Publication date: July 2017
Source:Oral Oncology, Volume 70
Author(s): Astrid De Meulenaere, Tijl Vermassen, Sandrine Aspeslagh, Wouter Huvenne, Jo Van Dorpe, Liesbeth Ferdinande, Sylvie Rottey
The use of cytotoxic and/or targeted agents is the gold standard in first- and second-line treatment of metastatic head and neck cancer. Currently the focus of oncologic research is shifting to the implementation of immune checkpoint inhibitor regimens. Many trials are being performed evaluating the survival benefit of various PD-1/PD-L1 blocking antibodies in both solid and haematological malignancies. Also, evaluation of the predictive value of PD-L1 expression on tumour cells and immune cells is being explored.We first review the current knowledge and possible pitfalls for PD-L1 expression in squamous cell carcinoma of the head and neck. Next, we provide an update on the therapeutic use of PD-1/PD-L1 blocking antibodies as treatment modality for patients with squamous cell carcinoma of the head and neck and we assess the predictive value of tumour PD-L1 positivity. Finally, we elaborate on other promising predictive biomarkers of interest in this patient population.
http://ift.tt/2qDOiQD
Παρασκευή 19 Μαΐου 2017
Turning the tide: Clinical utility of PD-L1 expression in squamous cell carcinoma of the head and neck
Integrating speech in time depends on temporal expectancies and attention
Source:Cortex
Author(s): Mathias Scharinger, Johanna Steinberg, Alessandro Tavano
Sensory information that unfolds in time, such as in speech perception, relies on efficient chunking mechanisms in order to yield optimally-sized units for further processing. Whether or not two successive acoustic events receive a one-unit or a two-unit interpretation seems to depend on the fit between their temporal extent and a stipulated temporal window of integration. However, there is ongoing debate on how flexible this temporal window of integration should be, especially for the processing of speech sounds. Furthermore, there is no direct evidence of whether attention may modulate the temporal constraints on the integration window. For this reason, we here examine how different word durations, which lead to different temporal separations of sound onsets, interact with attention. In an Electroencephalography (EEG) study, participants actively and passively listened to words where word-final consonants were occasionally omitted. Words had either a natural duration or were artificially prolonged in order to increase the separation of speech sound onsets. Omission responses to incomplete speech input, originating in left temporal cortex, decreased when the critical speech sound was separated from previous sounds by more than 250 ms, i.e. when the separation was larger than the stipulated temporal window of integration (125-150 ms). Attention, on the other hand, only increased omission responses for stimuli with natural durations. We complemented the event-related potential (ERP) analyses by a frequency-domain analysis on the stimulus presentation rate. Notably, power of stimulation frequency showed the same duration and attention effects than the omission responses. We interpret these findings on the background of existing research on temporal integration windows and further suggest that our findings may be accounted for within the framework of predictive coding.
http://ift.tt/2pVwtNX
Effects of calcium chloride coadministered with neostigmine on neuromuscular blockade recovery: A double-blind randomised study.
http://ift.tt/2q3a9Og
Intraoperative magnesium sulphate decreases agitation and pain in patients undergoing functional endoscopic surgery: A randomised double-blind study.
http://ift.tt/2rnOzYF
Comparison of laryngeal mask airway insertion methods, including the external larynx lift with pre-inflated cuff, on postoperative pharyngolaryngeal complications: A randomised clinical trial.
http://ift.tt/2q2IhKe
Perioperative factors related to the severity of vocal cord paralysis after thoracic cardiovascular surgery: A retrospective review.
http://ift.tt/2rnKWSG
Effects of dexamethasone on early cognitive decline after cardiac surgery: A randomised controlled trial.
http://ift.tt/2q2DNmQ
Anaesthesiology research in the European Union and the European Free Trade Association: An overview from 2001 to 2015.
http://ift.tt/2rnNjEO
Nanoparticle switches off blood vessel growth
Source:Nano Today
http://ift.tt/2rBWfTA
Extra- and intra-cellular fate of nanocarriers under dynamic interactions with biology
Publication date: Available online 19 May 2017
Source:Nano Today
Author(s): Seog-Jin Seo, Meiwan Chen, Hongxia Wang, Min Sil Kang, Kam W. Leong, Hae-Won Kim
Synthetic nanocarriers continue to play an important role in nanomedicine as the next generation of therapeutics demands effective intracellular delivery. Better understanding of the extra- and intra-cellular fate of the nanocarriers in relation with biological environments in vitro and in vivo is essential for the progress of nanocarrier-based therapeutics. As nanocarriers come into contact with biological fluid, interactions with various biomolecules alter their initial physicochemical status. Such dynamic modifications influence their interactions with cells and the subsequent endocytic process. Upon cellular uptake, intracellular machineries control their trafficking, release and degradation of cargoes, and exocytosis. In this Review, we highlight the navigation of nanocarriers through various extra- and intra-cellular barriers, with an emphasis on how dynamic interactions with biological components alter their fate and performance.
Graphical abstract
http://ift.tt/2qDHVwR
Self-assembly and morphological control of three-dimensional macroporous architectures built of two-dimensional materials
Publication date: Available online 19 May 2017
Source:Nano Today
Author(s): Ji-Eun Kim, Jung-Hwan Oh, Moumita Kotal, Nikhil Koratkar, Il-Kwon Oh
The three-dimensional (3D) macroscopic assembly of tailored porous architectures built of graphene derivatives or other two-dimensional (2D) materials has attracted great attention in both academia and industry. The reason being that such 3D assemblies with controlled morphology can provide ultra-large accessible surface areas and interconnected networks, as well as preventing the undesirable re-stacking phenomena of 2D materials. Herein, we review the synthetic routes and formation mechanism of bulk gel and interface mediated 3D architectures made of diverse 2D materials encompassing both graphene derivatives and non-graphene 2D materials. We also suggest universal strategies that can provide useful insight into application-oriented architecture design. The gelation mechanism is explained in detail; it involves controlled destabilization of the suspension involving a delicate balance between attractive and repulsive interactions. Further, interface mediated self-assembly processes between liquid-solid, liquid-liquid, liquid-gas, and ice-water phases are discussed with a view to tailoring 3D layered and interconnected morphologies. Finally, we highlight the demand for future applications of 2D material-based 3D macroporous architectures. Despite recent progress, more precise control strategies for tuning surface area, pore size distribution, orientation/interconnectivity of pores, density of architectures, and mechanical stability, remain as key scientific and technological barriers that must be addressed to enable practical applications. Further, an important frontier area for future research will involve multilateral hybridization, involving diverse combinations of materials, morphologies, and assembly methods This will provide researchers a multi-dimensional toolbox to access hitherto unavailable properties of 2D material-based 3D architectures for a whole host of applications.
Graphical abstract
http://ift.tt/2qDI0Rb
Neural interfaces engineered via micro- and nanostructured coatings
Publication date: Available online 19 May 2017
Source:Nano Today
Author(s): Nuan Chen, Lingling Tian, Anoop C. Patil, Shengjie Peng, In Hong Yang, Nitish V. Thakor, Seeram Ramakrishna
During the past decade, neural interfaces have attracted great interest due to their potential of body-machine communication for disease diagnosis and therapy. Considering the significant material mismatch between the electrode implants and the native tissue, a thin coating is employed on the electrode sites as an intermediate layer to bridge the material differences and has been proved to play an important role in the promotion of neural cell attachment and signal transmission. Micro- and nanostructured coating materials, together with surface functionalization such as biological cues, provide not only high surface areas for signal transduction but also a biomimetic platform for the cells. In this paper, we review the performance of different kinds of micro- and nanostructured coating materials including metallic materials, carbon materials, conducting polymeric materials and composite materials and then complement the discussion with the influence of the fabrication process on the performance of the coatings. The coating could be functionalized by various advanced techniques, which are also reviewed. The existing challenge and future research directions of electrode coatings are briefly discussed at the end of the review.
