Studies of CDK 8/19 inhibitors: Discovery of novel and selective CDK8/19 dual inhibitors and elimination of their CYP3A4 time-dependent inhibition potential

Publication date: 15 June 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
Author(s): Jun Fujimoto, Takaharu Hirayama, Yasuhiro Hirata, Yukiko Hikichi, Saomi Murai, Maki Hasegawa, Yuka Hasegawa, Kazuko Yonemori, Akito Hata, Kazunobu Aoyama, Douglas R. Cary
In this article, synthetic studies around a pyridylacrylamide-based hit compound (1), utilizing structure-based drug design guided by CDK8 docking models, is discussed. Modification of the pendant 4-fluorophenyl group to various heteroaromatic rings was conducted aiming an interaction with the proximal amino acids, and then replacement of the morpholine ring was targeted for decreasing potential of time-dependent CYP3A4 inhibition. These efforts led to the compound 4k, with enhanced CDK8 inhibitory activity and no apparent potential for time-dependent CYP3A4 inhibition (CDK8 IC50: 2.5nM; CYP3A4 TDI: 99% compound remaining). Compound 4k was found to possess a highly selective kinase inhibition profile, and also showed favorable pharmacokinetic profile. Oral administration of 4k (15mg/kg, bid. for 2weeks) suppressed tumor growth (T/C 29%) in an RPMI8226 mouse xenograft model.

Graphical abstract

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Identification of selective inhibitors of sphingosine kinases 1 and 2 through a structure–activity relationship study of 4-epi-jaspine B

Publication date: 15 June 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
Author(s): Hiroaki Ohno, Maho Honda, Naoka Hamada, Jun Miyagaki, Akira Iwata, Kazuhiro Otsuki, Toru Maruyama, Shinya Nakamura, Isao Nakanishi, Shinsuke Inuki, Nobutaka Fujii, Shinya Oishi
We recently reported that 4-epi-jaspine B exhibits potent inhibitory activity towards sphingosine kinases (SphKs). In this study, we investigated the effects of modifying the 2-alkyl group, as well as the functional groups on the THF ring of 4-epi-jaspine B using a diversity-oriented synthesis approach based on a late-stage cross metathesis reaction. The introduction of a p-phenylene tether to the alkyl group was favored in most cases, whereas the replacement of a carbon atom with an oxygen atom led to a decrease in the inhibitory activity. Furthermore, the introduction of a bulky alkyl group at the terminus led to a slight increase in the inhibitory activity of this series towards SphKs compared with 4-epi-jaspine B (the Q values of compound 13 for SphK1 and SphK2 were 0.2 and 0.4, respectively). Based on this study, we identified two isoform selective inhibitors, including the m-phenylene derivative 4 [IC50 (SphK1) ≥30μM; IC50 (SphK2)=2.2μM] and the methyl ether derivative 22 [IC50 (SphK1)=4.0μM; IC50 (SphK2) ≥30μM].

Graphical abstract

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Stereospecific cholinesterase inhibition by O,S-diethylphenylphosphonothioate

Publication date: 15 June 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
Author(s): Ahmed Mohammed, Jennifer Sneathen, Sara Glazier Frojen, Louis Kuo, Cynthia M. Dupureur
The inhibition kinetics and stereospecificity of the chiral nerve agent derivative O,S-diethylphenylphosphonothioate (DEPP) were examined for two forms of acetylcholinesterase (human and eel) and equine butyrylcholinesterase. Both S- and R-DEPP are poor inhibitors of eel AChE (IC50 150μM), consistent with a large, nondiscriminatory binding interaction in the active site of this enzyme. However, S-DEPP is active against human and equine AChE with low μM IC50s. DEPP stereospecificities (S/R) toward these enzymes are moderate (20) relative to other cholinesterase-organophosphate (OP) systems. Pralidoxime, a common rescue agent, affects a modest recovery of both hAChE and eqBChE from treatment with S-DEPP. This result is consistent with expected chemical modification by DEPP and indicates that a measurable amount of the enzyme-phosphonate adduct does not undergo aging. Kinetic analysis of inhibition of both hAChE and eqBChE by S-DEPP yields KI values near 8μM and k2 values of about 0.10min⁻¹. In both cases, the reaction is practically irreversible. Second order rate constants calculated from these values are similar to those obtained previously using other thio-substituted OPs with bulky groups. Since BChE has a more accommodating acyl pocket than AChE, the similar behaviors of both enzymes toward S-DEPP is notable and is likely a reflection of the weakened potency of DEPP relative to chemical warfare agents.

Graphical abstract

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The synthesis and evaluation of new butadiene derivatives as tubulin polymerization inhibitors

Publication date: 15 June 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
Author(s): Yanqing Pang, Jun Yan, Baijiao An, Ling Huang, Xingshu Li
A series of new butadiene derivatives was synthesized and evaluated as tubulin polymerization inhibitors for the treatment of cancer. The optimal butadiene derivative, 9a, exhibited IC50 values of 0.056–0.089μM for five human cancer cell lines. This paper included a mechanistic study of the antiproliferative activity, including a tubulin polymerization assay, an examination of morphological alterations of cancer cells, an analysis of cell cycle arrest and an apoptosis assay.

Graphical abstract

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Structure of a Myeloid cell leukemia-1 (Mcl-1) inhibitor bound to drug site 3 of Human Serum Albumin

Publication date: 15 June 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
Author(s): Bin Zhao, John Sensintaffar, Zhiguo Bian, Johannes Belmar, Taekyu Lee, Edward T. Olejniczak, Stephen W. Fesik
Amplification of the gene encoding Myeloid cell leukemia-1 (Mcl-1) is one of the most common genetic aberrations in human cancer and is associated with high tumor grade and poor survival. Recently, we reported on the discovery of high affinity Mcl-1 inhibitors that elicit mechanism-based cell activity. These inhibitors are lipophilic and contain an acidic functionality which is a common chemical profile for compounds that bind to albumin in plasma. Indeed, these Mcl-1 inhibitors exhibited reduced in vitro cell activity in the presence of serum. Here we describe the structure of a lead Mcl-1 inhibitor when bound to Human Serum Albumin (HSA). Unlike many acidic lipophilic compounds that bind to drug site 1 or 2, we found that this Mcl-1 inhibitor binds predominantly to drug site 3. Site 3 of HSA may be able to accommodate larger, more rigid compounds that do not fit into the smaller drug site 1 or 2. Structural studies of molecules that bind to this third site may provide insight into how some higher molecular weight compounds bind to albumin and could be used to aid in the design of compounds with reduced albumin binding.

Graphical abstract

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Synthesis and biological evaluation of novel aromatic and heterocyclic bis-sulfonamide Schiff bases as carbonic anhydrase I, II, VII and IX inhibitors

Publication date: 15 June 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
Author(s): Suleyman Akocak, Nabih Lolak, Alessio Nocentini, Gulcin Karakoc, Anzel Tufan, Claudiu T. Supuran
A series of sixteen novel aromatic and heterocyclic bis-sulfonamide Schiff bases were prepared by conjugation of well known aromatic and heterocyclic aminosulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor pharmacophores with aromatic and heterocyclic bis-aldehydes. The obtained bis-sulfonamide Schiff bases were investigated as inhibitors of four selected human (h) CA isoforms, hCA I, hCA II, hCA VII and hCA IX. Most of the newly synthesized compounds showed a good inhibitory profile against isoforms hCA II and hCA IX, also showing moderate selectivity against hCA I and VII. Several efficient lead compounds were identified among this bis-sulfonamide Schiff bases with low nanomolar to sub-nanomolar activity against hCA II (Kis ranging between 0.4 and 861.1nM) and IX (Kis between 0.5 and 933.6nM). Since hCA II and hCA IX are important drug targets (antiglaucoma and anti-tumor agents), these isoform-selective inhibitors may be considered of interest for various biomedical applications.

