Effective tumor immunity to melanoma mediated by B16F10 cancer stem cell vaccine

Publication date: November 2017
Source:International Immunopharmacology, Volume 52
Author(s): Fengshu Zhao, Rong Zhang, Jing Wang, Di Wu, Meng Pan, Miao Li, Mei Guo, Jun Dou
Although tumor vaccines have been considered a promising immunotherapy approach, therapeutic tumor vaccines are mostly disappointing in the clinic due to vaccine weak immunogenicity. Cancer stem cells (CSCs) may broaden the antigenic breadth and effectively induce the immune responses against autologous cancer cells. Here we report on the development of the B16F10 CD133⁺CD44⁺CSCs (B16F10 CSCs) vaccine to induce tumor immunity to melanoma in mice. Efficacy of against melanoma was evaluated by analysis of tumor growth and mouse survival. Immunogenicity was assessed by ELISA and flow cytometric assays, including serum cytokines, cytotoxic activity of NK cells and splenocytes in the immunized mice. The results showed that the B16F10 CSC vaccine resulted in tumor shrinkage and mouse lifespan extension. The cytotoxic activity and IFN-γ level were significantly increased in mice immunized with B16F10 CSC vaccine compared with the mice immunized with control vaccines. Additionally, New York esophageal squamous cell carcinoma-1, an efficient tumor associated antigen over-expressed by B16F10 CSCs, was markedly reduced in expression in melanoma tissue, suggesting decrease of CSC subpopulation due to B16F10 CSC vaccination. Collectively, the findings may represent a new powerful approach for treatment of melanoma by B16F10 CSC vaccination.



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No effect of insect repellents on the behaviour of Lymnaea stagnalis at environmentally relevant concentrations

Abstract

Insect repellents are widely applied to various materials and to both human and animal skin to deter mosquitoes and ticks. The most common deterrent compounds applied are DEET, EBAAP and icaridin (picaridin, Bayrepel). Due to their extensive application, these repellents are frequently detected in surface waters in considerable concentrations. As these compounds are designed to alter invertebrates' behaviour rather than to intoxicate them, we hypothesised that insect repellents have the potential to modify the natural behaviour of non-target invertebrates in natural freshwater bodies. To test this, we used a well-established laboratory assay designed to quantify the odour-mediated foraging behaviour of freshwater gastropods and the great pond snail Lymnaea stagnalis (Linnaeus, 1758) as a model organism to test for potential deterrent effects of insect repellents on aquatic snails. Using a wide concentration range from the picogramme per litre to microgramme per litre range (and by far exceeding the range of concentrations reported from natural waters), we found no evidence for a deterrent effect of either of the three repellents on foraging L. stagnalis. Our data and other recent studies give no indication for undesirable behavioural alterations by common insect repellents in surface waters.

http://ift.tt/2xBF6Qq

Rapid establishment of phenol- and quinoline-degrading consortia driven by the scoured cake layer in an anaerobic baffled ceramic membrane bioreactor

Abstract

Although toxic and refractory organics, such as phenol and quinoline, are decomposed by anaerobic bacteria, the establishment of specific degrading consortia is a relatively slow process. An anaerobic membrane bioreactor allows for complete biomass retention that can aid the establishment of phenol- and quinoline-degrading consortia. In this study, the anaerobic digestion of phenol (500 mg L⁻¹) and quinoline (50 mg L⁻¹) was investigated using an anaerobic baffled ceramic membrane bioreactor (ABCMBR). The results showed that, within 30 days, 99% of phenol, 98% of quinoline and 88% of chemical oxygen demand (COD) were removed. The substrate utilisation rates of the cake layer for phenol and quinoline, and specific methanogenic activity of the cake layer, were 7.58 mg phenol g⁻¹ mixed liquor volatile suspended solids (MLVSS) day⁻¹, 8.23 mg quinoline g⁻¹ MLVSS day⁻¹ and 0.55 g COD_CH4 g⁻¹ MLVSS day⁻¹, respectively. The contribution of the cake layer to the removals of phenol and quinoline was extremely underestimated because the uncounted scoured cake layer was disregarded. Syntrophus was the key population for phenol and quinoline degradation, and it was more abundant in the cake layer than in the bulk sludge. The highly active scattered cake layer sped up the establishment of phenol- and quinoline-degrading consortia in the ABCMBR.

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Radiation-induced lung toxicity in non-small-cell lung cancer: Understanding the interactions of clinical factors and cytokines with the dose-toxicity relationship

Publication date: Available online 23 September 2017
Source:Radiotherapy and Oncology
Author(s): Peter G. Hawkins, Philip S. Boonstra, Stephen T. Hobson, Jason W.D. Hearn, James A. Hayman, Randall K. Ten Haken, Martha M. Matuszak, Paul Stanton, Gregory P. Kalemkerian, Nithya Ramnath, Theodore S. Lawrence, Matthew J. Schipper, Feng-Ming (Spring) Kong, Shruti Jolly
Background and purposeCurrent methods to estimate risk of radiation-induced lung toxicity (RILT) rely on dosimetric parameters. We aimed to improve prognostication by incorporating clinical and cytokine data, and to investigate how these factors may interact with the effect of mean lung dose (MLD) on RILT.Materials and methodsData from 125 patients treated from 2004 to 2013 with definitive radiotherapy for stages I-III NSCLC on four prospective clinical trials were analyzed. Plasma levels of 30 cytokines were measured pretreatment, and at 2 and 4weeks midtreatment. Penalized logistic regression models based on combinations of MLD, clinical factors, and cytokine levels were developed. Cross-validated estimates of log-likelihood and area under the receiver operating characteristic curve (AUC) were used to assess accuracy.ResultsIn prognosticating grade 3 or greater RILT by MLD alone, cross-validated log-likelihood and AUC were −28.2 and 0.637, respectively. Incorporating clinical features and baseline cytokine levels increased log-likelihood to −27.6 and AUC to 0.669. Midtreatment cytokine data did not further increase log-likelihood or AUC. Of the 30 cytokines measured, higher levels of 13 decreased the effect of MLD on RILT, corresponding to a lower odds ratio for RILT per Gy MLD, while higher levels of 4 increased the association.ConclusionsAlthough the added prognostic benefit from cytokine data in our model was modest, understanding how clinical and biologic factors interact with the MLD-RILT relationship represents a novel framework for understanding and investigating the multiple factors contributing to radiation-induced toxicity.



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18F-FDG PET image biomarkers improve prediction of late radiation-induced xerostomia

Publication date: Available online 23 September 2017
Source:Radiotherapy and Oncology
Author(s): Lisanne V. van Dijk, Walter Noordzij, Charlotte L. Brouwer, Ronald Boellaard, Johannes G.M. Burgerhof, Johannes A. Langendijk, Nanna M. Sijtsema, Roel J.H.M. Steenbakkers
Background and purposeCurrent prediction of radiation-induced xerostomia 12months after radiotherapy (Xer12m) is based on mean parotid gland dose and baseline xerostomia (Xerbaseline) scores. The hypothesis of this study was that prediction of Xer12m is improved with patient-specific characteristics extracted from ¹⁸F-FDG PET images, quantified in PET image biomarkers (PET-IBMs).Patients and methodsIntensity and textural PET-IBMs of the parotid gland were collected from pre-treatment ¹⁸F-FDG PET images of 161 head and neck cancer patients. Patient-rated toxicity was prospectively collected. Multivariable logistic regression models resulting from step-wise forward selection and Lasso regularisation were internally validated by bootstrapping. The reference model with parotid gland dose and Xerbaseline was compared with the resulting PET-IBM models.ResultsHigh values of the intensity PET-IBM (90th percentile (P90)) and textural PET-IBM (Long Run High Grey-level Emphasis 3 (LRHG3E)) were significantly associated with lower risk of Xer12m. Both PET-IBMs significantly added in the prediction of Xer12m to the reference model. The AUC increased from 0.73 (0.65–0.81) (reference model) to 0.77 (0.70–0.84) (P90) and 0.77 (0.69–0.84) (LRHG3E).ConclusionPrediction of Xer12m was significantly improved with pre-treatment PET-IBMs, indicating that high metabolic parotid gland activity is associated with lower risk of developing late xerostomia. This study highlights the potential of incorporating patient-specific PET-derived functional characteristics into NTCP model development.



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Patient-specific bolus for range shifter air gap reduction in intensity-modulated proton therapy of head-and-neck cancer studied with Monte Carlo based plan optimization

Publication date: Available online 23 September 2017
Source:Radiotherapy and Oncology
Author(s): Steven Michiels, Ana Maria Barragán, Kevin Souris, Kenneth Poels, Wouter Crijns, John A. Lee, Edmond Sterpin, Sandra Nuyts, Karin Haustermans, Tom Depuydt
Background & purposeIntensity-modulated proton therapy (IMPT) of superficial lesions requires pre-absorbing range shifter (RS) to deliver the more shallow spots. RS air gap minimization is important to avoid spot size degradation, but remains challenging in complex geometries such as in head-and-neck cancer (HNC). In this study, clinical endpoints were investigated for patient-specific bolus and for conventional RS solutions, making use of a Monte Carlo (MC) dose engine for IMPT optimization.Methods and materialsFor 5 oropharyngeal cancer patients, IMPT spot maps were generated using beamlets calculated with MC. The plans were optimized for three different RS configurations: 3D printed on-skin bolus, snout- and nozzle-mounted RS. Organ-at-risk (OAR) doses and late toxicity probabilities were compared between all configuration-specific optimized plans.ResultsThe use of bolus reduced the mean dose to all OARs compared to snout and nozzle-mounted RS. The contralateral parotid gland and supraglottic larynx received on average 2.9Gy and 4.2Gy less dose compared to the snout RS. Bolus reduced the average probability for xerostomia by 3.0%. For dysphagia, bolus reduced the probability by 2.7%.ConclusionsQuantification of the dosimetric advantage of patient-specific bolus shows significant reductions compared to conventional RS solutions for xerostomia and dysphagia probability. These results motivate the development of a patient-specific bolus solution in IMPT for HNC.