Graphical abstract
http://ift.tt/2qDC8HB
3D nanoparticle structures emerge from the fog
Source:Nano Today
http://ift.tt/2qDCaPJ
Tethered nanoparticles charge ahead
Source:Nano Today
http://ift.tt/2rCcr7c
Rice agriculture impacts catchment hydrographic patterns and nitrogen export characteristics in subtropical central China: a paired-catchment study
Abstract
Increased nitrogen (N) concentrations in water bodies have highlighted issues regarding nutrient pollution in agricultural catchments. In this study, the ammonium-N (NH4+-N), nitrate-N (NO3−-N), and total N (TN) concentrations were observed in the stream water and groundwater of two contrasting catchments (named Tuojia and Jianshan) in subtropical central China from 2010 to 2014, to determine the rice agriculture impacts on the hydrographic patterns, and N export characteristics of the catchments. The results suggested that greater amounts of stream flow (523.0 vs. 434.7 mm year−1) and base flow (237.6 vs. 142.8 mm year−1) were produced in Tuojia than in Jianshan, and a greater base flow contribution to stream flow and higher frequencies of high-base flow days were observed during the fallow season than during the rice-growing season, indicating that intensive rice agriculture strongly influences the catchment hydrographic pattern. Rice agriculture resulted in moderate N pollution in the stream water and groundwater, particularly in Tuojia. Primarily, rice agriculture increased the NH4+-N concentration in the stream water; however, it increased the NO3−-N concentrations in the groundwater, suggesting that the different N species in the paddy fields migrated out of the catchments through distinct hydrological pathways. The average TN loading via stream flow and base flow was greater in Tuojia than in Jianshan (1.72 and 0.58 vs. 0.72 and 0.15 kg N ha−1 month−1, respectively). Greater TN loading via stream flow was observed during the fallow season in Tuojia and during the rice-growing season in Jianshan, and these different results were most likely a result of the higher base flow contribution to TN loading (33.5 vs. 21.3%) and greater base flow enrichment ratio (1.062 vs. 0.876) in Tuojia than in Jianshan. Therefore, the impact of rice agriculture on catchment eco-hydrological processes should be considered when performing water quality protection and treatment in subtropical central China.
http://ift.tt/2rnyUss
Characterization of arsenic availability in dry and flooded soils using sequential extraction and diffusive gradients in thin films (DGT) techniques
Abstract
Much attention has been paid to the availability of arsenic (As) in soils, while few studies were carried out on the comparison between the dry and flooded soils using different methods. In this study, chemical sequential extraction and diffusive gradients in thin films (DGT) techniques were employed to study the availability of As in soils amended with a range of exogenous As followed by one-year incubation under dry and flooded conditions, respectively. The results showed that the proportions of available solid As pools, including non-specifically adsorbed As (F1) and specifically adsorbed As (F2), had consistent increases with the increase of As amendment. The concentration of DGT-measured As (C DGT) and dissolved As in soil solution (C SOL) also increased up to 2573 (dry) and 1823 (flooded) times and 4067 (dry) and 3105 (flooded) times of the control, respectively, while their ratios (R) showing the extent of C SOL sustained from solid resupply decreased from 0.17 to 0.10 (dry) and 0.35 to 0.21 (flooded). Modelling with DGT-induced fluxes in soils (DIFS) further showed an increase of T c (the characteristic time to reach equilibrium from DGT perturbation) and decreases of desorption and adsorption rate constants (k 1 and k −1) with the increase of As amendment, reflecting a decrease in kinetic exchange rate of As between available solid As pool and soil solution. The flooded soils had greater values of R, k −1 and k 1 and lower value of T c in comparison with the dry soils, indicating a greater availability of As under the flooded condition.
http://ift.tt/2q2KSDL
Effect of tannery effluent on oxidative status of brain structures and liver of rodents
Abstract
Oxidative stress has been considered as a central mechanism of toxicity induced by xenobiotics. Previously, it was demonstrated that mice exposed to tannery effluent showed an anxiety-like behavior, without any comparable behavioral effects in rats. The aim of the present study was to investigate the impact of tannery wastewater on oxidative status in in vitro and in vivo assays with two mammal species, mice and rats. Specifically, homogenates of two brain areas and the liver were incubated with tannery wastewater; reactive species and lipid peroxidation levels and antioxidant enzyme activities were detected. In addition, the effects of in vivo exposure of mice to tannery effluents on and lipid peroxidation levels and the total reactive antioxidant capacity in brain areas and liver. Brain areas, the hippocampus and frontal cortex, and the liver of mice exposed to tannery wastewater showed oxidative stress. Our data suggest that divergent species-dependent hepatic enzymes adaptations, such as glutathione peroxidase and glutathione S-transferase activities, induced by tannery effluent could explain previous behavioral findings.
http://ift.tt/2rnjHYg
Temporal and spatial features of selected wastewater-marking pharmaceuticals and potential mechanisms of their removal from urban rivers
Abstract
The investigations on seasonal and spatial distribution of 12 selected wastewater-marking pharmaceuticals (WWMPs) belonging to different therapeutic classes were conducted in three major urban rivers of Yangpu District, Shanghai, East China. The potential mechanisms for the removal of WWMPs in the rivers were also experimentally investigated. The detection frequencies of most WWMPs were in the range of 56–100%, with the exception of clofibric acid, which was not detected during the storm events. The median concentrations ranged from not detected to 5821 ng/L (caffeine) and the maximum concentration was 8662 ng/L, found in caffeine. Part of WWMPs such as paracetamol and caffeine showed significant seasonal variation (P < 0.05), while most of pharmaceuticals displayed limited concentration fluctuation under different seasons for relative low levels. The spatial pattern of most WWMPs has not showed obvious difference in the three rivers (P > 0.05). WWMPs could come from different sources, such as wastewater treatment plants, hospitals, untreated domestic wastewater, or some unknown sources. Lab-scale tests showed that the biodegradation and adsorption were the main removal pathways for WWMPs with lesser contribution from photodegradation and hydrolysis.
http://ift.tt/2q2P6ew
Application of hyper-branched rolling circle amplification (HRCA) and HRCA-based strip test for the detection of Chattonella marina
Abstract
Harmful algal blooms (HABs) are global threats to marine ecosystems, fisheries, and human health. Therefore, developing effective and accurate methods for identifying causative algae and monitoring seawater quality is urgent. However, traditional, microscopy-based methods are complex, inaccurate, and time-consuming. Here, we present a novel method for effective and sensitive detection of Chattonella marina using hyper-branched rolling circle amplification (HRCA) and HRCA-based strip test (HBST). The large subunit (LSU) ribosomal DNA (rDNA) D1–D2 region of C. marina was firstly sequenced to design a species-specific padlock probe (PLP). The HRCA reaction with two amplification primers and further HBST for C. marina was established. The optimized reaction conditions for HRCA were PLP concentration, 20 pM; ligation temperature, 65 °C; ligation time, 60 min; amplification temperature, 61 °C; and amplification time, 60 min. The developed HBST detection procedure involved HRCA reaction, test strip preparation, hybridization, coloration, and judgment of hybridization by the naked eye. Specificity and sensitivity of the established methods were validated. Moreover, the results showed that the established detection methods were specific and sensitive to C. marina. The detection limits of HRCA and HBST assays were 10 copies and 1 copy μL–1 of plasmid with LSU rDNA of C. marina, which are of two and three respective magnitude orders higher than conventional PCR. Finally, the protocols were applied to the simulated field samples and the results showed that the developed HBST assay had higher detection sensitivity than HRCA and PCR. In conclusion, the methods presented in this study are promising for sensitive, intuitive, and specific detection of C. marina in field monitoring natural samples and may provide a good detection model for other harmful algae in the future.
http://ift.tt/2rn36nC
The effects of experimentally supplied lead nitrate on three common Mediterranean moss species
Abstract
We assess here, through an experimental simulation using lead nitrate, the response to lead deposition of three common Mediterranean bryophyte species in the family Pottiaceae. Five concentrations of lead nitrate (from 0 to 10−3 M) were sprayed for 4 months on plants belonging to Tortula muralis (reported as toxitolerant), Syntrichia ruralis (medium-tolerant), and Tortula subulata (less tolerant). The three species showed a remarkably high tolerance to lead nitrate, with a low incidence of damage even at concentrations as high as 10−4 M. The maximum concentration (10−3 M), although resulting eventually in serious damages in the gametophyte of the three species (high mortality rates in S. ruralis and T. subulata, or a significant percentage of damaged tissue in T. muralis), did not prevent the production of sporophytes in the two species with fertile samples (T. muralis and T. subulata). Growth parameters show limited value as bioindicators of lead deposition, as they only show clear effects at very high concentrations. Besides, we identified the existence of a lead exclusion strategy mediated by mucilage using histochemical analyses and scanning electron microscopy combined with energy-dispersive X-ray spectroscopy. This mechanism can hamper the usefulness of these mosses in quantitative estimation of lead deposition.
http://ift.tt/2q2l1vX
Exploration of an innovative draw solution for a forward osmosis-membrane distillation desalination process
Abstract
Forward osmosis (FO) has emerged as a viable technology to alleviate the global water crisis. The greatest challenge facing the application of FO technology is the lack of an ideal draw solution with high water flux and low reverse salt flux. Hence, the objective of this study was to enhance FO by lowering reverse salt flux and maintaining high water flux; the method involved adding small concentrations of Al2(SO4)3 to a MgCl2 draw solution. Results showed that 0.5 M MgCl2 mixed with 0.05 M of Al2(SO4)3 at pH 6.5 achieved a lower reverse salt flux (0.53 gMH) than that of pure MgCl2 (1.55 gMH) using an FO cellulose triacetate nonwoven (CTA-NW) membrane. This was due possibly to the flocculation of aluminum hydroxide in the mixed draw solution that constricted membrane pores, resulting in reduced salt diffusion. Moreover, average water fluxes of 4.09 and 1.74 L/m2-h (LMH) were achieved over 180 min, respectively, when brackish water (5 g/L) and sea water (35 g/L) were used as feed solutions. Furthermore, three types of membrane distillation (MD) membranes were selected for draw solution recovery; of these, a polytetrafluoroethylene membrane with a pore size of 0.45 μm proved to be the most effective in achieving a high salt rejection (99.90%) and high water flux (5.41 LMH) in a diluted draw solution.
