, and working characteristics. In this sample of German adults, we found a polarization of poor SRH between the working nonpoor and the working poor but no causal association of within-person differences in working poverty status with SRH.</span>

http://ift.tt/2kXaXVq

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