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A retrospective cohort study to assess adjuvant concurrent chemoradiation (CCRT) compared to adjuvant radiation therapy (RT) in the treatment of grade 2 and 3 extremity soft tissue sarcomas

Publication date: Available online 23 September 2017
Source:Radiotherapy and Oncology
Author(s): Jean Philippe Nesseler, Julia Salleron, Maria Rios, Philippe Nickers, Frederic Marchal, Fabien Brocard, Didier Peiffert, Guillaume Vogin
PurposeTo evaluate the efficacy and tolerance of adjuvant concurrent chemoradiation (CCRT) as treatment of grade 2 and 3 (G2-3) localized extremity soft tissue sarcomas (STS) by comparing CCRT with standard adjuvant radiation therapy (RT).Patients and methodsThis monocentric retrospective study included non-pediatric patients (>16years) treated by adjuvant RT with or without chemotherapy (CT) after conservative resection of non-recurrent G2-3 extremity STS.ResultsA total of 80 patients were treated between 1990 and 2012: 51 by RT and 29 by CCRT. Of the 29 CCRT patients, 25 received doxorubicin monotherapy (75mg/m²/3weeks). The CCRT group contained a greater proportion of grade 3 extremity STS (p<0.001). Median follow up was 68months (9–284). Multivariate analysis revealed greater local control in the CCRT group (1 local recurrence vs 8 in the RT group; HR=0.082, 95% CI 0.011–0.321) and incomplete resection as the major risk factor of local recurrence (HR=25.2, 95% CI 4.767–133.226). The two groups exhibited no differences in distant failure-free survival (HR=1.469, 95% CI 0.668–3.228), disease-free survival (HR=1.096, 95% CI 0.519–2.315) or overall survival (HR=1.378, 95% CI 0.498–3.814). Grade 3 was an adverse prognostic factor for overall survival (HR=3.11, 95% CI 1.04–9.32). Our analyses also revealed that CCRT tended to increase the risk of both grade ≥3 acute dermatitis (14 events vs 6 in the RT group; OR=6.99, 95% CI 2.28–21.47) and grade ≥2 late toxicity (6 events vs 3 in the RT group; p=0.0572).ConclusionCCRT could improve local control as part of a limb-preservation strategy. However, with a limited number of patients, CCRT showed no improvement in either distant control or survival and increased toxicity.



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Spatiotemporal fractionation schemes for liver stereotactic body radiotherapy

Publication date: Available online 23 September 2017
Source:Radiotherapy and Oncology
Author(s): Jan Unkelbach, Dávid Papp, Melissa R. Gaddy, Nicolaus Andratschke, Theodore Hong, Matthias Guckenberger
Background and purposeDose prescription in stereotactic body radiotherapy (SBRT) for liver tumors is often limited by the mean liver dose. We explore the concept of spatiotemporal fractionation as an approach to facilitate further dose escalation in liver SBRT.Materials and methodsSpatiotemporal fractionation schemes aim at partial hypofractionation in the tumor along with near-uniform fractionation in normal tissues. This is achieved by delivering distinct dose distributions in different fractions, which are designed such that each fraction delivers a high single fraction dose to complementary parts of the tumor while creating a similar dose bath in the surrounding noninvolved liver. Thereby, higher biologically effective doses (BED) can be delivered to the tumor without increasing the mean BED in the liver. Planning of such treatments is performed by simultaneously optimizing multiple dose distributions based on their cumulative BED. We study this concept for five liver cancer patients with different tumor geometries.ResultsSpatiotemporal fractionation presents a method of increasing the ratio of prescribed tumor BED to mean BED in the noninvolved liver by approximately 10–20%, compared to conventional SBRT using identical fractions.ConclusionsSpatiotemporal fractionation may reduce the risk of liver toxicity or facilitate dose escalation in liver SBRT in circumstances where the mean dose to the non-involved liver is the prescription-limiting factor.



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Adjuvant therapy in renal cell carcinoma

Publication date: Available online 23 September 2017
Source:Cancer Treatment Reviews
Author(s): Francesco Massari, Vincenzo Di Nunno, Chiara Ciccarese, Jeffrey Graham, Camillo Porta, Francesca Comito, Marta Cubelli, Roberto Iacovelli, Daniel Y.C. Heng
Several drugs have demonstrated clinical activity in metastatic renal cell carcinoma (mRCC). The identification of key metabolic pathways has led to the development of novel targeted therapies which have drastically changed the treatment paradigm of mRCC. Moreover, immune-checkpoint inhibitors have recently shown significant activity in advanced disease. Despite these advancements, the role of adjuvant therapy in localized, non-metastatic RCC remains unclear. The utility of many of these agents in the adjuvant setting is currently being actively explored. In this review, we will summarize the main clinical trials investigating adjuvant therapy in renal cell carcinoma, focusing primarily on immunotherapy and targeted agents.



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Personal exposure and health risk assessment of carbonyls in family cars and public transports—a comparative study in Nanjing, China

Abstract

To evaluate passenger health risks associated with inhalation exposure to carbonyl compounds mainly emitted from decoration materials of vehicles, we tested the carbonyl concentrations in interior air of 20 family cars, 6 metro lines, and 5 buses in the city of Nanjing. To assess non-carcinogenic health risks, we compared the data to the health guidelines of China, US Environmental Protection Agency (EPA), and Office of Environmental Health Hazard Assessment (OEHHA), respectively. To assess carcinogenic risks, we followed a standard approach proposed by the OEHHA to calculate lifetime cancer risks (LCR) of formaldehyde and acetaldehyde for various age groups. The results showed that there are formaldehyde, acetaldehyde, and acrolein concentrations in 40, 35, and 50% of family car samples exceeded the reference concentrations (RfCs) provided by Chinese guidelines (GB/T 27630-2011 and GB/T 18883-2002). Whereas, in the tested public transports, concentrations of the three carbonyls were all below the Chinese RfCs. Fifty and 90% of family cars had formaldehyde and acrolein concentrations exceeding the guidelines of OEHHA. Only one public transport sample (one bus) possesses formaldehyde and acetaldehyde concentrations above the chronic inhalation reference exposure limits (RELs). Furthermore, the assessments of carcinogenic risk of formaldehyde and acetaldehyde showed that lifetime cancer risks were higher than the limits of EPA for some family cars and public transports. In the study, buses and metros appear to be relatively clean environments, with total carbonyl concentrations that do not exceed 126 μg/m³. In family cars, carbonyl levels showed significant variations from 6.1 to 811 μg/m³ that was greatly influenced by direct emissions from materials inside the vehicles. Public transports seemed to be the first choice for resident trips as compared to family cars.

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Root bark extracts of Myrianthus arboreus P. Beauv. (Cecropiaceae) exhibit anti-diabetic potential by modulating hepatocyte glucose homeostasis

Publication date: Available online 23 September 2017
Source:Journal of Ethnopharmacology
Author(s): Pierre Betu Kasangana, Abir Nachar, Hoda M. Eid, Tatjana Stevanovic, Pierre S. Haddad
Ethnopharmacological relevanceMyrianthus arboreus P. Beauv. is a tropical tree used in African folk medicine, including for diabetes. However, little research has yet been conducted to support this ethnopharmacological use of this plant. The present study sought to determine the antidiabetic potential of root bark extracts through cell-based bioassays of liver and muscle glucose homeostasis.Materials and methodsFour extracts were obtained from crude root bark powder: 1 aqueous (AQ), 2 ethanol (EtOH), 3 alkaloid enriched (Alk) (obtained from methanol extract) and 4 dichloromethane (Dic) extracts. Moreover, extract 2 was further separated into two fractions: 2.1 ethyl acetate (EAc) and 2.2 hexane (Hex). To assess the antidiabetic activity of the plant extracts, inhibition of glucose-6-phosphatase (G6Pase), stimulation of glycogen synthase (GS) and modulation of glucose uptake were determined in cultured H4IIE and HepG2 hepatocytes as well as C2C12 myocytes, respectively. Phosphorylation of three kinases, AMP-activated protein kinase (AMPK), Akt and Glycogen Synthase Kinase-3 (GSK-3) were probed by Western blot.ResultsM. arboreus extracts/fractions did not stimulate glucose uptake in C2C12 cells albeit 2.2 (Hex) fraction showed a mild positive tendency. In contrast, extract 2 and its fractions as well as extract 3 were able to decrease hepatocyte G6Pase activity. Their effect on G6Pase activity involved both Akt and AMPK phosphorylation. No significant correlation was observed between activation of Akt and inhibition of G6Pase (R² = 0.50 p < 0.14), whereas that between stimulation of AMPK and inhibition of G6Pase was statistically significant (R² = 0.75 p < 0.05). On the other hand, extract 2, its fraction 2.2 and extract 3 were able to stimulate GS through GSK-3 phosphorylation. A high correlation was observed between the ability of M. arboreus extracts and fractions to phosphorylate GSK-3 and modulate GS activity (R²=0.81 p < 0.01). Extract 2 and its fraction 2.2 together with extract 3 were the only plant products to simultaneously and potently regulate G6Pase and GS, the key players of hepatic glucose homeostasis.ConclusionOverall, these data support the traditional antidiabetic uses of the root bark of M. arboreus.

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New Ti-IMAC magnetic polymeric nanoparticles for phosphopeptide enrichment from complex real samples

Publication date: 1 February 2018
Source:Talanta, Volume 178
Author(s): Anna Laura Capriotti, Chiara Cavaliere, Francesca Ferraris, Valentina Gianotti, Michele Laus, Susy Piovesana, Katia Sparnacci, Riccardo Zenezini Chiozzi, Aldo Laganà
The work describes the preparation of a new magnetic phase for batch enrichment of phosphopeptides. The material exploits the advantages of magnetic solid phase extraction and couples them with the most employed approach for phosphopeptide enrichment, i.e. Ti⁴⁺-IMAC. In order to immobilize Ti⁴⁺ ions on the surface of the magnetite nanoparticles, they were first covered by a silica shell and then modified to expose at the surface bromine containing groups. Glycidyl methacrylate was subsequently polymerized from these groups using the "grafting from" approach by the activator regenerated by electron transfer–atom transfer radical polymerization (ARGET-ATRP) technique. Finally, the glycidyl groups were reacted with iminodiacetic acid to functionalize the material with moieties suitable for coordination. The prepared material was extensively characterized and subsequently tested for enrichment of a bovine serum albumin mixture with casein to ascertain its potential. With positive results, the new magnetic polymeric material was further employed to set up an enrichment method on yeast protein digest based on shotgun proteomics. The sample to phase ratio was optimized and the best condition compared to a commercial TiO2 spin column. At the end of the comparison, the new material proved better and could enrich a larger total number of phosphopeptides with increased selectivity. All these conclusions and the test performed on a real complex sample within the final shotgun application further support the applicability of the new material in phosphopeptide analysis of real matrices.