Graphical abstract

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Design, synthesis, and pharmacological evaluation of 4-azolyl-benzamide derivatives as novel GPR52 agonists

Publication date: 15 June 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
Author(s): Kazuyuki Tokumaru, Yoshiteru Ito, Izumi Nomura, Takashi Nakahata, Yuji Shimizu, Emi Kurimoto, Kazunobu Aoyama, Kazuyoshi Aso
G protein-coupled receptor 52 (GPR52) agonists are expected to improve the symptoms of psychiatric disorders. During exploration for a novel class of GPR52 agonists with good pharmacokinetic profiles, we synthesized 4-(3-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methyl-1H-1,2,4-triazol-1-yl)-2-methylbenzamide (4u; half maximal effective concentration (EC50)=75nM, maximal response (Emax)=122%) starting from a high-throughput screening hit 3 (EC50=470nM, Emax=56%). The structural features of a reported GPR52 agonist were applied to 3, led to design 4-azolylbenzamides as novel GPR52 agonists. A structure–activity relationship study of 4-azolylbenzamide resulted in the design of the 1,2,4-triazole derivative 4u, which demonstrated excellent bioavailability in rats (F=53.8%). Oral administration of 4u (10mg/kg) significantly suppressed methamphetamine-induced hyperlocomotion in mice. Thus, 4u is a promising lead compound for drug discovery research of GPR52 agonists.

Graphical abstract

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Pyoderma Gangrenosum after Deep Inferior Epigastric Perforator Breast Reconstruction: Systematic Review and Case Report

Background: Pyoderma gangrenosum (PG) is a rare skin disorder of the neutrophilic dermatoses spectrum that can mimic wound infections in surgical patients. PG after breast surgery has been reported but in limited amounts in autologous breast reconstruction patients. We present the first case of PG after a delayed bilateral deep inferior epigastric perforator flap breast reconstruction in the setting of systemic disease along with a systematic review. Methods: PubMed, Ovid, and Web of Science were systematically searched to obtain cases of PG after autologous breast reconstruction. Sixty articles were identified but only 16 were relevant to this study. Results: Systemic disease was present in 2 patients (13%). Wound onset occurred typically 5 days after surgery. Fever and/or leukocytosis was observed in 10 patients (63%). Wound cultures were positive in 2 patients (13%). Donor-site wounds were present in 9 patients (56%). Bilateral breast wounds were present in 67% of bilateral cases. Debridement was performed in 10 cases (63%). Skin graft or substitute was performed in 6 cases (38%). Resection of autologous flap was performed in 3 cases (19%). All patients were treated with systemic steroids (81%) and/or immunosuppressive medications (50%). Complete wound healing occurred by 4 months on average. Conclusion: If early ulcerative wounds develop at multiple sites after autologous breast reconstruction with worsening after debridement and antibiotic therapy, then PG should be considered. It is imperative that an early diagnosis and subsequent treatment with steroids and/or immunosuppressive medications be initiated so further surgical procedures, flap loss, and scarring can be minimized.

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Contracted Nose Correction with Dermofat and Conchal Cartilage

No abstract available

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Stem cells: The different flavours of iPS cells

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Plant genetics: Spatial transcriptomics in plants

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Cancer genomics: Tracking cancer evolution

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Dynamic chromatin technologies: from individual molecules to epigenomic regulation in cells

A full understanding of chromatin in diverse cellular processes requires the consideration of its dynamics, but most standard chromatin assays provide only a static snapshot. This Review describes various emerging methods for probing chromatin dynamics across a wide range of temporal and spatial scales, and discusses the resulting biological insights.

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Effects of sex steroids on the pattern of methylation and expression of the promoter region of estrogen and androgen receptors in people with gender dysphoria under cross-sex hormone treatment

Publication date: Available online 21 May 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Gloria Aranda, Eduardo Fernández-Rebollo, Marta Pradas-Juni, Felicia Alexandra Hanzu, Susana G. Kalko, Irene Halperin, Mireia Mora
Cross-sex hormone therapy (CHT) is critical for phenotypical and physiological transition in adults with gender dysphoria (GD). However, the impact of the CHT onto the molecular level/epigenetic regulation has not been comprehensively addressed. We postulate that CHT in GD could drive changes at the androgen receptor (AR), estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2), affecting their DNA methylation pattern and mRNA expression that may influence in the phenotypical changes associated to CHT.We carried out a prospective observational study on individuals with a diagnosis of GD. 18 subjects (no previous CHT): 12 female to male (FtoM) and 6 male to female (MtoF). An Epityper Mass array TM method was used to study the DNA methylation and Real-time PCR quantitative reverse transcription PCR (qRT-PCR) was used to quantify the gene expression. The analysis of AR, ESR1 and ESR2 receptor was performed at baseline, 6 and 12 months after CHT. No differences in DNA methylation of ESR were found in MtoF, while DNA methylation was increased in FtoM at 6 and 12 months of CHT. The AR showed a significant increase of methylation in MtoF group after 12 months of estrogenic treatment Regarding the expression analysis, AR expression was significantly decreased in FtoM upon CHT treatment. AR, ESR1 and ESR2 methylation were correlated with anthropometric, metabolic and hormonal parameters in FtoM and MtoF.Our results support that CHT is associated to epigenetic changes that might affect the response to treatment with sex steroids.



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Development of a quantitative assessment method of pigmentary skin disease using ultraviolet optical imaging

Background/Purpose

The visual scoring method has been used as a subjective evaluation of pigmentary skin disorders. Severity of pigmentary skin disease, especially melasma, is evaluated using a visual scoring method, the MASI (melasma area severity index). This study differentiates between epidermal and dermal pigmented disease. The study was undertaken to determine methods to quantitatively measure the severity of pigmentary skin disorders under ultraviolet illumination.

Methods

The optical imaging system consists of illumination (white LED, UV-A lamp) and image acquisition (DSLR camera, air cooling CMOS CCD camera). Each camera is equipped with a polarizing filter to remove glare. To analyze images of visible and UV light, images are divided into frontal, cheek, and chin regions of melasma patients. Each image must undergo image processing. To reduce the curvature error in facial contours, a gradient mask is used.

Results

The new method of segmentation of front and lateral facial images is more objective for face-area-measurement than the MASI score. Image analysis of darkness and homogeneity is adequate to quantify the conventional MASI score. Under visible light, active lesion margins appear in both epidermal and dermal melanin, whereas melanin is found in the epidermis under UV light.

Conclusion

This study objectively analyzes severity of melasma and attempts to develop new methods of image analysis with ultraviolet optical imaging equipment. Based on the results of this study, our optical imaging system could be used as a valuable tool to assess the severity of pigmentary skin disease.

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Reflectance confocal microscopy analysis of equivocal melanocytic lesions with severe regression

Background

The differential diagnosis between regressing nevi and melanoma might be challenging; regressing areas can represent a confounding factor for the diagnosis and the histology still remain mandatory to rule out melanoma. Reflectance confocal microscopy may add valuable information by revealing features suggestive of the nature of the melanocytic proliferation.

Objective

To assess the impact of confocal microscopy in the management of regressive melanocytic lesions.

Methods

The dermoscopic analysis of 92 melanocytic lesions showing that more than 30% of regressions have been retrospectively considered, among them, 32 melanocytic lesions with a 7 check point list ≥3 they were assessed at the rcm and subsequently excised. For each selected lesion, dermoscopic features of regression (white scar-like areas, blue areas, blue white areas), distribution of regressing areas (central, peripheral, or both) and the percentage of regression have been examined by an expert in dermoscopy, blinded to the histological and confocal diagnosis. Subsequently, two experts in confocal microscopy revaluated, blinded from histology, RCM images.

Results

Of the 32 lesions analyzed, 23 (71.5%) were diagnosed histologically as nevi, and 9 (28.5%) as melanomas. 26 of 32 lesions (81.5%) exhibited regression >50% of the overall. On RCM, 11 lesions have been interpreted as malignant and 21 as benign. On RCM the majority of nevi exhibited regular architecture without cytological atypia. Epidermal disarray, pagetoid infiltration, disarranged dermo-epidermal junction architecture and atypical nests were considered as suspicious for malignancy. Good concordance between confocal readers has been detected.