http://ift.tt/2rnwOJf
The role of microstructural features on the electrical resistivity and mechanical properties of powder metallurgy Al-SiC-Al2O3 nanocomposites
Publication date: 15 September 2017
Source:Materials & Design, Volume 130
Author(s): F. Khodabakhshi, A. Simchi
There are many engineering applications in which composite materials are required to satisfy two or more criteria regarding physical and mechanical properties. In this article, Al-matrix nanocomposites reinforced with different volume fractions of SiC nanoparticles (~50nm; up to 6%) were processed by powder metallurgy (P/M) routes through mechanical milling and hot consolidation techniques. Microstructural studies showed that nano-metric Al2O3 particles with a size of ~20nm and volume fraction of ~2% were formed and distributed in the metal matrix, owing to the surface oxides breaking. Microstructural analysis also revealed that the size of cellular structure and the density of dislocations increased with the concentration of hard inclusions. However, the limit of deformability of the nanocomposite materials containing a high amount of nanoparticles (>4vol%) led to less densification upon hot consolidation stages deteriorating mechanical strength. It was shown that the formation of non-equilibrium grain boundaries with high residual stresses as well as scattering around nano-metric inclusions and dislocations influenced the electrical resistivity of the nanocompsites. A linear relationship between the concentration of hard inclusions, electrical resistivity and yield strength was found. This observation demonstrates the importance of substructure and microstructures on the physico-mechanical properties of metal matrix nanocomposites.
Graphical abstract
http://ift.tt/2rBLRLG
Suspended carbon black fluids reinforcing and toughening of poly(vinyl alcohol) composites
Publication date: 15 September 2017
Source:Materials & Design, Volume 130
Author(s): Xianze Yin, Puxin Weng, Shiwen Yang, Lu Han, Yeqiang Tan, Fei Pan, Dongzhi Chen, Luoxin Wang, Jun Qin, Hua Wang
A convenient and green approach was utilized to prepare the suspended carbon black fluids (SCBF) using carboxylic CB nanoparticles with diameters of 15nm as the core and poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (PEO-b-PPO-b-PEO) as surface modifier via hydrogen bonding interaction. It was found that when the total polymer content (strongly adsorbed layer and weakly adsorbed or free layer) was greater than 60wt%, the SCBF exhibited liquid-like behavior without solvent. More interestingly, the flow mechanism mainly related to surface polymer content, which greatly differed from ionically or covalently nanofluids systems. Besides, the thermal, dispersibility, electrical conductivity properties and rheological behaviors, as well as microstructure of SCBF were systematically investigated using various methods. Moreover, the SCBF as fillers were used to prepare SCBF/Poly(vinyl alcohol) (PVA) composites for producing the simultaneous reinforcement and plasticization effect due to the unique fluidity of SCBF and interfacial interactions between the PVA molecules and SCBF via hydrogen bondings.
Graphical abstract
http://ift.tt/2qDnKis
Corrosion of Mg-9Al alloy with minor alloying elements (Mn, Nd, Ca, Y and Sn)
Publication date: 15 September 2017
Source:Materials & Design, Volume 130
Author(s): B. Mingo, R. Arrabal, M. Mohedano, C.L. Mendis, R. del Olmo, E. Matykina, N. Hort, M.C. Merino, A. Pardo
Microstructure and corrosion behaviour of a Mg-9Al alloy with minor alloying additions (Mn, Y, Nd, Ca and Sn) are evaluated. All of the additions form Al-rich intermetallics with varying amounts of Fe, while Ca and Sn are also incorporated into the eutectic β-phase (β-Mg17Al12). Special attention is given to the surface potential values of the microconstituents, which are related to the formation of microgalvanic couples. Scanning Kelvin Probe Force Microscopy (SKPFM) measurements revealed that all the alloying elements, except Sn, reduced the potential difference between the secondary phases and the matrix, which is the main reason for the improvement of the corrosion resistance of Mn-, Y- and Nd-modified alloys. The beneficial effect of Ca is additionally related to the microstructure refinement and an increased area fraction of the β-phase.
Graphical abstract
http://ift.tt/2qDqaOd
Optical Mammography in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy
Source:Academic Radiology
Author(s): Pamela G. Anderson, Sirishma Kalli, Angelo Sassaroli, Nishanth Krishnamurthy, Shital S. Makim, Roger A. Graham, Sergio Fantini
Rationale and ObjectivesWe present an optical mammography study that aims to develop quantitative measures of pathologic response to neoadjuvant chemotherapy (NAC) in patients with breast cancer. Such quantitative measures are based on the concentrations of oxyhemoglobin ([HbO2]), deoxyhemoglobin ([Hb]), total hemoglobin ([HbT]), and hemoglobin saturation (SO2) in breast tissue at the tumor location and at sequential time points during chemotherapy.Materials and MethodsContinuous-wave, spectrally resolved optical mammography was performed in transmission and parallel-plate geometry on 10 patients before treatment initiation and at each NAC administration (mean number of optical mammography sessions: 12, range: 7–18). Data on two patients were discarded for technical reasons. The patients were categorized as responders (R, >50% decrease in tumor size), or nonresponders (NR, <50% decrease in tumor size) based on imaging and histopathology results.ResultsAt 50% completion of the NAC regimen (therapy midpoint), R (6/8) demonstrated significant decreases in SO2 (−27% ± 4%) and [HbT] (−35 ± 4 µM) at the tumor location with respect to baseline values. By contrast, NR (2/8) showed nonsignificant changes in SO2 and [HbT] at therapy midpoint. We introduce a cumulative response index as a quantitative measure of the individual patient's response to therapy. At therapy midpoint, the SO2-based cumulative response index had a sensitivity of 100% and a specificity of 100% for the identification of R.ConclusionsThese results show that optical mammography is a promising tool to assess individual response to NAC at therapy midpoint to guide further decision making for neoadjuvant therapy.
http://ift.tt/2r21KPb
Health Care Resource Utilization and Associated Costs Among Metastatic Cutaneous Melanoma Patients Treated with Ipilimumab (INTUITION Study)
Background.
There are limited real-world data on health care resource utilization (HCRU) among advanced melanoma patients. The objective of this study was to describe HCRU and health care costs associated with the management of advanced melanoma patients receiving ipilimumab.
Methods.This retrospective multinational, observational study included advanced melanoma patients from Australia, Germany, Italy, and Spain who had received at least 1 dose of ipilimumab. Data extracted from medical charts included inpatient admissions, outpatient visits, surgical procedures, laboratory investigations, radiation therapy, imaging studies, and concomitant medications. Cost estimates were based on unit costs from country-specific standard reimbursement sources. Subgroup analyses were performed for BRAF mutation status and ipilimumab refractory patients, who had disease progression within 24 weeks of their last dose of ipilimumab.
Results.Mean age of 362 enrolled patients was 60.6 years (standard deviation [SD] 14.4). During a median follow-up period of 30.2 weeks, 57% of patients were admitted to hospital and 16% underwent surgery. Health care resource utilization rates varied substantially across countries and were highest in Germany. Concomitant medications to treat adverse events were commonly used. Subgroup analyses showed higher utilization rates among ipilimumab refractory and BRAF mutant patients. Mean weekly total costs associated with HCRU were lower in the pre-progression period (107; 95% confidence interval (CI): 79–145) than in the post-progression period (216; 95% CI: 180–259).
Conclusions.Health care resource utilization pattern and associated costs among patients treated with ipilimumab varied greatly among countries and between pre- and post-progression periods. There is a high economic burden associated with ipilimumab refractory melanoma. The Oncologist 2017;22:1–13
Implications for practice.Metastatic melanoma patients treated with the anti-CTLA-4 inhibitor ipilimumab have a high utilization of various types of health care services, such as inpatient hospital stays or doctor visits. There are differences across countries regarding patterns of health care utilization and economic burden of the disease. Health care services are used more frequently after patients experience progression of their disease. The study highlights that better therapies leading to durable response in patients with metastatic melanoma have the potential to decrease health care costs and patient burden in terms of hospitalizations and other health care services.
http://ift.tt/2qDhzLh
Phase II Study of Modified Carboplatin Plus Weekly Nab-Paclitaxel in Elderly Patients with Non-Small Cell Lung Cancer: North Japan Lung Cancer Study Group Trial 1301
Lessons Learned.