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Preparation and evaluation of magnetic molecularly imprinted polymers for the specific enrichment of phloridzin

Publication date: 1 February 2018
Source:Talanta, Volume 178
Author(s): Die Gao, Dan-Dan Wang, Qi-Feng Fu, Lu-Jun Wang, Kai-Lian Zhang, Feng-Qing Yang, Zhi-Ning Xia
In present study, magnetic molecularly imprinted polymers (MMIPs) were successfully prepared for specific recognition and selective enrichment of phloridzin from the leaves of Malus doumeri (Bois) A. Chev and rats' plasma. The magnetic Fe3O4 were prepared by the solvothermal reaction method and followed by the modification of TEOS and functionalization with APTES. Using functionalized Fe3O4 particles as the magnetic cores, phloridzin as template, ethylene glycol dimethacrylate (EGDMA) as cross-linker and 2,2-azobisisobutyonnitrile (AIBN) as initiator, the MMIPs were prepared through APTES to associate the template on the surface of the magnetic substrate. The structural features and morphological characterizations of MMIPs were performed by FT-IR, SEM, TEM, XRD, TGA and VSM. The adsorption experiments revealed that the MMIPs presented high selective recognition property to phloridzin. The selectivity experiment indicated that the adsorption capacity and selectivity of polymers to phloridzin was higher than that of baicalin and 2,3,5,4′-ttrahydroxy stilbene-2-O-β-D-glucoside. Furthermore, the MMIPs were employed as adsorbents for extraction and enrichment of phloridzin from the leaves of M. doumeri and rats' plasma. The recoveries of phloridzin in the leaves of M. doumeri ranged from 81.45% to 90.27%. The maximum concentration (Cmax) of phloridzin in rats' plasma was detected as 12.19 ± 0.84μg/mL at about 15min after oral administration of phloridzin (200mg/kg). These results demonstrate that the prepared MMIPs are suitable for the selective adsorption of phloridzin from complex samples such as natural medical plants and biological samples.

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Fluorescent ligand fishing combination with in-situ imaging and characterizing to screen Hsp 90 inhibitors from Curcuma longa L. based on InP/ZnS quantum dots embedded mesoporous nanoparticles

Publication date: 1 February 2018
Source:Talanta, Volume 178
Author(s): Yue Hu, Anchen Fu, Zhaoyi Miao, Xiaojing Zhang, Tianlin Wang, An Kang, Jinjun Shan, Dong Zhu, Wei Li
Although ligand fishing has been shown to be an efficient technique for the identification of bioactive components from complex mixtures such as natural products, it cannot be applied to biomedical image processing. Herein, a specific fluorescent ligand fishing combined with in situ imaging approach is presented for the identification of heat shock protein 90 (Hsp 90) inhibitors from complex matrixes, Curcuma longa L., using N-terminus immobilized Hsp 90α functionalized InP/ZnS quantum dots embedded mesoporous nanoparticles (i.e. Hsp 90α (NT)-FQDNs) as extraction sorbents and fluorescent tracer. The fished ligands were identified by liquid chromatography time-of-flight/mass spectrometry (LC-TOF/MS) and gas chromatography-mass spectrometry (GC-MS). Moreover, in situ imaging by confocal laser scanning microscopy (CLSM) was applied for evaluating the effect of fished-ligands on bioactivity-induced apoptosis morphologically in HeLa cells. MTT assay verified the bioactivity of the ligands and molecular docking results further provided convincing information to verify the feasible binding mode between ligands and protein. Twelve ligands as potential Hsp 90 inhibitors were ultimately fished and identified from Curcuma longa L. crude extracts. The proposed approach based on Hsp 90α functionalized nanocomposites is superior in the combination of highly specific screening efficiency and concurrent visual in situ imaging, which could have great promise for the development of other plant-derived Hsp 90 inhibitors, and providing a rapid and reliable platform for discovering biologically active molecules in natural products.

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Assessment of potential false positives via orbitrap-based untargeted lipidomics from rat tissues

Publication date: 1 February 2018
Source:Talanta, Volume 178
Author(s): Lina Xu, Xueying Wang, Yupei Jiao, Xiaohui Liu
Untargeted lipidomics is increasingly popular due to the broad coverage of lipid species. Data dependent MS/MS acquisition is commonly used in order to acquire sufficient information for confident lipid assignment. However, although lipids are identified based on MS/MS confirmation, a number of false positives are still observed. Here, we discuss several causes of introducing lipid false identifications in untargeted analysis. Phosphotidylcholines and cholesteryl esters generate in-source fragmentation to produce dimethylated phosphotidylethanolamine and free cholesterol. Dimerization of fatty acid results in false identification of fatty acid ester of hydroxyl fatty acid. Realizing these false positives is able to improve confidence of results acquired from untargeted analysis. Besides, thresholds are established for lipids identified using LipidSearch v4.1.16 software to reduce unreliable results.

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Thin-film microextraction coupled to surface enhanced Raman scattering for the rapid detection of benzoic acid in carbonated beverages

Publication date: 1 February 2018
Source:Talanta, Volume 178
Author(s): Lemei Cai, Jing Dong, Yiru Wang, Xi Chen
Benzoic acid (BA) is widely used as an antimicrobial preservative in carbonated beverages. In this study, silica gel thin-film microextraction (TFME) coupled to surface enhanced Raman scattering (SERS) was applied for the rapid detection of BA in carbonated beverages. The TFME process was performed by placing small pieces of silica gel substrate in a simple homemade device, and then the content of BA was detected using SERS after colloidal gold was uniformly dropped onto the substrate. The obtained SERS signals of BA were strong and of high reproducibility. A good linearity between the concentration of BA and the SERS signal intensity at 994cm⁻¹ in the range of 25–500μgmL⁻¹ was obtained under optimal experimental conditions. The detection limit value was found to be 3.6μgmL⁻¹ and the recovery of the spiked BA was in the range 85.0–103.0%. The developed method was successfully applied to detect BA in carbonated beverage samples as the results were consistent with those using high performance liquid chromatography, suggesting that it is a rapid, convenient and sensitive way to achieve BA detection in carbonated beverages.

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Use of a small molecule as an initiator for interchain staudinger reaction: A new ATP sensing platform using product fluorescence

Publication date: 1 February 2018
Source:Talanta, Volume 178
Author(s): Huan Yu, Jing Zheng, Sheng Yang, Abdullah M. Asiri, Khalid A. Alamry, Mingtai Sun, Kui Zhang, Suhua Wang, Ronghua Yang
We demonstrated that a small molecule induced interchain Staudinger reaction can be employed for highly selective detection of adenosine triphosphate (ATP), an important energy-storage biomolecule. A designed ATP split aptamer (A1) was first functionalized with a weakly fluorescent coumarin derivative due to an azide group (azido-coumarin). The second DNA strand (A2) was covalently linked with triphenylphosphine, which could selectively and efficiently reduce azido to amino group through the Staudinger reaction. The A2 was then hybridized with a half of another designed longer DNA strand (T1). The second half of T1 was a split aptamer and selectively recognized ATP with A1 to form a sandwich structure. The specific interaction between ATP and the aptamers drew the two functionalized DNA strands (A1 and A2) together to initiate the interchain Staudinger reduction at fmol-nmol concentration level, hence produced fluorescent 7-aminocoumarin which could be used as an indicator for the presence of trace ATP. The reaction process had a concentration dependent manner with ATP in a large concentration range. Such a strategy of interchain Staudinger reaction can be extended to construct biosensors for other small functional molecules on the basis of judiciously designed aptamers.

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Determining moisture content in pasta by vibrational spectroscopy

Publication date: 1 February 2018
Source:Talanta, Volume 178
Author(s): Tomasz Czaja, Ewelina Kuzawińska, Aldona Sobota, Roman Szostak
Pasta aside from bread is the most consumed cereal-based product in the world. Its taste and cooking ease makes it the basis of many cuisines. The pasta dough formed by mixing flour and water is extruded through an extrusion die to mould the appropriate pasta form and is dried to obtain a stable product. The concentration of moisture in the pasta dough is a one of key parameters determining the final quality of the product. Monitoring the moisture content of pasta after extrusion is also critically important. It enables a selection of suitable drying conditions that ensure the appropriate parameters of pasta, such as texture, color and taste, are met. A method for the quantitative determination of moisture content in pasta dough and in pasta based on the partial least squares treatment of infrared spectra registered using a single-reflection attenuated total reflectance diamond accessory is described. Results of a similar quality were found using models derived from near infrared spectra obtained in a diffuse reflectance mode and slightly worse based on Raman spectra. Relative standard errors of prediction calculated for moisture quantification by ATR/NIR/Raman techniques amounted to 2.54/3.16/5.56% and 2.15/3.32/5.67%, for calibration and validation sets, respectively. The proposed procedures can be used for fast and efficient pasta moisture quantification and may replace the current, more laborious methods used.

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Double-blind, proof-of-concept (POC) trial of Low-Field Magnetic Stimulation (LFMS) augmentation of antidepressant therapy in treatment-resistant depression (TRD)

Publication date: Available online 23 September 2017
Source:Brain Stimulation
Author(s): Maurizio Fava, Marlene P. Freeman, Martina Flynn, Bettina B. Hoeppner, Richard Shelton, Dan V. Iosifescu, James W. Murrough, David Mischoulon, Cristina Cusin, Mark Rapaport, Boadie W. Dunlop, Madhukar H. Trivedi, Manish Jha, Gerard Sanacora, Gretchen Hermes, George I. Papakostas
BackgroundLow-Field Magnetic Stimulation (LFMS) is a novel, non-invasive, sub-threshold neuromodulation technique, shown in preliminary studies to have immediate mood elevating effects in both unipolar and bipolar depressed patients.ObjectiveWe aimed to assess the antidepressant augmentation effects at 48 h of LFMS administered on two consecutive days compared to sham treatment in treatment resistant depression (TRD) subjects, using the Sequential Parallel Comparison Design (SPCD).MethodsEighty-four eligible subjects with TRD were randomly assigned to double-blind treatment with LFMS 20 min/day for four days, sham treatment 20 min/day for four days, or sham treatment 20 min/day for 2 days followed by LFMS treatment 20 min/day for two days, using the pre-randomization version of the SPCD (randomization 1:1:1). The SPCD analyses used a repeated measures linear modeling approach with maximum likelihood estimation to use all available data, and using a 60–40 weighting of Stage 1 vs. 2 responses, with the primary outcome being measured after 2 and 4 days.ResultsBoth primary and secondary outcome measures consistently showed no differences between LFMS-treated patients and those treated with sham, with the exception of a slight, non-significantly greater improvement than sham in the visual analogue scale (VAS) sad mood on LFMS-treated patients. LFMS treatment was relatively well tolerated.ConclusionsWe did not observe a significantly greater, rapid efficacy of LFMS compared to sham therapy. Future studies need to examine the possible therapeutic effects of more intensive forms of LFMS, as other forms of neurostimulation typically require longer duration of exposure.