Conclusion

A combined dermoscopic/confocal approach can be used for the management of lesions exhibiting dermoscopic features of regression in order to provide a more conclusive pre-histological diagnosis avoiding a high number of unnecessary excisions. Limits of this study were represented by the relatively small number of lesions and the retrospective approach. Further, prospective studies on a larger number of cases, will be necessary in order to compare the efficacy of dermoscopy alone versus dermoscopy in combination with RCM for the evaluation of regression, suspected pigmented lesions.

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Racial differences in colorectal cancer survival at a safety net hospital

Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): Umit Tapan, Shin Yin Lee, Janice Weinberg, Vijaya B. Kolachalama, Jean Francis, Marjory Charlot, Kevan Hartshorn, Vipul Chitalia
BackgroundWhile racial disparity in colorectal cancer survival have previously been studied, whether this disparity exists in patients with metastatic colorectal cancer receiving care at safety net hospitals (and therefore of similar socioeconomic status) is poorly understood.MethodsWe examined racial differences in survival in a cohort of patients with stage IV colorectal cancer treated at the largest safety net hospital in the New England region, which serves a population with a majority (65%) of non-Caucasian patients. Data was extracted from the hospital's electronic medical record. Survival differences among different racial and ethnic groups were examined graphically using Kaplan-Meier analysis. A univariate cox proportional hazards model and a multivariable adjusted model were generated.ResultsBlack patients had significantly lower overall survival compared to White patients, with median overall survival of 1.9 years and 2.5 years respectively. In a multivariate analysis, Black race posed a significant hazard (HR 1.70, CI 1.01–2.90, p=0.0467) for death. Though response to therapy emerged as a strong predictor of survival (HR=0.4, CI=0.2-0.7, p=0.0021), it was comparable between Blacks and Whites.ConclusionsDespite presumed equal access to healthcare and socioeconomic status within a safety-net hospital system, our results reinforce findings from previous studies showing lower colorectal cancer survival in Black patients, and also point to the importance of investigating other factors such as genetic and pathologic differences.



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IFC (Ed. Board)

Publication date: May 2017
Source:Brain Research Bulletin, Volume 131





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Significance and Nature of Bystander Responses Induced by Various Agents

Publication date: Available online 21 May 2017
Source:Mutation Research/Reviews in Mutation Research
Author(s): Neha Verma, Ashu Bhan Tiku
Bystander effects in a biological system are the responses shown by non-targeted neighbouring cells/tissues/organisms. These responses are triggered by factors released from targeted cells when exposed to a stress inducing agent. The biological response to stress inducing agents is complex, owing to the diversity of mechanisms and pathways activated in directly targeted and bystander cells. These responses are highly variable and can be either beneficial or hazardous depending on the cell lines tested, dose of agent used, experimental end points and time course selected. Recently non-targeted cells have even been reported to rescue the directly exposed cells by releasing protective signals that might be induced by non-targeted bystander responses. The nature of bystander signal/s is not yet clear. However, there are evidences suggesting involvement of ROS, RNS, protein factors and even DNA molecules leading to the activation of a number of signaling pathways. These can act independently or in a cascade, to induce events leading to changes in gene expression patterns that could elicit detrimental or beneficial effects.Many review articles on radiation induced bystander responses have been published. However, to the best of our knowledge, a comprehensive review on bystander responses induced by other genotoxic chemicals and stress inducing agents has not been published so far. Therefore, the aim of the present review is to give an overview of the literature on different aspects of bystander responses: agents that induce these responses, factors that can modulate bystander responses and the mechanisms involved.



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Coste-efectividad de la utilización de la tirotropina recombinante humana previa a la ablación con radioyodo en el tratamiento del cáncer de tiroides en hospitales españoles

Publication date: Available online 20 May 2017
Source:Revista Española de Medicina Nuclear e Imagen Molecular
Author(s): J.A. Vallejo, M.A. Muros
ObjetivosPrevio a la ablación con radioyodo en el tratamiento del cáncer de tiroides, se necesita aumentar los niveles de tirotropina (TSH) mediante estimulación exógena (con tirotropina humana recombinante [rhTSH]) o endógena, retirando la terapia con hormona tiroidea (THW). La utilización de rhTSH evita el hipotiroidismo y favorece la eliminación posterior de radioyodo pero supone un coste del producto. Por tanto, era necesario realizar un análisis de coste-efectividad que tuviera en cuenta todos los costes y los beneficios de la utilización de esta terapia.Material y métodosMediante un modelo de Markov con 2 brazos de análisis (rhTSH y THW), estratificado en dosis altas (100mCi/3.700 MBq) y bajas (30mCi/1.110 MBq) de radioyodo, y utilizando 17 ciclos semanales se determinó el coste incremental por años de vida ajustados por calidad (AVAC) asociados a la utilización de rhTSH. Los parámetros clínicos incluidos en el modelo se basan en estudios publicados y en una encuesta realizada en España.ResultadosLa preparación con rhTSH para la radioablación es superior a la THW, presentando beneficios adicionales (0,048AVAC) a la vez que un ahorro en costes (–614,16€), con un ratio de coste-efectividad incremental (ICER) de –12.795€/AVAC. Los análisis de sensibilidad univariantes y multivariantes demuestran que el resultado es consistente.ConclusionesLa utilización de rhTSH previa a la radioablación en España supone un ahorro de costes a la vez que una serie de beneficios de salud para el paciente, por lo que es altamente coste-efectiva.ObjectivesIn thyroid cancer treatment, the thyroid-stimulating hormone (TSH) must be elevated before radioiodine ablation, either by exogenous (with recombinant human thyrotropin [rhTSH]) or endogenous stimulation by thyroid hormone withdrawal (THW). The use of rhTSH avoids hypothyroidism and favours the subsequent elimination of radioiodine, but involves the cost of the product. For this reason, a cost-effectiveness analysis was performed, taking into account all costs involved and the benefits associated with the use of this therapy.Material and methodsUsing a Markov modelling with two analysis arms (rhTSH and THW), stratified into high (100mCi/3700 MBq) and low (30mCi/1110 MBq) radioiodine doses, and using 17 weekly cycles, the incremental cost per quality-adjusted life-year (QALY) related to the use of rhTSH was determined. The clinical inputs included in the model were based on published studies and in a treatment survey conducted in Spain.ResultsRadioablation preparation with rhTSH is superior to THW, showing additional benefits (0.048 AVAC), as well as cost savings (–€614.16), with an incremental cost-effectiveness rate (ICER) of –€12,795/QALY. The univariate and multivariate sensitivity analyses showed the result to be robust.ConclusionsThe use of rhTSH previous to radioablation in Spain has cost savings, as well as a series of health benefits for the patient, making it highly cost-effective.



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Dietary Approaches to Stop Hypertension Diet, Weight Status, and Blood Pressure among Children and Adolescents: National Health and Nutrition Examination Surveys 2003-2012

Publication date: Available online 20 May 2017
Source:Journal of the Academy of Nutrition and Dietetics
Author(s): Juliana F.W. Cohen, Megan E. Lehnerd, Robert F. Houser, Eric B. Rimm
BackgroundThe Dietary Approaches to Stop Hypertension (DASH) diet is associated with lower blood pressure and reduced risk of cardiovascular disease among adults, but little is known about accordance with this dietary pattern or health benefits among children and adolescents.ObjectiveThe objectives were to evaluate accordance with the DASH diet, differences over time, and the association with health attributes among a nationally representative sample of US children and adolescents.DesignCross-sectional data from the 2003-2012 National Health and Nutrition Examination Surveys (NHANES) were analyzed.Participants/settingData from 9,793 individuals aged 8 to 18 years were examined.Main outcome measuresDASH accordance was estimated based on nine nutrient targets: total fat, saturated fat, protein, cholesterol, fiber, calcium, magnesium, potassium, and sodium; possible score range is 0 to 9.Statistical analyses performedAccordance with the DASH diet across time was examined comparing the 2011-2012 to 2003-2004 NHANES surveys. The association between DASH score and weight status was examined using multinomial logistic regression, and the associations with waist circumference, systolic blood pressure, and diastolic blood pressure were examined using multivariable linear regression.ResultsAccordance with the DASH diet was low across the age groups, with a range of mean DASH scores from 1.48 to 2.14. There were no significant changes across time. DASH score was inversely associated with systolic blood pressure (mm Hg) among 14- to 18-year-olds (β=−.46; 95% CI −.83 to −.09) among the larger sample of participants who completed at least one dietary recall, but no significant differences were seen in other age categories. In the subsample of participants with both dietary recalls, a significant inverse association was seen between DASH score and systolic blood pressure for 11- to 13-year-olds (β=−.57; 95% CI −1.02 to −.12). There were no significant associations between this dietary pattern and weight status, waist circumference, or diastolic blood pressure.ConclusionsFew US children and adolescents have diets that are in alignment with the DASH diet. Future research should explore strategies to encourage fruit, vegetable, and whole-grain consumption, as well as sodium reductions to help meet DASH nutrient targets in children and adolescents, as well as examine the potential benefits of this eating pattern on health in this population group.