Weekly nanoparticle albumin-bound-paclitaxel (75 mg/m2) in combination with carboplatin (area under the curve 6 mg/mL/min) in elderly patients with previously untreated, advanced non-small cell lung cancer showed favorable efficacy, was well tolerated, and showed less neuropathic toxicity.
This modified regimen offers potential for the treatment of elderly patients.
Background.The CA031 trial suggested weekly nanoparticle albumin-bound-paclitaxel (nab-PTX) was superior in efficacy to paclitaxel (PTX) once every 3 weeks when combined with carboplatin (CBDCA) for advanced non-small cell lung cancer (NSCLC) patients; a subgroup analysis of elderly patients looked promising. In a multicenter phase II trial, we prospectively evaluated the efficacy and tolerability of modified CBDCA plus weekly nab-PTX for elderly patients with untreated advanced NSCLC.
Methods.Eligible patients received CBDCA (area under the curve [AUC] 6 mg/mL/min) on day 1 and nab-PTX (75 mg/m2) on days 1, 8, and 15 every 4 weeks. The primary endpoint was an overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity.
Results.Of 32 patients (median age of 78 years), 84% were male, 56% had stage IV NSCLC, and 56% had squamous cell carcinoma. ORR and disease control rates were 50% (95% confidence interval (CI): 33–67) and 94% (95% CI: 85–100), respectively. Median PFS and OS were 6.4 months (95% CI: 4.8–8.0) and 17.5 months (95% CI: 11.9–23.1), respectively. Grade ≥3 toxicities were neutropenia (47%), leukopenia (38%), anemia (34%), thrombocytopenia (25%), and anorexia (9%). Febrile neutropenia and treatment-related deaths were not observed.
Conclusion.Modified CBDCA plus weekly nab-PTX demonstrated significant efficacy and acceptable toxicities in elderly patients with advanced NSCLC. The Oncologist 2017;22:1–5
http://ift.tt/2rBsTou
From SNOMED CT to Uberon: Transferability of evaluation methodology between similarly structured ontologies
Source:Artificial Intelligence in Medicine
Author(s): Gai Elhanan, Christopher Ochs, Jose L.V. Mejino, Hao Liu, Christopher J. Mungall, Yehoshua Perl
ObjectiveTo examine whether disjoint partial-area taxonomy, a semantically-based evaluation methodology that has been successfully tested in SNOMED CT, will perform with similar effectiveness on Uberon, an anatomical ontology that belongs to a structurally similar family of ontologies as SNOMED CT.MethodA disjoint partial-area taxonomy was generated for Uberon. One hundred randomly selected test concepts that overlap between partial-areas were matched to a same size control sample of non-overlapping concepts. The samples were blindly inspected for non-critical issues and presumptive errors first by a general domain expert whose results were then confirmed or rejected by a highly experienced anatomical ontology domain expert. Reported issues were subsequently reviewed by Uberon's curators.ResultsOverlapping concepts in Uberon's disjoint partial-area taxonomy exhibited a significantly higher rate of all issues. Clear-cut presumptive errors trended similarly but did not reach statistical significance. A sub-analysis of overlapping concepts with three or more relationship types indicated a much higher rate of issues.ConclusionsOverlapping concepts from Uberon's disjoint abstraction network are quite likely (up to 28.9%) to exhibit issues. The results suggest that the methodology can transfer well between same family ontologies. Although Uberon exhibited relatively few overlapping concepts, the methodology can be combined with other semantic indicators to expand the process to other concepts within the ontology that will generate high yields of discovered issues.
http://ift.tt/2r1PePQ
Synthesis and preliminary biological evaluation of radiolabeled 5-BDBD analogs as new candidate PET radioligands for P2X4 receptor
Publication date: Available online 18 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Min Wang, Mingzhang Gao, Jill A. Meyer, Jonathan S. Peters, Hamideh Zarrinmayeh, Paul R. Territo, Gary D. Hutchins, Qi-Huang Zheng
P2X4 receptor has become an interesting molecular target for treatment and PET imaging of neuroinflammation and associated brain diseases such as Alzheimer's disease. This study reports the first design, synthesis, radiolabeling and biological evaluation of new candidate PET P2X4 receptor radioligands using 5-BDBD, a specific P2X4 receptor antagonist, as a scaffold. 5-(3-Hydroxyphenyl)-1-[11C]methyl-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (N-[11C]Me-5-BDBD analog, [11C]9) and 5-(3-Bromophenyl)-1-[11C]methyl-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (N-[11C]Me-5-BDBD, [11C]8c) were prepared from their corresponding desmethylated precursors with [11C]CH3OTf through N-[11C]methylation and isolated by HPLC combined with SPE in 30-50% decay corrected radiochemical yields with 370-1110 GBq/µmol specific activity at EOB. 5-(3-[18F]Fluorophenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one ([18F]F-5-BDBD, [18F]5a) and 5-(3-(2-[18F]fluoroethoxy)phenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one ([18F]FE-5-BDBD, [18F]11) were prepared from their corresponding nitro- and tosylated precursors by nucleophilic substitution with K[18F]F/Kryptofix 2.2.2 and isolated by HPLC-SPE in 5-25% decay corrected radiochemical yields with 111-740 GBq/µmol specific activity at EOB. The preliminary biological evaluation of radiolabeled 5-BDBD analogs indicated these new radioligands have similar biological activity with their parent compound 5-BDBD.
Graphical abstract
http://ift.tt/2qDsiFp
Small molecule enabled chemical biology and drug discovery
Publication date: 1 June 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 11
Author(s): Xiaoguang Lei
http://ift.tt/2rBGA6Y
BACE1 inhibitory activity and molecular docking analysis of meroterpenoids from Sargassum serratifolium
Publication date: Available online 18 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Su Hui Seong, Md Yousof Ali, Hyeung-Rak Kim, Hyun Ah Jung, Jae Sue Choi
A wide range of pharmacological properties of Sargassum spp. extracts and isolated components have been recognized. Although individual meroterpenoids of Sargassum species have been reported to possess strong activity against Alzheimer's disease (AD), the active compounds of Sargassum serratifolium have not been fully explored. Therefore, we evaluated the anti-AD activity of S. serratifolium extract through enzyme inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1). Three meroterpenoids (sargahydroquinoic acid (1), sargachromenol (2) and sargaquinoic acid (3)) were isolated from S. serratifolium. These compounds showed moderate AChE inhibitory activity, but exhibited potent inhibitory activity against BChE and BACE1 (15.1, 9.4, and 10.4 µM for BChE; 4.3, 6.9, and 12.5 µM for BACE1, respectively). Kinetic study and molecular docking simulation of these compounds demonstrated that 1 and 3 interacted with both catalytic aspartyl residues and allosteric sites of BACE1, whereas 2 interacted with the allosteric site of BACE1. The results of the present study demonstrate that meroterpenoids from S. serratifolium might be beneficial in the treatment of AD.
Graphical abstract
http://ift.tt/2rBlpSk
Editorial board
Publication date: 1 June 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 11
http://ift.tt/2qDAB45
Design, synthesis and biological evaluation of renin inhibitors guided by simulated annealing of chemical potential simulations
Publication date: Available online 19 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Ian S. Cloudsdale, John K. Dickson, Thomas E. Barta, Brian S. Grella, Emilie D. Smith, John L. Kulp, Frank Guarnieri, John L. Kulp
We have applied Simulated Annealing of Chemical Potential (SACP) to a diverse set of ∼150 very small molecules to provide insights into new interactions in the binding pocket of human renin, a historically difficult target for which to find low MW inhibitors with good bioavailability. In one of its many uses in drug discovery, SACP provides an efficient, thermodynamically principled method of ranking chemotype replacements for scaffold hopping and manipulating physicochemical characteristics for drug development. We introduce the use of Constrained Fragment Analysis (CFA) to construct and analyze ligands composed of linking those fragments with predicted high affinity. This technique addresses the issue of effectively linking fragments together and provides a predictive mechanism to rank order prospective inhibitors for synthesis. The application of these techniques to the identification of novel inhibitors of human renin is described. Synthesis of a limited set of designed compounds provided potent, low MW analogs (IC50s < 100 nM) with good oral bioavailability (F >20-58%).