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Efficacy of aprepitant for CHOP chemotherapy-induced nausea, vomiting and anorexia

Publication date: Available online 23 September 2017
Source:Current Problems in Cancer
Author(s): Mihoko Morita, Shinji Kishi, Miyuki Ookura, Yasufumi Matsuda, Katsunori Tai, Takahiro Yamauchi, Takanori Ueda
The objective of this study was to evaluate whether aprepitant in addition to 5-HT3 receptor antagonist is useful for preventing chemotherapy-induced nausea and vomiting (CINV) and anorexia in patients receiving CHOP therapy, and to evaluate the relationship between in vivo kinetics of plasma substance P and these adverse events. Patients with malignant lymphoma who received CHOP chemotherapy or THP (THP-ADR)-COP therapy were investigated CINV and anorexia for 5 days after start of chemotherapy. With the first course of chemotherapy, all patients received only granisetron on day1 as an antiemetic. Patients who experienced nausea, vomiting or anorexia exceeding grade 1 in the first course received aprepitant for 3 days in addition to granisetron with the second course of CHOP chemotherapy. Plasma substance P concentrations at 24 and 72h after chemotherapy were measured. Nineteen patients were evaluated. Nausea, vomiting or anorexia was observed with the first course in 7 of 19 patients. During the second course with aprepitant, no patients experienced vomiting, and the toxicity grade of nausea, vomiting or anorexia was decreased compared with those in the first course. Substance P concentrations showed no differences after chemotherapy, in patients with nausea, vomiting or anorexia and in patients without. Addition of aprepitant to 5-HT3 receptor antagonist appears effective for CINV or anorexia for patients who received CHOP chemotherapy.



http://ift.tt/2hqNgkI

An atypical presentation of cardiac tamponade and periorbital swelling in a patient with eosinophilic granulomatosis with polyangiitis: a case report

Eosinophilic granulomatosis with polyangiitis is a rare, necrotizing systemic vasculitis associated with asthma and hypereosinophilia. Its cause and pathophysiology are still being elucidated.

http://ift.tt/2wKQqu1

Characteristics and trends on global environmental monitoring research: a bibliometric analysis based on Science Citation Index Expanded

Abstract

A bibliometric analysis based on the Science Citation Index Expanded from Web of Science was carried out to provide insights into research activities and trends of the environmental monitoring from 1993 to 2012. Study emphases covered publication outputs, language, categories, journals, countries/territories, institutions, words, and hot issues. The results indicated that the annual output of environmental monitoring publications increased steadily. The environmental sciences and analytical chemistry were the two most common categories. Environmental Monitoring and Assessment published the most articles. The USA and the UK ranked in the top two in terms of all five indicators. The U.S. Environmental Protection Agency took the leading position of the institutions in terms of publication output. The synthesized analysis by words in title, author keywords, and KeyWords Plus provided important clues for hot issues. Researchers paid more attention on water environment monitoring than other environmental factors. The contaminants including organic contaminants, heavy metal, and radiation were most common research focuses, and the organic contaminants and heavy metal of the degree of concern were gradually rising. Sensor and biosensor played an important role in the field of environmental monitoring devices. In addition to conventional device detection method, the remote sensing, GIS, and wireless sensor networks were the mainstream environmental monitoring methods. The international organization, social awareness, and the countries' positive and effective political and policies promoted the published articles.

http://ift.tt/2fpy3U8

Seasonal water chemistry variability in the Pangani River basin, Tanzania

Abstract

The stable isotopes of δ¹⁸O, δ²H, and ⁸⁷Sr/⁸⁶Sr and dissolved major ions were used to assess spatial and seasonal water chemistry variability, chemical weathering, and hydrological cycle in the Pangani River Basin (PRB), Tanzania. Water in PRB was NaHCO₃ type dominated by carbonate weathering with moderate total dissolved solids. Major ions varied greatly, increasing from upstream to downstream. In some stations, content of fluoride and sodium was higher than the recommended drinking water standards. Natural and anthropogenic factors contributed to the lowering rate of chemical weathering; the rate was lower than most of tropical rivers. The rate of weathering was higher in Precambrian than volcanic rocks. ⁸⁷Sr/⁸⁶Sr was lower than global average whereas concentration of strontium was higher than global average with mean annual flux of 0.13 × 10⁶ mol year⁻¹. Evaporation and altitude effects have caused enrichment of δ¹⁸O and δ²H in dry season and downstream of the river. Higher d-excess value than global average suggests that most of the stations were supplied by recycled moisture. Rainfall and groundwater were the major sources of surface flowing water in PRB; nevertheless, glacier from Mt. Kilimanjaro has insignificant contribution to the surface water. We recommend measures to be taken to reduce the level of fluoride and sodium before domestic use.

http://ift.tt/2xB1Srp

Genomic signatures as predictive biomarkers of homologous recombination deficiency in ovarian cancer

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Adriaan Vanderstichele, Pieter Busschaert, Siel Olbrecht, Diether Lambrechts, Ignace Vergote
DNA repair deficiency is a common hallmark of many cancers and is increasingly recognised as a target for cancer therapeutics. Selecting patients for these treatments requires a functional assessment of multiple redundant DNA repair pathways. With the advent of whole-genome sequencing of cancer genomes, it is increasingly recognised that multiple signatures of mutational and chromosomal alterations can be correlated with specific DNA repair defects. The clinical relevance of this approach is underlined by the use of poly-(ADP-ribose) polymerase inhibitors (PARPi) in homologous recombination (HR) deficient high-grade serous ovarian cancers. Beyond deleterious mutations in HR-related genes such as BRCA1/2, it is recognised that HR deficiency endows ovarian cancers with specific signatures of base substitutions and structural chromosomal variation. Multiple metrics quantifying loss-of-heterozygosity (LOH) events were proposed and implemented in trials with PARPi. However, it was shown that some of the HR-deficient cases, i.e. CDK12–mutated tumours, were not associated with high LOH-based scores, but with distinct patterns of genomic alterations such as tandem duplication. Therefore, more complex signatures of structural genomic variation were identified and quantified. Ultimately, optimal prediction models for treatments targeting DNA repair will need to integrate multiples of these genomic signatures and will also need to assess multiple resistance mechanisms such as genomic reversion events that partially or fully re-activate DNA repair.



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PIKHER2: A phase IB study evaluating buparlisib in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Mathilde Guerin, Keyvan Rezai, Nicolas Isambert, Mario Campone, Aurélie Autret, Jihane Pakradouni, Magali Provansal, Jacques Camerlo, Renaud Sabatier, François Bertucci, Emmanuelle Charafe-Jauffret, Alice Hervieu, Jean-Marc Extra, Patrice Viens, François Lokiec, Jean-Marie Boher, Anthony Gonçalves
BackgroundPhosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms.Patients and methodsPIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80 mg) and lapatinib (750, 1000 or 1250 mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokinetic (PK) assessments.ResultsA total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80 mg/d + lapatinib 1250 mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80 mg + lapatinib 1000 mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug–drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57–92%], one patient obtained a complete remission, and six additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate of 29% [95% CI 12–51%]).ConclusionCombining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidence of antitumour activity was observed in this heavily pre-treated population.Trial registration IDNCT01589861.



http://ift.tt/2xrHzuq

Determination of poor prognostic immune features of tumour microenvironment in non-smoking patients with lung adenocarcinoma

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Tomonari Kinoshita, Chie Kudo-Saito, Reiko Muramatsu, Tomonobu Fujita, Miyuki Saito, Haruna Nagumo, Toshiharu Sakurai, Shinobu Noji, Emi Takahata, Tomonori Yaguchi, Nobuo Tsukamoto, Yuichiro Hayashi, Kaoru Kaseda, Ikuo Kamiyama, Takashi Ohtsuka, Kenji Tomizawa, Masaki Shimoji, Tetsuya Mitsudomi, Hisao Asamura, Yutaka Kawakami
We have previously demonstrated that the prognostic significance of tumour-infiltrating CD8⁺ T cells significantly differs according to histological type and patient smoking habits in non-small cell lung cancer (NSCLC). This work suggested that infiltrating CD8⁺ T cells may not be activated sufficiently in the immunosuppressive microenvironment in non-smokers with adenocarcinoma. To understand the immunogenic microenvironment in NSCLC, we characterised immune cells comprehensively by performing an immunohistochemical evaluation using an alternative counting method and multicolour staining method (n = 234), and assessed immune-related gene expression by using genetic analytical approaches (n = 58). We found that high infiltration of activated CD8⁺ T cells expressing interferon gamma (IFN-γ) and granzyme was correlated with postoperative survival in patients with non-adenocarcinoma. On the contrary, CD8⁺ T-cell accumulation was identified as a worse prognostic factor in patients with adenocarcinoma, particularly in non-smokers. Infiltrating CD8⁺ T cells were significantly less activated in this microenvironment with high expression of various immunoregulation genes. Potentially immunoregulatory CD8⁺ FOXP3⁺ T cells and immunodysfunctional CD8⁺ GATA3⁺ T cells were increased in adenocarcinoma of non-smokers. CD4⁺ FOXP3⁺ regulatory T cells expressing chemokine receptor-4 (CCR4)- and chemokine ligand (CCL17)-expressing CD163⁺ M2-like macrophages also accumulated correlatively and significantly in adenocarcinoma of non-smokers. These characteristic immune cells may promote tumour progression possibly by creating an immunosuppressive microenvironment in non-smoking patients with lung adenocarcinoma. Our findings may be helpful for refining the current strategy of personalised immunotherapy including immune-checkpoint blockade therapy for NSCLC.



http://ift.tt/2yjQCwQ

Population demography of alpine butterflies: Boloria pales and Boloria napaea (Lepidoptera: Nymphalidae) and their specific adaptations to high mountain environments

Publication date: November 2017
Source:Acta Oecologica, Volume 85
Author(s): Stefan Ehl, Marlene Ebertshäuser, Patrick Gros, Thomas Schmitt
High mountain ecosystems are extreme habitats, and adaptation strategies to this ecosystem are still poorly understood in most groups. To unravel such strategies, we performed a MRR study in the Hohe Tauern National Park (Salzburg, Austria) with two nymphalid butterfly species, Boloria pales and B. napaea. We analysed their population structure over one flight period by studying the development of population size and wing wear. B. pales had more individuals and a higher survival probability than B. napaea; the sensitivity to extreme weather conditions or other external influences was higher in B. napaea. We only observed proterandry in B. pales. Imagines of both species survived under snow for at least some days. Additionally, we observed a kind of risk-spreading, in that individuals of both species, and especially B. pales, have regularly emerged throughout the flight period. This emergence pattern divided the population's age structure into three phases: an initial phase with decreasing wing quality (emergence > mortality), followed by an equilibrium phase with mostly constant average wing condition (emergence = mortality) and a final ageing phase with strongly deteriorating wing condition (mortality » emergence). Consequently, neither species would likely become extinct because of particularly unsuitable weather conditions during a single flight period. The observed differences between the two species suggest a better regional adaptation of B. pales, which is restricted to high mountain systems of Europe. In contrast, the arctic-alpine B. napaea might be best adapted to conditions in the Arctic and not the more southern high mountain systems. However, this needs to be examined during future research in the Arctic.



http://ift.tt/2xrj3ts

Contrasting roles of phenol and pyrocatechol on the degradation of 4-chlorophenol in a photocatalytic–biological reactor