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Enhancing hair growth in male androgenetic alopecia by a combination of fractional CO 2 laser therapy and hair growth factors

Abstract

Laser therapy and growth factors have been used as alternative treatments for male androgenetic alopecia (MAA). The aim of this study is to determine the efficacy and safety of hair growth factors alone or combined with ablative carbon dioxide (CO₂) fractional laser therapy in MAA. Twenty-eight men were enrolled in this randomized half-split study based on a left-head to right-head pattern. Fractional CO₂ laser treatment was unilaterally performed; hair growth factors were bilaterally applied. Six sessions with 2-week intervals were performed. Global photographs and dermoscopy assessments were performed at the baseline and 4 months after first treatment. Global photographs underwent blinded review by three independent dermatologists. Scanning electron microscopy was used to compare changes in hair-follicle phase and hair-shaft diameter. Twenty-seven participants completed the 4-month treatment schedule. One patient was lost. Mean hair density increased from 114 ± 27 to 143 ± 25/cm² (P < 0.001) in the combined group and from 113 ± 24 to 134 ± 19/cm² in the growth factor group (P < 0.001). The mean change from baseline between two groups was also compared (P = 0.003). Global photographs showed improvement in 93% (25/27) patients in the combined group and 67% (18/27) patients in the growth factor group. Under scanning electron microscopy, hair follicles appeared to transition from telogen to anagen, and hair-shaft diameter increased in five randomly selected patients. Ablative fractional CO₂ laser combined with hair growth factors may serve as an alternative treatment for MAA in individuals unwilling/unable to undergo medical or surgical treatment.

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Sol–gel-derived bioactive glass nanoparticle-incorporated glass ionomer cement with or without chitosan for enhanced mechanical and biomineralization properties

Publication date: Available online 20 May 2017
Source:Dental Materials
Author(s): Dong-Ae Kim, Jung-Hwan Lee, Soo-Kyung Jun, Hae-Won Kim, Mohamed Eltohamy, Hae-Hyoung Lee
ObjectiveThis study investigated the mechanical and in vitro biological properties (in immortalized human dental pulp stem cells (ihDPSCs)) of bioactive glass nanoparticle (BGN)-incorporated glass ionomer cement (GIC) with or without chitosan as a binder.MethodsAfter the BGNs were synthesized and characterized, three experimental GICs and a control (conventional GIC) that differed in the additive incorporated into a commercial GIC liquid (Hy-bond, Shofu, Japan) were produced: BG5 (5wt% of BGNs), CL0.5 (0.5wt% of chitosan), and BG5+CL0.5 (5wt% of BGNs and 0.5wt% of chitosan). After the net setting time was determined, weight change and bioactivity were analyzed in simulated body fluid (SBF) at 37°C. Mechanical properties (compressive strength, diametral tensile strength, flexural strength and modulus) were measured according to the incubation time (up to 28 days) in SBF. Cytotoxicity (1day) and biomineralization (14 days), assessed by alizarin red staining, were investigated using an extract from GIC and ihDPSCs. Data were analyzed using one-way analysis of variance (ANOVA) followed by Tukey's post hoc test; p<0.05.ResultsBGNs were sol–gel synthesized to be approximately 42nm in diameter with a spherical morphology and amorphous structure. After the bioactivity and suspension ability of the BGNs were confirmed, all the experimental GIC groups had setting times of less than 6min and approximately 1% weight loss after 28days of incubation. In addition, BGNs incorporated into GIC (BG5 and BG5+CL0.5) exhibited surface bioactivity. The mechanical properties were increased in the BGN-incorporated GICs compared to those in the control (p<0.05). Without cytotoxicity, the biomineralization capacity was ranked in the order BG5, BG5+CL0.5, control, and CL0.5 (p<0.05).SignificanceBGN-incorporated GIC showed enhanced mechanical properties such as compressive, diametral tensile and flexural strength as well as in vitro biomineralization properties in ihDPSCs without cytotoxicity. Therefore, the developed BGN-incorporated GIC is a promising restorative dental material, although further in vivo investigation is needed before clinical application.

Graphical abstract

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The effects of different opacifiers on the translucency of experimental dental composite resins

Publication date: Available online 20 May 2017
Source:Dental Materials
Author(s): Karine Haas, Gulelala Azhar, Duncan J. Wood, Keyvan Moharamzadeh, Richard van Noort
ObjectiveThe aim of this study was to evaluate the effects of different opacifiers on the translucency of experimental dental composite-resins.MethodsThree metal oxides that are used as opacifiers were tested in this study: titanium oxide (TiO2), aluminium oxide (Al2O3) and zirconium oxide (ZrO2). Experimental composite-resins were fabricated containing 25wt.% urethane dimethacrylate (UDMA)-based resin matrix and 75% total filler including different concentrations of metal oxides (0, 0.25, 0.5, 0.75 and 1wt.%) blended into silane treated barium-silicate filler. The specimens (15.5mm diameter and 1mm thickness) were light-cured and tested in the transmittance mode using a UV/VIS spectrophotometer at wavelengths from 380 to 700nm under a standard illuminant D65. The color differences (ΔE* ab) between different concentrations of opacifiers were also measured in transmittance mode based on their Lab values.ResultsStatistical analysis by ANOVA and Tukey's test showed a significant decrease (p<0.05) in light transmittance with the addition of opacifiers to the experimental composite-resins. There was a linear correlation between different concentrations of TiO2 and Al2O3 and total transmittance. Total transmittance was also found to be wavelength dependent. The color differences for the concentrations of 0–1wt.% of the opacifiers were above 1 ΔE* unit, with Al2O3 showing the smallest color shift.SignificanceThe type and the amount of the opacifiers used in this study had a significant effect on the translucency of the experimental UDMA-based dental composite resins. The most effective opacifier was TiO2, followed by ZrO2 and Al2O3 in decreasing order, respectively.



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Utility of an electronic database and checklist system for Improvement in MRI acquisition

Publication date: Available online 20 May 2017
Source:Current Problems in Diagnostic Radiology
Author(s): Juan E. Small, Laura Semine, Jaclyn Therrien, Patricia Doyle, Lorraine Kelly, Robert Marquis, Curtis W. Bakal
PurposeTo determine whether implementation of an easily accessible electronic database promotes significant reporting of MRI acquisition errors. Additionally, we wanted to see if analysis of the error reports could be used to create a comprehensive checklist to avoid the most common errors.MethodsA new, simple and efficient electronic database reporting system was written in-house and implemented at our institution. Over the course of four months, use of this database enabled collection and analysis of sufficient data for trend analysis. A simple 4 point checklist for MRI technologist use was developed based on the most commonly reported errors. Reported MRI acquisition error rates were collected and analyzed thereafter.ResultsBy the first full month of implementation, MRI scan error reporting increased from a previous negligible baseline rate to 3.03%. The comprehensive checklist was based on the four most common issues reported. Verification of checklist use showed that adherence to this requirement averaged greater than 94%. Immediately following roll out of the checklist, the percentage of errors reported fell to 1.7% with a continued decline in error reports thereafter. An approximately 60% reduction in errors in the last month of the study was evident as compared to the first month of data collection.ConclusionsThe use of an efficient error reporting system and implementation of a checklist based on the most common MRI acquisition errors results in a substantial decrease in the baseline MRI acquisition error rates.