Graphical abstract
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The synthesis and evaluation of triazolopyrimidines as anti-tubercular agents
Publication date: Available online 19 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Edison S. Zuniga, Aaron Korkegian, Steven Mullen, Erik J. Hembre, Paul L. Ornstein, Guillermo Cortez, Kallolmay Biswas, Naresh Kumar, Jeffrey Cramer, Thierry Masquelin, Philip A. Hipskind, Joshua Odingo, Tanya Parish
We identified a di-substituted triazolopyrimidine with anti-tubercular activity against Mycobacterium tuberculosis. Three segments of the scaffold were examined rationally to establish a structure-activity relationship with the goal of improving potency and maintaining good physicochemical properties. A number of compounds displayed sub-micromolar activity against Mycobacterium tuberculosis with no cytotoxicity against eukaryotic cells. Non-substituted aromatic rings at C5 and a two-carbon chain connecting a terminal aromatic at C7 were preferred features; the presence of NH at C7 and a lack of substituent at C2 were essential for potency. We identified compounds with acceptable metabolic stability in rodent and human liver microsomes. Our findings suggest that the easily-synthesized triazolopyrimidines are a promising class of potent anti-tubercular agents and warrant further investigation in our search for new drugs to fight tuberculosis.
Graphical abstract
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Development of novel N-3-bromoisoxazolin-5-yl substituted 2,3-benzodiazepines as noncompetitive AMPAR antagonists
Publication date: Available online 19 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Milad Espahbodinia, Roberta Ettari, Wei Wen, Andrew Wu, Yu-Chuan Shen, Li Niu, Silvana Grasso, Maria Zappalà
In this work, we designed and synthesized novel N-3-bromoisoxazolin-5-yl substituted 2,3-benzodiazepines as noncompetitive AMPAR antagonists, with the aim that this heterocycle could establish favourable interactions with a putative binding pocket of the receptor, like the thiadiazole nucleus of GYKI 47409 does. Within this investigation, we identified some active molecules and, among these 2,3-benzodiazepines, 4c showed a much improved inhibitory potency as compared with unsubstituted 2,3-benzodiazepines.
Graphical abstract
http://ift.tt/2rBll52
Synthesis, docking study and neuroprotective effects of some novel pyrano[3,2-c]chromene derivatives bearing morpholine/phenylpiperazine moiety
Publication date: Available online 19 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Bilqees Sameem, Mina Saeedi, Mohammad Mahdavi, Hamid Nadri, Farshad Homayouni Moghadam, Najmeh Edraki, Muhammad Imran Khan, Mohsen Amini
Novel pyrano[3,2-c]chromene derivatives bearing morpholine/phenylpiperazine moiety were synthesized and evaluated against acetylcholinestrase (AChE) and butylcholinestrase (BuChE). Among the synthesized compounds, N-(3-cyano-4-(4-methoxyphenyl)-5-oxo-4,5-dihydropyrano[3,2-c]chromen-2-yl)-2-(4-phenylpiperazin-1-yl)acetamide (6c) exhibited the highest acetylcholinestrase inhibitory (AChEI) activity (IC50 = 1.12 µM) and most of them showed moderate butylcholinestrase inhibitory activity (BChEI). Kinetic study of compound 6c confirmed mixed type of inhibition towards AChE which was in covenant with the results obtained from docking study. Also, it was evaluated against β-secretase which demonstrated low activity (inhibition percentage: 18%). It should be noted that compounds 6c, 7b, 6g, and 7d showed significant neuroprotective effects against H2O2-induced PC12 oxidative stress.
Graphical abstract
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An Orthogonally Protected CycloTriVeratrylene (CTV) as a Highly Pre-organized Molecular Scaffold for Subsequent Ligation of Different Cyclic Peptides towards Protein Mimics
Publication date: Available online 18 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Ondřej Longin, Helmus van de Langemheen, Rob M.J. Liskamp
The synthesis of a (semi)orthogonally protected CycloTriVeratrilene (CTV) scaffold derivative as well as the sequential introduction of three different peptide loops onto this molecular scaffold via Cu(I)-catalyzed azide alkyne cycloaddition towards a medium-sized protein mimic is described. This approach for the construction of medium-sized protein mimics is illustrated by the synthesis of a paratope mimic of the monoclonal antibody Infliximab (Remicade®) and provides a convenient access to a range of highly pre-organised molecular constructs bearing three different peptide segments. This approach may find wide applications for development of protein-protein interaction disruptors as well as synthetic vaccines.
Graphical abstract
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Searching for novel N1-substituted benzimidazol-2-ones as non-nucleoside HIV-1 RT inhibitors
Publication date: Available online 19 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Stefania Ferro, Maria Rosa Buemi, Laura De Luca, Fatima E. Agharbaoui, Christophe Pannecouque, Anna-Maria Monforte
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent an integral part of the currently available combination antiretroviral therapy (cART) contributing to reduce the AIDS-mortality and turned the disease from lethal to chronic. In this context we recently reported a series of 6-chloro-1-(3-methylphenylsulfonyl)-1,3-dihydro-2Hbenzimidazol-2-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors. In this paper, we describe the design and the synthesis of two novel series of benzimidazolone analogues in which the linker moiety between the phenyl ring and the sulfonyl group was modified and new small lipophilic groups on the benzyl sulfonyl pendant were introduced. All the new obtained compounds were evaluated as RT inhibitors and were also tested against RTs containing single amino acid mutations. Finally, molecular docking studies were performed in order to rationalize the observed activity of the most promising compound.
Graphical abstract
http://ift.tt/2rBCADe
Development of WNK Signaling Inhibitors as a New Class of Antihypertensive Drugs
Publication date: Available online 19 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Mari Ishigami-Yuasa, Yuko Watanabe, Takayasu Mori, Hiroyuki Masuno, Shinya Fujii, Eriko Kikuchi, Shinichi Uchida, Hiroyuki Kagechika
Pseudohypoaldosteronism type II (PHAII) is characterized by hyperkalemia and hypertension despite a normal glomerular filtration rate. Abnormal activation of the signal cascade of with-no-lysine kinase (WNK) with OSR1 (oxidative stress-responsive kinase 1)/SPAK (STE20/SPS1-related proline/alanine-rich kinase) and NCC (NaCl cotransporter) results in characteristic salt-sensitive hypertension. Thus, inhibitors of the WNK-OSR1/SPAK-NCC cascade are candidates for a new class of antihypertensive drugs. In this study, we developed novel inhibitors of this signal cascade from the 9-aminoacridine lead compound 1, one of the hit compounds obtained by screening our chemical library for WNK-SPAK binding inhibitors. Among the synthesized acridine derivatives, several acridine-3-amide and 3-urea derivatives, such as 10 (IC50: 6.9 μM), 13 (IC50: 2.6 μM), and 20 (IC50: 4.8 μM), showed more potent inhibitory activity than the lead compound 1 (IC50: 15.4 μM). Compounds 10 and 20 were confirmed to inhibit phosphorylation of NCC in vivo.
Graphical abstract
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Effect of the 3-halo substitution of the 2′-deoxy aminopyridinyl-pseudocytidine derivatives on the selectivity and stability of antiparallel triplex DNA with a CG inversion site
Publication date: Available online 19 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Lei Wang, Yosuke Taniguchi, Hidenori Okamura, Shigeki Sasaki
Triplex formation against a target duplex DNA has the potential to become a tool for the genome research. However, there is an intrinsic restriction on the duplex DNA sequences capable of forming the triplex DNA. Recently, we demonstrated the selective formation of the stable antiparallel triplexes containing the CG inversion sites using the 2′-deoxy-1-methylpseudocytidine derivative (ΨdC), whose amino group was conjugated with the 2-aminopyridine at its 5-position as an additional hydrogen bonding unit (AP-ΨdC). The 1-N of 2-aminopyridine was supposed to be protonated to form the hydrogen bond with the guanine of the CG inversion site. In this study, to test the effect of the 3-substitution of the 2-aminopyridine unit of AP-ΨdC on the triplex stability, we synthesized the 3-halogenated 2-aminopyridine derivatives of AP-ΨdC. The pKa values 1-N of the 2-aminopyridine unit of AP-ΨdC as the monomer nucleoside were determined to be 6.3 for 3-CH3 (MeAP-ΨdC), 6.1 for 3-H (AP-ΨdC), 4.3 for 3-Cl (ClAP-ΨdC), 4.4 for 3-Br (BrAP-ΨdC), and 4.7 for 3-I (IAP-ΨdC), suggesting that all the halogenated AP-ΨdCs are not protonated under neutral conditions. Interestingly, although the recognition selectivity depends on the sequence context, the TFO having the sequence of the 3′-G- (IAP-ΨdC)-A-5′ context showed the selective triplex formation with the CG inversion site. These results suggest that the protonation at the 1-N position plays an important role in the stable and selective triplex formation of AP-ΨdC derivatives in any sequences.