Abstract

Intimate coupling of photocatalysis and biodegradation (ICPB) provides superior treatment for the degradation of bio-recalcitrant compounds, such as chlorophenol. Photocatalytically generated intermediates can be promptly used by the enclosed biofilms. Chlorophenol degradation can theoretically be accelerated by a co-substrate or be compromised by the competition for photocatalytic reactive oxygen species (ROS); however, studies to examine the comparison are limited in number. Non-chlorinated phenols commonly co-exist in real wastewater; thus, we evaluated the influence of phenol (hard to photo-oxidize) and pyrocatechol (easy to photo-oxidize) on the degradation of 4-chlorophenol (4CP). The removal efficiency of 4CP was 51%, which increased to 62% after phenol addition. Meanwhile, the dechlorination efficiency of 4CP increased from 47 to 63%; similarly, the living/dead cell ratio increased from 49/51 to 79/21. However, pyrocatechol addition led to a decrease in 4CP removal efficiency to 32% and a reduction in living/dead cell ratio to 35/65. The differences in the results were attributed to the extra electron donors provided by the photodegraded products of phenol to bacteria, which enhanced 4CP degradation; meanwhile, pyrocatechol competed with 4CP for ROS, thus inhibiting its degradation. Competition for ROS and co-substrate properties should be considered in the treatment of phenolic wastewater by ICPB.

http://ift.tt/2hr9S4H

Design and synthesis of bioactive compounds

Publication date: 1 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
Author(s): Andrea Trabocchi




http://ift.tt/2yl9nA6

Identification of galiellalactone-based novel STAT3-selective inhibitors with cytotoxic activities against triple-negative breast cancer cell lines

Publication date: 1 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
Author(s): Hyun Su Kim, Taewoo Kim, Hyejin Ko, Jeeyeon Lee, Yeong Shik Kim, Young-Ger Suh
Signal transducer and activator of transcription 3 (STAT3) is phosphorylated in breast cancer cells, particularly triple-negative breast cancers (TNBCs). Therefore, the inhibition of constitutive phosphorylated STAT3 is a promising therapeutic for TNBC treatment. Recently, a series of novel STAT3 inhibitors based on natural (−)-galiellalactone have been identified to inhibit STAT3 phosphorylation at the Tyr705 residue. Interestingly, the truncation of the cyclohexene moiety of (−)-galiellalactone to [3.3] bicyclic lactone as a pharmacophoric core produced improved cytotoxic effects against TNBCs. The potent analogues 16 and 17, identified from a STAT3-mediated luciferase reporter assay, selectively inhibited the STAT3 signaling pathway without affecting STAT1 or STAT5.

Graphical abstract

http://ift.tt/2xroIQd

Azobenzene-containing photoswitchable proteasome inhibitors with selective activity and cellular toxicity

Publication date: 1 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
Author(s): Beatriz Blanco, Kathryn A. Palasis, Alaknanda Adwal, David F. Callen, Andrew D. Abell
A series of azobenzene-containing peptidic boronate esters was prepared and the activity of the thermally adapted states (TAS), enriched in trans isomer, and the photostationary states (PSS), enriched in cis isomer, for each compound were evaluated against β5 and β1 proteasome subunits. Compounds with a sterically demanding phenyl-substituted azobenzene at P2 (4c), and a less sterically demanding unsubstituted azobenzene at the N-terminus (5a), showed the greatest difference in activity between the two states. In both cases, the more active trans-enriched TAS had activity comparable to bortezomib and delanzomib. Furthermore, cis-enriched 4c inhibited tumor growth in both breast and colorectal carcinoma cell lines. Significantly, the initial trans-enriched TAS of 4c was not cytotoxic against the non-malignant MCF-10A cells.

Graphical abstract

http://ift.tt/2xrM1cR

Potential peptidic proteasome inhibitors by incorporation of an electrophilic trap based on amino acid derived α-substituted sulfonyl fluorides

Publication date: 1 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
Author(s): Natalia Herrero Alvarez, Helmus van de Langemheen, Arwin J. Brouwer, Rob M.J. Liskamp
Peptido sulfonyl fluoride derivatives were designed and synthesized containing a substituent on the alpha position (αPSFs) with respect to the sulfonyl fluoride electrophilic trap. The chemical reactivity of these α-substituted amino sulfonyl fluorides was studied and compared with the previously described β-substituted amino sulfonyl fluorides in order to get a deeper insight into the importance of the immediate structural environment of the sulfonyl fluoride moiety. Unfortunately, the poor solubility of the resulting αPSFs precluded a proper evaluation of their biological activity.

Graphical abstract

http://ift.tt/2xqNvE9

Editorial board

Publication date: 1 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19





http://ift.tt/2xrewaq

Bortezomib inhibits mammalian carbonic anhydrases

Publication date: 1 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
Author(s): Claudiu T. Supuran
We investigated the carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the clinically used antitumor agent bortezomib, a marketed proteasome inhibitor, against all the catalytically active mammalian isoforms CA I–VII, IX, XII–XV. Bortezomib effectively inhibited all these CAs in the micromolar range. hCA II, the physiologically dominant cytosolic isoform showed the highest affinity for the drug, with a KI of 1.16μM. The cytosolic slow isoform hCA I was also effectively inhibited, with a KI of 1.29μM, whereas the next best affinity was observed for the membrane-anchored form mCA XV, with a KI of 2.68μM, followed by two transmembrane isoforms, hCA IX and XIV (KIs of 3.28–3.38μM). The remaining cytosolic (CA III, VII and XIII), membrane-anchored (CA IV), mitochondrial (CA VA, VB), transmembrane (CA XII) and secreted (CA VI) isoforms were slightly less inhibited by bortezomib compared to isoforms discussed above, with KIs ranging between 4.38 and 8.45μM. These data may shed some light on possible side effects and novel antitumor mechanisms of action of this drug.

Graphical abstract

http://ift.tt/2yl9gEm

Anticancer potential of aminomethylidene-diazinanes I. Synthesis of arylaminomethylidene of diazinetriones and its cytotoxic effects tested in glioblastoma cells

Publication date: 1 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
Author(s): Nichole A. Pianovich, Mathew Dean, Adam Lassak, Krzysztof Reiss, Branko S. Jursic
Diazinane and aryl moieties with vinylamine linkers were synthesized to investigate the importance of their structural variations as potential anti-glioblastoma agents. Structural variations incorporated on to the diazinane moiety included oxa and thio derivatives, each with a variety of nitrogen-bound substituents. The size and shape of the aromatic moiety was varied, with the final variation introducing two carbonyl groups, yielding a substituted anthraquinone. Readily available diazinanes and aryl amines were used asan advantageous foundation. Several parameters were calculated whilst engineering these compounds, including: ClogP, molecular polarizability, polar surface area, minimal molecular projected area, and pKa. In addition, a simple and efficient procedure was developed to synthesize these compounds. It was demonstrated that a vinylamine with 1,3-diazinane-2,4,6-trione and 1-anthraquinone moiety is the most promising drug candidate causing almost 70% of LN229 tumor cell death at 1µg/ml. In addition, its molecular polarizability, polar surface area and minimal molecular projected area indicate a possible potential of this molecule for crossing BBB.

Graphical abstract

http://ift.tt/2ykTpFP

Potent haloperidol derivatives covalently binding to the dopamine D2 receptor

Publication date: 1 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
Author(s): Tobias Schwalbe, Jonas Kaindl, Harald Hübner, Peter Gmeiner
The dopamine D2 receptor (D2R) is a common drug target for the treatment of a variety of neurological disorders including schizophrenia. Structure based design of subtype selective D2R antagonists requires high resolution crystal structures of the receptor and pharmacological tools promoting a better understanding of the protein-ligand interactions. Recently, we reported the development of a chemically activated dopamine derivative (FAUC150) designed to covalently bind the L94C mutant of the dopamine D2 receptor. Using FAUC150 as a template, we elaborated the design and synthesis of irreversible analogs of the potent antipsychotic drug haloperidol forming covalent D2R-ligand complexes. The disulfide- and Michael acceptor-functionalized compounds showed significant receptor affinity and an irreversible binding profile in radioligand depletion experiments.

Graphical abstract

http://ift.tt/2ylxgXV

Synthesis and biological evaluation of Aspergillomarasmine A derivatives as novel NDM-1 inhibitor to overcome antibiotics resistance

Publication date: 1 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
Author(s): Jian Zhang, Sanshan Wang, Qi Wei, Qianqian Guo, Yingjie Bai, Shaoqiang Yang, Fuhang Song, Lixin Zhang, Xiaoguang Lei
The β-lactam antibiotic resistance of Gram-negative bacteria has shown to be a critical global health problem. One of the primary reasons for the drug resistance is the existence of β-lactamases especially metallo-β-lactamases such as New Delhi metallo-β-lactamase (NDM-1) and Verona Integron-encoded metallo-β-lactamase (VIM-2). The fungal natural product Aspergillomarasmine A (AMA) has proven to be a promising inhibitor of NDM-1 and VIM-2 both in vitro and in vivo. Seven new analogues of AMA were synthesized by utilizing different strategies. The biological evaluation of these analogues was performed to study the structure-activity relationship of AMA both in vitro and in vivo. Remarkably, the lead compound 4 showed synergistic effect in combination with Meropenem to overcome the antibiotic resistance of the Gram-negative bacteria such as K. pneumoniae (BAA-2146) expressing NDM-1.

Graphical abstract

http://ift.tt/2ykzLda

α-Geminal disubstituted pyrrolidine iminosugars and their C-4-fluoro analogues: Synthesis, glycosidase inhibition and molecular docking studies

Publication date: 1 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
Author(s): Kishor S. Gavale, Shrawan R. Chavan, Navanath Kumbhar, Sonali Kawade, Pooja Doshi, Ayesha Khan, Dilip D. Dhavale
A simple strategy for the synthesis of α-geminal disubstituted pyrrolidine iminosugars 3a-c and their C-4 fluorinated derivatives 4a-c has been described from d-glucose. The methodology involves the Corey-Link and Jocic-Reeve reaction with 3-oxo-α-d-glucofuranose and nucleophilic displacement reaction to get the furanose fused pyrrolidine ring skeleton with requisite CH2OH/CO2H functionalities at C-3. The fluorine substituent in target molecules was introduced by nucleophilic displacement of -OTf in 9a/9c with CsF. Appropriate manipulation of the anomeric carbon in the furanose fused pyrrolidine ring skeleton afforded α-geminal disubstituted pyrrolidine iminosugars 3a–c and C-4 fluoro derivatives 4a–c. The pyrrolidine iminosugars 3a and 3c were found to be potent inhibitors of α-galactosidase while, the fluoro derivatives 4a and 4b showed strong inhibition of β-glucosidase and β-galactosidase, respectively. These results were substantiated by in silico molecular docking studies.