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Communicative Access Measures for Stroke: Development and Evaluation of a Quality Improvement Tool

Publication date: Available online 20 May 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Aura Kagan, Nina Simmons-Mackie, J. Charles Victor, Melodie T.Y. Chan
Objective1) To develop a systems level quality improvement tool targeting communicative access to information and decision-making for stroke patients with language disorders and 2) to evaluate the resulting tool – Communicative Access Measures for Stroke (CAMS).DesignSurvey development and evaluation was in line with accepted guidelines, and included item generation and reduction, survey formatting and composition, pre-testing, pilot-testing, and reliability assessment.SettingDevelopment and evaluation were carried out in hospital and community agency settings.ParticipantsThe project utilized a convenience sample of 31 participants for the survey development, and 63 participants for the CAMS reliability study (broken down into 6 administrators/managers, 32 frontline staff, 25 participants with aphasia). The number of eligible participants invited to the reliability study included 45 community-based organizations in Ontario as well as 4400 individuals from communities of practice.InterventionsNot applicable.Main Outcome Measure(s)Data were analyzed using kappa statistics and intraclass correlations for each item score on all surveys.ResultsA tool, the Communicative Access Measures for Stroke (CAMS), comprising three surveys, was developed for health facilities from the perspectives of 1) administrators/policy makers, 2) staff/frontline health care providers, and 3) patients with aphasia (using a communicatively accessible version). Reliability for items on the CAMS Administrator and CAMS Staff surveys was moderate to high (Kappa/ICCs ranging from 0.54 to 1.00). As expected, reliability was lower for the CAMS Patient survey with most items having ICCs between 0.4 and 0.6.Conclusion(s): These findings suggest that CAMS may provide useful quality improvement information for health care facilities with an interest in improving care for patients with stroke and aphasia.



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Microarray data and gene expression statistics for Saccharomyces cerevisiae exposed to simulated asbestos mine drainage

Publication date: August 2017
Source:Data in Brief, Volume 13
Author(s): Heather E. Driscoll, Janet M. Murray, Erika L. English, Timothy C. Hunter, Kara Pivarski, Elizabeth D. Dolci
Here we describe microarray expression data (raw and normalized), experimental metadata, and gene-level data with expression statistics from Saccharomyces cerevisiae exposed to simulated asbestos mine drainage from the Vermont Asbestos Group (VAG) Mine on Belvidere Mountain in northern Vermont, USA. For nearly 100 years (between the late 1890s and 1993), chrysotile asbestos fibers were extracted from serpentinized ultramafic rock at the VAG Mine for use in construction and manufacturing industries. Studies have shown that water courses and streambeds nearby have become contaminated with asbestos mine tailings runoff, including elevated levels of magnesium, nickel, chromium, and arsenic, elevated pH, and chrysotile asbestos-laden mine tailings, due to leaching and gradual erosion of massive piles of mine waste covering approximately 9km². We exposed yeast to simulated VAG Mine tailings leachate to help gain insight on how eukaryotic cells exposed to VAG Mine drainage may respond in the mine environment. Affymetrix GeneChip® Yeast Genome 2.0 Arrays were utilized to assess gene expression after 24-h exposure to simulated VAG Mine tailings runoff. The chemistry of mine-tailings leachate, mine-tailings leachate plus yeast extract peptone dextrose media, and control yeast extract peptone dextrose media is also reported. To our knowledge this is the first dataset to assess global gene expression patterns in a eukaryotic model system simulating asbestos mine tailings runoff exposure. Raw and normalized gene expression data are accessible through the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) Database Series GSE89875 (http://ift.tt/2rF7prB).



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Workflow sensitivity of post-processing methods in renal DCE-MRI

Publication date: Available online 20 May 2017
Source:Magnetic Resonance Imaging
Author(s): Erik Hanson, Eli Eikefjord, Jarle Rørvik, Erling Andersen, Arvid Lundervold, Erlend Hodneland
Objective: Estimation of renal filtration using dynamic contrast-enhanced imaging (DCE-MRI) requires a series of analysis steps. The possible number of distinct post-processing chains is large and grows rapidly with increasing number of processing steps or options. In this study we introduce a framework for systematic evaluation of the post-processing chains. The framework is later used to highlight the workflow processing chain sensitivity towards accuracy in estimation of glomerular filtration rate (GFR).Methods: Twenty healthy volunteers underwent DCE-MRI examinations as well as iohexol clearance for reference GFR measurements. In total, 692 different combinations of post-processing steps were explored for analysis, including options for kidney segmentation, B1 inhomogeneity correction, placement of arterial input function, gadolinium concentration estimation as well as handling of motion-corrupted volumes and breathing motion. The evaluation of various processing chains is presented using a classification tree framework and random forest ensemble learning.Results: Among the processing steps subject to testing, methods for calculating the gadolinium concentration as well as B1 inhomogeneity correction had the largest impact on accuracy of GFR estimations. Different segmentation methods did not play an important role in the post-processing of the MR data except from one processing chain where the automated segmentation outperformed the manual segmentation.Conclusion: The proposed classification trees were efficiently used as a statistical tool for visualization and communication of results to distinguish between important and less influential processing steps in renal DCE-MRI. We also identified several crucial factors in the processing chain.



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The Current Value Of Determining The Mismatch Repair Status Of Colorectal Cancer: A Rationale For Routine Testing

Publication date: Available online 20 May 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): E. Ryan, K. Sheahan, B. Creavin, H.M. Mohan, D.C. Winter
Colorectal Cancer (CRC) is the third most prevalent cancer in men and women. Up to 15% of CRCs display microsatellite instability (MSI). MSI is reflective of a deficient mismatch repair (MMR) system and is most commonly caused by hypermethylation of the MLH1 promoter. However, it may also be due to autosomal dominant constitutional mutations in DNA MMR, termed Lynch Syndrome. MSI may be diagnosed via polymerase chain reaction (PCR) or alternatively, immunohistochemistry (IHC) can identify MMR deficiency (dMMR). Many institutions now advocate universal tumour screening of CRC via either PCR for MSI or IHC for dMMR to guide Lynch Syndrome testing. The association of sporadic MSI with methylation of the MLH1 promoter and an activating BRAF mutation may offer further exclusion criteria for genetic testing. Aside from screening for Lynch syndrome, MMR testing is important because of its prognostic and therapeutic implications. Several studies have shown MSI CRCs exhibit different clinicopathological features and prognosis compared to microsatellite-stable (MSS) CRCs. For example, response to conventional chemotherapy has been reported to be less in MSI tumours. More recently, MSI tumors have been shown to be responsive to immune-checkpoint inhibition providing a novel therapeutic strategy. This provides a rationale for routine testing for MSI or dMMR in CRC.



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Brain metastases from Non-Small Cell Lung Carcinoma: changing concepts for improving patients’ outcome

Publication date: Available online 20 May 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Chloé Rancoule, Alexis Vallard, Jean-Baptiste Guy, Sophie Espenel, Peng Diao, Cyrus Chargari, Nicolas Magné
The management of Non Small Cell Lung Cancer (NSCLC) brain metastases is challenging, as this frequent complication negatively impacts patients' quality of life, and can be a life-threatening event.Through a review of the literature, we discuss the main therapeutic options and the recent developments that improved (and complicated) the management of NSCLC brain metastases patients. Most current validated approaches are local with exclusive or combined surgery, whole brain radiotherapy (WBRT) and stereotactic radiotherapy (SRT). At the same time, there is a growing role for systemic treatments that might significantly postpone WBRT. Targeted therapies efficacy/toxicity profile remains to be defined but predictive and prognostic molecular factors integration could help to select treatments fully adapted to life expectancy and progression risk.