Graphical abstract
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Structure-activity relationships for flavone interactions with amyloid β reveal a novel anti-aggregatory and neuroprotective effect of 2',3',4'-trihydroxyflavone (2-D08)
Publication date: Available online 19 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Dylan T. Marsh, Sukanya Das, Jessica Ridell, Scott D. Smid
Naturally-occurring flavonoids have well documented anti-aggregatory and neuroprotective properties against the hallmark toxic protein in Alzheimer's disease, amyloid β (Aβ). However the extensive diversity of flavonoids has limited the insight into the precise structure-activity relationships that confer such bioactive properties against the Aβ protein. In the present study we have characterised the Aβ binding properties, anti-aggregatory and neuroprotective effects of a discreet set of flavones, including the recently described novel protein sumoylation inhibitor 2',3',4'-trihydroxyflavone (2-D08). Quercetin, transilitin, jaceosidin, nobiletin and 2-D08 were incubated with human Aβ1-42 for 48 hrs in vitro and effects on Aβ fibrillisation kinetics and morphology measured using Thioflavin T (ThT) and electron microscopy respectively, in addition to effects on neuronal PC 12 cell viability. Of the flavones studied, only quercetin, transilitin and 2-D08 significantly inhibited Aβ1-42 aggregation and toxicity in PC12 cells. Of those, 2-D08 was the most effective inhibitor. The strong anti-amyloid activity of 2-D08 indicates that extensive hydroxylation in the B ring is the most important determinant of activity against β amyloid within the flavone scaffold. The lack of efficacy of jaceosidin and nobiletin indicate that extension of B ring hydroxylation with methoxyl groups result in an incremental loss of anti-fibrillar and neuroprotective activity, highlighting the constraint to vicinal hydroxyl groups in the B ring for effective inhibition of aggregation. These findings reveal further structural insights into anti-amyloid bioactivity of flavonoids in addition to a novel and efficacious anti-aggregatory and neuroprotective effect of the semi-synthetic flavone and sumoylation inhibitor 2',3',4'-trihydroxyflavone (2-D08). Such modified flavones may facilitate drug development targeting multiple pathways in neurodegenerative disease.
Graphical abstract
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Novel pyridyl nitrofuranyl isoxazolines show antibacterial activity against multiple drug resistant Staphylococcus species.
Publication date: Available online 19 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Pietro Picconi, Priya Prabaharan, Jennifer Auer, Stephanie Sandiford, Francesco Cascio, Madiha Chowdhury, Charlotte Hind, Matthew E. Wand, J. Mark Sutton, Khondaker M. Rahman
A novel series of pyridyl nitrofuranyl isoxazolines were synthesized and evaluated for their antibacterial activity against multiple drug resistant (MDR) Staphylococcus strains. Compounds with piperazine linker between the pyridyl group and isoxazoline ring showed better activity when compared to compounds without the piperazine linker. 3-pyridyl nitrofuranyl isoxazoline with a piperazine linker was found to be more active than corresponding 2-and 4-pyridyl analogues with MICs in the range of 4-32 µg/mL against MDR Staphylococcus strains. The eukaryotic toxicity of the compounds was tested by MTT assay and were found to be non-toxic against both non-tumour lung fibroblast WI-38 and cervical cancer cell line HeLa. The most active pyridyl nitrofuranyl isoxazoline compound showed improved activity against a panel Staphylococcus strains compared to nitrofuran group containing antibiotic nitrofurantoin.
Graphical abstract
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Halogen-substituted catechol bisphosphates are potent and selective inhibitors of the transcription factor STAT5b
Publication date: Available online 18 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Nagarajan Elumalai, Kalaiselvi Natarajan, Thorsten Berg
The transcription factor STAT5b is an antitumor target. Recently, we presented the small molecules Stafib-1 and Stafib-2 as potent, selective inhibitors of the STAT5b SH2 domain. Here we report that halogen substitutions on the terminal phenyl ring of Stafib-1 and a close derivative are tolerated and specificity over the STAT5a SH2 domain is maintained, albeit with a slight reduction in activity. Our data demonstrate that the synthetic methodology used for generating Stafib-1 and Stafib-2 can be utilized to synthesize a small library of halogen-substituted derivatives, and extend the panel of catechol bisphosphate-based submicromolar and selective STAT5b inhibitors.
Graphical abstract
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The test retest reliability of gait outcomes in subjects with anterior knee pain
Publication date: Available online 19 May 2017
Source:Journal of Bodywork and Movement Therapies
Author(s): Dominique Claire Leibbrandt, Quinette Louw
IntroductionAnterior knee pain (AKP) is a common condition frequently causing young, athletic patient to attend sports rehabilitation centres. Abnormal biomechanics are thought to contribute towards the development and chronicity of the condition. Gait analysis is commonly used to identify abnormal biomechanics in subjects with AKP, however the reliability of these measurements are unknown. Therefore, the aim of this study was to quantify the test retest reliability of hip, knee and ankle kinematics during gait in an AKP population so the true effects of an intervention can be established.MethodsThirty-one subjects with AKP attended the 3D Motion Analysis Laboratory at Tygerberg Medical Campus of Stellenbosch University in Cape Town, South Africa, for gait analysis. Participants returned seven days later at approximately the same time to repeat the gait analysis assessment from day one. The same assessor tested all subjects on both occasions. The intra-class correlation coefficients (ICC) and standard error of measurement (SEM) were calculated for hip, knee and ankle kinematic outcomes on the affected side and used for analysis.ResultsAll outcomes obtained were acceptable to excellent test retest reliability scores for both measures of relative reliability (ICC=0.78-0.9) and measures of absolute reliability (SEM= 0.94 - 4.2 degrees). Hip frontal plane and ankle sagittal plane outcomes were the most reliable and had the lowest measurement error. Hip transverse plane outcomes were least reliable and demonstrated the highest measurement error.ConclusionHip, knee and ankle kinematic factors that are commonly associated with AKP can be measured reliably using gait analysis. Daily and weekly variation in symptoms in an AKP population may influence the reliability of knee sagittal plane outcomes. Therefore, it is important to document factors that could influence the kinematics such as pain, activity levels and the use of pain medication.
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Cutaneous Apocrine Carcinoma With an In Situ Component and Histiocytoid and Signet-Ring Cells
http://ift.tt/2qDcBy7
Decreased contralateral breast volume after mastectomy, adjuvant chemotherapy, and anti-estrogen therapy, in particular in breasts with high density
Adjuvant chemotherapy and anti-estrogenic therapy can result in decreased volume of the contralateral breast, following mastectomy for the treatment of breast cancer. However, no data on the effect of adjuvant therapy on contralateral breast volume have previously been reported. We aimed to evaluate the extent to which adjuvant therapy and differences in breast density contribute to decreased breast volume.We conducted a prospective cohort study, selecting 40 nonconsecutive patients who underwent immediate breast reconstruction with mastectomy and expander insertion followed by expander replacement.
http://ift.tt/2rBnSwa
Clonal Seborrheic Keratosis Versus Pagetoid Bowen Disease: Histopathology and Role of Adjunctive Markers
http://ift.tt/2rBjPjB
“Is it possible to calculate surface areas of intraoral structures from preoperative CT scan?”
Microsurgical reconstruction of intraoral structures requires accurate planning of flap shape and dimensions. The goal of this study is to describe a method that allows to calculate surfaces of oral structures from preoperative CT-scan in order to determine a precise flap design before the surgery. We created casts of the human mouth from cadavers with a head and neck CT-scan available using an impression material. We digitalized the mouth casts and unwrapped the surfaces of the different structures of the mouth in a bi-dimensional plane in order to measure the area.
http://ift.tt/2qD8QIW
A Direct Comparison of Porcine (Strattice™) and Bovine (Surgimend™) Acellular Dermal Matrices in Implant-Based Immediate Breast Reconstruction
Acellular dermal matrix (ADM) assisted implant-based breast reconstruction (IBBR) has grown in popularity over traditional submuscular techniques. Numerous human, bovine or porcine derived ADMs are available with the type used varying considerably worldwide. Yet, comparative evidence for the efficacy of different ADMs particularly xenogenic is limited. This study directly compares early outcomes of porcine (StratticeTM) and bovine (SurgimendTM) ADMs in IBBR.