Graphical abstract

http://ift.tt/2ykTJV7

Piperidine and octahydropyrano[3,4-c] pyridine scaffolds for drug-like molecular libraries of the European Lead Factory

Publication date: 1 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
Author(s): Bharat D. Narhe, Arjen C. Breman, Jalindar Padwal, Dirk A.L. Vandenput, Joeri M. Scheidt, Jorg C.J. Benningshof, Gijsbert A. van der Marel, Herman S. Overkleeft, Mario van der Stelt, Dmitri V. Filippov
We report short and efficient scalable syntheses of enantiomerically pure (3R,4S)-3-(hydroxymethyl4-(hydroxyethyl))-piperidine and 1-hydroxymethyl-octahydro-1H-pyrano[3,4-c]pyridine scaffolds. The alkaloid core was readily synthesized from naturally occurring quinine and can serve as a valued starting point for drug-discovery. Cleavage of a terminal 1,2-diol and acid catalysed epoxide opening cyclization are the key steps involved. A number of members of a projected small-molecular library is synthesized for each scaffold.

Graphical abstract

http://ift.tt/2ykTHMZ

Facile access to modified and functionalized PNAs through Ugi-based solid phase oligomerization

Publication date: 1 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
Author(s): Jacques Saarbach, Daniela Masi, Claudio Zambaldo, Nicolas Winssinger
Peptide nucleic acids (PNAs) derivatized with functional molecules are increasingly used in diverse biosupramolecular applications. PNAs have proven to be highly tolerant to modifications and different applications benefit from the use of modified PNAs, in particular modifications at the γ position. Herein we report simple protocols to access modified PNAs from iterative Ugi couplings which allow modular modifications at the α, β or γ position of the PNA backbone from simple starting materials. We demonstrate the utility of the method with the synthesis of several bioactive small molecules (a peptide ligand, a kinase inhibitor and a glycan)-PNA conjugates.

Graphical abstract

http://ift.tt/2yl9bkm

Recently Reported Biological Activities of Pyrazole Compounds

Publication date: Available online 23 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Jéssica Venância Faria, Percilene Fazolin Vegi, Ana Gabriella Carvalho Miguita, Maurício Silva dos Santos, Nubia Boechat, Alice Maria Rolim Bernardino
The pyrazole nucleus is an aromatic azole heterocycle with two adjacent nitrogen atoms. Pyrazole derivatives have exhibited a broad spectrum of biological activities, and approved pyrazole-containing drugs include celecoxib, antipyrine, phenylbutazone, rimonabant, and dipirone. Many research groups have synthesized and evaluated pyrazoles against several biological agents. This review examines recent publications relating the structures of pyrazoles with their corresponding biological activities.

Graphical abstract

http://ift.tt/2ykTFER

Synthesis and structure activity relationships of carbamimidoylcarbamate derivatives as novel vascular adhesion protein-1 inhibitors

Publication date: Available online 23 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Susumu Yamaki, Hiroyoshi Yamada, Akira Nagashima, Mitsuhiro Kondo, Yoshiaki Shimada, Keitaro Kadono, Kosei Yoshihara
Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted structural optimization of the glycine amide derivative 1, which we previously reported as a novel VAP-1 inhibitor, to improve stability in dog and monkey plasma, and aqueous solubility. By chemical modification of the right part in the glycine amide derivative, we identified the carbamimidoylcarbamate derivative 20c, which showed stability in dog and monkey plasma while maintaining VAP-1 inhibitory activity. We also found that conversion of the pyrimidine ring in 20c into saturated rings was effective for improving aqueous solubility. This led to the identification of 28a and 35 as moderate VAP-1 inhibitors with excellent aqueous solubility. Further optimization led to the identification of 2-fluoro-3-{3-[(6-methylpyridin-3-yl)oxy]azetidin-1-yl}benzyl carbamimidoylcarbamate (40b), which showed similar human VAP-1 inhibitory activity to 1 with improved aqueous solubility. 40b showed more potent ex vivo efficacy than 1, with rat plasma VAP-1 inhibitory activity of 92% at 1 h after oral administration at 0.3 mg/kg. In our pharmacokinetic study, 40b showed good oral bioavailability in rats, dogs, and monkeys, which may be due to its improved stability in dog and monkey plasma.

Graphical abstract

http://ift.tt/2yl98Fc

A Rhodamine B-based fluorescent probe for imaging Cu2+ in maize roots

Publication date: Available online 23 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Ting Lv, Yongqian Xu, Hongjuan Li, Fengyu Liu, Shiguo Sun
A new Rhodamine B-based fluorescent probe (RBO) is successfully designed and synthesized, which is a higher selective and sensitive chemosensor for Cu²⁺ than other ions. Under physiological conditions (pH = 7.0), the non emission RBO displays a rapid fluorescence increase together with a color change after addition of Cu²⁺ and the detection limit is down to 28 nM, which can clearly illustrate the distribution of Cu²⁺ with the help of laser scanning confocal microscope in plant tissues. Eventually, it confirmed that the Cu²⁺ accumulates mostly in the vascular cylinder and very less in the epidermal cells of maize roots, which is important to understand how the plants take up, transport and store in the Cu²⁺.

Graphical abstract

http://ift.tt/2ykTDwJ

In vivo Programming of Endogenous Antibodies via Oral Administration of Adaptor Ligands

Publication date: Available online 23 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Masanobu Nagano, Nancy Carrillo, Nobumasa Otsubo, Wataru Hakamata, Hitoshi Ban, Roberta F. Fuller, Nasir K. Bashiruddin, Carlos F. Barbas
Vaccination is a reliable method of prophylaxis and a crucial measure for public health. However, the majority of vaccines cannot be administered orally due to their degradation in the harsh gut environment or inability to cross the GI tract. In this study, we report the first proof-of-concept study of orally producible chemically programmed antibodies via specific conjugation of adaptor ligands to endogenous antibodies, in vivo. Pre-immuniztion with 2,4-dinitrophenyl (DNP), or the reactive hapten, 1,3-diketone (DK), or a novel reactive hapten, vinyl sulfone (VS) in mice, followed by oral administration of adaptor ligands composed of the hapten and biotin to the pre-immunized mice resulted in successful in vivo formation of the biotin-hapten-antibody complexes within 2 hours. Pharmacokinetic evaluations revealed that apparent serum concentrations of programmed antibodies were up to 144 nM and that the serum half-lives reached up to 34.4 h. These findings show promise for the future development of orally bioavailable drug-hapten-antibody complexes as a strategy to quickly and easily modulate immune targets for aggressive pathogens as well as cancer.

Graphical abstract

http://ift.tt/2yl96x4

Synthesis and photophysical properties of a fluorescent cyanoquinoline probe for profiling ERBB2 kinase inhibitor response

Publication date: Available online 23 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Heajin Lee, Ralf Landgraf, James N. Wilson
A fluorescent probe targeting the ERBB2 receptor tyrosine was designed, synthesized and evaluated as reporter of ERBB2 dynamics in overexpressing BT474, i.e. Her2(+), cells. Two cyanoquinazoline (CQ) probes modeled after type-I (CQ1) or active state and type-II (CQ2) or inactive state inhibitors were designed and synthesized with extended π systems that impart binding-induced, turn-on fluorescence. Solution spectroscopy revealed that CQ1 exhibited attractive photophysical properties and displayed turn-on emission in the presence of purified, soluble ERBB2 kinase domain, while CQ2 was found to be non-emissive, likely due to quenching via a photoinduced electron transfer mechanism. Live cell imaging with CQ1 revealed that this probe targeted an intracellular population of ERBB2, which increased following treatment with type-I inhibitors, gefinitib and canertinib, but showed no response to type-II inhibitors. CQ1 thus provides a novel means of imaging the dynamic response of ERBB2(+) cells to kinase inhibitors.

Graphical abstract

http://ift.tt/2ykTwBj

Cancer as an ecomolecular disease and a neoplastic consortium

Publication date: Available online 23 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Santiago Ramón y Cajal, Claudia Capdevila, Javier Hernandez-Losa, Leticia de Mattos, Abhishek Ghosh, Julie Lorent, Ola Larsson, Trond Aasen, Lynne-Marie Postovit, Ivan Topisirovic
Current anticancer paradigms largely target driver mutations considered integral for cancer cell survival and tumor progression. Although initially successful, many of these strategies are unable to overcome the tremendous heterogeneity that characterizes advanced tumors, resulting in the emergence of resistant disease. Cancer is a rapidly evolving, multifactorial disease that accumulates numerous genetic and epigenetic alterations. This results in wide phenotypic and molecular heterogeneity within the tumor, the complexity of which is further amplified through specific interactions between cancer cells and the tumor microenvironment. In this context, cancer may be perceived as an "ecomolecular" disease that involves cooperation between several neoplastic clones and their interactions with immune cells, stromal fibroblasts, and other cell types present in the microenvironment. This collaboration is mediated by a variety of secreted factors. Cancer is therefore analogous to complex ecosystems such as microbial consortia.In the present article, we comment on the current paradigms and perspectives guiding the development of cancer diagnostics and therapeutics and the potential application of systems biology to untangle the complexity of neoplasia. In our opinion, conceptualization of neoplasia as an ecomolecular disease is warranted. Advances in knowledge pertinent to the complexity and dynamics of interactions within the cancer ecosystem are likely to improve understanding of tumor etiology, pathogenesis, and progression. This knowledge is anticipated to facilitate the design of new and more effective therapeutic approaches that target the tumor ecosystem in its entirety.



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Pre-operative Duplex Ultrasonography in Arteriovenous Fistula Creation: Intra- and Inter-observer Agreement

Publication date: Available online 22 September 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Niek Zonnebeld, Tommy M.G. Maas, Wouter Huberts, Magda M. van Loon, Tammo Delhaas, Jan H.M. Tordoir
ObjectiveAlthough clinical guidelines on arteriovenous fistula (AVF) creation advocate minimum luminal arterial and venous diameters, assessed by duplex ultrasonography (DUS), the clinical value of routine DUS examination is under debate. DUS might be an insufficiently repeatable and/or reproducible imaging modality because of its operator dependency. The present study aimed to assess intra- and inter-observer agreement of DUS examination in support of AVF surgery planning.MethodsTen end stage renal disease patients were included, to assess intra- and inter-observer agreement of pre-operative DUS measurements. All measurements were performed by two trained and experienced vascular technicians, blinded to measurement readings. From the routine DUS protocol, representative measurements (venous diameters, and arterial diameters and volume flow in the upper arm and forearm) were selected. For intra-observer agreement the measurements were performed in triplicate, with the probe released from the skin between each. Intraclass correlation coefficients were calculated for intra- and inter-observer agreement, and Bland-Altman plots used to graphically display mean measurement differences and limits of agreement.ResultsTen patients (6 male, 59.4±19.7 years) consented to participate, and all predefined measurements were obtained. Intraclass correlation coefficients for intra-observer agreement of diameter measurements were at least 0.90 (95% CI 0.74–0.97; radial artery). Inter-observer agreement was at least 0.83 (0.46–0.96; lateral diameter upper arm cephalic vein). The Bland-Altman plots showed acceptable mean measurement differences and limits of agreement.ConclusionIn experienced hands, excellent intra- and inter-observer agreement can be reached for the discrete pre-operative DUS measurements advocated in clinical guidelines. DUS is therefore a reliable imaging modality to support AVF surgery planning. The content of DUS protocols, however, needs further standardisation.