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Nutritional composition of mungbean and soybean sprouts compared to their adult growth stage

Publication date: 15 December 2017
Source:Food Chemistry, Volume 237
Author(s): Andreas W. Ebert, Ching-Huan Chang, Miao-Rong Yan, Ray-Yu Yang
This study determined the level of phytonutrients in mungbean and soybean sprouts compared to mature mungbean grain and vegetable soybean. The comparison included landraces and improved mungbean and soybean varieties to assess the effect of breeding on the phytonutrient content of both crops. Sprouting mungbean enhanced vitamin C content 2.7-fold compared to mature mungbean grain. Relatively old mungbean accessions were superior in protein, calcium (Ca), iron (Fe), zinc (Zn), carotenoid and vitamin C content compared to improved mungbean lines at the fully mature stage. With regard to nutritional value, the vegetable soybean stage was superior to soybean sprouts in terms of content of protein (14% increase), Zn (45%), Ca (72%), and Fe (151%). Isoflavones, reported to have beneficial effects on human health, are found at high concentrations in soybean sprouts and could easily provide the recommended anticarcinogenic dose range from 1.5 to 2.0mg/kg of body weight per day.



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Predictors and Delays Associated with the Need for Advanced Techniques for Intravenous Access

Publication date: Available online 20 May 2017
Source:The Journal of Emergency Medicine
Author(s): Michael D. Witting, Siamak Moayedi, Latoya A. Brown, Ammar Ismail
BackgroundThe need for advanced techniques for intravenous access (ATIVA) can lead to delays in care and contribute to emergency department (ED) crowding.ObjectiveIn this article, we estimate the delay and predictors associated with the need for ATIVA.MethodsIn this case-control study, we collected data from ED cases requiring ATIVA and control patients in whom i.v. access was gained by traditional inspection and palpation. We included two control groups—a random retrospective sample and a prospective limited convenience sample. We collected time and acuity data from all groups and data on predictor variables from cases and prospective controls. We analyzed time data using quartile regression and predictor variable data using contingency table analysis and logistic regression.ResultsWe collected data from 116 cases (91 of which had time interval data), 98 retrospective controls, and 144 prospective controls. The median time from triage to i.v. line establishment was 199 min for cases vs. 64 min for prospective controls and 81 min for retrospective controls. The need for ATIVA was associated with a 1.1-greater quartile time interval (95% confidence interval [CI] 0.8–1.3). Two variables—i.v. drug use (IVDU; odds ratio 3.7; 95% CI 1.8–7.3) and prior need for ATIVA (odds ratio 5.2; 95% CI 2.7–9.8)—were associated with a need for ATIVA; obesity, renal failure, and diabetes were not.ConclusionsThe need for ATIVA increases median time to i.v. line placement by 118 to 135 min compared with traditional inspection and palpation. IVDU and prior need for an advanced technique are associated with a need for ATIVA.



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mTOR signaling in the differentiation and function of regulatory and effector T cells

Publication date: June 2017
Source:Current Opinion in Immunology, Volume 46
Author(s): Hu Zeng, Hongbo Chi
The mechanistic target of rapamycin (mTOR) signaling pathway integrates environmental signals and cellular metabolism to regulate T cell development, activation and differentiation. Recent studies reveal the importance of exquisite control of mTOR activity for proper T cell function, and detailed molecular mechanisms that regulate mTOR signaling in different T cell subsets. Here, we review the latest advances in our understanding of the mTOR pathway and its regulation in the differentiation and function of regulatory T cells and effector T cells.



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Metabolic signatures of T-cells and macrophages in rheumatoid arthritis

Publication date: June 2017
Source:Current Opinion in Immunology, Volume 46
Author(s): Cornelia M Weyand, Markus Zeisbrich, Jörg J Goronzy
In most autoimmune diseases, a decade-long defect in self-tolerance eventually leads to clinically relevant, tissue-destructive inflammatory disease. The pathogenic potential of chronic persistent immune responses during the pre-clinical and clinical phase is ultimately linked to the bioenergetic fitness of innate and adaptive immune cells. Chronic immune cell stimulation, high cellular turn-over, structural damage to the host tissue and maladaptive wound healing, all require a reliable supply of nutrients, oxygen, and biosynthetic precursors. Here, we use the model system of rheumatoid arthritis (RA) to discuss immunometabolism from the vantage point of T-cells and macrophages that encounter fundamentally different metabolic stress scenarios in the RA host. We outline the general principle that both insufficient nutrient supply, as well as nutrient excess generate cellular stress responses and guide immune function. ATP^low, NADPH^high, ROS^low T-cells hyperproliferate and are forced into premature senescence. ATP^high, ROS^high macrophages dimerize the glycolytic enzyme pyruvate kinase to amplify STAT3-dependent inflammatory effector functions. A corollary of this model is that simple nutraceutical interventions will be insufficient to re-educate the immune system in RA. Instead, interference with cell-type-exclusive and differentiation-stage-dependent metabolic setpoints will be needed to reprogram arthritogenic pathways.



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Mining for osteogenic surface topographies: In silico design to in vivo osseo-integration

Publication date: August 2017
Source:Biomaterials, Volume 137
Author(s): Frits F.B. Hulshof, Bernke Papenburg, Aliaksei Vasilevich, Marc Hulsman, Yiping Zhao, Marloes Levers, Natalie Fekete, Meint de Boer, Huipin Yuan, Shantanu Singh, Nick Beijer, Mark-Anthony Bray, David J. Logan, Marcel Reinders, Anne E. Carpenter, Clemens van Blitterswijk, Dimitrios Stamatialis, Jan de Boer
Stem cells respond to the physicochemical parameters of the substrate on which they grow. Quantitative material activity relationships – the relationships between substrate parameters and the phenotypes they induce – have so far poorly predicted the success of bioactive implant surfaces. In this report, we screened a library of randomly selected designed surface topographies for those inducing osteogenic differentiation of bone marrow-derived mesenchymal stem cells. Cell shape features, surface design parameters, and osteogenic marker expression were strongly correlated in vitro. Furthermore, the surfaces with the highest osteogenic potential in vitro also demonstrated their osteogenic effect in vivo: these indeed strongly enhanced bone bonding in a rabbit femur model. Our work shows that by giving stem cells specific physicochemical parameters through designed surface topographies, differentiation of these cells can be dictated.



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QX-OH, a QX-314 derivative agent, produces long-acting local anesthesia in rats

Publication date: 15 July 2017
Source:European Journal of Pharmaceutical Sciences, Volume 105
Author(s): YuJun Zhang, Jun Yang, QinQin Yin, LingHui Yang, Jin Liu, WenSheng Zhang
QX-314 has been shown to produce long-acting local anesthesia in vivo in animals; however, translation to humans has been impeded by concerns about toxicity. We investigated whether the newly emerged QX-OH molecule could confer long-lasting anesthesia with a low local toxicity in rats. In rat sciatic nerve block model, QX-OH 25mM produced a longer sensory block than QX-314 25mM (median [25th, 75th percentiles], 5.5 [4.25, 6] h vs. 3 [3, 4] h; P=0.03). QX-OH 35mM produced a longer sensory block than QX-314 35mM (8 [6, 12] h vs. 6 [4, 6.5] h, P=0.038). QX-OH at 35 and 45mM generated longer motor blocks than QX-314, with tissue toxicity less than that of QX-314 at the same concentration. In contrast with bupivacaine, QX-OH was clearly superior in terms of sensory and motor blockade durations after a single bolus injection. There was no significant difference in tissue toxicity between QX-OH (25 and 35mM) and bupivacaine. In rat cutaneous trunci pinprick model, the QX-OH-induced pain threshold remained significantly different from baseline at 6h (25mM, P<0.0001), 10h (35mM, P<0.0001), and 12h (45mM, P<0.0001). The time required for full recovery from the subcutaneous anesthetic effect was significantly longer for QX-OH than for QX-314 and bupivacaine. So QX-OH produced concentration-dependent, reversible, and long-acting local anesthesia in animal models with a moderate local toxicity.