http://ift.tt/2qDn8cq
Depletion of Epidermal Langerhans Cells in the Skin Lesions of Pellagra Patients
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Bullous Pyoderma Gangrenosum With Subungual Involvement Associated With Ulcerative Colitis
http://ift.tt/2qDhya4
Epidermolytic Ichthyosis Sine Epidermolysis
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Counterfeit Pennies: Distinguishing Chromoblastomycosis From Phaeohyphomycotic Infections
http://ift.tt/2qDnMa1
Beta Human Papillomavirus Infection Is Prevalent in Elephantiasis and Exhibits a Productive Phenotype: A Case-Control Study
http://ift.tt/2qDmU5n
Diagnostic Criteria in Intraepithelial Pagetoid Neoplasms: A Histopathologic Study and Evaluation of Select Features in Paget Disease, Bowen Disease, and Melanoma In Situ
http://ift.tt/2rBsPF1
A Pseudoxanthoma Elasticum–Like Papular Eruption: Challenge
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Chronic Localized Fibrosing Leukocytoclastic Vasculitis Associated With Lymphedema, Intralymphatic and Intravascular Lymphocytosis, and Chronic Myelogenous Leukemia: A Case Report of Unilateral Erythema Elevatum Diutinum
http://ift.tt/2rBjUDy
Asymptomatic Annular Plaques in a 67-Year-Old Man: Challenge
http://ift.tt/2rBjT2s
Necrotizing Thrombophlebitis Secondary to Mycobacterium Chelonae in a Hemodialyzed Patient
http://ift.tt/2rBi8SX
Congenital Infantile Fibrosarcoma Associated With a Lipofibromatosis-Like Component: One Train May Be Hiding Another
http://ift.tt/2rBLqki
Isofraxidin inhibited proliferation and induced apoptosis via blockage of Akt pathway in human colorectal cancer cells
Publication date: August 2017
Source:Biomedicine & Pharmacotherapy, Volume 92
Author(s): Peng Shen, Hong-Gang Wang, Miao-Miao Li, Qian-Yun Ma, Chuan-Wen Zhou, Feng Pan, Rui Xie
BackgroundIsofraxidin (IF), a natural coumarin compound, has been reported to possess anti-cancer activity in human liver cancer. However, whether IF is involved in the regulation of colorectal cancer tumorigenesis and development has been not well elucidated.MethodsThe cell proliferation were assessed by Cell Counting Kit-8 (CCK-8) and colony formation test, respectively. The transwell assays were conducted to estimate cell migration and invasion abilities. Further, cell apoptosis was evaluated by confocal microscopy analysis, flow cytometry detection and TdT-mediated dUTP Nick-End Labeling (TUNEL) method. Western blot were performed to detect the expression of related protein.ResultsHerein, the result indicated that IF remarkably bated cell proliferation in human colorectal cancer cells HT-29 and SW-480 in a dose- and time-dependent manner. In addition, IF treatment showed obvious inhibitory activity to cell colony formation in HT-29 and SW-480 cells. Confocal microscopy analysis and flow cytometry detection revealed that IF dramatically induced cell apoptosis in HT-29 and SW-480 cells compared with the control. And IF markedly decreased the expression of anti-apoptotic protein bcl-2, whereas the expression of pro-apoptotic proteins, including caspase-3, caspase-9 and bax, notably increased in HT-29 and SW-480 cells. Besides, IF blocked Akt pathway via inhibition expression of p-Akt. Furthermore, MK2206, an Akt inhibitor, could inhibit cell colony formation and induced apoptosis. This effect is even more obvious in the presence of MK2206 and IF compared to that of either agent alone.ConclusionsTogether, the present study reports a novel use of IF in mitigating human colorectal cancer proliferation and inducing apoptosis via blockage of Akt pathway.
http://ift.tt/2rAEyEX
Simvastatin ameliorate memory deficits and inflammation in clinical and mouse model of Alzheimer’s disease via modulating the expression of miR-106b
Publication date: August 2017
Source:Biomedicine & Pharmacotherapy, Volume 92
Author(s): Wenzhong Huang, Zhenyu Li, Liandong Zhao, Wei Zhao
BackgroundAlzheimer's disease (AD) as a neurodegenerative brain disorder is a devastating pathology leading to disastrous cognitive impairments and dementia, and several studies have shown that AD is closely related to the inflammation, so anti-inflammatory treatment may provide therapeutic benefits. In this study, the effect of simvastatin on inflammation was investigated and the underlying mechanisms were explored.MethodsFirst, we tested the effect of simvastatin on AD in clinical research. The fasting venous blood was collected in order to evaluate the levels of interleukin-6 (IL-6), interleukine-1 beta (IL-1β), antichymotrypsin (ACT) and human tumor necrosis factor α (TNF-α), which were measured with the enzyme-linked immunosorbent assay (ELISA) kits. Amyloid-β (Aβ), amyloid-β precursor protein (APP) and β-site APP-cleaving enzyme 1(BACE1) were tested by western blotting. Second, we used an APPswe/PS1E9 (APP/PS1) double transgenic mice to evaluate the amelioration ability of simvastatin against the memory impairment in vivo. Spatial learning and memory of mice were investigated by the Morris water maze test (MWM). The mRNA of inflammatory cytokines were measured using real-time PCR. Third, the phospho-proteome profile of SH-SY5Y human neuroblastoma cells treated with simvastatin was used to investigate the possible mechanisms.ResultsThe results showed that simvastatin ameliorated the memory deficits both in clinical AD patients and animal model of AD. Simvastatin could reduce the mRNA expression of inflammatory cytokines and mediators, suppress the apoptosis of neural stem cells and improve the survival rate of neurons. Moreover, long non-coding RNA (lnc RNA) n336694 and miR-106b was overexpressed in APP/PS1 mice brain tissues, the relationship between lnc RNA n336694 and miR-106b was explored using the method of Target Scan bioinformatics predictions, the results revealed that miR-106b might be a potential target of lnc RNA n336694. Furthermore, miR-106b mediated apoptosis in SH-SY5Y cell and simvastatin could suppressed this process.ConclusionOur results suggested that simvastatin could be of benefit in preventing the progression of AD and expected to be potentially used as a lead drug for further anti-AD treatment.
http://ift.tt/2r1zoou
ACE-2/Ang1-7/Mas cascade mediates ACE inhibitor, captopril, protective effects in estrogen-deficient osteoporotic rats
Publication date: August 2017
Source:Biomedicine & Pharmacotherapy, Volume 92
Author(s): Hatem M. Abuohashish, Mohammed M. Ahmed, Dina Sabry, Mahmoud M. Khattab, Salim S. Al-Rejaie
The local role of the renin angiotensin system (RAS) was documented recently beside its conventional systemic functions. Studies showed that the effector angiotensin II (AngII) alters bone health, while inhibition of the angiotensin converting enzyme (ACE-1) preserved these effects. The newly identified Ang1-7 exerts numerous beneficial effects opposing the AngII. Thus, the current study examines the role of Ang1-7 in mediating the osteo-preservative effects of ACEI (captopril) through the G-protein coupled Mas receptor using an ovariectomized (OVX) rat model of osteoporosis. 8 weeks after the surgical procedures, captopril was administered orally (40mgkg−1 d−1), while the specific Mas receptor blocker (A-779) was delivered at infusion rate of 400ngkg−1min−1 for 6 weeks. Bone metabolic markers were measured in serum and urine. Minerals concentrations were quantified in serum, urine and femoral bones by inductive coupled plasma mass spectroscopy (ICP-MS). Trabecular and cortical morphometry was analyzed in the right distal femurs using micro-CT. Finally, the expressions of RAS peptides, enzymes and receptors along with the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) were determined femurs heads. OVX animals markedly showed altered bone metabolism and mineralization along with disturbed bone micro-structure. Captopril significantly restored the metabolic bone bio-markers and corrected Ca2+ and P values in urine and bones of estrogen deficient rats. Moreover, the trabecular and cortical morphometric features were repaired by captopril in OVX groups. Captopril also improved the expressions of ACE-2, Ang1-7, Mas and OPG, while abolished OVX-induced up-regulation of ACE-1, AngII, Ang type 1 receptor (AT1R) and RANKL. Inhibition of Ang1-7 cascade by A-779 significantly eradicated captopril protective effects on bone metabolism, mineralization and micro-structure. A-779 also restored OVX effects on RANKL expression and ACE-1/AngII/AT1R cascade and down-regulated OPG expression and ACE-2/Ang1-7/Mas pathway. In line with the clinical observations of the bone-preservative properties following ACE-1 inhibition, local activation of ACE-2/Ang1-7/Mas signaling and suppressed osteoclastogenesis seem responsible for the osteo-preservative effect of captopril, which could offers a potential therapeutic value in treatment of disabling bone and skeletal muscular diseases.