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Speech sound disorders or differences: Insights from bilingual children speaking two Chinese languages

Publication date: Available online 23 September 2017
Source:Journal of Communication Disorders
Author(s): Kitty K.Y. Lam, Carol K.S. To
The study investigated how Putonghua-Cantonese bilingual children differ from monolinguals in their acquisition of speech sound and phonological patterns. Fifty-four typically developing Putonghua-Cantonese bilingual children aged 3;6-6;0 were recruited from nurseries in the North District of Hong Kong. The Hong Kong Cantonese Articulation Test (Cheung, Ng, & To, 2006) and a Putonghua picture-naming task (Zhu & Dodd, 2000) were used to elicit single-word samples of both languages. Acquisition of speech sound and phonological patterns exhibited by ≥20% of the children in an age group were compared to the normative data on children who were Cantonese native or Putonghua monolingual speakers. The bilingual children demonstrated smaller sound inventory in both languages and more delayed and atypical phonological processes. The atypical patterns could be explained by phonological interference between Putonghua and Cantonese. The findings serve as a preliminary reference for clinicians in differentiating language difference from true speech sound disorders in Putonghua-Cantonese bilingual children in Hong Kong.



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Effect of dronedarone on the pharmacokinetics of carvedilol following oral administration to rats

Publication date: 1 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 111
Author(s): Min-Soo Kim, In-hwan Baek
Dronedarone is a CYP2D6 inhibitor; therefore, it is prudent to exercise caution when concurrently administering CYP2D6-metabolized β-blockers because of a lack of published data on potential drug interactions. The aim of this study was to investigate the effect of dronedarone on the pharmacokinetics of orally administered carvedilol in rats. Twenty male Sprague-Dawley rats were randomly divided into two groups and 10mg/kg carvedilol was administered to the rat with or without dronedarone pretreatment in a parallel design. Blood samples were collected before and after 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, and 24h of drug administration. The plasma concentration of carvedilol was determined using LC-MS/MS. The systemic exposure to carvedilol was significantly increased and elimination of carvedilol was significantly decreased in the dronedarone-pretreated rats than in the vehicle-pretreated rats. The one-compartment model with first-order absorption and elimination was sufficient to explain the pharmacokinetic characters after single oral administration of carvedilol to both vehicle-pretreated and dronedarone-pretreated rats. This study suggests that dronedarone inhibits CYP2D6-mediated carvedilol metabolism, and dose adjustment is needed in carvedilol and dronedarone combination therapy. Further studies are needed to clarify the effect of dronedarone on carvedilol and CYP2D6 substrates in clinical use.

Graphical abstract

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A physiologically-based model to predict individual pharmacokinetics and pharmacodynamics of remifentanil

Publication date: 1 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 111
Author(s): Sara Cascone, Gaetano Lamberti, Ornella Piazza, Roberto Andrea Abbiati, Davide Manca
Remifentanil based anesthesia is nowadays spread worldwide. This drug is characterized by a rapid onset of the analgesic effects, but also by a rapid onset of the side effects. For this reason, the knowledge of the remifentanil concentration in the human body is a key topic in anesthesiology. The aims of this work are to propose and validate a physiologically based pharmacokinetic model capable to predict both the pharmacokinetics and pharmacodynamics of remifentanil, and to take into account the inter-individual differences among the patients (such as height and body mass). The blood concentration of remifentanil has been successfully simulated and compared with experimental literature data. The pharmacodynamics, in terms of effect of remifentanil on minute ventilation and electroencephalogram, has been implemented in this model. Moreover, the remifentanil concentration in various organs and tissues is predicted, which is a significant improvement with respect to the traditional compartmental models. The availability of the model makes possible the prediction of the effects of remifentanil administration, also accounting for individual parameters.

Graphical abstract

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Information for Readers

Publication date: September–October 2017
Source:Current Problems in Cancer, Volume 41, Issue 5





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Table of Contents

Publication date: September–October 2017
Source:Current Problems in Cancer, Volume 41, Issue 5





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Title Page

Publication date: September–October 2017
Source:Current Problems in Cancer, Volume 41, Issue 5





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Effects of co-composting of farm manure and biochar on plant growth and carbon mineralization in an alkaline soil

Abstract

In the present study, the effects of co-composts of biochar (BC) and farm manure (FM) on the growth of wheat (Triticum aestivum L.) and carbon mineralization in an alkaline soil were investigated. The co-composts of FM and BC were prepared at various ratios (FM₁₀₀:BC₀, FM₇₅:BC₂₅, FM₅₀:BC₅₀, FM₂₅:BC₇₅, FM₀:BC₁₀₀) using aboveground piles and were used in two separate experiments conducted simultaneously. In the plant growth trial, prepared co-composts were applied at a rate of 2% w/w and wheat was grown at two fertilizer levels (half and full) until maturity. In the incubation experiment, same treatments were used and carbon mineralization was studied over a period of 79 days. The priming effect and net CO₂ efflux were calculated using CO₂ release data. Analysis of postincubation soil showed no significant effect of treatments on the pH of soil. However, electrical conductivity and organic matter were significantly influenced by all treatments. The increasing BC ratio in the compost reduced the carbon mineralization in soil in a dose-additive manner. Increase in BC proportion in composts (FM₅₀:BC₅₀, FM₂₅:BC₇₅, FM₀:BC₁₀₀) stabilized the native carbon of the soil and caused negative priming effect (−1.9, −5.6, and −8.48%, respectively). Regarding plant growth, the results showed an enhancement in the grain yield with the application of compost than control. Total nitrogen (N), phosphorus, and potassium (K) contents of the soil were also increased by the application of compost than control (un-amended soil). Significantly higher N and K concentrations in wheat plants were also examined when soil was treated with compost than control. The use of compost with half fertilizer was better in increasing grain yield, especially with higher BC proportion in the compost than FM.

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Activation of peroxymonosulfate by surfactants as the metal-free catalysts for organic contaminant removal

Abstract

The present work described that tertiary ammonium surfactants containing bromide ion as novel metal-free catalysts were innovatively coupled with peroxymonosulfate (PMS) to build a simple catalytic oxidation system, possessing outstanding catalytic ability with organic dye Reactive Red M-3BE (RR M-3BE) as the target pollutant. Furthermore, cetyltrimethylammonium bromide (CTAB), a representative of cationic surfactant, was selected to further investigate the catalytic oxidation performance. It is found that at the critical micelle concentration (CMC) of CTAB, the oxidation efficiency of the CTAB/PMS system was optimal due to the strong electrostatic attraction between the CTA⁺ micelle and reactive anions (Br⁻ and HSO₅⁻), concentrating HSO₅⁻ and Br⁻ at the micellar surface, which accelerated the catalytic oxidation reaction between Br⁻ and HSO₅⁻, generating a mass of highly active reactive species. A hybrid method that combined radical scavenger (methanol) with electron paramagnetic resonance (EPR) technology was adopted for the investigation of reactive species, and the results indicated that hydroxyl radical (•OH) was generated and had a major role in the process. The findings from this work provide a practicable pathway for highly efficient PMS activation in wastewater treatment, and also initiate a promising research area of surfactants in the field of environmental catalysis.

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Iron deficiency anemia and hearing loss

We read with great interest the article published in your prestigious journal entitled: "Protein energy malnutrition associates with different types of hearing impairments in toddlers: Anemia increases cochlear dysfunction" by Kamel TB et al. [1]. The authors describe their experience on the early detection of hearing impairment in toddlers with protein energy malnutrition (PEM) and neuro-cognitive effect of PEM in relation to hemoglobin blood level.

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Audio-visual speech perception in prelingually deafened Japanese children following sequential bilateral cochlear implantation

An effect of audio-visual (AV) integration is observed when the auditory and visual stimuli are incongruent (the McGurk effect). In general, AV integration is helpful especially in subjects wearing hearing aids or cochlear implants (CIs). However, the influence of AV integration on spoken word recognition in individuals with bilateral CIs (Bi-CIs) has not been fully investigated so far. In this study, we investigated AV integration in children with Bi-CIs.

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Dry deposition of NO2 over China inferred from OMI columnar NO2 and atmospheric chemistry transport model

Publication date: November 2017
Source:Atmospheric Environment, Volume 169
Author(s): X.Y. Zhang, X.H. Lu, L. Liu, D.M. Chen, X.M. Zhang, X.J. Liu, Y. Zhang
The NO2 dry deposition over China was estimated based on an inferential model, in which the surface NO2 concentrations and deposition velocities were derived from OMI columnar NO2 and the simulation results from atmospheric chemistry transport models. Nationally, the annual NO2 dry deposition fluxes ranged from 0.0005 to 8.54 kg N ha⁻¹, with an average of 0.48 kg N ha⁻¹. The total NO2 dry deposition over China was 0.46 Tg N yr⁻¹, mainly contributed by northern and southeast China. Due to contrary seasonal trends of the NO2 concentrations (high in cold months) and deposition velocities (high in warm months), the estimated NO2 dry depositions did not show strong seasonal pattern, instead showing relatively high values from August to October and low ones in February. The annual NO2 dry deposition has an increasing trend from 2007 to 2014, with the highest deposition level achieved in 2011. This research conducts a thorough validation between estimated NO2 dry depositions with ground measurements of NO2 concentrations and provides an objective spatial perspective and insight on the existing NO2 dry deposition maps in China.



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Impact of aromatics and monoterpenes on simulated tropospheric ozone and total OH reactivity

Publication date: November 2017
Source:Atmospheric Environment, Volume 169
Author(s): William C. Porter, Sarah A. Safieddine, Colette L. Heald
The accurate representation of volatile organic compounds (VOCs) in models is an important step towards the goal of understanding and predicting many changes in atmospheric constituents relevant to climate change and human health. While isoprene is the most abundant non-methane VOC, many other compounds play a large role in governing pollutant formation and the overall oxidative capacity of the atmosphere. We quantify the impacts of aromatics and monoterpenes, two classes of VOC not included in the standard gas-phase chemistry of the chemical transport model GEOS-Chem, on atmospheric composition. We find that including these compounds increases mean total summer OH reactivity by an average of 11% over the United States, Europe, and Asia. This increased reactivity results in higher simulated levels of O3, raising maximum daily 8-h average O3 in the summer by up to 14 ppb at some NOx-saturated locations.