Graphical abstract

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Inhibition of Neddylation Modification Sensitizes Pancreatic Cancer Cells to Gemcitabine

Publication date: June 2017
Source:Neoplasia, Volume 19, Issue 6
Author(s): Hua Li, Weihua Zhou, Lihui Li, Jianfu Wu, Xiaoli Liu, Lili Zhao, Lijun Jia, Yi Sun
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the USA with a 5-year survival rate less than 3% to 5%. Gemcitabine remains as a standard care for PDAC patients. Although protein neddylation is abnormally activated in many human cancers, whether neddylation dysregulation is involved in PDAC and whether targeting neddylation would sensitize pancreatic cancer cells to gemcitabine remain elusive. Here we report that high expression of neddylation components, NEDD8 and NAE1, are associated with poor survival of PDAC patients. Blockage of neddylation by MLN4924, a small molecule inhibitor targeting this modification, significantly sensitizes pancreatic cancer cells to gemcitabine, as evidenced by reduced growth both in monolayer culture and soft agar, reduced clonogenic survival, decreased invasion capacity, increased apoptosis, G2/M arrest, and senescence. Importantly, combinational treatment of MLN4924-gemcitabine near completely suppressed in vivo growth of pancreatic cancer cells. Mechanistically, accumulation of NOXA, a pro-apoptotic protein and ERBIN, a RAS signal inhibitor, appears to play, at least in part, a causal role in MLN4924 chemo-sensitization. Our study demonstrates that neddylation modification is a valid target for PDAC, and provides the proof-of-concept evidence for future clinical trial of MLN4924-gemcitabine combination for the treatment of pancreatic cancer patients.



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Staphylococcus aureus colonization is associated with increased inhaled corticosteroid requirements in patients with atopic dermatitis and asthma.

Related Articles

Staphylococcus aureus colonization is associated with increased inhaled corticosteroid requirements in patients with atopic dermatitis and asthma.

J Allergy Clin Immunol Pract. 2017 May 16;:

Authors: Uong P, Curran-Everett D, Leung DYM

PMID: 28526276 [PubMed - as supplied by publisher]

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Effect of vitamin D replacement on immunological biomarkers in patients with multiple sclerosis

Publication date: Available online 20 May 2017
Source:Clinical Immunology
Author(s): May F. Mrad, Nabil K. El Ayoubi, Maria O. Esmerian, Jalal M. Kazan, Samia J. Khoury
We aimed to investigate the immunologic effects of vitamin D replacement in RRMS patients. In a controlled single center study, patients deficient in 25-hydroxyvitamin D (serum level<25ng/ml) received 10,000IU/week cholecalciferol for 3months. Sufficient vitamin D patients (serum level>35ng/ml) were followed for the same period. Assessments were performed at baseline and at 3months. 25-hydroxyvitamin D levels increased significantly from baseline to month-3 in the deficient group after treatment and remained stable in the sufficient group. We observed a decreased interferon-γ (IFNγ) secretion by CD4⁺ T cells in vitamin D deficient group but not in the sufficient group, and a negative correlation between baseline serum vitamin D and IFNγ production. There was no change in the frequency of T helper or regulatory T cell subsets in either group. Increasing serum levels of 25-hydroxyvitamin D are associated with decreased production of IFNγ by CD4⁺ T cells.



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Time-course assessment of the aggregation and metabolization of magnetic nanoparticles

Publication date: Available online 20 May 2017
Source:Acta Biomaterialia
Author(s): José M. Rojas, Helena Gavilán, Vanesa del Dedo, Eduardo Lorente-Sorolla, Laura Sanz-Ortega, Gustavo B. da Silva, Rocío Costo, Sonia Perez-Yagüe, Marina Talelli, Marzia Marciello, M. Puerto Morales, Domingo F. Barber, Lucía Gutiérrez
To successfully develop biomedical applications for magnetic nanoparticles, it is imperative that these nanoreagents maintain their magnetic properties in vivo and that their by-products are safely metabolized. When placed in biological milieu or internalized into cells, nanoparticle aggregation degree can increase which could affect magnetic properties and metabolization. To evaluate these aggregation effects, we synthesized citric acid-coated iron oxide nanoparticles whose magnetic susceptibility can be modified by aggregation in agar dilutions and dextran-layered counterparts that maintain their magnetic properties unchanged. Macrophage models were used for in vitro uptake and metabolization studies, as these cells control iron homeostasis in the organism. Electron microscopy and magnetic susceptibility studies revealed a cellular mechanism of nanoparticle degradation, in which a small fraction of the particles is rapidly degraded while the remaining ones maintain their size. Both nanoparticles types produced similar iron metabolic profiles but these profiles differed in each macrophage model. Thus, nanoparticles induced iron responses that depended on macrophage programming. In vivo studies showed that nanoparticles susceptible to changes in magnetic properties through aggregation effects had different behavior in lungs, liver and spleen. Liver ferritin levels increased in these animals showing that nanoparticles are degraded and their by-products incorporated into normal metabolic routes. These data show that nanoparticles iron metabolization depends on cell type and highlight the necessity to assess nanoparticle aggregation in complex biological systems to develop effective in vivo biomedical applications.Statement of significanceMagnetic iron oxide nanoparticles have great potential for biomedical applications. It is however imperative that these nanoreagents preserve their magnetic properties once inoculated, and that their degradation products can be eliminated. When placed in a biological milieu nanoparticles can aggregate and this can affect their magnetic properties and their degradation. In this work, we showed that iron oxide nanoparticles trigger the iron metabolism in macrophages, the main cell type involved in iron homeostasis in the organism. We also show that aggregation can affect nanoparticles magnetic properties when inoculated in animal models. This work confirms iron oxide nanoparticle biocompatibility and highlights the necessity to assess in vivo nanoparticle aggregation to successfully develop biomedical applications.

Graphical abstract

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Scholar : These new articles for The Aging Male are available online

The online platform for Taylor & Francis Online content New for The Aging Male and online now on Taylor & Francis Online: Original Article Prostate-specific antigen decline pattern in advanced prostate cancer receiving androgen deprivation therapy and relationship with prostate-specific antigen progression Erdem Akbay, Murat Bozlu, Selahittin Çayan, Pelin Özcan Kara, Mesut Tek & Cuma Aytekin Pages: 1-9 | DOI: 10.1080/13685538.2017.1328675 Free access World Diabetes Day research collection – Eyes on Diabetes. To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Graphene oxide-supported carbon nanofiber-like network derived from polyaniline: A novel composite for enhanced glucose oxidase bioelectrode performance

Publication date: 15 October 2017
Source:Biosensors and Bioelectronics, Volume 96
Author(s): Zepeng Kang, Kailong Jiao, Xinping Xu, Ruiyun Peng, Shuqiang Jiao, Zongqian Hu
A three-dimensional architecture of PANI@GO hybrid was synthesized via in-situ polymerization of aniline monomers on the surface of graphene oxide (GO) and carbonized at 1600°C. The SEM images showed that surfaces of planar GO were covered by a compact nanofiber-like polyaniline (PANI) layer which presented an interconnected network. Nanofiber-like PANI on the GO surface was mostly preserved and became the carbon nanofibers (CNFs) after carbonization. The TEM images showed that the carbonized PANI grew seamlessly on the GO surface and served as conductive "network" between interlayers of GO. The carbonized PANI@GO hybrid was used to modify a glassy carbon electrode (GCE) based on GOx, resulting in efficient direct electron transfer (DET) and excellent bio-catalytic performance. In addition, a glucose/O2 fuel cell constructed using Nafion/GOx/PANI1600@GO/GCE as the anode and an E-TEK Pt/C modified GCE as the cathode generated a maximum power density of 0.756mWcm⁻² at 0.42V. Findings in this study may be helpful for exploiting novel materials for immobilization of enzymes through carbonizing conducting polymers or their composites with inorganic materials at high temperature for applications in enzymatic biofuel cells or biosensors.