http://ift.tt/2rASUVw
Anti-inflammatory and antioxidant effect of cerium dioxide nanoparticles immobilized on the surface of silica nanoparticles in rat experimental pneumonia
Publication date: August 2017
Source:Biomedicine & Pharmacotherapy, Volume 92
Author(s): Z. Serebrovska, R.J. Swanson, V. Portnichenko, A. Shysh, S. Pavlovich, L. Tumanovska, A. Dorovskych, V. Lysenko, V. Tertykh, Y. Bolbukh, V. Dosenko
A massage with the potent counter-inflammatory material, cerium dioxide nanoparticles, is promising and the antioxidant properties of CeO2 are considered the main, if not the only, mechanism of this action. Nevertheless, the elimination of ceria nano-particles from the organism is very slow and there is a strong concern for toxic effect of ceria due to its accumulation. To overcome this problem, we engineered a combined material in which cerium nanoparticles were immobilized on the surface of silica nanoparticles (CeO2 NP), which is shown to be easily removed from an organism and could be used as carriers for nano-ceria. In our study particle size was 220±5nm, Zeta-potential −4.5mV (in water), surface charge density −17.22μC/cm2 (at pH 7).Thirty-six male Wistar rats, 5 months old and 250–290g were divided into four groups: 1) control; 2) CeO2 NP treatment; 3) experimental pneumonia (i/p LPS injection, 1mg/kg); and 4) experimental pneumonia treated with CeO2 NP (4 times during the study in dosage of 0.6mg/kg with an orogastric catheter). Gas exchange and pulmonary ventilation were measured four times: 0, 1, 3 and 24h after LPS injection in both untreated and CeO2 NP-treated animals. The mRNA of TNF-α, Il-6, and CxCL2 were determined by RT-PCR. ROS-generation in blood plasma and lung tissue homogenates were measured by means of lucigenin- and luminol-enhanced chemiluminescence.Endotoxemia in the acute phase was associated with: (1) pathological changes in lung morphology; (2) increase of ROS generation; (3) enhanced expression of CxCL2; and (4) a gradual decrease of VO2 and VE. CeO2 NP treatment of intact animals did not make any changes in all studied parameters except for a significant augmentation of VO2 and VE. CeO2 NP treatment of rats with pneumonia created positive changes in diminishing lung tissue injury, decreasing ROS generation in blood and lung tissue and decreasing pro-inflammatory cytokine expression (TNF-α, Il-6 and CxCL2). Oxygen consumption in this group was increased compared to the LPS pneumonia group.In our study we have shown anti-inflammatory and antioxidant effects of CeO2 NP. In addition, this paper is the first to report that CeO2 NP stimulates oxygen consumption in both healthy rats, and rats with pneumonia. We propose the key in understanding the mechanisms behind the phenomena lies in the property of CeO2 NP to scavenge ROS and the influence of this potent antioxidant on mitochondrial function. The study of biodistribution and elimination of СеО2NP is the purpose of our ongoing study.
http://ift.tt/2r1G8Ta
Stimuli-directed self-organized chiral superstructures for adaptive windows enabled by mesogen-functionalized graphene
Publication date: Available online 18 May 2017
Source:Materials Today
Author(s): Ling Wang, Hari Krishna Bisoyi, Zhigang Zheng, Karla G. Gutierrez-Cuevas, Gautam Singh, Satyendra Kumar, Timothy J. Bunning, Quan Li
Harnessing the distinct characteristics of nanomaterials integrated into host matrices to enable multi-responsive, multi-functional and adapting capabilities of the resulting materials and systems is a thriving research frontier in contemporary nanoscience. Herein, we have judiciously designed and synthesized a mesogen-functionalized graphene (MFG) to facilitate homogeneous dispersion and compatibility with our newly developed liquid crystal (LC) medium. We then demonstrate the concept of an adaptive window system that can autonomously change the optical transparency in response to external multiple stimuli by the fabrication of polymer-stabilized MFG-containing liquid crystalline films with self-organized chiral superstructures. The light transmittance of films could be expediently modulated through the reversible phase transition between the chiral smectic A (SmA*) and the chiral nematic (N*) phases either by environmental temperature change or shining infrared radiation, where the transparent state is furnished by the homeotropic SmA* phase whilst the opaque state results from the focal conic configuration of the N* phase. Importantly, when desired, the opaque state of the devices could be facilely switched into a transparent state by applying an electric field. The research disclosed here provides a convenient and versatile method to dynamically control over the light transmittance through the windows with adaptive behavior in response to multiple environmental cues such as surrounding temperature and infrared exposure from solar radiations, which holds great potential in architectural and automotive applications with intelligent adaptability and energy efficiency.
Graphical abstract
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Are we a step closer to 3D printed carbon nanotube composites?
Source:Materials Today
Author(s): Laurie Winkless
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Effect of Valgus Knee Alignment on Gait Biomechanics in Healthy Women
Publication date: Available online 19 May 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Matthew C. Hoch, Joshua T. Weinhandl
The purpose of this study was to compare lower extremity kinematics and kinetics between women with greater or lesser degrees of valgus knee alignment during gait. Nine women with greater valgus knee alignment (11.9±1.6o) were compared to nine women with lesser valgus knee alignment (6.6±2.4o). Participants completed a biomechanical assessment of overground walking for the right limb. Dependent variables included sagittal and frontal plane joint angles and moments for the hip, knee, and ankle at peak vertical ground reaction force, along with knee abduction angular impulse. Sagittal and frontal plane excursions for the hip, knee, and ankle were calculated from heel strike to the peak angle for each variable. The greater valgus alignment group demonstrated lower knee abduction moment (p=0.007), lower knee adduction angle (p<0.001), and greater ankle inversion moment (p=0.034) at peak vertical ground reaction force, as well as lower knee abduction angular impulse (p=0.007), and knee adduction ROM (p=0.026). No other group differences were identified for any kinematic or kinetic variables (p>0.05). Less knee adduction angle and excursion coupled with lower knee abduction moment and angular impulse in women with greater knee valgus indicates these individuals may be experiencing biomechanics which promote lateral tibiofemoral joint loading.
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Finite element method simulating temperature distribution in skin induced by 980-nm pulsed laser based on pain stimulation
Abstract
For predicting the temperature distribution within skin tissue in 980-nm laser-evoked potentials (LEPs) experiments, a five-layer finite element model (FEM-5) was constructed based on Pennes bio-heat conduction equation and the Lambert-Beer law. The prediction results of the FEM-5 model were verified by ex vivo pig skin and in vivo rat experiments. Thirty ex vivo pig skin samples were used to verify the temperature distribution predicted by the model. The output energy of the laser was 1.8, 3, and 4.4 J. The laser spot radius was 1 mm. The experiment time was 30 s. The laser stimulated the surface of the ex vivo pig skin beginning at 10 s and lasted for 40 ms. A thermocouple thermometer was used to measure the temperature of the surface and internal layers of the ex vivo pig skin, and the sampling frequency was set to 60 Hz. For the in vivo experiments, nine adult male Wistar rats weighing 180 ± 10 g were used to verify the prediction results of the model by tail-flick latency. The output energy of the laser was 1.4 and 2.08 J. The pulsed width was 40 ms. The laser spot radius was 1 mm. The Pearson product-moment correlation and Kruskal-Wallis test were used to analyze the correlation and the difference of data. The results of all experiments showed that the measured and predicted data had no significant difference (P > 0.05) and good correlation (r > 0.9). The safe laser output energy range (1.8–3 J) was also predicted. Using the FEM-5 model prediction, the effective pain depth could be accurately controlled, and the nociceptors could be selectively activated. The FEM-5 model can be extended to guide experimental research and clinical applications for humans.
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Circulating Tumor DNA Measurement by Picoliter Droplet-Based Digital PCR and Vemurafenib Plasma Concentrations in Patients with Advanced BRAF- Mutated Melanoma
Abstract
Background
Circulating tumor DNA (ctDNA) has been reported as a prognostic marker in melanoma. In BRAF V600-mutant melanoma, a plasma under-exposure to vemurafenib could favor emerging resistance but no biological data are available to support this hypothesis.
Objective
We aimed to investigate the relationship between vemurafenib plasma concentrations and the ctDNA plasma concentration during follow-up of BRAF-mutated melanoma patients.
Patients and Methods
Eleven patients treated with single-agent vemurafenib for advanced BRAF V600-mutant melanoma were analyzed in an exploratory monocentric study. The vemurafenib plasma concentration was measured by liquid chromatography. ctDNA was extracted from plasma samples and the ctDNA concentration was evaluated using picoliter droplet-based digital PCR with Taqman® detection probes targeting the BRAF p.V600E/K mutation and wild-type BRAF sequences.
Results
At baseline, plasma ctDNA was detectable in 72% (n = 8/11) of patients and the ctDNA concentration decreased in 88% of these patients (n = 7/8) from day (D) 0 to D15 after vemurafenib initiation. During follow-up, an increased ctDNA concentration was detected in nine patients: in five patients, the first increase in ctDNA concentrations followed a decrease in vemurafenib concentrations. More interestingly, an inverse correlation between vemurafenib concentration and ctDNA concentrations was demonstrated (p = 0.026). The ctDNA concentration at baseline was associated with overall survival (hazard ratio = 2.61, 95% CI 1.04–6.56; p = 0.04).
Conclusions
This study demonstrates the relevance of vemurafenib plasma monitoring during the follow-up of metastatic melanoma patients. Plasma drug monitoring and ctDNA concentrations could be combined to monitor tumor evolution in melanoma patients treated with anti-BRAF therapies.
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Editorial Board and Contents
Source:Trends in Cell Biology, Volume 27, Issue 6
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