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Development of the GC-MS organic aerosol monitor (GC-MS OAM) for in-field detection of particulate organic compounds

Publication date: November 2017
Source:Atmospheric Environment, Volume 169
Author(s): Paul M. Cropper, Devon K. Overson, Robert A. Cary, Delbert J. Eatough, Judith C. Chow, Jaron C. Hansen
Particulate matter (PM) is among the most harmful air pollutants to human health, but due to its complex chemical composition is poorly characterized. A large fraction of PM is composed of organic compounds, but these compounds are not regularly monitored due to limitations in current sampling and analysis techniques. The Organic Aerosol Monitor (GC-MS OAM) combines a collection device with thermal desorption, gas chromatography and mass spectrometry to quantitatively measure the carbonaceous components of PM on an hourly averaged basis. The GC-MS OAM is fully automated and has been successfully deployed in the field. It uses a chemically deactivated filter for collection followed by thermal desorption and GC-MS analysis. Laboratory tests show that detection limits range from 0.2 to 3 ng for 16 atmospherically relevant compounds, with the possibility for hundreds more. The GC-MS OAM was deployed in the field for semi-continuous measurement of the organic markers, levoglucosan, dehydroabietic acid, and polycyclic aromatic hydrocarbons (PAHs) from January to March 2015. Results illustrate the significance of this monitoring technique to characterize the organic components of PM and identify sources of pollution.

Graphical abstract

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Minimization of model representativity errors in identification of point source emission from atmospheric concentration measurements

Publication date: November 2017
Source:Atmospheric Environment, Volume 169
Author(s): Maithili Sharan, Amit Kumar Singh, Sarvesh Kumar Singh
Estimation of an unknown atmospheric release from a finite set of concentration measurements is considered an ill-posed inverse problem. Besides ill-posedness, the estimation process is influenced by the instrumental errors in the measured concentrations and model representativity errors. The study highlights the effect of minimizing model representativity errors on the source estimation. This is described in an adjoint modelling framework and followed in three steps. First, an estimation of point source parameters (location and intensity) is carried out using an inversion technique. Second, a linear regression relationship is established between the measured concentrations and corresponding predicted using the retrieved source parameters. Third, this relationship is utilized to modify the adjoint functions. Further, source estimation is carried out using these modified adjoint functions to analyse the effect of such modifications. The process is tested for two well known inversion techniques, called renormalization and least-square. The proposed methodology and inversion techniques are evaluated for a real scenario by using concentrations measurements from the Idaho diffusion experiment in low wind stable conditions. With both the inversion techniques, a significant improvement is observed in the retrieval of source estimation after minimizing the representativity errors.



http://ift.tt/2wJO26W

Whole exome sequencing in inborn errors of immunity: use the power but mind the limits.

Purpose of review: Next-generation sequencing, especially whole exome sequencing (WES), has revolutionized the molecular diagnosis of inborn errors of immunity. This review summarizes the generation and analysis of next-generation sequencing data. Recent findings: The focus is on prioritizing strategies for unveiling the potential disease-causing variant. We also highlighted oversights and imperfections of WES and targeted panel sequencing, as well as the need for functional validation. Summary: The information is crucial for a judicious use of WES by researchers, but even more so by the clinical immunologist. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Dynamics of defensive response mobilization during repeated terminations of exposure to increasing interoceptive threat

Publication date: Available online 23 September 2017
Source:International Journal of Psychophysiology
Author(s): Christoph Benke, Elischa Krause, Alfons O. Hamm, Christiane A. Pané-Farré
Resistant avoidance behaviors play a crucial role in the maintenance of anxiety disorders and are therefore central targets of therapeutic interventions. In the present study, the development of avoidance behavior was investigated in 24 healthy participants who repeatedly prematurely terminated the exposure to increasing interoceptive threat, i.e., the feeling of dyspnea induced by increasing inspiratory resistive loads that were followed by the ultimate threat, a short breathing occlusion. Physiological responses and subjective anxiety preceding terminations were compared to matched intervals of a matched control group (N=24) who completed the exposure. Initially, participants terminated during the ultimate threat, i.e., during occlusion. This first termination was preceded by a strong surge in autonomic arousal and reported anxiety. Startle reflex and the P3 component of event-related brain potentials to startle probes were strongly inhibited, indicating preparation for defensive action. With repetitive terminations, individuals successively terminated earlier, avoiding exposure to the occlusion. This avoidant behavior was accompanied by alleviated autonomic arousal as compared to the first termination. In addition, no indication of physiological response preparation was found implying that the avoidance behavior was performed in a rather habitual way. Matched controls did not show any indication of a defensive response surge in the matched intervals. In matched controls, no changes in physiological response patterns were detected while anxiety levels increased with repetitions. The present results shed new light on our understanding of the motivational basis of avoidance behavior and may help to refine etiological models, behavioral analysis and therapeutic strategies in treating anxiety disorders.



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Comparison of the accuracy of maxillary position between conventional model surgery and virtual surgical planning

The aim of this study was to determine whether virtual surgical planning (VSP) is an accurate method for positioning the maxilla when compared to conventional articulator model surgery (CMS), through the superimposition of computed tomography (CT) images. This retrospective study included the records of 30 adult patients submitted to bimaxillary orthognathic surgery. Two groups were created according to the treatment planning performed: CMS and VSP. The treatment planning protocol was the same for all patients.

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Natural variation of the zygomaticomaxillary complex symmetry in normal individuals

The most frequently encountered midfacial fractures are zygomaticomaxillary complex (ZMC) fractures (Gupta et al., 2009; van Hout et al., 2013; Arangio et al., 2014). In ZMC fracture cases, the restoration of facial symmetry is the main treatment goal after functional recovery (Ellis, 2013; Ellis and Perez, 2014) because symmetry plays an important role in the visual perception of faces (Grammer and Thornhill, 1994; Perrett et al., 1998; Rhodes, 2006). Furthermore, a symmetrical face is correlated with perceived healthiness and attractiveness (Rhodes et al., 1998; Jones et al., 2001; Fink et al., 2006).

http://ift.tt/2fhuVpH

4 Medical applications

Publication date: 2018
Source:Biodegradable and Biocompatible Polymer Composites
Author(s): Ivan Djordjevic, Samira Hosseini, José I. Gómez Quiñones
Interfacial properties of synthetic, biodegradable composite materials are of crucial importance for clinical outcome of fabricated medical implants, tissue engineering scaffolds, and drug delivery carriers. In this chapter we outline selected types of synthetic composite biomaterials with specific fillers dispersed into polymer matrices. By definition, the choice of both polymer and filler components, together with unavoidable release of biodegradation products in tissue proximity, would have significant implications on physiological environment and tissue regeneration at tissue–biomaterial interface. In addition, careful choice of composite components will determine immunological response on surgical implantation. This chapter explains some fundamental aspects of composite biomaterials in regard to their clinical performance from the recent studies. A new aspects and strategies for biological activation of fillers by protein surface attachment are highlighted in separate sections in this chapter. At the end of the chapter we explain a novel type of polymer composite hydrogels, called "double networks" or "interpenetrated networks" with their unique properties and their potential for fabrication of new generation biomedical devices with high degree of control over material properties.



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3 Self-assembled nanomaterials

Publication date: 2018
Source:Nanobiomaterials
Author(s): M.C. García, C. Aloisio, R. Onnainty, G. Ullio-Gamboa
Therapeutically effective and biocompatible nanomaterials based on polymer and lipid carriers continuously lead researchers to design novel tools and strategies. Because of their potential ability to improve current therapies, these nanodevices are extensively used as delivery devices for drugs and/or imaging agents to improve the efficacy and safety of treatments by increasing therapeutic performance and reducing side effects of several drugs, proteins, and vaccines. Among all the approaches proposed in recent years, this chapter presents the most outstanding contributions of self-assembled nanomaterials, because they have been identified as one of the key subjects in nanoscience. We will focus on preparation and characterization methods and on the main biomedical applications reported in recent years.



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10 Use of nanostructured materials in hard tissue engineering

Publication date: 2018
Source:Nanobiomaterials
Author(s): L.C. du Toit, P. Kumar, Y.E. Choonara, V. Pillay
The human population is aging with a consequent rise in the incidence of hard tissue disease. Thus there is a rising requirement for innovative hard tissue engineering approaches. Combining advancements in nanotechnology and tissue engineering has resulted in the evolution of nanostructured materials for tissue engineering, which are proffered as a promising avenue for enhanced and less invasive repair and regeneration of damaged hard tissues. In this chapter, the architectural and molecular intricacies of hard tissue are examined, with the ultimate goal being successful biomimicry of this tissue for enhanced regeneration and repair. Subsequently, the diverse biomaterials and approaches for hard tissue engineering are exemplified through analysis of specific investigations for design of nanostructured materials for hard tissue engineering scaffolds.



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Cultural and moral dimensions of sexual aggression: The role of moral disengagement in men's likelihood to sexually aggress

Publication date: Available online 23 September 2017
Source:Aggression and Violent Behavior
Author(s): Arielle Sagrillo Scarpati, Afroditi Pina
Social norms inform individuals in a given society about what is right and wrong, and it is through their environment (and its symbolic elements) that people learn how to behave morally. These norms help shape not only people's behaviors, but also the way in which society in general, works: they are not, however, sufficient to compel all individuals to refrain from detrimental conduct. In fact, according to Paciello (2008), in some cases, these same norms may serve to legitimize harmful behavior towards others. In societies plagued by gender inequality, for example, some forms of violence (e.g. marital rape, domestic violence, homophobia) might be tolerated and/or justified as a result of individuals' adherence to traditional gender norms. As a result, detrimental behavior becomes socially and morally acceptable, and any conflicting moral beliefs and behaviors are experienced largely without self-reproach. Drawing from that, the primary goal of this narrative review is to explore the idea that some social norms may influence the acceptability of perpetration of sexual violence. Building on the findings from our review, we address existing gaps in the literature, and present a different approach to individuals' likelihood to engage in sexually aggressive behavior, via consideration of moral values and moral disengagement strategies.



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Comparison between the Ki-hap technique and verbal encouragement on activation of abdominal muscles in healthy participants

Publication date: Available online 23 September 2017
Source:Journal of Bodywork and Movement Therapies
Author(s): Chang-Yong Kim, Hyeong-Dong Kim
The aim of this study was to investigate the comparison between a Ki-hap defined as a psyching-up technique, and verbal encouragement defined as a verbal command by a third party, on abdominal muscle activation during performance of the crunch exercise in healthy participants. Ninety participants were randomly allocated to the following three groups: crunch only exercise group (CG, n1 = 30), crunch exercise with Ki-hap group (CKG, n2 = 30), and crunch exercise with Ki-hap and verbal encouragement group (CKVG, n3 = 30). The interventions were conducted over three trials in each group, and measurements on each participant were performed by a single examiner. The activation of the rectus abdominis (RA), external oblique (EO), and internal oblique (IO) muscles were evaluated using electromyography (EMG) during performance of the crunch exercise in the CG, CKG, and CKVG. Our results showed a significantly greater increase in the EMG patterns of all muscles during performance of the crunch exercise in the CKG (p < 0.05) compared to those in the CG and CKVG. The results also showed that there was a significantly greater increase in the activation of the EO and IO muscles in the CKVG (p < 0.05) compared with that in the CG. These findings demonstrated that the addition of the Ki-hap technique and verbal encouragement during performance of the crunch exercise improves activation of the abdominal muscles.



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