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Improved Adherence to a Stepped-care Model Reduces Costs of Intermittent Claudication Treatment in The Netherlands

Publication date: Available online 20 May 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): D. Hageman, H.J.P. Fokkenrood, P.P.M. Essers, M.J.W. Koelemay, J.C. Breek, A.C. Vahl, M.R.M. Scheltinga, J.A.W. Teijink
Objective/BackgroundA previous budget impact analysis regarding a supervised exercise therapy (SET) first treatment strategy (stepped care model [SCM]) for Dutch patients with intermittent claudication (IC) showed a low referral rate in 2009, despite solid evidence of the effectiveness of SET programs. Recently, several campaigns have stimulated stakeholders in the field to adopt a SET first strategy in patients with IC. The aim of the present study was to reassess SCM adherence after a 2 year period.MethodsIC related invoices of patients in 2011 were obtained from a large Dutch health insurance company (3.5 million persons). Patients were divided into two groups based on their initial treatment. A SET group had started SET between 12 months before (initiated by general practitioner) and 3 months after (initiated by vascular surgeon) presentation at a vascular surgery outpatient clinic. An intervention (INT) group was treated by revascularisation within 3 months of outpatient presentation. Costs of IC treatment in this 2011 cohort were compared with the earlier 2009 cohort.ResultsIC related invoices of 4135 patients were available. In 2011, the initial treatment was SET in 56% (2009: 34%; +22% [p < .001]) and INT in 44% (2009: 66%; −22% [p < .001]) of the IC population. Additional revascularisation was performed in 19% of patients in the SET group (2009: 6%; +13% [p < .001]) and also in 19% of patients in the INT group (2009: 35%; −16% [p < .001]). Later on, 29% of patients in the INT group were referred for SET (2009: 10%; +19% [p < .001]). Average costs of IC treatment per patient in 2011 were 6% lower than in 2009 (€6885 vs. €7300; p = .020).ConclusionA 22% increase in adherence to SET as a first treatment strategy in Dutch patients with IC was attained between 2009 and 2011. This shift suggests successful SCM implementation resulting in lower costs for the national healthcare system.



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Contents

Publication date: June 2017
Source:European Journal of Vascular and Endovascular Surgery, Volume 53, Issue 6





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Editorial Board

Publication date: June 2017
Source:European Journal of Vascular and Endovascular Surgery, Volume 53, Issue 6





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EJVES vol. 53, issue 6 (June 2017) - Spanish Translated Abstracts

Publication date: June 2017
Source:European Journal of Vascular and Endovascular Surgery, Volume 53, Issue 6





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One year on: Test your knowledge from the previous year

Publication date: June 2017
Source:European Journal of Vascular and Endovascular Surgery, Volume 53, Issue 6





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Selected Abstracts from the June Issue of the Journal of Vascular Surgery

Publication date: June 2017
Source:European Journal of Vascular and Endovascular Surgery, Volume 53, Issue 6





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Forthcoming Events

Publication date: June 2017
Source:European Journal of Vascular and Endovascular Surgery, Volume 53, Issue 6





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Endovascular Treatment of Symptomatic Renal Artery Aneurysm with Hostile Anatomy

Publication date: June 2017
Source:European Journal of Vascular and Endovascular Surgery, Volume 53, Issue 6
Author(s): J. Sousa, A. Mansilha




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The Significance of Inflow Artery and Tourniquet Derived Cephalic Vein Diameters on Predicting Successful Use and Patency of Arteriovenous Fistulas for Haemodialysis

Publication date: June 2017
Source:European Journal of Vascular and Endovascular Surgery, Volume 53, Issue 6
Author(s): S.K. Kakkos, N. Kaplanis, E.C. Papachristou, S.I. Papadoulas, G.C. Lampropoulos, I.A. Tsolakis, D.S. Goumenos
ObjectiveTo investigate the significance of inflow artery and cephalic vein diameters on predicting patency of radiocephalic and brachiocephalic arteriovenous fistulas (AVFs).DesignSingle centre study with retrospective analysis of prospectively collected data between November 2010 and July 2015.MethodsA detailed history and physical examination was undertaken, including age, gender, history and duration of haemodialysis, cause of chronic kidney disease, and the presence of comorbidities/risk factors. Pre-operative arterial and venous upper extremity mapping was performed and inner vessel diameter was recorded, using a tourniquet for the veins. Outcome measures included AVF use (functionality), primary, primary assisted, secondary, and functional secondary patency.ResultsOne hundred and thirty five AVFs (57 and 78 radiocephalic and brachiocephalic AVFs, respectively) were constructed and followed up for 5 years. A cephalic vein diameter <4.3 mm (lower three quartiles) was the single independent predictor of inferior secondary and also functional secondary patency of radiocephalic AVFs (p = .02, HR 11.2, 95% CI 1.44–90.9). A brachial artery diameter ≤4.1 mm (lowest quartile) was an independent predictor of AVF functionality (57% vs. 83% for larger arteries, p = .017), and inferior primary, primary assisted, secondary, and functional secondary patency of brachiocephalic AVFs (primary assisted patency 21.9% vs. 55.9% at 3 years, p = .001/log-rank test, HR 3.1, p = .002/Cox regression). The presence of lower extremity PAD or use of dual antithrombotics was also independently associated with an inferior secondary patency. The number of risk factors (brachial artery diameter ≤4.1 mm, PAD, and use of dual antithrombotics) demonstrated risk stratification capabilities for functional secondary patency.ConclusionsAmong patients undergoing radiocephalic AVFs, a tourniquet derived cephalic vein diameter <4.3 mm was the single independent predictor of inferior secondary and functional secondary patency. Among patients undergoing brachiocephalic AVFs, all patency rates were inferior in the presence of a brachial artery diameter ≤4.1 mm and secondary patency was inferior in the presence of multiple risk factors.



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Taking control! Structural and behavioural plasticity in response to game-based inhibition training in older adults

Publication date: 1 August 2017
Source:NeuroImage, Volume 156
Author(s): Simone Kühn, Robert C. Lorenz, Markus Weichenberger, Maxi Becker, Marten Haesner, Julie O'Sullivan, Anika Steinert, Elisabeth Steinhagen-Thiessen, Susanne Brandhorst, Thomas Bremer, Jürgen Gallinat
While previous attempts to train self-control in humans have frequently failed, we set out to train response inhibition using computer-game elements. We trained older adults with a newly developed game-based inhibition training on a tablet for two months and compared them to an active and passive control group. Behavioural effects reflected in shorter stop signal response times that were observed only in the inhibition-training group. This was accompanied by structural growth in cortical thickness of right inferior frontal gyrus (rIFG) triangularis, a brain region that has been associated with response inhibition. The structural plasticity effect was positively associated with time spent on the training-task and predicted the final percentage of successful inhibition trials in the stop task. The data provide evidence for successful trainability of inhibition when game-based training is employed. The results extend our knowledge on game-based cognitive training effects in older age and may foster treatment research in psychiatric diseases related to impulse control.



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A new class of self-healable hydrophobic materials based on ABA triblock copolymer via RAFT polymerization and Diels-Alder “click chemistry”

Publication date: 16 June 2017
Source:Polymer, Volume 119
Author(s): Nabendu B. Pramanik, Prantik Mondal, Rabibrata Mukherjee, Nikhil K. Singha
This investigation reports the preparation of a new self-healing ABA tri-block copolymer (BCP) poly(furfuryl methacrylate-b-poly(dimethyl siloxane)-b-poly(furfuryl methacrylate) (PFMA-b-PDMS-b-PFMA) (FDF) via RAFT polymerization using PDMS-CTA as macro-RAFT agent. The formation of FDF triblock copolymer was confirmed by ¹H NMR, GPC and DSC analyses. The phase segregated domain morphology of the synthesized BCP films as a function of PFMA fraction was studied via an AFM. In this BCP, Diels-Alder (DA) click reaction was carried out between the reactive furfuryl group in PFMA unit as diene with different maleimides as dienophile. While the presence of the PFMA unit makes the triblock copolymer thermally amendable and the PDMS present in the matrix makes the BCP ideally suited for hydrophobic self-healing applications. The hydrophobic nature of the triblock copolymer was studied by water contact angle (WCA) measurement and the self-healing property was studied by DSC and SEM analyses.

Graphical abstract

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